1
Synthesis and Properties of Acetylenic Derivatives of Pyrazoles
SERGEI F. VASILEVSKY AND EUGENE V. TRETYAKOV
Institute of Chemical Kinetics and Combustion, Siberian Branch of the Russian Academy of
Sciences, 630090, Novosibirsk, Russian Federation.
JOSE ELGUERO
Institutos de Química Física y Química Médica, Consejo Superior de Investigaciones
Científicas, 28006 Madrid, Spain.
I. INTRODUCTION......................................................................................................................3
II. SYNTHESIS OF ACETYLENYLPYRAZOLES ..................................................................4
A. REACTIONS OF CYCLIZATION .......................................................................................................4
B. REACTIONS OF ELIMINATION ......................................................................................................29
C. CROSS-COUPLING OF HALOGENOPYRAZOLES WITH TERMINAL ACETYLENES AND ITS COPPER(I)
SALTS ............................................................................................................................................. 39
D. PYROLYSIS .................................................................................................................................65
III. CHEMICAL PROPERTIES OF ACETYLENYLPYRAZOLES ....................................66
A. REACTIONS OF TERMINAL ACETYLENES WITH PARTICIPATION OF C-H BOND .............................66
1. The Favorsky reaction ...............................................................................................................66
2. Homo-coupling ..........................................................................................................................70
3. Cross-coupling ..........................................................................................................................72
4. Aminomethylation ......................................................................................................................76
5. Halogenation .............................................................................................................................80
6. Alkylation ...................................................................................................................................82
7. Metalation..................................................................................................................................82
B. REACTIONS WITH PARTICIPATION OF CC BOND ........................................................................83
1. Halogenation .............................................................................................................................83
2. Hydration ...................................................................................................................................83
3. Hydrohalogenation ....................................................................................................................85
2. Hydratation................................................................................................................................85
4. Hydrazination ............................................................................................................................86
5. Oxidation ...................................................................................................................................86
C. REACTIONS WITH PARTICIPATION OF C-X BOND ......................................................................91
1. Retro Favorsky reaction ............................................................................................................91
2. Desilylation................................................................................................................................97
3. Destannylation ...........................................................................................................................98
4. Decarboxylation ........................................................................................................................98
5. Cineamination .........................................................................................................................100
6. Transhalogenation ...................................................................................................................101
D. HETEROCYCLIZATIONS OF VICINAL FUNCTIONALLY SUBSTITUTED PYRAZOLYLACETYLENES ....91
1. Aminopyrazolylacetylenes .......................................................................................................105
2. Nitroacetylenylpyrazoles .........................................................................................................107
3. Acetylenylpyrazolcarboxylic acids ..........................................................................................107
4. Amides of acetylenylpyrazolcarboxylic acids ..........................................................................115
5. Hydrazides of acetylenylpyrazolcarboxylic acids ...................................................................119
2
6. Diazonium salts of acetylenylpyrazoles...................................................................................123
IV. STRUCTURE, SPECTRA AND PROPERTIES OF ACETYLENYLPYRAZOLES .129
A. MOLECULAR DIMENSIONS .......................................................................................................129
C. IR SPECTRA..............................................................................................................................130
B. UV SPECTRA ............................................................................................................................131
D. 1H NMR SPECTRA ....................................................................................................................133
E. 13C NMR SPECTRA ...................................................................................................................134
F. THERMODYNAMIC CH-ACIDITY OF ETHYNYLPYRAZOLES.........................................................134
G. MAGNETIC PROPERTIES OF SPIN-LABELLED ALKYNYLPYRAZOLES ...........................................137
V. BIOLOGICAL PROPERTIES OF ACETYLENYLPYRAZOLES ................................ 141
VI. CONCLUSIONS .................................................................................................................145
REFERENCES ..........................................................................................................................146
3
I. Introduction
The acetylenic derivatives of the pyrazoles1 analogs have aroused great interest in recent
years due to the wide variety of their biological and pharmacological properties (72IZV2524;
93MIP1; 96BMC797; 99USP5925769, 99BMC979).
On the other hand, acetylenylpyrazoles are highly valuable intermediates because a triple
bond is susceptible to reactions of nucleophilic, electrophilic, radical and cycloaddition, and
terminal acetylenes display the unusually high CH-acidity which can be used for both
functionalizing and building up C-C bonds. In addition, compounds with a vicinal arrangement
of a multiple bond and a functional group prone to intramolecular addition, make it possible to
produce the annealed heterocyclic systems. This predetermines the potentialities of
alkynylpyrazoles as highly reactive syntons (83IZV688; 85IZV1367; 98HC519;
99JCS(P1)3721).
At the same time, the results of works on the chemistry of acetylenic derivatives of pyrazole
are scattered over original papers, patents, dissertations and are unavailable for a wide circle of
chemists. This review is aimed at compensating this gap.
1
The review described syntheses and properties of alkynylpyrazoles and its annelated analogs in which triple bond
directly connected with the heterocycle.
4
II. Synthesis of acetylenylpyrazoles
A. Reactions of cyclization
This type of reactions is represented by 1,3-dipolar addition classified by Huzgen (69MI1).
The 1,3-bipolar addition is the interaction between 1,3-dipole and a multiple system d=e, i.e.
“dipolarophyl”, followed by a cyclic shift of electrons and completed with a 5-membered ring
closure (Scheme 1).
b
a
c
d e
b
a
c
d e
Scheme 1
The first representative of acetylenic derivatives  3(5)-ethynylpyrazole, was produced by
condensation of diacetylene with diazomethane by Kuhn and Henkel (41LA279), and later by
other authors (69IZV2546), or of acetylene with diazopropyne (62AG252; 68LA113) (Scheme
2).
HC C C CH
N+
N-
+
N
HC CH
HC C
+
N+
N-
C
N
H
CH
Scheme 2
The mixture of products of different composition forms depending on the diacetylenediazomethane ratio (68LA124).
HC
C
CH2N2
HC C C CH
0 oC
N
N
H
C
+
CH
N
N
C
+
CH
N
+
N
HN N
N NH
Scheme 3
With ratio 1:1 of butadiyne and diazomethane, 3(5)-ethynylpyrazole dominates (55%). The
yields of isomeric 3- and 5-ethynyl-1-methylpyrazoles are 8 and 11%, respectively. The double
excess of diazomethane leads mainly to the mixture of N-methylated isomers (81%), 10% of
3(5)-ethynylpyrazole and a small amount (3%) of bipyrazole (68LA124) (Scheme 3).
The monosubstituted diacetylenes including the 3-triethylstannyl derivative (81%)
(71ZOB2230) reacts with 1,3-dipole, first, with a terminal acetylenic group with a 3(5)-alkyn-1ylpyrazole closure (65ZOR610; 68KGS695) (Scheme 4).
5
CH 2N2
R C C C CH
N
C C
R
N
H
R = Me, Et, C(CH3)2OCH(Me)OBu, Sn(Et)3
Scheme 4
1,3-Dipolar additions of diazomethane to acetylenes under the mild conditions are restricted
to monosubstituted acetylenes, and thus the formation of pyrazole derivatives 1 (1,3-dipolar
additions, C=C isomerization, then methylation) reinforces the existence of the terminal
acetylene in caryoynencins (87TL3981) (Scheme 5).
O
O
OH
HC C C C
O
CH 2N2
3
R
N N
OH
C C
3
1 R = Me,
2R=H
OH
Scheme 5
While Kakisawa et al. (87TL3981) reported formation of N-methylpyrazole 1, later
Yamaguchi et al. obtained N-H derivative 2 by reaction of caryoynencins with diazomethane in
ethyl acetate at 0 oC (94BSJ1717; 95JMC5015). The 1,3-dipolar addition was quite sensitive to
the solvent employed, and very low yield of pyrazole derivative 2 was formed in ether or
methanol (Scheme 5).
As compared with monosubstituted diacetylenes, the disubstituted ones add diazomethane to
form 4-alkynylpyrazoles (58CB1841; 60CB1931; 68LA124). Diazomethane reacts similarly
with either ethers of polyacetylenic acids (57JCS2012) or free acids (57CB124; 60CB1931;
68LA124), which is the method for synthesizing the esters of pyrazole-3-carboxylic acids with
acetylenic substituent at position 4 of the cycle (Scheme 6).
COOMe
R1 C C COOR2
n
CH 2N2
N
HN
C C R1
n-1
R1 = Et, R2 = Me, n = 2;
R1 = Me, R2 = H, n = 2;
R1 = Me, R2 = H, n = 3
Scheme 6
Thus, 1,4-dibenzoylbutadiyne-1,3 with dizomethane forms 3(5)-benzoylethynylpyrazole
(yield 59%) (68LA124). In a similar way, the reaction of 2,7-dimethyl-octadiyne-2,7-diol-2,7
with diazomethane leads to 4-[3-(1-hydroxy-1-methyl-ethyl)-1H-pyrazol-4-yl]-2-methyl-but-3yn-2-ol in 64% yield (58CB1841) (Scheme 7).
6
R
CH 2N2
N
HN
R C C C C R
C C R
R = C(O)-C6H5, C(CH3)2OH, CH2O-C(O)-C6H5, CH2O-C(O)-p-Br-C6H4,
CH2O-C(O)-m-Br-C6H4,
Scheme 7
1,6-Dicarboaryloxyhexadiynes-1,6 react like the 1,4-disubstituted butadiynes giving rise to
the corresponding 3-(aroyloxymethylene)-4-(3-aroyloxypropynyl-1)pyrazole in a 84-89% yield
(87MI1). Reaction of symmetric diacetylene esters of aromatic acids with diazomethane gave 3(benzoyloxymethyl)-4-(benzoyloxypropyn-1-yl-1)pyrazoles
(Scheme
7
with
R
=
-CH2OC(O)C6H4-Y; Y = H, Br-2, Br-4, NO2-2, NO2-4, (NO2)2-3,5, OMe-2, OMe-3, OMe-4
(87MI2); R = -3-Py, -4-Py (84MI1) and with R = CH2OC(O)C6H4-Y; Y = Cl-4, Cl-2, Cl2-2,4, I2, 3-I (86MI2)).
Note that the 1,4-substituted butadiynes with diazomethane can form two isomers. Kuznetsov
with co-workers have considered in detail this problem and established that diphenyldiacetylene
with diazomethane form, in standard conditions (ether, 0oC, 9 days), only one of two possible
regioisomers, i.e., 4-phenyl-3(5)-phenylethynylpyrazole (yield 86%) (93ZOB1107). The
cyclization of derivatives of phenoxy-2,4-hexadiyn-6-oles with diazomethane leads only to one
isomer of alkynylpyrazole (Scheme 8) (76MI1; 77MI1).
Ar
O
CH 2N2
C C C C
Ar O
N
HN
OH
C C
OH
Ar = o-Br-C6H4, p-Br-C6H4, 2,4-Br2-C6H3, o-NO2-C6H4,
m-NO2-C6H4, p-NO2-C6H4
Scheme 8
At the same time, according to the data (68LA113; 71CAS1731), the disubstituted
diacetylenes with diazomethane form both the 3- and 4-acetylenylsubstituted pyrazoles. In this
case, the former are formed in trace amounts (cheme 9).
R
O
Ar C C C C
R
CH 2N2
N
HN
Ar
C
C
O
O
C C Ar
+
maijor product
Ar = C6H5, p-Br-C6H4, p-Cl-C6H4, p-CH3-C6H4; R = CH3
Ar = C6H5, R = C6H5;
Ar = C6H5, R = OCH3
cheme 9
N
HN
R
minor product
7
As follows from the Table I, the 4-acetylenylderivative yields depend on both the reaction
time and the structure of aromatic and acylic components (molecule polarity). If more than one
equivalent of diazomethane used the N-methylation of pyrazole occurs.
TABLE I
Dependence of the Yield of Alkynylpyrazoles and Its N-Methyl Derivatives on the Composition
of Diyne/Diazomethane Mixture and Reaction Timea
R3
N
R4
N
R1
R5
Diyne and reaction condition
R1
R3
R4
R5
m.p., oC
Yield
(%)
C6H5-CC-CC-COCH3
H
COCH3
CC-C6H5
H
157
52
3 min.
H
CC-C6H5
COCH3
H
C6H5-CC-CC-COCH3
H
COCH3
CC-C6H5
H
40 min.
H
CC-C6H5
COCH3
H
C6H5-CC-CC-COCH3
H
COCH3
CC-C6H5
H
24 h, 2 equivalents of CH2N2
CH3
H
CC-C6H5
COCH3
44
CH3
COCH3
CC-C6H5
H
29
H
COCH3
CC-p-BrC6H5
H
210
92
H
COCH3
CC-p-Br-C6H5
H
210
51
CH3
H
CC-p-Br-C6H5
COCH3
19
CH3
COCH3
CC-p-Br-C6H5
H
12
H
CC-p-BrC6H5
COCH3
H
1.7
H
COCH3
CC-p-Cl-C6H5
H
205
90
H
COCH3
CC-p-Cl-C6H5
H
205
38
CH3
H
CC-p-Cl-C6H5
COCH3
32
CH3
COCH3
CC-p-Cl-C6H5
H
27
H
COCH3
CC-p-CH3-C6H5
H
H
H
CC-p-CH3-C6H5
COCH3
H
COCH3
CC-p-CH3-C6H5
H
CH3
H
CC-p-CH3-C6H5
COCH3
21
CH3
COCH3
CC-p-CH3-C6H5
H
13
H
CC-p-CH3C6H5
COCH3
H
5
p-Br-C6H5-CC-CCCOCH3
6
157
74
7
157
4
40 min.
p-Br-C6H5-CC-CCCOCH3
16 h, 2 equivalents of CH2N2
p-Cl-C6H5-CC-CCCOCH3
40 min.
p-Cl-C6H5-CC-CCCOCH3
7 days, 2 equivalents of
CH2N2
p-CH3-C6H5-CC-CCCOCH3
199
81
5
40 min.
p-CH3-C6H5-CC-CCCOCH3
16 days
199
38
(continued)
8
TABLE I (continued)
Diyne and reaction condition
R1
R3
R4
R5
m.p., oC
Yield
(%)
p-CH3-C6H5-CC-CCCOCH3
H
COCH3
CC-p-CH3-C6H5
H
199
53
CH3
H
CC-p-CH3-C6H5
COCH3
14
CH3
COCH3
CC-p-CH3-C6H5
H
7
H
CC-p-CH3C6H5
COCH3
H
7
H
COC6H5
CC-C6H5
H
130
33
C6H5-CC-CC-COC6H5
H
COC6H5
CC-C6H5
H
130
70
40 min.
H
CC-C6H5
COC6H5
H
C6H5-CC-CC-COC6H5
H
COC6H5
CC-C6H5
H
19 days, 2 equivalents of
CH2N2
CH3
H
CC-C6H5
COC6H5
50
CH3
COC6H5
CC-C6H5
H
34
C6H5-CC-CC-COOCH3
H
COOCH3
CC-C6H5
H
36
3 min.
CH3
H
CC-C6H5
COOCH3
4
H
CC-C6H5
COOCH3
H
3
C6H5-CC-CC-COOCH3
H
COOCH3
CC-C6H5
H
72
40 min.
CH3
H
CC-C6H5
COOCH3
0.8
H
CC-C6H5
COOCH3
H
6
CH3
H
CC-C6H5
COOCH3
49
COOCH3
CC-C6H5
H
16
17 h, 2 equivalents of CH2N2
C6H5-CC-CC-COC6H5
3 min.
C6H5-CC-CC-COOCH3
CH3
19 days, 2 equivalents of
CH2N2
a
From reference (71CAS1731).
6
130
14
The standard technique for obtaining alkynylpyrazoles consists in mixing up the ether
solutions of diazoalkane and diacetylene or its derivatives (or diazopropyne and acetylene) and
keeping reaction mass for either several hours or three weeks within a narrow temperature range
(0-20 oC).
According to the literature data, the selectivity degree of interaction between diazoalkanes
and diacetylenes is high enough. The main products can be represented by both of the
regioisomeric ethynylpyrazoles. However, the reaction course substantially depends on the
structures of both diazoalkane and diacetylene (91ZOB2286). Thus, the addition of
diazomethane to the activated CC bond in arylacyldiacetylenes leads, according to the Auwers
rule (29LA284) mainly or exclusively to 4-arylethynyl-3(5)-acylpyrazoles (68LA124;
71CAS1731). The interaction between diazomethane and diacetylene, its mono- and
disubstituted derivative (of both aliphatic and aromatic series) (93ZOB1107; 91ZOB2286) gives
3-alkynylpyrazoles which can also regioselectively react with the second diazoalkane molecule
to form symmetric bipyrazoles.
In case of reaction between 2-diazopropane and diphenyldiacetylene the reverse (as
compared with other diynes) orientation of addition of the first molecule of diazocompound with
a predominant formation of 4-phenylethynylpyrazole is observed. Therefore, it is noteworthy
that whereas the regiodirectedness of the addition of diazoalkanes to alkenes is well studied and
its products have, as a rule, the structure predicted with respect to electron effects, the problem of
orientation of 1,3-dipoles in reactions with a triple carbon-carbon bond is not solved. Authors
9
(91ZOB2286; 93ZOB1107) consider not the electron (the Auwers rule) but steric factors that are
most likely to determine the courses of both of the reactions with 2-diazopropane. Indeed, in
each case, the adducts form in which the bulky group C(CH3)2 adds to the triple bond carbon
atom containing the less sterically bulk substituent (H< -CCR< Ph <pyrazolyl). No wonder that
the main product in the reaction between 2-diazopropane and diphenyldiacetylene is 4phenylethynylpyrazole. At the same time the interaction between diacetylene and diazomethane
leads to the corresponding 5-ethynylpyrazole. The authors (91ZOB2286; 93ZOB1107) attribute
this to the space effect.
Diazopropyne reacts similarly with a monosubstituted acetylene to form 3(5)alkynylpyrazoles (68LA113). Thus, the reaction of diazopropyne with methyl ether of
acetylenecarboxylic acid results in 5-ethynyl-1H-pyrazole-3-carboxylic asid methyl ether in 48 h
in 62% yield. 5-Ethynyl-1H-pyrazole-3,4-dicarboxylic acid dimethyl ester was prepared by
reaction of diazopropyne with methyl ether of acetylenedicarboxylic acid (Scheme 10).
H3CO 2C
R
HC C CHN 2
H3CO 2C C C R
N
N
H
C
CH
R = CO2CH3, H
Scheme 10
Under similar conditions, the interaction between diacetylene and diazoethane (68CB3700)
gives rise to 5-ethynyl-3-methyl-1H-pyrazole in 34% yield (Scheme 11).
CH 3CHN 2
HC C C CH
N
N
H
C CH
+
HN N
N NH
Scheme 11
Ethyl diazoacetate is added endo to Me3Si(CC)2SiMe3 to give 3-ethoxyarbonyl-4trimethylsilylethynyl-5-trimethylsilylpyrazole (88JOM247).
10
TABLE II
Alkynylpyrazoles Prepared by Cyclizations of 1,3-Diynes with Diazomethane
1,3-Diyne
Alkynylpyrazoles
Structural formula
Formula index
m.p., oC
[b.p., oC/mm Hg]
Reported
yield (%)
Literature
C5H4N2
45-46 [86-87/4]
41
41LA279
55-56 [65-67/0.5]
–
69IZV2546
RCCCCR’
Unsubstituted
HCCCCH
3-Ethynyl-1H-pyrazoleab
HN N
C CH
–
55
53.5-55
(petroleum ether)
–
71ZOB2230
C6H6N2
71-72 [112-114/6]
–
65ZOR610
C7H8N2
38-39 [120-122/5]
–
65ZOR610
C11H18N2Sn
[141-143/0.8]
81
71ZOB2230
c
68LA124
Monosubstituted
RCC-CCH
R = CH3
3-Prop-1-ynyl-1H-pyrazole
HN N
R = C2H5
3-But-1-ynyl-1H-pyrazole
HN N
R = SnEt3
3-Triethylstannanylethynyl-1Hpyrazole
HN N
C C
C C
C C SnEt3
d420
1.3873
nD20 1.5475
A mixture of 7E, 9E; 7Z,
9E; 7E, 9Z;
H-(CC)4-(CH=CH)2CHOH(CH2)4CO2CH3
A mixture of 2E,4E and
2E,4Z-isomers of H(CC)4CH(OH)(CH=CH)2-CH3
6-Hydroxy-16-(1H-pyrazol-3-yl)hexadeca-7,9-diene-11,13,15triynoic acid methyl ester
12-(1H-Pyrazol-3-yl)-dodeca-2,4diene-7,9,11-triyn-6-ol
HN N
C C R
C20H20N2O3
-
59d
94BSJ1717e
C15H12N2O
-
32f
95JMC5015
R = corresponding
(CC)2(CH=CH)2CHOH(CH2)4CO2CH3
R = (CC)3CH(OH)-(CH=CH)2-CH3
11
1,3-Diyne
Alkynylpyrazoles
Structural formula
Formula index
m.p., oC
[b.p., oC/mm Hg]
Reported
yield (%)
Literature
12-(1H-Pyrazol-3-yl)-dodeca-3,5diene-7,9,11-triyn-2-ol
A 2:1 mixture of 3E,5E and 3E,5Z-isomers
R = (CC)3(CH=CH)2CH(OH)CH3
C15H12N2O
-
56g
95JMC5015
Acetic acid 1-methyl-11-(1Hpyrazol-3-yl)-undeca-2,4-diene6,8,10-triynyl ester
A 1:1 mixture of 3E,5E and 3E,5Z-isomers
R = (CC)3(CH=CH)2CH(OAc)CH3
C17H14N2O2
-
69h
95JMC5015
RCCCCR’
A 1:1 mixture of 3E,5E
and 3E,5Z-isomers of
H-(CC)4-(CH=CH)2CH(OH)-CH3
A 1:1 mixture of 3E,5E
and 3E,5Z-isomers of
H-(CC)4-(CH=CH)2CH(OAc)-CH3
R
Symmetrically disubstituted
HN
N
RCC-CCR
C C R
R = CH2OC(=O)-CH3
Acetic acid 4-(3-acetoxy-prop-1ynyl)-2H-pyrazol-3-ylmethyl ester
R = CH2OC(=O)-CH3
C11H12N2O4
oil
72
78MI3
R = С(CH3)2OH
4-[5-(1-Hydroxy-1-methyl-ethyl)1H-pyrazol-4-yl]-2-methyl-but-3yn-2-ol
R = С(CH3)2OH
C11H16N2O2
152-153 (EtOAc)
64
58CB1841
R = CH2OC(=O)-(CH2)2CH3
Butyric acid 4-(3-butyryloxy-prop1-ynyl)-2H-pyrazol-3-ylmethyl ester
R = CH2OC(=O)-(CH2)2-CH3
C15H20N2O4
oil
75
78MI3
R = CH2OC(=O)-(CH2)4CH3
Hexanoic acid 4-(3-hexanoyloxyprop-1-ynyl)-2H-pyrazol-3-ylmethyl
ester
R = CH2OC(=O)-(CH2)4-CH3
C19H28N2O4
oil
80
78MI3
R = CH2OC(=O)-3,5(NO2)2-C6H3
3-(3,5-Dinitrobenzoyloxymethylene)-4-(3-(3,5dinitrobenzoyloxy)propynyl-1)pyrazole
R = CH2OC(=O)-3,5-(NO2)2-C6H3
C21H12N6O12
80-82
94
87MI2
R = CH2OC(=O)-2-BrC6H4
3-(2-Bromo-benzoyloxymethylene)4-(3-(2-bromobenzoyloxy)propynyl1)-pyrazole
R = CH2OC(=O)-2-Br-C6H4
C21H14Br2N2O4
91-93
82
87MI1
91-93
89
87MI2
12
Alkynylpyrazoles
Structural formula
Formula index
m.p., oC
[b.p., oC/mm Hg]
Reported
yield (%)
Literature
R = CH2OC(=O)-4-BrC6H4
3-(4-Bromo-benzoyloxymethylene)4-(3-(4-bromobenzoyloxy)propynyl1)-pyrazole
R = CH2OC(=O)-4-Br-C6H4
C21H14Br2N2O4
98-100
84
87MI1
98-100
91
87MI2
R = CH2OC(=O)-4-ClC6H4
3-(4-Chloro-benzoyloxymethylene)4-(3-(4-chlorobenzoyloxy)propynyl1)-pyrazole
R = CH2OC(=O)-4-Cl-C6H4
C21H14Cl2N2O4
62-63
83
86MI2
R = CH2OC(=O)-2-ClC6H4
3-(2-Chloro-benzoyloxymethylene)4-(3-(2-chlorobenzoyloxy)propynyl1)-pyrazole
R = CH2OC(=O)-2-Cl-C6H4
C21H14Cl2N2O4
oil
81
86MI2
R = CH2OC(=O)-2,4-Cl2C6H3
3-(2,4-Dichlorobenzoyloxymethylene)-4-(3-(2,4dichlorobenzoyloxy)propynyl-1)pyrazole
R = CH2OC(=O)-2,4-Cl2-C6H3
C21H12Cl4N2O4
101-102
89
86MI2
R = CH2OC(=O)-2-I-C6H4
3-(2-Iodo-benzoyloxymethylene)-4(3-(2-iodobenzoyloxy)propynyl-1)pyrazole
R = CH2OC(=O)-2-I-C6H4
C21H14I2N2O4
34-45
92
86MI2
R = CH2OC(=O)-3-I-C6H4
3-(3-Iodo-benzoyloxymethylene)-4(3-(3-iodobenzoyloxy)propynyl-1)pyrazole
R = CH2OC(=O)-3-I-C6H4
C21H14I2N2O4
oil
89
86MI2
R = CH2OC(=O)-2-NO2C6H4
3-(2-Nitro-benzoyloxymethylene)-4(3-(2-nitrobenzoyloxy)propynyl-1)pyrazole
R = CH2OC(=O)-2-NO2-C6H4
C21H14N4O8
58-60
90
87MI2
R = CH2OC(=O)-4-NO2C6H4
3-(4-Nitro-benzoyloxymethylene)-4(3-(4-nitrobenzoyloxy)propynyl-1)pyrazole
R = CH2OC(=O)-4-NO2-C6H4
C21H14N4O8
68-70
92
87MI2
R = CH2OC(=O)Ph
3-(Benzoyloxymethylene)-4-(3benzoyloxypropynyl-1)-pyrazole
R = CH2OC(=O)Ph
C21H16N2O4
43-44
89
87MI1
43-44
89
87MI2
3-(2-Methoxybenzoyloxymethylene)-4-(3-(2methoxybenzoyloxy)propynyl-1)pyrazole
R = CH2OC(=O)-2-OCH3-C6H4
48-50
81
87MI2
1,3-Diyne
RCCCCR’
R = CH2OC(=O)-2-OCH3C6H4
C23H20N2O6
13
Alkynylpyrazoles
Structural formula
Formula index
m.p., oC
[b.p., oC/mm Hg]
Reported
yield (%)
Literature
R = CH2OC(=O)-3-OCH3C6H4
3-(3-Methoxybenzoyloxymethylene)-4-(3-(3methoxybenzoyloxy)propynyl-1)pyrazole
R = CH2OC(=O)-3-OCH3-C6H4
C23H20N2O6
61-62
89
87MI2
R = CH2OC(=O)-4-OCH3C6H4
3-(4-Methoxybenzoyloxymethylene)-4-(3-(4methoxybenzoyloxy)propynyl-1)pyrazole
R = CH2OC(=O)-4-OCH3-C6H4
C23H20N2O6
73-74
92
87MI2
R = CH2OC(=O)-(CH2)8CH3
Decanoic acid 4-(3-decanoyloxyprop-1-ynyl)-2H-pyrazol-3-ylmethyl
ester
R = CH2OC(=O)-(CH2)8-CH3
C27H44N2O6
oil
81
78MI3
R = CH2OC(=O)-3-Py
3-(3-Pyridinoyloxymethylene)-4-(3(3-pyridinoyloxy)propynyl-1)pyrazole
C19H14N4O4
103-104
89
84MI1
C19H14N4O4
110-112
90
84MI1
C17H12N2
167-168 (hexane –
ether)
41
93ZOB1107
C8H8N2O2
102
-
60CB1931
1,3-Diyne
RCCCCR’
O
3-(4-Pyridinoyloxymethylene)-4-(3(4-pyridinoyloxy)propynyl-1)pyrazole
C C
O
O
N
N
O
O
HN
N
C6H5-CC-CC-C6H5
N
O
HN
N
R = CH2OC(=O)-4-Py
N
O
C C
O
Ph
4-Phenyl-3-phenylethynyl-1Hpyrazole
HN N
C C Ph
Unsymmetrically
disubstituted
RCC-CCR’
CH3-(CC)2-CO2Hi
O
4-Prop-1-ynyl-2H-pyrazole-3carboxylic acid methyl ester
HN
N
O
C C
14
1,3-Diyne
Alkynylpyrazoles
Structural formula
Formula index
m.p., oC
[b.p., oC/mm Hg]
Reported
yield (%)
Literature
C9H10N2O2
92-94 (benzene –
light petroleum)
-
57JCS2012
C10H8N2O2
184 (benzene)
-
57CB124
C13H9BrN2O
210
92
71CAS1731
C13H9ClN2O
205
90
71CAS1731
C13H10N2O
157
74
71CAS1731
C13H10N2O2
-
72
71CAS1731
C14H12N2O
199
81
71CAS1731
C18H12N2O
130
70
71CAS1731
RCCCCR’
C2H5-(CC)2-CO2CH3
O
4-But-1-ynyl-2H-pyrazole-3carboxylic acid methyl ester
O
HN
N
CH3-(CC)3-CO2Hj
C C
O
4-Penta-1,3-diynyl-2H-pyrazole-3carboxylic acid methyl ester
O
HN
N
p-BrC6H5-CC-CCCOCH3
C C C C
O
1-[4-(4-Bromo-phenylethynyl)-2Hpyrazol-3-yl]-ethanone
HN
N
p-ClC6H5-CC-CCCOCH3
C C
O
1-[4-(4-Chloro-phenylethynyl)-2Hpyrazol-3-yl]-ethanone
HN
N
C6H5-(CC)2-COCH3
C C
O
1-(4-Phenylethynyl-2H-pyrazol-3yl)-ethanone
HN
N
C6H5-CC-CC-COOCH3
4-Phenylethynyl-2H-pyrazole-3carboxylic acid methyl ester
O
C C Ph
HN
N
C6H5-CC-CC-COC6H5
O
O
1-(4-p-Tolylethynyl-2H-pyrazol-3yl)-ethanone
Cl
C C Ph
HN
N
p-CH3C6H5-CC-CCCOCH3
Br
C C
O
Phenyl-(4-phenylethynyl-2Hpyrazol-3-yl)-methanone
HN
N
Ph
C C Ph
15
1,3-Diyne
Alkynylpyrazoles
Structural formula
Formula index
m.p., oC
[b.p., oC/mm Hg]
Reported
yield (%)
Literature
RCCCCR’
O
ROCH2-CC-CC-CH2OH
R
HN
N
OH
C C
4-Br-C6H5-OCH2-CCCC-CH2OH
3-[5-(4-Bromo-phenoxymethyl)-1Hpyrazol-4-yl]-prop-2-yn-1-ol
R = 4-Br-C6H4
C13H11BrN2O2
-
79
76MI1
2-Br-C6H5-OCH2-CCCC-CH2OH
3-[5-(2-Bromo-phenoxymethyl)-1Hpyrazol-4-yl]-prop-2-yn-1-ol
R = 2-Br-C6H4
C13H11BrN2O2
-
80
76MI1
2,4-Br2-C6H5-OCH2-CCCC-CH2OH
3-[5-(2,4-Dibromo-phenoxymethyl)1H-pyrazol-4-yl]-prop-2-yn-1-ol
R = 2,4-Br2-C6H4
C13H10Br2N2O2
-
62
76MI1
4-NO2-C6H5-OCH2-CCCC-CH2OH
3-[5-(4-Nitro-phenoxymethyl)-1Hpyrazol-4-yl]-prop-2-yn-1-ol
R = 4-NO2-C6H4
C13H11N3O4
127-128
82
76MI1
3-NO2-C6H5-OCH2-CCCC-CH2OH
3-[5-(3-Nitro-phenoxymethyl)-1Hpyrazol-4-yl]-prop-2-yn-1-ol
R = 3-NO2-C6H4
C13H11N3O4
-
77
76MI1
3-[5-(2-Nitro-phenoxymethyl)-1HR = 2-NO2-C6H4
C13H11N3O4
nD = 1.5983
79
76MI1
2-NO2-C6H5-OCH2-CCpyrazol-4-yl]-prop-2-yn-1-ol
CC-CH2OH
a
3-Ethynyl-1H-pyrazole was also prepared by cyclization of diazopropine with acetylene (m.p. 55 oC, 62252; yield 17%, m.p. 55 oC (petroleum ether), b.p. 94/2 mm Hg, 68LA113).
b
The chemical names with the exception of the italic chemical names were generated by AutoNom from Beilstein Informationssysteme GmbH.
c
The main product was prepared by reaction of 1 mole diacetylene with 1 mole of diazomethane. Minor products were 3-ethynyl-1-methylpyrazole (8%), 5-ethynyl-1methylpyrazole (11%, 73-73.5/30 torr). A reaction of 1 mole diacetylene with 2 mole diazomethane gave 3-ethynylpyrazole (10%), 3,3’-bipyrazolyl (3%, m.p. 256 oC), a mixture of
3-ethynyl-1-methylpyrazole and 5-ethynyl-1-methylpyrazole (81%).
d
It is calculated yield on two stages: 1 – removing of protecting group from t-BuPh2Si-(CC)4(CH=CH)2CHOH(CH2)4CO2CH3 with NaOH, Bu4N+Br-; 2 – reaction with
diazomethane.
e
87TL3981 reported that only N –methylated product was isolated.
f
Yield from a 5:1 mixture of 2E,4E- and 2Z,4E-isomers of t-BuPh2Si -(CC)4CH(OH)-(CH=CH)2-CH3; 1. Bu4N+Br-, AcOH, 2. CH2N2.
g
Calculated yield on to stage from t-BuPh2Si-(CC)4(CH=CH)2CH(OH)-CH3; 1. 3M NaOH and Bu4N+Br-, 2. CH2N2.
h
Yield from t-BuPh2Si-(CC)4(CH=CH)2CH(OAc)-CH3; 1. 3M NaOH and Bu4N+Br-, 2. CH2N2.
i
Intermediate compounds from ozonolysis of CH3-(CC)2-(СH=CH)3-CH2-CH2OR (R = COCH3, or H) that is reacted with diazomethane. Yield is given on two stages.
j
Intermediate compounds from ozonolysis of CH3-(CC)3-(СH=CH)3-(CH2)4-CH=CH2 that is reacted with diazomethane. Yield is given on two stages.
16
TABLE III
Alkynylpyrazoles Prepared by Cyclizations of Alkynes with Diazocompounds
Alkyne
Diazocompound
Alkynylpyrazoles
Formula index
Structural formula
m.p., oC
Reported
yield (%)
Literature
34
68CB3700
114-117
62
68LA113
205.2-205.5 (ethyl
ethanoate)
25
88JOM247
71-73 (ethanol –
water 1:1 v/v)
76a
[b.p., oC/mm Hg]
HCC-CCH
CH3CHN2
3-Ethynyl-5-methyl-1H-pyrazole
C6H6N2
82
C CH
HN N
HCCCOOCH3
N2CH-CCH
5-Ethynyl-2H-pyrazole-3-carboxylic acid methyl
ester
[132-133/14]
O
C7H6N2O2
O
N N
H
Me3Si-(CC)2SiMe3
N2CH-COOEt
5-Trimethylsilanyl-4-trimethylsilanylethynyl1H-pyrazole-3-carboxylic acid ethyl ester
C14H24N2O2Si2
Si
HN
N
C C Si
O
O
3,3-Dimethyl-5-phenyl-4-phenylethynyl-3Hpyrazole
PhCC-CCPh
N2
3,3-Dimethyl-4-phenyl-5-phenylethynyl-3Hpyrazole
N
N
C19H16N2
C C Ph
Ph
Major product. It is maximum yield reported.
91ZOB2286
Ph
N N
a
C CH
C C Ph
87-88 (ethanol –
water 1:1 v/v)
11
17
It is interesting that when one molecule contains triple and double bonds, diazomethane adds
exclusively (or mostly) to the C=C bond (68LA124; 91GEP4001600; 97JCS(P1)695). The
addition of diazomethane to enyne sulfones occurs stereo- and regioselectively and gives
pyrazolenines (50-85%) that under the action of methyllithium in THF at -78 oC are subjected to
dehydrosulfonation resulting in 4-alkynyl-1H-pyrazoles (Scheme 12, Table IV) (97JCS(P1)695).
CH 2N2
R1 C C
SO2Ph
R2
N
N
R1 C C
H
MeLi
N
NH
R1 C C
H SO2Ph
R2
R1 = t-Bu, R2 = H; R1 = Ph, R2 = H; R1 = t-Bu, R2 = (CH2)2Ph;
R1 = t-Bu, R2 = SO2Ph; R1 = Bu, R2 = SO2Ph; R1 = Ph, R2 = SO2Ph
Scheme 12
4,5-Bis(alkynyl)-1H-pyrazoles, are also obtained by the same procedure. The reaction of (Z)enediyne sulfones and with diazomethane gave bis(alkynyl)-3H-pyrazoles, accompanied by
formation of the 1H-bis(alkynyl)pyrazole. The dehydrosolfonylation of adducts gave the 4,5bis(alkynyl)pyrazoles (Scheme 13).
CH 2N2
R C C
SO2Ph
C
C
Ph
N
R C C
H
N
C SO2Ph
C
Ph
MeLi
N
NH
R C C
C
C
R = t-Bu, Bu
Ph
Scheme 13
Using chlor- or bromenines, one can immediately obtain 4-ethynylpyrazoles (omitting the
stage of pyrazolenine isolation) which is accompanied by methylation and the formation of the
mixture of 3- and 5-sulfonyl-1-methyl-4-acetylenylpyrazoles in about 1:2 ratio (total yield 37%).
CH2N2
t-Bu C C
t-Bu C C
SO2Ph
X
N
N
+
N
N
t-Bu C C
PhO2S
PhO2S
X = Cl, Br
Scheme 14
Diazomethane adds both to the double and triple bonds (the latter predominating) of
dipolarophyl activated by a carbomethoxy group (68LA124).
H3CO 2C
CH 2N2
R C C
CO 2CH 3
R C C
N
NH
H3CO 2C
NH
N
+
R
R = H, CO2CH3
Scheme 15
18
TABLE IV
4-Alkynylpyrazoles Prepared from Enynes and Diazomethanea
CH2N2
R1 C C
R2
Enyne
C C
SO2Ph
Ph C C
SO2Ph
C C
SO2Ph
PhO2S
Bu C C
SO2Ph
PhO2S
C C
SO2Ph
X
X = Cl, Brc
Ph C C
SO2Ph
PhO2S
Bu C C
SO2Ph
C
C
SO2Ph
R1 C C
4-Alkynylpyrazoles
Formula
index
4-(3,3-Dimethyl-but-1ynyl)-1H-pyrazole
C9H12N2
4-Phenylethynyl-1Hpyrazole
C11H8N2
5-Benzenesulfonyl-4(3,3-dimethyl-but-1ynyl)-1H-pyrazole
C15H16N2O2S
5-Benzenesulfonyl-4hex-1-ynyl-1H-pyrazole
C15H16N2O2S
3-Benzenesulfonyl-4(3,3-dimethyl-but-1ynyl)-1-methyl-1Hpyrazole
5-Benzenesulfonyl-4(3,3-dimethyl-but-1ynyl)-1-methyl-1Hpyrazole
SO2Ph
C
C
SO2Ph
Ph
a
N
NH
R1 C C
THF
R2
Structural
formula
M.p. (oC)
Summary
yield (%)
C C
N
NH
160-163
(CH2Cl2hexane)
70
Ph C C
N
NH
99-101
(CH2Cl2hexane)
83
C C
N
NH
170-172
(CHCl3Et2O)
50
N
NH
49
PhO2S
96-98
(CHCl3Et2O)
PhO2S
oil
21 (X =
Cl); 34 (X
= Br)
103-104
(CH2Cl2hexane)
16 (X =
Cl); 17 (X
= Br)
N
NH
178-180
(CHCl3Et2O)
76
N
NH
56-58
(CHCl3Et2O)
69
N
NH
139-141
(CH2Cl2hexane)
26
N
NH
107-110
(CH2Cl2hexane)
30
PhO2S
Bu C C
C C
N
N
C16H18N2O2S
PhO2S
C C
5-Benzenesulfonyl-4phenylethynyl-1Hpyrazole
C17H12N2O2S
4-Hex-1-ynyl-5phenylethynyl-1Hpyrazole
C17H16N2
4-(3,3-Dimethyl-but-1ynyl)-5-phenylethynyl1H-pyrazoleb
C17H16N2
4-(3,3-Dimethyl-but-1ynyl)-5-phenethyl-1Hpyrazole
C17H20N2
Ph C C
N
N
PhO2S
Bu C C
C
C
Ph
C C
C
C
Ph
Ph
C C
MeLi
R2 SO Ph
2
Ph
C C
N
N
C C
Ph
From reference (97JCS(P1)695).
b
The reaction of (Z)-enediyne sulfones with diazomethane gave a mixture of the bis(alkynyl)-substituted 3Hpyrazole and the 1H-bis(alkynyl)pyrazole.
c
The -halogene enyne sulfones gave the N-methylpyrazoles but not the pyrazolines.
19
Other 1,3-dipoles, in particular, 1,3-diphenylnitrilimine (DPNI) can be used to synthesize the
acetylenic derivatives of pyrazole. A series of the papers of Petrov et al. are devoted to the
reactions of 1,3-bipolar addition to the unsaturated compounds giving acetylenylpyrazoles
(63ZOB3558; 65ZOR51; 66ZOR615). A study has been made of the cycloaddition of DPNI to
vinyl-,
vinylmethyl-,
vinylpropyl-,
vinyl-t-butyland
vinylallylacetylenes,
dimethylvinylacetylenylcarbonyl and methyl ether of vinylpropiolic acid. It is shown that in all
cases, addition occurs to the double bond giving rise to pyrozolines which can be easily
dehydrated with chloranyl into the corresponding 5-acetylenylpyrazoles (Scheme 16).
Cl
Ph
Et3N
R C C
N
HN Ph
Ph C N
Ph
Ph
N
N
Ph
N
Ph
C C
N
R
N
Ph
C C
R
R = H, Me, Et, Pr, t-Bu, CH2-CH=CH2, C(Me)2OH, C(O)OMe,
SMe, SEt, SCH2-CH(Me)2, SeMe, SeEt, TeMe, TeEt
Scheme 16
The direction of addition verified by acetylene oxidation into the known acid, testifies that
the nitrilimine carbon atom adds the terminal atom of the enyne system, which is inconsistent
with the assumed polarization of the unsaturated compound H2C CH C C R . The authors
(63ZOB3558) assign this to a possible transfer of the reaction center in nitrilamine as a particle
with a nucleophilic center on a carbon.
Ph C N
Ph C N N
Ph
N
Ph
The easiness with which the dipolarophile interacts with vinylacetylenes depends mainly on a
spatial factor. The study of the reactions of alkylthiobuten-3-ynones-1 and their selenic and
telluric analogs with DPNI shows that in this case, nitrilimine also acts as a nucleophilic agent
with a nucleophilic center on the carbon atom of 1,3-dipole and always adds to the terminal
carbon of the enyne system to form 1,3-diphenyl-5-R-2-pyrazolenines. The oxidation of the latter
with chloranyl leads to alkynylpyrazoles (65ZOR51).
Using diacetylenic rather than vinylacetylenic derivatives as dipolarophyl gives at once the
aromatic heterocycle by passing the stage of aromatization. Thus, the addition of H5C2OOCCN+-N-C6H5 to H3C-CC-CCH gives rise to 1-phenyl-5-prop-1-ynyl-1H-pyrazole-3carboxylic acid ethyl ester (66ZOR615). The author reported about synthesis of 5-but-1-ynyl-1phenyl-1H-pyrazole-3-carboxylic acid ethyl ester and 5-but-1-ynyl-1,3-diphenyl-1H-pyrazole
but they can be able to pure the compounds (Scheme 17).
20
R2 C N N
Ph
R1 C C C CH
C6H6, 80o
R2
N
N
Ph
C C 1
R
R1 = COOEt, R2 = Me; R1 = COOEt, R2 = Et; R1 = Ph, R2 = Et
Scheme 17
Thus, the reaction of diazoalkanes and nitrilimines with diacetylenic derivatives can be used
as a method for synthesizing acetylenylpyrazoles.
Another type of cyclization leading to acetylenylpyrazoles is the interaction between acetylenic and -diacetylenic ketones and nitrogen-containing binucleophyls.
The reaction between hydrazine (usually at 0oC or room temperature in methanol or wateralcohol solution) with both -butadiynylketones (73S47) and geminal diacetylenylketones
(68LA113; 69LA117; 74JOC843) always results in the 5(3)-substituted 3(5)-alkynylpyrazoles.
The isomeric 1,5-diphenylpentadione-3 with hydrazine in ethanol solution gives 3(5)-phenyl5(3)-phenylethynylpyrazole (69LA117; 73UK511) in 79% yield (Scheme 18).
R
O
R
C
C
NH 2NH 2
C
C
N
R
N
H
C C
R
R = CH3, C6H5
Scheme 18
Aryl trimethylsilylbutadiynyl ketones upon treatment with hydrazine hydrate in acidified
methanol give 3(5)-aryl-5(3)-trimethylsilylethynylpyrazoles in moderate to good yield (73S47)
(Scheme 19).
N2H4, HCl
O
C C C C Si(CH 3)3
Ar
methanol
Ar
N
N
H
C C
Si(CH 3)3
Ar = C6H5, p-Cl-C6H4, p-H3CO-C6H4, p-NO2-C6H4, 2-thienyl, 2-furanyl
Scheme 19
The diketone 3 is converted to the dipyrazole 4 (73S47) (Scheme 20).
21
O
(H 3C)3Si C C C C C
O
C C C C C Si(CH 3)3
N2H4, HCl
methanol
3
N NH
(H 3C)3Si C C
HN N
C C Si(CH 3)3
4
Scheme 20
The use of substituted hydrazines, phenylhydrazine and 2,4-dinitrophenylhydrazine
(68T4285; 74JOC843) can give both 5- and 3-acetylenylpyrazole. In this case, the direction of
cyclization depends on both hydrazine structure and experimental conditions.
The interaction between 1,5-diphenylpentadiyn-2,4-one-1 and its aliphatic analog  1,5dimethylpentadiyn-2,4-one  with substituted hydrazines gives rise to a linear adduct,
vinylacetylenylketone, which then cycles into 5-phenylethynylpyrazoles and 5-methyl-3propynylpyrazoles in 70-90% yields, respectively (73S47).
O
Ph
C
C
PhNHNH2
C
C
O
ethanol
Ph
Ph
C
HN
C
Ph
NH
Ph
N
N
Ph
C
Ph C
Ph
Scheme 21
Phenylhydrazine is added to 1,5-diphenylketone at 0oC in ethanol to give both 1,3-diphenyl5-phenylethynyl- and 1,5-diphenyl-5-phenylethynylpyrazole, while 2,4-dinitrophenylhydrazine
yield 1,3-diaryl-5-arylethynylderivative. In acidic solution 2,4-dinitrophenylhydrazine gives
corresponding hydrazone, which was rearranged to 3-arylethynyl isomer at elevated
temperatures (68T4285).
Ph
C
C
H
N
N
Ph
DMSO
Ph
O2N
Ph
O
+
C
C
C
+
C
O2N
NHNH 2
N
MeOH
Ph
NO 2
N
C C
Ph
O2N
NO 2
NO 2
Scheme 22
It is interesting that the cyclization of 2,4-dinitrophenylhydrazine of the aliphatic analog, 1,5dimethylpentadione-3, can also be performed in alkaline conditions. Heating hydrazine in boiling
methanol in the presence of sodium methoxide results in 1-(2,4-dinitrophenyl)-3-propynyl-5methylpyrazole (84%) (74JOC843).
Similarly, dipropynylketone behaves as an aliphatic analog which forms the corresponding 5methyl-3-(1-propynyl)pyrazoles (yield 7090%) with hydrazine or monosubstituted hydrazine in
methyl alcohol at room temperature (74ZOR136).
22
CH 3
C
O
H3C
C
C
C
RNHNH 2
C
C
H3C
CH 3
N
N
R
R = CH3, C2H5, C3H7, C4H9
Scheme 23
The same type of reactions includes the work of Hauptman (76T1293), who, studying the
chemistry of diethynylcarbenes, has found that, the pyrolysis of the lithium salts of
diethynylketone tosylhydrazones (140-150oС) in the presence of olefines leads to the
cyclopropane derivatives. This process results in the formation of the corresponding 3ethynylpyrazoles. The formation of 1-p-tolylsulfonyl-3-alkynyl-pyrazoles from hydrazone runs
in milder conditions (50 oC, 14 h) (Scheme 24).
N
R
C
C
R
Tos
NLi
C
C
C
C
R
R
N
N
Tos
R = CH3, C(CH3)3, Si(CH3)3, C6H5
Scheme 24
While the addition of hydrazine and its derivatives to acetylenic ketones has been studied
quite in detail, their interaction with hydrazones and monoalkylhhydrazones is less known.
Yandrovskii and Klindukhova (74ZOR730) have studied the reaction between hydrazones and
alkylhydrazones of aliphatic ketones with dipropynylketones and showed that hydrazones of
acetone, methylethylketone and cyclohexane easily add to one of the triple bonds of
dipropynylketone to form 4-methyl-1,1,3-trialkyl-2,3-diaza-1,4-nonadien-7-yn-6-ones (yields
50-80%). Being boiled in the water-dioxane solution in the presence of acids, these compounds
turn into 1-alkyl-3-propynyl-5-methylpyrazoles (Scheme 25).
R1
N
R N
O
H3C
C
C
C
C
R2
C
C
R1
CH 3
CH 3
O
N
2
R
N
R
CH 3
C
H+
C
CH3
-R1R2C=O
H3C
N
N
R
R = CH3, C2H5, C4H9, H
Scheme 25
The transformation of pyrazoles causes the splitting of the C=N bond followed by cyclization
of intermediate hydrazine.
23
An example of the reaction of hydrazones with enynes is reported in German patent
(91GEP4001600). The alkynylpyrazoles were prepared by treating of RNHN=CR3CO2R2 with
CH2=CR1OR4 (R3 = Cl, Br; R4 = alkyl) followed by aromatization with acid (Scheme 26).
R3
N
R NH
4
R O
O
C
C
R2 O
O
R2
O
aromatization
C
R1 C
R1
N
R
N
Scheme 26
The authors (74ZOR1510) have introduced another type of binucleophyl, 3,3dialkyldiaziridine, to the reaction with dipropynylketone. Condensation was performed by
mixing dipropynylketone with the equimolar amount of aziridine in absolute methanol at 0 oC
(16 h). The resulting vinylacylaziridines (50%) can lead, depending on experimental conditions,
to a linear hydrazone and cyclic alkyliden-N-amino-pyridon and 3(5)-propynyl-5(3)methylpyrazole (Scheme 27).
HN
HN
O
H3C
C
C
C
C
CH3
R1
CH3
O
R2
C
C
HN N
R1
CH3
R2
Scheme 27
C
H+
C
CH3
H3C
N
N
H
24
TABLE VI
Alkynylpyrazoles Prepared by Cyclizations of Diynones with Hydrazine
Diynone
Me
Alkynylpyrazoles
Formula
index
Structural formula
3-Methyl-5-prop-1-ynyl-1H-pyrazole
C7H8N2
Me
C
C
N
N
H
C C Me
O
n-Bu
3-Butyl-5-hex-1-ynyl-1H-pyrazole
n-Bu
C13H20N2
C
C
N
N
H
C C n-Bu
O
O
C C C C SiMe3
3-Furan-2-yl-5trimethylsilanylethynyl-1H-pyrazole
3-Thiophen-2-yl-5trimethylsilanylethynyl-1H-pyrazole
Cl
3-(4-Chloro-phenyl)-5trimethylsilanylethynyl-1H-pyrazole
93.5-94.5 (CHCl3)
-
74JOC843
93.5-94 (C6H6-hexane)
-
74ZOR136a,b
28-30 (n-hexane) [133136/0.01]
-
68T4285
oil
38
73S47
90.5-91.5 (methanolwater with trace of HCl)
17
73S47
144-145.5 (methanolwater with trace of HCl)
44
73S47
C C
SiMe3
S
N
C C C C SiMe3
N
H
C12H14N2SSi
S
O
References
O
N
C C C C SiMe3
Yield
(%)
C C
n-Bu
C12H14N2OSi
O
O
C C
Me
M.p. (oC)
C14H15ClN2Si
N
H
C C
SiMe3
Cl
N
N
H
C C
SiMe3
25
Diynone
O
C C C C SiMe3
Alkynylpyrazoles
Formula
index
3-(4-Nitro-phenyl)-5trimethylsilanylethynyl-1H-pyrazole
C14H15N3O2Si
Structural formula
O2N
O2N
N
O
3-Phenyl-5-trimethylsilanylethynyl1H-pyrazole
C C C C SiMe3
Ph
O
C C C C SiMe3
3-(4-Methoxy-phenyl)-5trimethylsilanylethynyl-1H-pyrazole
N
N
3-Phenyl-5-phenylethynyl-1Hpyrazole
C
C
N
C C Ph
O
Me3Si
SiMe3
C
C
C
C
O
a
C
C
C
C
1,4-Bis(3-(trimethylsilylethynyl)pyrazol-5-yl)benzene
C22H26N4Si2
N
H
N
H
C C
Ph
Me3Si
SiMe3
C
C
HN N
189-190 (methanolwater with trace of HCl)
80
73S47
103-104.5 (methanolwater with trace of HCl)
43
73S47
132.5-133 (methanolwater with trace of HCl)
25
73S47
112-114 (hexane)
79
68LA113
110-111 (MeOH water)
-
68T4285
250 (dec) (methanolwater with trace of HCl)
85
73S47
C C
SiMe3
Ph
C17H12N2
References
C C
SiMe3
N
H
O
C15H18N2OSi
Yield
(%)
C C
SiMe3
Ph
C14H16N2Si
O
Ph
N
H
M.p. (oC)
C
C
N NH
O
The same compound was prepared by reaction of acetone hydrazones with dipropynylketone at 0 oC in methanol to give 4-methyl-1,1-dialkyl-2,3-diaza-1,4-nonadien-7-yn-6-on
that was cyclized when boiling in aqueous acidified with HCl dioxane (74ZOR730).
b
5-Methyl-3-propynylpyrazole was prepared by addition of 3,3-dialkyldiaziridines to dipropynylketones to give vinilic derivatives of N-acyldiaziridines and following with
cyclization in acidified acetone (74ZOR1510).
26
TABLE VII
Alkynylpyrazoles Prepared by Cyclizations of Diynones with Substituted Hydrazines
Diynone
Hydrazine
Alkynylpyrazoles
Formula index
1,3-Dimethyl-5-prop-1-ynyl-1H-pyrazole
C8H10N2
Structural formula
M.p. (oC)
Yield
(%)
References
138-139 (CCl4)
70-90
74ZOR136
RNHNH2
Me
CH3NHNH2
C
C
Me
N
C C Me
O
Me
C2H5NHNH2
C
C
1-Ethyl-3-methyl-5-prop-1-ynyl-1Hpyrazole
C9H12N2
N
O
C3H7NHNH2
C
C
3-Methyl-1-propyl-5-prop-1-ynyl-1Hpyrazole
C10H14N2
N
O
Me
C4H9NHNH2
C
C
1-Butyl-3-methyl-5-prop-1-ynyl-1Hpyrazole
C11H16N2
N
O
Me
2,4-(NO2)2C6H3-NHNH2
C
C
1-(2,4-Dinitro-phenyl)-3-methyl-5-prop1-ynyl-1H-pyrazolea
C13H10N4O4
N
C3H7
N
O
74ZOR136
nD20 = 1.5232
70-90
74ZOR136
nD20 = 1.5186
70-90
74ZOR136
74ZOR730
74ZOR730
C C
N
Me
C4H9
Me
C C Me
70-90
Me
Me
C C Me
64.5-65 (C6H6hexane)
C C
N
Me
C2H5
Me
C C Me
74ZOR730
C C
Me
Me
C C Me
Me
N
Me
C C
Me
N
137-139
(absolute
ethanol)
80
74JOC843
nD20 = 1.6024
70-90
74ZOR136
O2N
NO 2
Me
PhNHNH2
C
C
C C Me
O
3-Methyl-1-phenyl-5-prop-1-ynyl-1Hpyrazole
C13H12N2
Me
N
N
Ph
C C
Me
27
Diynone
Hydrazine
Alkynylpyrazoles
Formula index
5-Methyl-3-prop-1-ynyl-1-(toluene-4sulfonyl)-1H-pyrazole
C14H14N2O2S
M.p. (oC)
Yield
(%)
References
48b
76T1293
C C Me
129-130
(petroleum
ether)
114-116
(petroleum
ether)
42b
76T1293
C C SiMe3
-
68T4285
121-122
(petroleum
ether)
37b
76T1293
144-146
(ethanol)
69
75ZOR47
Structural formula
RNHNH2
Me
TosNHNH2
C
C
Me
N N
Tos
C C Me
O
Me3Si
TosNHNH2
C
C
1-(Toluene-4-sulfonyl)-5-trimethylsilanyl3-trimethylsilanylethynyl-1H-pyrazole
C18H26N2O2SSi2
Me3Si
N N
Tos
C C SiMe3
O
n-Bu
5-Butyl-3-hex-1-ynyl-1-phenyl-1Hpyrazole
n-Bu
C
C
PhNHNH2
nD25 = 1.5506
Ph N
N
C19H24N2
C C n-Bu
C
C
n-Bu
n-Bu
O
3-Butyl-5-hex-1-ynyl-1-phenyl-1Hpyrazole
TosNHNH2
C
C
5-tert-Butyl-3-(3,3-dimethyl-but-1-ynyl)1-(toluene-4-sulfonyl)-1H-pyrazole
N
N
Ph
C C
n-Bu
C20H26N2O2S
N N
Tos
C C
C C
nD27 = 1.5534
O
Ph
PhNHNH2
C
C
C C Ph
O
1,3-Diphenyl-5-phenylethynyl-1Hpyrazolec
C23H16N2
Ph
N
N
Ph
C C
Ph
28
Diynone
Hydrazine
Alkynylpyrazoles
Formula index
Structural formula
M.p. (oC)
Yield
(%)
169.5-171
(MeOH –
EtOAc)
24
RNHNH2
References
Ph
N
O2N
N
1-(2,4-Dinitro-phenyl)-5-phenyl-3phenylethynyl-1H-pyrazole
Ph
C
C
C C Ph
2,4-(NO2)2C6H3-NHNH2
NO 2
N
1-(2,4-Dinitro-phenyl)-3-phenyl-5phenylethynyl-1H-pyrazole
C
Ph
Ph
C23H14N4O4
O
C
68T4285
N
C C
Ph
O2N
205-206 (EtOH)
83
121-122
(petroleum
ether)
38b
NO 2
Ph
TosNHNH2
5-Phenyl-3-phenylethynyl-1-(toluene-4sulfonyl)-1H-pyrazole
C
C
C24H18N2O2S
Tos
C C Ph
O
a
The compound was synthesized by the cyclization of hydrazone with MeONa.
b
It is the yield of hydrazone, the cyclization occurred to give the alkynylpyrazole with quantity yield.
Ph
C
Ph
C
c
The same product was prepared from
Ph
O
O
Ph
in 67% yield, m.p. 144-145 oC (ethanol) (75ZOR47).
N N
C C Ph
76T1293
29
B. Reactions of elimination
The dehydrochlorination of saturated dihalides or monohalideolefins is the commonly used
method of elimination applied to synthesize alkyl- and arylacetylenes. The starting compounds
commonly used to produce halide derivatives are, as a rule, the corresponding olefins whose
interaction with halides causes the formation of vic-dihalides. The other one are ketones that
during reaction with PCl5 give the mixture of hem-dihalides and chlorovinyl derivatives. The
preparing of acetylenic derivatives of nitrogen 5- and 6-membered heterocycles by this method
creates complications and the yields of desired products substantially depend on the cycle
structure. Thus, an attempt to dehyrobrominate pyrroldibromoacrylate under the action of
sodium ethylate in alcohol has failed (30LA113). The yields of all possible isomers of
ethynylpyridine and ethynylquinoline obtained by the dehydrohalogenation varied from 0.1 to
33% (60CB593).
A detailed study of transformations of methylpyrazolylketones into acetylenes under an
action of PCl5 and then a base indicates to the sensitivity of these reactions to experimental
conditions, the structure of starting ketones and the origin of the base (69IZV927, 69KGS1055;
76IZV2288).
Kotlyarevsky et al. (69IZV927) found that, ketones, which are not substituted on the nitrogen
of the ring, lead to certain complications. Thus, under normal conditions (60CB593), 4-acetyl3,5-dimethylpyrazole (6) gave a product containing commensurable quantities of the respective
acetylene derivative 11 and an unexpected chloroacetylene 10.
Cl Cl
Cl
N
PCl5
O
N
N
H
6
20 oC
PCl5
+
N
H
7
Cl
80 oC
N
NaNH 2
N
H
8
CH
C
C
Cl
C
NaNH 2
N
N
Cl
N
N
H
9
BuLi
N
H
11
N
H
10
Scheme 28
Variations in the reaction temperature and in the proportions of ketone and phosphorus
pentachloride were appreciably reflected in the ratio of the amounts of compound 9 obtained in
the first stage to the total content of 7 and 8 and then proportionally in the composition of the
final products. In the interaction of the ketones with PCl5 an excess of the latter and high
temperature make the anomalous reactions more significant. 4-(1,2-Dichlorovinyl)-3,5-dimethyl1H-pyrazole (9) was obtained individually by the action of more than a two-fold excess of PCl5
on the acetylpyrazole 6 at 80oC in yield 50%. Under the influence of NaNH2 in liquid NH3 the
dichloroethylene 9 split off a molecule of HCl and was converted into chloroacetylene 10 (yield
77%) (Scheme 28).
Early the elimination of hydrogen halides from dichloroethylenes as a method for the
synthesis of halogenoacetylenes has not been sufficiently developed on account of secondary
reactions between the halogenoacetylene and bases. The exception is sodium (or lithium)
chloroacetylide, which is formed almost quantitatively in the reaction of 1,2- or 1,1-
30
dichloroethylene with sodium amide (or lithium amide) in ammonia or phenyllithium (or
methyllithium) in ether (59CB1270, 59CB1950). The absence of side reactions of exchange of
the halogen in the case of 4--chloroethynyl-3,5-dimethylpyrazole is probably explained by the
fact that the sodium salt in the form of which it is obtained, is insufficiently soluble with
ammonia and is similar in this respect to the chloroacetylide.
After having determined the nature of the side reaction it became clear that to obtain the
desired ethynylpyrazole 11 the reaction between the ketone and PCl5 would have to be carried
out at low temperature. Indeed, authors carried out the reaction in CH2Cl2 at room temperature
and obtained a mixture of chlorides 7 and 8. Dehydrochlorination of this mixture gave 66% of
3,5-dimethyl-4-ethynylpyrazole (11). Thus, by varying the conditions it is possible to carry out
the reaction of the ketone with phosphorus pentachloride selectively in any of the abovementioned directions.
During investigation of the effect of the specific characteristics of the structure of starting
compound on its behavior in this reaction it was found that N-methylated pyrazolyl ketones 12ad can also be converted in yields of 50-90% either into the "normal" products 13a-c, 14a-c from
substitution of the carbonyl oxygen by chlorine or to the corresponding ,-dichloroethylenes
17a-d (76IZV2288) (Scheme 29).
O
Cl
PCl 5
Pz
Cl
Cl
+
Pz
12a-d
NaNH 2
CH
Pz C
Pz
13a-c
15a-c
14a-c
PCl 5
Cl
Pz
Cl
PCl 5
Pz
Cl
NaNH 2
Cl
17a-d
Cl
C
Pz C
18a-d
Cl
16a-d
H3C
H3C
Pz =
N
N
N
CH 3
a
CH 3
N
CH 3
N
H3C
CH 3
N
CH 3
c
b
N
CH 2Cl
N
CH 3
d
Scheme 29
The formation of the dichlorides is aided by increased temperature (60-80oC) and by an
excess of phosphorus pentachloride [2-2.3 moles/mole of 4-acetylpyrazole]. With a larger excess
of phosphorus pentachloride further chlorlnation of the compounds occurs. With 3 moles of
phosphorus pentachloride at 80oC in benzene the ketones 12a-d gave pyrazolyltrichloroethylenes
16a-d in 75% yield. Then the dichlorides 17a-d are converted quantitatively into
pyrazolyltrichloroethylenes 16a-d in 1 h under the same conditions.
Chlorination at the -position of the side chain is probably the result from phosphorylation of
the intermediate vinyl chlorides followed by degradation of the phosphorus-containing products
(72ZOB802).
Following the data in (54IZV803; 72ZOB802; 74KGS310) that the vinyl compounds are
phosphorylated more readily in benzene than in POC13 authors carried out reaction in last
solvent. In accordance with this only the chlorides 13a, 14a were formed from 4-acetyl-l,3dimethylpyrazole (12a) in POCl3, in spite of the 35% excess of PCl5, whereas it is not possible to
31
avoid the formation of the vicinal dichloride completely in benzene even with an equlmolar
amount of PCl5.
In addition, it was clear that the presented scheme does not exhaust all the possible paths of
"anomalous" chlorination. Thus, 4-acetyl-l,3,5-trimethylpyrazole with 4-5 moles of phosphorus
pentachloride gave mainly 4-,-dichlorovinyl-5-chloromethyl-l,3-dimethylpyrazole, and its
precursor (according to GLC data) was the dichloride. It is not impossible that in the case of 4chlorovinyl derivatives of pyrazole the chlorination at the -position is facilitated on account of
the electron-donating characteristics of the 4-pyrazolyl radical (86TH1).
By using sodium amide in ammonia, ethynyl-N-methylpyrazoles 15a-c were synthesized by
dehydrohalogenation of dichlorides 13a-c, 14a-c in 60-85% yields, calculated on acetylpyrazoles
12a-c (Table VIII).
It is known that cloroethynylpyrazoles can enter different conversions with sodium amide
(see part “Reactions with participation of C-X bond”). Authors (76IZV2288) supposed that the
rate of dehydrochlorination of vicinal dichlorides by sodium amide is higher than the rates of the
succeeding processes. Indeed, by using the stoichiometric amount of the base, the
chloroacetylenes 18a-d were obtained from dichlorides 17a-d in 80-90% yields (Table IX).
Thus, depending on the conditions, the reaction of methylpyrazolylketones with phosphorus
pentachloride leads to products from substitution of the carbonyl oxygen by chlorine, ,dichlorovinylpyrazoles, that can be dehydrihalogenated with sodium amide to ethynylpyrazoles,
or ,-dichloroethylenes, that by eliminating a molecule of hydrogen chloride under the
influence of an equimolar amount of sodium amide in ammonia give high yields of the
respective 1-chloroacetylenes (Scheme 29).
The above method can also be used to simultaneously transform two acetylic groups into
acetylenic ones in positions 3 and 5 of the pyrazole cycle. This is demonstrated by the synthesis
of 3,5-diethynyl-1-methylpyrazole (yield 62%) from 3,5-diacetyl-1-methylopyrazole (Scheme
30).
O
HC
C
1. PCl 5
N
O
N
2. NaNH2
N
N
C
CH
Scheme 30
Moreover, the authors have managed to apply this synthesis scheme to the labile and difficult
for access butadiynylpyrazole (yield 36%) from 4-acetoacetyl-1,3,5-trimethylpyrazole (Scheme
31).
CH
O
C
O
O
C
C
EtOAc,
MeONa
N
1. PCl 5
N
N
N
2. NaNH2
N
N
H
Scheme 31
The reaction of bromine with (pyrazol-4-yl)acrylic acid and its esters acid and following
dehydrobromination of the products has been investigated by Finar and Okoh (73JCS(P1)2008).
Attempts to dehydrobrominate the bromoacrylic acids (20) to 3-(1-phenylpyrazol-4-yl)propyolic
acids 22 failed, but were successful when the bromoesters 21 were used (Scheme 32).
32
R
Ph
O
N
N
NaOH
R' = H
Ph
R
N
N
NaOH
O R'
R' = Et, t-Bu
R Br
O
Ph
C C
OH
R
R = H, CH3
19
O
N
N
22
20 R' = H
21 R' = Alk
Scheme 32
Popov et al. (75KGS1678) have described similar transformations for -(1-methyl-3indazolyl)--bromoacrylic and -(2-methyl-3-indazolyl)--bromoacrylic acids (Table X). The
treatment of the bromacryl acids with alcohol potassium hydroxide at 60oC for two hours results
in 1-methyl- and 2-methyl-3-indazolylpropynoic acids in 75% and 78% yields, respectively
(Table X).
It has been shown (87KGS787) that the dehydrobromination of (2-bromopropen-3yl)pyrazole 23 by KOH in triethylenglycol (150oC, 0.5 h) gives the intermediate allene that is
transformed into 3,5-dimethyl-1-phenyl-4-prop-1-ynyl-1H-pyrazole (24).
Ph
N
N
KOH
Ph
Br
N
N
C C
23
24
Scheme 33
Patent (93EUP571326) describes the synthesis of the large series of 3-hydroxy-2-(2-methyl4-prop-1-ynyl-2H-pyrazol-3-yl)-acrylic acid methyl esters 26 and methoxyimino-(2-methyl-4prop-1-ynyl-2H-pyrazol-3-yl)-acetic acid methyl esters 27 by dehydrohalogenation of the
corresponding chloroolefins 25 under the action of bases. In this case, the functional groups in
position 5 of the pyrazole cycle undergo transformations (Scheme 34).
R3
R3
4
R1
N
for A = CH; R = H
NaH, HCOOMe
Cl
O
N
R2
C
O
O
25
C
R1
for A = N; R4 = Me
1. NaH, amyl nitrite;
2. MeI
N
N
R2
O
A
O
26 A = CH; R4 = H
27 A = N; R4 = Me
R4
R1 = H, alkyl, substituted aryl, CF3; R2 = alkyl, substituted aryl;
R3 = substituted hydrocarbyl or heteroaryl
Scheme 34
Refluxing of 2-bromo-1-(2-ethylpiperidin-1-yl)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propenone (28) in ethanol (1.5 h) in presence of potassium hydroxide gives disubstituted
propynone 29 (Scheme 35). A number of conversions like this are described (89EUP299209;
92USP5102869).
33
O
O
N
N
C
C
KOH
Br
N N
N N
28
29
Scheme 35
In article (99USP5925769) is presented examples of dehydrobromination leading to
bromoethynylpyrazole derivatives as illustrated by the Scheme 36. Treatment of 1,1dibromolefines with tetrabutylammonium fluoride in THF at room temperature for about 24 h
under N2 gives the 1-bromo-2-(pyrazol-3-yl)acetylenes where R1, R2, R3 and R4 are
independently selected from H and alkyl, alkoxy, phenyl, halo, hydroxy, alkylsulfonyl, alkylthio,
trihaloalkyl, amino, nitro and 2-quinolinylmethoxy group.
R4
R4
N
R3
(n-Bu) 4N+F-
N
Br
R3
THF
Br
R2
N
N
C C Br
R2
1
R1
R
Scheme 36
In 1987 Przhiyalgovskaya proposed an original method for producing aryl- and
hetarylacetylenes by fragmentation of the Fisher’s acylic derivative bases (87KGS915). The
enaminoketones of indole series (Fisher bases) are readily obtained by acylation of 1,3,3trimethyl-2-methylenindoline. The heating of Fisher bases with POC13 in dioxane and a
subsequent action of aqueous alkali solution gives rise to oxyindole and 3-ethynyl-1methylpyrazole in 77% yield (Scheme 37).
O
+
N
N N
1. POCl 3
Cl
N
O
O
N
+
N N
N N
2. NaOH
C CH
Scheme 37
Other type of the elimination reaction is the reaction of 1-(5-methyl-1-phenyl-1H-pyrazol-4yl)-ethanone with Vilsmeier complex to give 3-chloro-3-(5-methyl-1-phenyl-1H-pyrazol-4-yl)propenal which in turn suffers dichloroforylation to form 4-ethynyl-5-methyl-1-phenyl-1Hpyrazole (Scheme 38) (77AMC135). (Polymerization of the alkyne with PdCl2 gave an oligomer
which did not give EPR signal at room temp. Treatment of the polymer with chloroanil gave a
charge-transfer complex with EPR spectra.)
34
O
Cl
N
C
N
N
Ph
CH
CHO
Vilsmeier
complex
N
N
Ph
N
Ph
Scheme 38
El-Shekeil et al. (88PPA25) as well as Shiokawa et al. (90EUP379979) reported about the
synthesis of alkynylpyrazoles via addition of bromine to alkene and following
dehydrobromation. The pyrazolylpropenones prepared by condensation of 5-chloro-1,3dimethylpyrazole-4-carboxaldehyde with RCOMe were brominated to give the dibromides. The
dibromides were treated with nucleophiles (KOH, HONH2, NH2NH2) that caused the
dehydrobromation and in cases of two last nucleophiles a cyclization such as on Scheme 39 for
example (88PPA25).
COR 1
O
Ph
Ph
R1COMe
N
N
Ph
COR 1
Br
Ph
Br2
N
Cl
N
Ph
Cl
Br
N
N
Ph
Cl
R1
COR 1
C
Ph
N
N
R2
C
Ph
N
N
Ph
Cl
N
R1 = Ph, p-MeC6H4; R2 = Ac, Ph
Scheme 39
N
Ph
Cl
R2NHNH2
35
TABLE VIII
Monosubstituted Acetylenylpyrazoles Prepared by the Elimination
Starting compound
Alkynylpyrazoles
Structural formula
3-Ethynyl-1-methyl-1H-pyrazole
N N
N
M.p. (oC)
Yield (%)
References
C6H6N2
[121/30 mm Hg]
57
87KGS915
20
nD 1.538
N N
O
4-Ethynyl-3,5-dimethyl-1H-pyrazole
O
N
HN
N
HN
O
N
N
4-Ethynyl-1,5-dimethyl-1H-pyrazole
3,5-Diethynyl-1-methyl-1H-pyrazole
O
N
N
C CH
N
N
C CH
HC
C
N
N
C7H8N2
129.5-130.5 (petroleum ether)
66
69IZV927
C7H8N2
34.5-35.5 (petroleum ether)
87
76IZV2288
C7H8N2
63-63.5 (petroleum ether)
69
76IZV2288
C8H6N2
41-41.5 (petroleum ether)
62
69KGS1055
C8H10N2
78 (petroleum ether)
75
69KGS1055
C10H10N2
109-110 (sublimation)
37
69KGS1055
C CH
4-Ethynyl-1,3-dimethyl-1H-pyrazole
O
N
N
N
C CH
Formula index
N
C CH
O
N
N
4-Ethynyl-1,3,5-trimethyl-1H-pyrazole
O
N
N
N
N
C CH
4-Buta-1,3-diynyl-1,3,5-trimethyl-1H-pyrazole
O
O
N
N
C C C CH
36
TABLE IX
Halogenoethynylpyrazoles Prepared by the Elimination
Starting compound
N
N
Cl
N
N
Cl
Alkynylpyrazoles
Structural formula
4-Chloroethynyl-1,3-dimethyl-1H-pyrazole
Cl
4-Chloroethynyl-1,5-dimethyl-1H-pyrazole
Cl
N
N
C C Cl
N
HN
Cl
4-Chloroethynyl-5-chloromethyl-1,3dimethyl-1H-pyrazole
Cl
N
HN
C C Cl
4-Chloroethynyl-3,5-dimethyl-1H-pyrazole
Cl
N
HN
N
N
References
C7H7ClN2
32-33 (petroleum ether)
86
76IZV2288
C7H7ClN2
nD20 1.5513
89
76IZV2288
C7H7ClN2
155-156 with decomp.
(petroleum ether)
77
69IZV927
C8H8Cl2N2
81-82 (petroleum ether)
37
76IZV2288
C8H9ClN2
83-84 (petroleum ether)
90
76IZV2288
Cl
4-Chloroethynyl-1,3,5-trimethyl-1Hpyrazole
Cl
N
N
Cl
O
3-Bromoethynyl-1-(4-methoxy-phenyl)-5-ptolyl-1H-pyrazoleb
N
Yield
(%)
C C Cl
Cl
N
N
M.p. (oC)
C C Cl
N
N
Cl
Formula
index
N
88a
C C Cl
O
C19H15BrN2O
N
N
C C Br
Br
Br
a
b
Potassium hydroxide in ethanol at 80 oC was used.
Different compounds of the general formula were obtained; physical data, yield are reported only for the title compound.
120-122
96
99USP5925769
37
TABLE X
Disubstituted Acetylenylpyrazoles and Acetylenylindazoles Prepared by the Elimination
Starting compound
Alkynylpyrazoles
Structural formula
(1-Methyl-1H-indazol-3-yl)-propynoic acid
Formula
index
M.p. (oC)
Yield
(%)
References
C11H8N2O2
135-136 with decomp.
(equeous ethanol)
75
75KGS1678
C11H8N2O2
132 with decomp. (equeous
ethanol)
78
75KGS1678
C12H8N2O2
151.5-152.5 with decomp.
(equeous ethanol)
82
73JCS(P1)2008
C14H12N2O2
136-137 with decomp.
(acetone-light petroleum)
44-53
73JCS(P1)2008
C14H14N2
[132-133/2 mm Hg]
88
87KGS787
42
90EUP379979
O
O
N N
Br
C C
N N
OH
O
(2-Methyl-2H-indazol-3-yl)-propynoic acid
O
O
N N
Br
O
Br
Ph
N N
OH
O
N
N
Ph
C C
(1-Phenyl-1H-pyrazol-4-yl)-propynoic acid
Ph
O
N
N
O R
(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)-propynoic
acid
Ph
Br
O
N
N
C C
OH
O
N
N
C C
OH
O
R = Et, tert-Bu
3,5-Dimethyl-1-phenyl-4-prop-1-ynyl-1H-pyrazole
N
N
Ph
Ph
N
N
20
nD 1.5982
C C
d204 1.0925
Br
O
Br
N N
O
Br
(2-Phenyl-pyrazolo[1,5-a]pyridin-3-yl)-propynoic
acid
O
C
C
N N
OH
C16H10N2O2
> 250
38
Starting compound
Ph
N
N
Cl
O
Alkynylpyrazoles
3-Hydroxy-2-(2-methyl-4-phenylethynyl-2Hpyrazol-3-yl)-acrylic acid methyl estera
a
C C Ph
M.p. (oC)
Yield
(%)
References
C16H14N2O3
-
-
93EUP571326
C23H23N3O
oil
87
89EUP299209;
OH
O
N
Br
N N
N
N
Formula
index
O
O
O
Structural formula
1-(2-Ethyl-piperidin-1-yl)-3-(2-phenyl-pyrazolo[1,5a]pyridin-3-yl)-propynone
O
N
C
C
N N
Different compounds of the general formula were obtained; physical data, yields are not reported.
92USP5102869
39
C. Cross-coupling of halogenopyrazoles with terminal acetylenes and its
copper(I) salts
In 1963 Sladkov (63IZV2213) and Castro (63JOC3313) have discovered reaction
between copper acetylides and aromatic halogen derivatives. This method was of limited
usefulness because of the necessity of preparing explosive copper acetylenides.
Nevertheless, an actual possibility of substituting of a halogen atom in pyrazole derivatives
has been shown using 3-, 5-, and less active 4-iodopyrazoles containing substituents of
both acceptor and donor character in its cycle (77IZV23063; 83IZV6888; 86IZVSO105;
90IZV2089). The cross-coupling of iodopyrazoles with copper salts of terminal acetylenes
is carried out in boiling pyridine or dimethylformamide. The reaction takes 9-18 h. The
product yields amount to 70-90%. For the activated 1-methyl-3-nitro-4-iodopyrazole the
time of condensation with copper phenylacetylide is 1.5 h, the product yield was 94%
(86MI1).
In 1971 was suggested a new experimental conitions for the synthesis of acetylenic
derivatives of pyrazole (71IZV1764, 72IZV2524), which is based on the reaction of the
catalytic replacement of halogen in aromatic rings by acetylenic moieties (69MIP1). 1Prop-2-ynylpiperidine and 3-(1-ethoxyethoxy)-3-methylbut-1-yne (acetal of 2-methylbut3-yn-2-ol) were used as the starting terminal acetylenes (71IZV1764, 72IZV2524).
It should be noted that these were the first examples of the Cu-catalyzed cross-coupling
of arylhalides with terminal acetylenes. Authors (71IZV1764) carried out the acetylenic
condensation with unreactive 4-iodo-l,3,5-trimethylpyrazole, a compound in which the
halogen atom is not only found in a position more unfavorable for replacement, but is also
further passivated by the introduction of electron-donor methyl groups (Scheme 40).
O
HO
O
C
R
I
C
R
H2O, H+
Alkyne
N
N
R Cu, K CO N N
2
3
C
N
R
C
R
R
N
R = H, CH3
Scheme 40
For comparison the cross-coupling of the presumably more active 5-iodo-lmethylpyrazole with alk-1-ynes was carried out (Scheme 41).
O
Alkyne
N
N
I
N
Cu, K 2CO 3
N
C C
H2O, H+
O
N
N
C C
OH
Scheme 41
The cross-coupling was run in refluxing pyridine, in the argon atmosphere, in the
presence of К2СОз and copper. The 5-iodopyrazole proved to be much more active than
the 4-iodopyrazole. The latter reacted with the acetal alkyne to the extent of only 55% for
40
23 h, while the reaction of 5-iodo-l-methylpyrazole under the same conditions was
completely ended in 9 h. It is noteworthy that no tarring of the reaction mixture was
observed despite the long heating, and the yield of the alkynylpyrazoles reached 90%.
In order to ascertain the possibility of inserting more than one acetylenic moieties into
the pyrazole ring, it was ran the replacement of two and three iodine atoms in the
appropriate halides by different alk-1-ynes. In order to increase the total rate of
replacement the cross-coupling of diiodopyrazoles and triiodopyrazole was carried out
with higher initial concentrations of the reactants than for the monoiodides. The reaction of
diiodopyrazoles with the acetal was completed for the most part in 40 h, and in 64 h in the
case of triiodopyrazole. The yields of the di- and triacetals reached 70-90% (Table XIV).
A number of di- and tri-(3-N-morpholinopropyn-1-yl)-1-methylpyrazoles were
prepared by the condensation of corresponding iodopyrazoles with 4-prop-2ynylmorpholine in presence of Cu(0), K2CO3 in boiling pyridine, but without palladium
catalyst. Despite of the low activity of this catalytic system and the long condensation time
(75-95 h) the yield of the 3,4-di-, 4,5-di- and 3,4,5-tri-(3-N-morpholinopropyn-1-yl)-1methylpyrazoles reached 70-80% (Scheme 42, Scheme 43).
N
O
C
I
N
C
Alkyne
I
N
C C
N
Cu, K2CO 3
N
N
O
Scheme 42
O
N
N
I
I
O
C
C
C
C
O
Alkyne
N
N
I
Cu, K2CO 3
N
N
C C
N
Scheme 43
The chief disadvantage of the method is the long heating of mixture at high
temperature.
New experimental conditions for the catalyzed cross-coupling reaction were proposed
in 1975 by Heck [catalyst - PdCl2(PPh3)2], Cassar [catalyst - Ni(PPh3)3 or PdCl2(PPh3)2]
(75JOM253, 75JOM259) and Japanese investigators (75TL4467) who suggested new
effective catalytic system PdCl2(PPh3)2 - CuI for introduction of acetylenic moiety into
arenes and hetarenes. From the various articles dealing with Pd/Cu-catalyzed crosscouplings of acetylenes with sp2-halides it may be concluded that this reaction has a very
broad scope (98MI1).
Beginning from the discovery of these methods and up to now, the cross-coupling of
arylhalides with monosubstituted acetylenes or their copper salts is the main method for
producing aryl- or hetarylacetylenes. The catalytic variant of SonogashiraHeck is a most
effective (75TL4467). Indeed, this method was used for preparing of different
41
acetylenylpyrazoles. This reaction needs no preparation of explosive copper acetylenides
and often occurs at room temperature.
The reactivity of arylhalides in acetylenic condensation sharply decreases in the series
Ar-I, Ar-Br, Ar-Cl. The rate of reaction of phenylacetylene with iododerivatives is 800
times higher than that of the reaction with bromoderivatives and is 105 higher than that of
the reaction with corresponding chlorides (75JOM253). Taking into account a very low
activity of halogenopyrazoles (66MI1) the catalytic variant of acetylenic condensation
mainly involves the most active iododerivatives.
Similarly, limitations and peculiarities of the cross-coupling of pyrazolylhalides with
terminal acetylenes have been fully and systematically studied by Russian chemists
(86TH1; 97TH1).
As one can expect, the 5-halogen derivatives are more active (83IZV688; 85MI1;
90IZV2089; 92IZV507) than 3- or 4-iodopyrazoles. The influence of the nature of
substituent in position 4 of the cycle conjugated with the halogen atom in position 5 on the
rate of cross-coupling reaction has investigated. As a halide component, authors have
chosen 5-iod-1,3-dimethylpyrazole and its derivatives with a substituent in position 4 of
both acceptor (NO2, Cl, Br, CONH2) and donor character (NHAc, NH2). Terminal alkynes
HCCR where R = alkyl, aryl, including bifunctional p-diethynylbenzene were used as
acetylenic component. Electron-withdrawing substituents are increasing the rate of crosscoupling (Table XI).
It is noteworthy that the only deiodinated product (4-nitro-1,3-dimethylpyrazole) was
isolated in a 70% yield (86TH1) by cross-coupling phenylacetylene with 5-iod-4-nitro-1,3dimethylpyrazole (Scheme 44).
NO 2
NO 2
HC C Ph
N
N
I
N
Pd(PPh3)4,
CuI, NHEt 2
N
Scheme 44
A similar phenomenon was observed for 3-amino- and 5-amino-4-iododerivatives of
the pyrazole. The anomalous reaction where the products of oxidative coupling of terminal
acetylenes (up to 90%) are present along with the products of deiodination (up to 90%) has
been revealed for the first time (99JCS(P1)3713) and will be considered in the part related
with cross-coupling of 4-iodopyrazoles.
The next group of halogenoderivatives consists of 3-iodopyrazoles whose activity is
close to that of 5-halogen derivatives (90IZV2089). Vicinal 3-iodopyrazoles containing
carboxyl, carbamine, N-acetylamino and amino groups were introduced for cross-coupling
under standard conditions (75TL4467). The reaction time was varied within small limits
(5-13 h) and was actually dependent on the structure of terminal acetylenes. The yields of
3-acetylenylpyrazoles were 55-75% (Table XII).
Annelation of the pyrazole cycle with -electrono deficit diazine ring lead to increasing
of the reactivity of halogenopyrazole. Large series of oligonucleotides containing
acetylenylpyrazolo[3,4-d]pyrimidies was synthesised by cross-coupling reaction by Seela
et al. (97NN821; 98JCS(P1)3233; 99JCS(P1)479, 99HCA1640; 2000HCA910). The
iododerivatives 31 were shown to be much more active than their bromoanalogs 30. In the
first case, the reaction runs for 4-7 h at room temperature. In the second case, it needs the
heating (45oC, 48 h or 70oC, 6 h). Note that in both cases, the ten-fold excess of terminal
acetylenes was used instead of the usually used 20-30% (Table XVI).
42
R
NH 2
Hal
N
N
O
NH 2
N
C
N
HC C R
N
Pd(PPh3)4, CuI,
NEt3, DMF
HO
C
N
O
N
N
HO
HO
HO
30 Hal = Br,
31 Hal = I
Scheme 45
Special attention was given in literature to preparation of alkynylpyrazoles with
electron-donating sustituents connected with the pyrazole cycle (99JCS(P1)3713). Both 332 and 5-iodo derivatives 33 underwent successful coupling with either p-nitrophenyl- or
phenylacetylene using the catalyst system Pd(PPh3)2Cl2CuI in hot triethylamine under an
argon atmosphere. The reactions completed within 0.5-4 h at 80°C, depending on the
acetylene reactivity, and gave the alkynylaminopyrazoles in moderate to good yields
(Scheme 46).
NH2
H3C
I
N
N
CH3
32 3-I,
33 5-I
NH2
HC C R
H3C
N
Pd(PPh3)2Cl 2,
CuI, NEt 3
C C R
N
CH3
R = 4-O2N-C6H4, C6H4
Scheme 46
However, attempts to carry out similar couplings between iodoaminopyrazoles 32 and
33 with more electron-rich alk-1-ynes, specifically p-methoxyphenylacetylene and oct-1yne under the same conditions but for 40 h, were unsuccessful; up to 76% of the starting
iodopyrazoles was returned. Authors (99JCS(P1)3713) tried to avoid these difficulties by
applying the alternative Stephens-Castro reaction (63JOC3313) of pre-formed copper pmethoxyphenylacetylenide and oct-1-ynide to obtain alkynylaminopyrazoles. However,
reactions between iodopyrazoles 32 and 33 and the copper acetylides in refluxing pyridine
(63JOC3313) gave a large number of products and much intractable polymer. These
complications were avoided by protection of the aminopyrazoles as the corresponding Nacetyl derivatives. The resulting (N-acetylamino)iodopyrazoles 34 and 35 coupled
smoothly with the copper acetylides in pyridine at 110-115°C. The reactions required 4-10
h for completion; a similar coupling of iodobenzene with copper phenylacetylide required
10 h at 115°C (63JOC3313) (Scheme 47).
43
NHAc
H3C
NHAc
I
N
H3C
CuC C R
N
N
pyridine
CH3
34 3-I,
35 5-I
C C R
N
CH3
R = 4-MeO-C6H4, n-C6H13
Scheme 47
Note that iodopyrazoles 34 and 35 did not react with p-methoxyphenylacetylene and
oct-1-yn in the presence of Pd(PPh3)2Cl2 and Cul in boiling triethylamine. Only using of
the more reactive p-nitrophenyl- or phenylacetylene gave the target alkynylpyrazoles under
these conditions.
Thus, the rate of Pd-catalyzed couplings between 4-aminoiodopyrazoles and alk-1-ynes
depends upon the electronic character of the acetylenic substituent and an approximate
criterion for choosing the method of coupling is the acidity of the alk-1-yne component
(84IZV923). It is concluded that terminal alkynes with pKa < 29 (CH-acidity of
phenylacetylene) were able to undergo the HeckSonogashira couplings using the
Pd(PPh3)2Cl2-CuI-Et3N system with derivatives of 3- and 5-aminoiodopyrazoles. The same
iodopyrazoles with less acidic alkynes (pKa > 29) however require the use of the copper
acetylide method and, for maximized yields, acetylation of the amino group.
The greatest group of acetylene derivatives consists of 4-alkynylpyrazoles owing to the
accessibility of starting 4-iodo derivatives. On the other hand, because of high electron
density in position 4 of the ring, the substitution of halogen atom is more difficult.
Therefore, the starting 4-halogen derivatives often contain electron-withdrawing groups in
the pyrazole cycle and the duration of their reaction with terminal acetylenes is almost the
same as that for 3- and 5-iododerivatives.
Thus, Coilla described (96MCR293, 96BML1279) synthesis of 1-(3,4-bis-benzoyloxy5-benzoyloxymethyl-tetrahydro-furan-2-yl)-4-trimethylsilanylethynyl-1H-pyrazole-3carboxylic acid methyl ester by coupling reaction between corresponding 4-iododerivatives
with trimethylsilylacetylene with a catalytic amount of bis(triphenylphosphine)palladium
dichloride and CuI in triethylamine at 80oC for 2 h (yield 91%).
SiMe3
O
C
C
O
N
O
N
BzO
BzO
OBz
The time of reaction between 4-iodopyrazoles and 1-alkynes amounts to 5-25 h and the
yield of products is 55-95%. It is noteworthy that the nature of terminal acetylene has
greater effect on the rate of halogen atom substitution for low reactive 4-iodopyrazoles.
Thus, the reaction time for ethynylarenes is 5-6 h and for less acid aliphatic 1-alkines it is
10-25 h (Table XIII).
Similarly annelation of the pyrazole cycle with -electrono deficit diazine ring lead to
increasing of the reactivity of halogenopyrazole. Thus, Neidlein showed (99H513) that (7methyl-8-phenylethynyl-pyrazolo[5,1-c][1,2,4]triazin-3-yl)-phosphonic acid dialkyl ester
44
could be prepared by the Heck-Sonogashira reaction with corresponding 8-iododerivatives
in presence of Pd(PPh3)2Cl2 and CuI in (i-Pr)2NH at 70-84oC.
(Alk-O) 2OP
(Alk-O) 2OP
N
N
R
N
N
I
N
N
HC C Ph
R
Pd(PPh3)2Cl 2,
CuI, NEt 3
N
N
C C
R = Ph, NH2
Scheme 48
Amino-4-iodopyrazoles demonstrate the lower reactivity of the iodine atom in
halogenopyrazoles. Iodopyrazoles 36 and 37 were coupled with p-nitrophenylacetylene in
Et3N in the presence of Pd(PPh3)2Cl2 and Cul at 80°C to give good yields of the N-acetyl
4-alkynyl-pyrazoles (Scheme 49).
R = 4-O2N-C6H4
C C R
R'
I
NHAc
R'
N
N
Alk
NHAc
N
HC C R
Pd(PPh3)2Cl 2,
CuI, NEt 3
N
Alk
36,38 5-NHAc, R' = CH3,
37,39 3-NHAc, R' = H
H
36, 37
R'
NHAc
N
R = C6H4, 4-H3CO-C6H4,
(CH2)5CH3
N
Alk
+
R C C C C R
40
38, 39
Scheme 49
However, attempts to couple (N-acetyl)-4-iodopyrazole 36 under the same conditions
with phenylacetylene, p-methoxyphenylacetylene and oct-1-yne, once again, were
unsuccessful; instead, reductive deiodination to give 5-(N-acetylamino)-3-methyl-lethylpyrazole and homo-coupling of alk-1-yne occurred (Scheme 49). The isomeric 3-(Nacetylamino)pyrazole 37 was somewhat less inclined to deiodination.
Similarly the cross-coupling of N-protected 4-ethynylpyrazole with 1-(1-ethoxyethyl)4-iodo-1H-pyrazole leads only to disubstituted butadiyne (2001UP1) (Scheme 50).
45
N
N
O
I
N
N
O
C CH
N
N
Pd(PPh3)4, CuI,
NEt3, DMF
C C C C
N
N
O
O
Scheme 50
Therefore, the Pd/Cu-catalyzed cross-coupling of acetylenes with 3- and 5-(Nacetylamino)-4-iodopyrazoles was complicated by reductive deiodination. According to
the generally accepted mechanism, this catalytic cross-coupling involves initial reaction of
the
pre-catalyst
and
copper
acetylide
with
the
formation
of
bis(triphenylphosphine)dialkynylpalladium(II),
which
decomposes
to
give
bis(triphenylphosphine)palladium(0) and the "dimeric" acetylene (98MI1). In such
reactions, the homo-coupled product is formed in amounts corresponding to the quantity of
the pre-catalyst used.
It was found (99JCS(P1)3713) that, in all cases, the formation of the deiodinated
products 38 and 39 was accompanied by formation of the diynes 40 which were isolated in
60-90% yields. Authors believed that the mechanism of deiodination may be represented
as an interaction of bis(triphenylphosphine)phenylethynylpalladium(II) hydride with the 4iodopyrazole,
giving
rise
to
the
complex
bis(triphenylphosphine)phenylethynylpalladium(II) iodide which, due to the reductive
elimination of 1-iodoalkyne and subsequent addition of alk-1-yne, converts into the initial
palladium complex. Further, the interaction of 1-iodoalkynes with the initial alkyne in the
presence of Cul and Et3N (the Cadiot-Chodkiewicz reaction) results in formation of the
observed disubstituted butadiynes 40 (Scheme 51).
(RC C) 2PdL2
(RC C) 2 + PdL2
PdL2 + RC CH
HPd(C CR)L 2
HPd(C CR)L 2
HC CR
PzI
PdL2
IC CR
IPd(C CR)L 2
RC CI + RC CH
CuI
Et3N
PzH
RC C C CR
Scheme 51
Taking into account the differences in the mechanisms of the Cu- and Pd-catalyzed
coupling reactions, authors (99JCS(P1)3713) supported that the foregoing difficulties
might again be overcome by resorting to the Stephens-Castro copper acetylide method
(63JOC3313) to access the 3- and 5-(N-acetylamino)-4-alkynylpyrazoles. Thus, iodides 36
and 37 were treated with copper acetylides in pyridine at 110-115°C. Under these
conditions, both iodopyrazoles were again relatively unreactive: couplings with copper
acetylides required 14-18 h. However, generally good yields of the coupled products were
secured (Scheme 52).
46
I
NHAc
R'
N
C C R
R'
CuC C R
N
Alk
NHAc
N
pyridine
N
Alk
36, 37
R = C6H4, 4-H3CO-C6H4,
(CH2)5CH3
Scheme 52
Thus, cross-coupling of 3- and 5-(N-acetylamino)-4-iodopyrazoles using the Pd(0)
complex occurred only with relatively high CH-acidic acetylenes and the more vigorous
copper acetylide method for halide substitution by an acetylene group is evidently more
general. However, condensation of aryl halides with a functional group in the vicinal
position can often be followed by cyclisation of the primary reaction products (see Part D.
“Heterocyclizations of vicinal functionally substituted pyrazolylacetylenes”). The
foregoing syntheses of vic-aminoalkynylpyrazoles were possible due to their low reactivity
in such cyclisations, probably due to the strain inherent in a condensed system consisting
of two 5-membered heterocycles. However, cross-coupling of iodopyrazole 36 with copper
p-phenylbenzoylacetylide 41 gave pyrrolo[2,3-c]pyrazole 42 directly; presumably,
cyclisation is aided by the ketone group (Scheme 53).
H3C
H3C
N
O
CuC C C
I
N
Et
NHAc
O
Ph 41
Py, Ar
N
N
Et
N
Ac
42
Ph
36
Scheme 53
Production of nitrogen-nonsubstituted acetylenyl derivatives is a special case in the
reactions of cross-coupling in the pyrazole series.
The cross-coupling of nitrogen-nonsubstituted activated halogenopyrazoles with alk-1ynes proceeds without complication. Thus, series of ethynylated 7H-pyrazolo[3,4d]pyrimidines were prepared (92T8089) by palladium-catalyzed C-C coupling of dimethyl
N-(4-ethynylbenzoyl)-L-glutamate with corresponding 5-bromo- (or iodo) -4(3H)-oxo-7Hpyrazolo[3,4-d]pyrimidines in presence of tetrakis(triphenylphosphine)palladium(0), CuI,
triethylamine in DMF. Should be noticed that bromo derivatives require more hard the
reaction conditions (3-18 h at 105-110oC, yields 45-60%) then iodopyrazole (3.5 h., at
85oC, yield 75%).
47
R1
N
R1
R2
N
HN N
R2
N
Alkyne
Hal
N
Pd(PPh3)4, CuI,
NEt3, DMF
O
C C
HN N
NH
MeOOC
Hal = Br, I
COOMe
R1 = H, NH2, CH3; R2 = OH, NH2
Scheme 54
4-Bromo-and 4-iodopyrazoles does not react with terminal acetylenes in standard
conditions of the HeckSonogashira reaction in the presence of organic bases and solvents.
But when the nitrogen atom was substituted C-alkynylation can occur. If the N-substituent
can be later removed, it serves as a protecting group for the pyrazole N-H. From the
synthetic point of the view, the value of a protecting group should be judged by its
availability, by its ease of introduction and of removal under mild conditions that do not
damage other sensitive functionalities.
In the course of investigation of methodologies for the protection of iodopyrazoles
during acetylenic cross-coupling, different chemist groups have been seeking protecting
groups which satisfy the criterion that both protection and deprotection should occur
efficiently under mild conditions so as not damage sensitive functionalities.
Interesting example is given in article (96BML797). The 4-iodo-(1-t-Boc)-pyrazole and
4-iodo-(1-MEM)-pyrazole were introduced into cross-coupling reaction with bisalkynylcyclic urea in presence of tetrakis(triphenylphosphine)palladium(0), CuI in Et2NH.
The protecting group manipulations were employed to improve isolated yields.
We report a successful methodology using ethylvinilic ether as a protecting group for
the heterocyclic NH of pyrazole in the synthesis of alkynylpyrazoles (2001UP1). The
reaction sequence consists of three stages: protection, main reaction (catalytic
deiodoalkynylation), and deprotaction. The protecting is readily introduced by reaction of
4-iodopyrazole with ethylvinilic ether in benzene at 20oC. The cross-coupling is carried out
in benzene at 60-70oC by treatment with 1-alkynes at presence of Pd(PPh3)2Cl2 and Cul.
Deprotection is accomplished readily by the acid-catalysed hydrolysis of the resulting
alkynylpyrazoles to give the desired N-unsubstituted alkynylpyrazoles in acceptable
overall yield on 4-iodopyrazole (Scheme 55).
R
R
C
I
N
I
protection
N
H
N
C
Sonogashira
cross-coupling
O
C
deprotection
N
N
C
N
N
N
H
O
R = C6H5, 4-CHO-C6H4, (CH3)2OH
Scheme 55
It is noticed that a considerable acceleration of reaction for low reactive 4iodopyrazoles is observed for substrates with acceptor substituents at pyrazole nitrogen
atom additionally playing role of protecting group. Thus, it is shown (88MOC253) that Nphenacyl- and N-p-tosyl-4-iodpyrazoles interact with phenylacetylene, 2-methyl-3-butyn-
48
2-ol and trimethylsilylacetylene at room temperature for 3-24 h in 70-95% yields (Scheme
56).
R2
C
I
C
HC C R2
N
N
R1
Pd(PPh3)4,
CuI, NEt 3
N
N
R1
R1 = PhC(O), p-Tosyl
R2 = Ph, C(CH3)2OH, Si(CH3)3
Scheme 56
A similar acceleration owing the influence of N-electron-withdrawing group was
observed by other chemists (87USP4663334) for N-acetyl-4-iodpyrazole in the reaction
with alkynes (Pd(PPh3)2Cl2, CuI, triethylamine, THF, room temperature, 1 h, 20oC).
Cosford (95SL1115; 99BML2815) and Elguero (98MO76) applied for 4-iodpyrazole
the method De la Rosa (90SC2059) based on cross-coupling of arylhalogenides with 1alkynes in catalytic system Pd/C, PPh3 and CuI in a rate of 1:4:2 with 2.5 equivalents of
K2CO3 in DME, H2O 1:1 at 80oC. Yields of 4-(4-hydroxybutyn-1-yl)pyrazole and 4-(3hydroxypropyn-1-yl)pyrazole were 85% and 60% correspondingly. Necessary to
emphasize that above mentioned method with using of heterogeneous palladium (10%
Pd/C) and 1,2-dimethoxyethane (DME) combined with aqueous potassium carbonate
allows to avoid applying of the protecting group and using expensive and air sensitive
reagent Pd(PPh3)Cl2 (Scheme 57).
N
HN
HC C (CH 2)nOH
I
Pd/C, PPh3, CuI,
K2CO3, DME, H2O
N
HN
C C (CH 2)nOH
n = 1, 2
Scheme 57
Thus, the Castro (63JOC3313) and the Heck-Sonogashira cross-couplings (75TL4467;
91COS521) are very attractive method for obtaining of the different alkynylpyrazoles.
49
TABLE XI
5-Alkynylpyrazoles Prepared by Pd/Cu or Cu-Catalyzed Couplings between Acetylenes and Pyrazolyliodides
Alkynylpyrazoles
4-(4-Chloro-2,5dimethyl-2H-pyrazol-3yl)-2-methyl-but-3-yn2-ol
4-(2,5-Dimethyl-2Hpyrazol-3-yl)-2-methylbut-3-yn-2-ol
1,3-Dimethyl-5-(4nitro-phenylethynyl)1H-pyrazol-4-ylamine
Structural formula
Cl
N
N
N-[1,3-Dimethyl-5-(4nitro-phenylethynyl)1H-pyrazol-4-yl]acetamide
C C
N
Catalyst(s) and
reagent(s)
Reaction
conditions
M.p. (oC)
Yield (%)
References
C10H13ClN2O
Et2NH
Pd(PPh3)2Cl2,
CuI
52-55oC, 12 h
41-42
(hexane)
76
92IZV507
C10H14N2O
Et2NH
Pd(PPh3)2Cl2,
CuI
52-55oC, 6 h
76.5-77
(hexane)
86
85MI1
C13H12N4O2
NEt3
Pd(PPh3)2Cl2,
CuI
80oC, 0.5 h
215-216
(CHCl3 –
hexane)
71
99JCS(P1)3713
C13H13N3
Et2NH
Pd(PPh3)2Cl2,
CuI
30oC, 3 h and
50oC, 3 h
66-66.5
(petroleum
ether)
82
83IZV688
Et3N
Pd(PPh3)2Cl2,
CuI
80oC, 6 h
86
99JCS(P1)3713
C13H20N2O2
Pyridine
Cu, K2CO3
reflux, 9 h
nD20 =
1.4890
94
71IZV1764
C15H14N4O3
NEt3
Pd(PPh3)2Cl2,
CuI
80 oC, 0.5 h
227-228
(CHCl3)
88
99JCS(P1)3713
OH
C C
N N
Solvent
OH
NH2
NO 2
NH2
1,3-Dimethyl-5phenylethynyl-1Hpyrazol-4-ylamine
5-[3-(1-Ethoxyethoxy)-3-methyl-but1-ynyl]-1-methyl-1Hpyrazole
C C
N
Formula index
C C Ph
N N
O
N
C C
N
O
O
HN
N N
C C
62-64
(benzene –
hexane)
NO2
50
Alkynylpyrazoles
Structural formula
O
1,3-Dimethyl-5-(3phenoxy-prop-1-ynyl)1H-pyrazole-4carboxylic acid amide
Formula index
Solvent
Catalyst(s) and
reagent(s)
Reaction
conditions
M.p. (oC)
Yield (%)
References
C15H15N3O2
Et2NH
Pd(PPh3)2Cl2,
CuI
50-55oC, 13 h
158-159
(AcOEt)
75
90IZV2089
C15H15N3O3
NEt3
Pd(PPh3)2Cl2,
CuBrSMe2
70oC, 1 h
-
91
2000TL4713
-
95
2000TL4713
112-113
94
2000TL4713
NH 2
N
3-[5-Isopropyl-2-(4nitro-phenyl)-2Hpyrazol-3-yl]-prop-2yn-1-ol
O Ph
C C
N
OH
N N
C C
(from corresp.
bromopyrazole)
NO 2
3-Methyl-1-(4-nitrophenyl)-5trimethylsilanylethynyl1H-pyrazole
C15H17N3O2Si
N N
NEt3
C C Si
Pd(PPh3)2Cl2,
CuBrSMe2
70oC, 1 h
(from corresp.
bromopyrazole)
NO 2
Ph
4-[2-(4-Chloro-phenyl)5-phenyl-2H-pyrazol-3yl]-2-methyl-but-3-yn2-ol
C20H17ClN2O
OH
N N
NEt3
C C
Pd(PPh3)2Cl2,
CuBrSMe2
70oC, 1 h
(from corresp.
bromopyrazole)
Cl
1,4-Di((1,3dimethylpyrazol-5yl)ethynyl)benzene
4-(5-Non-1-ynyl-1phenyl-1H-pyrazol-3yl)-benzonitrile
N
N
N
C C
C C
N
Et2NH
Pd(PPh3)2Cl2,
CuI
52-55oC, 8 h
181-182
(C6H6)
80
86TH1
C25H25N3
NEt3
Pd(PPh3)2Cl2,
CuBrSMe2
70oC, 1 h
-
94
2000TL4713
N
C
N N
Ph
C20H18N4
C C C7H15
(from corresp.
bromopyrazole)
51
TABLE XII
3-Alkynylpyrazoles Prepared by Pd/Cu-Catalyzed Couplings between Acetylenes and Pyrazolylhalides
Alkynylpyrazoles
Structural formula
O
3-(3-Methoxy-prop-1-ynyl)-1,5-dimethyl-1Hpyrazole-4-carboxylic acid methyl ester
O
Catalyst(s)
Reaction
conditions
M.p. (oC)
Yield
(%)
References
C11H14N2O3
Et2NH
Pd(PPh3)2Cl2,
CuI
52-55oC, 5 h
55-56
(hexane)
67
81IZV1342
C13H12N4O2
Et3N
Pd(PPh3)2Cl2,
CuI
80oC, 1.5 h
216-217
(EtOH)
73
99JCS(P1)3713
C13H13N3
Et2NH
Pd(PPh3)2Cl2,
CuI
52-55oC, 8 h
138.5-139.5
(CCl4)
66
86TH1
36
99JCS(P1)3713
OMe
NH2
C C
N N
NO2
NH 2
1,5-Dimethyl-3-phenylethynyl-1H-pyrazol-4ylamine
O
1,5-Dimethyl-3-phenylethynyl-1H-pyrazole4-carboxylic acid amide
NH 2
O
O
O
Et2NH
Pd(PPh3)2Cl2,
CuI
52-55oC, 6 h
148.5-149.5
(C6H6)
61
86TH1
C14H19N3O3
Et2NH
Pd(PPh3)2Cl2,
CuI
52-55oC, 13 h
88-89
(hexane)
54
81IZV1342
C15H14N2O2
Et2NH
Pd(PPh3)2Cl2,
CuI
52-55oC, 6 h
93-94
(hexane)
65
81IZV1342
C15H14N4O3
Et3N
Pd(PPh3)2Cl2,
CuI
80oC, 1.5 h
195-196
(CHCl3)
73
99JCS(P1)3713
C C
N N
O
O
C C
N N
O
HN
N N
80 C, 8 h
C14H13N3O
N
1,5-Dimethyl-3-phenylethynyl-1H-pyrazole4-carboxylic acid methyl ester
o
C C
N N
1,5-Dimethyl-3-(3-morpholin-4-yl-prop-1ynyl)-1H-pyrazole-4-carboxylic acid methyl
ester
Et3N
C C
N N
N-[1,5-Dimethyl-3-(4-nitro-phenylethynyl)1H-pyrazol-4-yl]-acetamide
Solvent
C C
N N
1,5-Dimethyl-3-(4-nitro-phenylethynyl)-1Hpyrazol-4-ylamine
Formula
index
C C
NO2
52
TABLE XIII
4-Alkynylpyrazoles Prepared by Pd/Cu or Cu Catalyzed Couplings between Acetylenes and Pyrazolylhalides
Alkynylpyrazoles
3-(1H-Pyrazol-4-yl)-prop-2-yn-1ol
4-(1H-Pyrazol-4-yl)-but-3-yn-1-ol
Structural formula
N
HN
C C
Formula index
C C
Catalyst(s)
Reaction
conditions
M.p. (oC)
[b.p./mm Hg]
Yield
(%)
References
C6H6N2O
DME and
H2O
Pd/C, CuI,
PPh3
K2CO3,
80oC, 24 h
171
60
98MO76
C7H8N2O
DME and
H2O
Pd/C, CuI,
PPh3
K2CO3,
80oC, 16 h
102-104
85
98JOC1109
C9H12N2O
Et2NH
Pd(PPh3)2Cl2,
CuI
52-55oC,
20 h
85-86 (C6H6 –
petroleum
ether)
93
86TH1
C13H20N2O2
Pyridine
Cu
K2CO3,
reflux, 75
h
[120-123/1]
84
72IZV2524
OH
N
HN
Solvent
95SL1115
HO
2-Methyl-4-(1-methyl-1H-pyrazol4-yl)-but-3-yn-2-ol
OH
N
N
C C
4-[3-(1-Ethoxy-ethoxy)-3-methylbut-1-ynyl]-1-methyl-1H-pyrazole
O
O
N
N
4-(3-Methoxy-prop-1-ynyl)-2methyl-2H-pyrazole-3-carboxylic
acid methyl ester
N
N
4-(3-Hydroxy-3-methyl-but-1ynyl)-2-methyl-2H-pyrazole-3carboxylic acid methyl ester
N
N
C10H12N2O3
Et2NH
Pd(PPh3)2Cl2,
CuI
52-55oC,
20 h
55-56 (hexane)
74
81IZV1342
OH
C11H14N2O3
Et2NH
Pd(PPh3)2Cl2,
CuI
52-55oC,
20 h
94-95 (CCl4)
85
86TH1
C12H9N3O2
NEt3
Pd(PPh3)2Cl2,
CuI
50-60oC, 6
h
115-116
(benzene)
96
99JCS(P1)3713
C12H10N2
(i-Pr)2NH
Pd(PPh3)2Cl2,
CuI, PPh3
35oC, 3 h
and 90oC,
1h
70-72
-
93EUP571326
O
O
NO 2
1-Methyl-3-nitro-4-phenylethynyl1H-pyrazole
1-Methyl-4-phenylethynyl-1Hpyrazole
OMe
C C
O
N
N
N
N
nD = 1.4905
C C
C C
O
20
C C Ph
C C
[116-118/0.3
mbar]
53
Alkynylpyrazoles
Structural formula
NH2
1-Methyl-4-phenylethynyl-1Hpyrazol-3-ylamine
N
N
2-Methyl-4-(3-morpholin-4-ylprop-1-ynyl)-2H-pyrazole-3carboxylic acid methyl ester
N
N
Et2NH
N
C14H10F4N2
C C
N
N
(i-Pr)2NH
F
C C Ph
O
M.p. (oC)
[b.p./mm Hg]
Pd(PPh3)2Cl2,
CuI
52-55oC, 3
h
144-145 (CCl4)
Pd(PPh3)2Cl2,
CuI
52-55oC,
26 h
83-85
Pd(PPh3)2Cl2,
CuI, PPh3
35oC, 3 h
and 90oC,
1h
Yield
(%)
References
37
86TH1
99JCS(P1)3713
55
81IZV1342
-
93EUP571326
(hexane)
O
[135-140/0.05
mbar]
C14H12N2O2
Et2NH
Pd(PPh3)2Cl2,
CuI
52-55oC,
5.5 h
116-117
(EtOH)
75
81IZV1342
C14H12N2O2
Et2NH
Pd(PPh3)2Cl2,
CuI
52-55oC,
5.5 h
154-155
(EtOH)
80
81IZV1342
C14H12N4O3
NEt3
Pd(PPh3)2Cl2,
CuI
80oC, 6 h
241-241.5
(chloroform –
ethanole)
58
99JCS(P1)3713
C15H14N2O2
NEt3
Pd(PPh3)2Cl2,
CuI
Room
temp., 3 h
106-108
(Cycloxehane)
91
88MOC253
C15H14N2O3
Et2NH
Pd(PPh3)2Cl2,
CuI
52-55oC,
10 h
72.5-73.5
(petroleum
ether)
61
85MI2
C C Ph
O
HN
N
N
61-62
O
N
N
C C
NO 2
OH
N
N
Ph
Reaction
conditions
O
N
N
1-Methyl-4-phenylethynyl-1Hpyrazole-3-carboxylic acid methyl
ester
Et2NH
Catalyst(s)
O
O
[4-(3-Hydroxy-3-methyl-but-1ynyl)-pyrazol-1-yl]-phenylmethanone
C13H17N3O3
C C
CF 3
2-Methyl-4-phenylethynyl-2Hpyrazole-3-carboxylic acid methyl
ester
N-[1-Methyl-4-(4-nitrophenylethynyl)-1H-pyrazol-3-yl]acetamide
C12H11N3
Solvent
C C Ph
O
4-(4-Fluoro-phenylethynyl)-1,5dimethyl-3-trifluoromethyl-1Hpyrazole
Formula index
C C
O
2-Methyl-4-(3-phenoxy-prop-1ynyl)-2H-pyrazole-3-carboxylic
acid methyl ester
N
N
C C
OPh
O
O
54
Alkynylpyrazoles
Structural formula
Phenyl-(4-trimethylsilanylethynylpyrazol-1-yl)-methanone
N
N
Ph
Formula index
C C Si
Solvent
Catalyst(s)
Reaction
conditions
M.p. (oC)
[b.p./mm Hg]
Yield
(%)
References
C15H16N2OSi
NEt3
Pd(PPh3)2Cl2,
CuI
Room
temp., 24 h
[140/0.03
mbar]
70
88MOC253
C15H24N2O2
Pyridine
Cu
K2CO3,
reflux, 23
h
[112-115/1.5]
96
71IZV1764
98EUP846686
O
4-[3-(1-Ethoxy-ethoxy)-3-methylbut-1-ynyl]-1,3,5-trimethyl-1Hpyrazole
O
O
N
N
C C
CN
5-Amino-1-(2,6-dichloro-4trifluoromethyl-phenyl)-4trimethylsilanylethynyl-1Hpyrazole-3-carbonitrile
nD20 = 1.4873
N
N
Cl
NEt3,
DMF
Pd(OAc)2,
CuI
50-60oC,
1.5 h
181-182 (ether
– hexane)
-
C16H14N2O4
Et2NH
Pd(PPh3)2Cl2,
CuI
52-55oC, 5
h
93-94 (EtOH)
88
86TH1
C16H16N2O2
(i-Pr)2NH
Pd(PPh3)2Cl2,
CuI, PPh3
35oC, 3 h
and 90oC,
1h
97-98
-
93EUP571326
C16H16N2O3
Et2NH
Pd(PPh3)2Cl2,
CuI
52-55oC,
25 h
109.5-110.5
(C6H6 –
petroleum
ether)
99
81IZV1342
C16H16N4O3
NEt3
Pd(PPh3)2Cl2,
CuI
80oC, 5.5 h
188-189
(benzene –
chloroform)
63
99JCS(P1)3713
C16H13Cl2F3N4Si
C C SiMe3
Cl
99EUP933363
NH 2
F3C
4-(2-Methoxycarbonylphenylethynyl)-2-methyl-2Hpyrazole-3-carboxylic acid methyl
ester
N
N
C C
2,5-Dimethyl-4-phenylethynyl-2Hpyrazole-3-carboxylic acid ethyl
ester
O
N
N
C C Ph
O
O
4-(3-Hydroxy-3-phenyl-but-1ynyl)-2-methyl-2H-pyrazole-3carboxylic acid methyl ester
Ph OH
C C
N
N
O
O
N-[2-Ethyl-5-methyl-4-(4-nitrophenylethynyl)-2H-pyrazol-3-yl]acetamide
O
O
O
N
N
C C
HN
O
NO2
55
Alkynylpyrazoles
Structural formula
O
1-(Tetrahydro-pyran-2-yl)-4trimethylsilanylethynyl-1Hpyrazole-3-carboxylic acid ethyl
ester
7-Chloro-4-(4trimethylsilanylethynyl-pyrazol-1yl)-quinolinea
C16H24N2O3Si
O
N
N
O
Formula index
Solvent
NEt3
Catalyst(s)
Reaction
conditions
Pd(PPh3)2Cl2,
CuI
60oC, 2 h
M.p. (oC)
[b.p./mm Hg]
oil
Yield
(%)
References
93
96ADD193
96INP9640704
C C SiMe3
N
N
Cl
C C SiMe3
C17H16ClN3Si
NEt3
Pd(PPh3)2Cl2,
CuI
Room
temp. 2 h
106-112
85
96EUP703234
C18H12N2O
NEt3
Pd(PPh3)2Cl2,
CuI
Room
temp., 24 h
146-149 (1Butanol)
90
88MOC253
Dioxane
Pd(PPh3)2Cl2,
CuI
Et3N,
70oC, 1.5 h
170-172
(CHCl3)
84
93JHC755
C18H14N2O2S
NEt3
Pd(PPh3)2Cl2,
CuI
Room
temp., 24 h
119-121
(EtOH)
95
88MOC253
C20H18N4
Et2NH
Pd(PPh3)2Cl2,
CuI
52-55oC,
14 h
226-227 (C6H6)
89
86TH1
C22H22FN3O2Si
Et2NH
Pd(PPh3)2Cl2,
CuI
Room
temp., 8 h
133-136
85
2000JMC953
C22H27N3O4
THF,
NEt3
Pd(PPh3)4,
CuI
“without
external
heating”
oil
93
87USP4663334
N
Phenyl-(4-phenylethynyl-pyrazol1-yl)-methanone
N
N
Ph
C C Ph
O
4-(4-Methoxy-phenylethynyl)-1(4-nitro-phenyl)-1H-pyrazole
N
N
C C
OMe
C18H13N3O3
O2N
4-Phenylethynyl-1-(toluene-4sulfonyl)-1H-pyrazole
1,4-Di((1,3-dimethylpyrazol-4yl)ethynyl)benzene
[3-Fluoro-4-(4trimethylsilanylethynyl-pyrazol-1yl)-phenyl]-carbamic acid benzyl
ester
Acetic acid 2-[2-(1-acetyl-1Hpyrazol-4-ylethynyl)-phenoxy]-1(tert-butylamino-methyl)-ethyl
ester
Tos
N
N
N
N
C C Ph
C C
F
C C
N
N
N
N
C C SiMe3
Cbz N
H
Ac
N
N
C C
O
NH
OAc
1h
56
Alkynylpyrazoles
1-(3,4-Bis-benzoyloxy-5benzoyloxymethyl-tetrahydrofuran-2-yl)-4trimethylsilanylethynyl-1Hpyrazole-3-carboxylic acid methyl
ester
Structural formula
SiMe3
O
C36H34N2O9Si
C
Solvent
NEt3
C
O
N
O
Formula index
Catalyst(s)
Pd(PPh3)2Cl2,
CuI
Reaction
conditions
80oC, 2 h
M.p. (oC)
[b.p./mm Hg]
68
Yield
(%)
References
91
96MCR293
96BML1279
96INP9640704
N
BzO
BzO
OBz
COOC(CH 3)3
{[6-(4-(4-Amino-phenylethynyl)3-{6-[(bis-tertbutoxycarbonylmethyl-amino)methyl]-pyridin-2-yl}-pyrazol-1yl)-pyridin-2-ylmethyl]-tertbutoxycarbonylmethyl-amino}acetic acid tert-butyl ester
N
THF,
NEt3
Pd(PPh3)2Cl2,
CuI
55-60oC,
40 hb
oil
24
97EUP770610
DMF
Pd(PPh3)2Cl2,
CuI, NEt3
35oC,
overnight
-
45
99EUP967205
COOC(CH 3)3
N
N
N
C C
NH 2
N
N
COOC(CH 3)3
C47H61N7O8
COOC(CH 3)3
COO- t-Bu
[4-(1,3-Bis-{6-[(bis-tertbutoxycarbonylmethyl-amino)methyl]-pyridin-2-yl}-1H-pyrazol4-ylethynyl)-phenoxy]-acetic acid
methyl ester
N
COO- t-Bu
N
N
N
C C
O
OMe
O
N
N
COO- t-Bu
C50H64N6O11
COO- t-Bu
a
Different acetylenic compounds of the general formula were synthesized; experimental details are reported only for the title compound.
b
Prepared from corresponding bromo-derivative.
57
TABLE XIV
Polyalkynylpyrazoles Pprepared by Cu or Pd/Cu-Catalyzed Couplings between Acetylenes and Pyrazolylhalides
Alkynylpyrazoles
Structural formula
HO
4-[3-(3-Hydroxy-3-methyl-but-1-ynyl)1,5-dimethyl-1H-pyrazol-4-yl]-2methyl-but-3-yn-2-ol
Catalyst(s)
Reaction
conditions
M.p. (oC)
Yield
(%)
References
C15H20N2O2
Et2NH
Pd(PPh3)2Cl2,
CuI
52-55oC, 18
h
176-177 (C6H6 –
petroleum ether)
65
86TH1
C18H18N2O
Et2NH
Pd(PPh3)2Cl2,
CuI
52-55oC, 14
h
89-90 (hexane)
65
92IZV507
C18H24N4O2
Pyridine
Cu
K2CO3,
reflux, 75 h
79-80 (petroleum
ether)
72
72IZV2524
C18H24N4O2
Pyridine
Cu
K2CO3,
reflux, 75 h
oil
75
72IZV2524
C22H16N2O2
Et2NH
Pd(PPh3)2Cl2,
CuI
52-55oC, 18
h
145.5-146.5
(EtOH)
58
86TH1
OH
C C
Ph
4-(2,5-Dimethyl-4-phenylethynyl-2Hpyrazol-3-yl)-2-methyl-but-3-yn-2-ol
C
C
N
O
OH
C C
N
N
C
C
C
N
4,5-Di(3-N-morpholinopropyn-1-yl)-1methyl-1H-pyrazole
N
O
O
C C
N
N
C C Ph
N
N
C C Ph
O
O
N
C
N
N
C
C
2-Methyl-4,5-bis-phenylethynyl-2Hpyrazole-3-carboxylic acid methyl ester
Solvent
C
C
N
N
3,4-Di(3-N-morpholinopropyn-1-yl)-1methyl-1H-pyrazole
Formula
index
O
58
Alkynylpyrazoles
Structural formula
3,4-Bis-[3-(1-ethoxy-ethoxy)-3-methylbut-1-ynyl]-1-methyl-1H-pyrazole
O
O
C
C
Formula
index
Solvent
Catalyst(s)
Reaction
conditions
M.p. (oC)
Yield
(%)
References
C22H34N2O4
Pyridine
Cu
K2CO3,
reflux, 40 h
oil
75
71IZV1764
90
71IZV1764
90-91 (petroleum
ether – benzene
8:1)
80
72IZV2524
oil
68
71IZV1764
nD20 = 1.4970
O
O
N
N
C C
4,5-Bis-[3-(1-ethoxy-ethoxy)-3-methylbut-1-ynyl]-1-methyl-1H-pyrazole
C22H34N2O4
O
Pyridine
Cu
O
K2CO3,
reflux, 40 h
oil
nD20 = 1.4932
C
C
N
3,4,5-Tri(3-N-morpholinopropyn-1-yl)1-methyl-1H-pyrazole
O
O
N
C
N
C
C
N
3,4,5-Tris-[3-(1-ethoxy-ethoxy)-3methyl-but-1-ynyl]-1-methyl-1Hpyrazole
O
C C
N
C
O
O
C
C
C
N
C
N
Cu
K2CO3,
reflux, 95 h
C31H48N2O6
Pyridine
Cu
K2CO3,
reflux, 64 h
N
O
O
Pyridine
O
C C
N
C25H33N5O3
O
O
C C
O
20
nD = 1.4972
59
TABLE XV
Alkynylpyrazoles Prepared by Condensation of Copper(I) Acetylides with Pyrazolyliodides
Alkynylpyrazoles
Structural formula
NO 2
1-Methyl-3-nitro-4-phenylethynyl-1Hpyrazole
N
N
NH 2
N
N
N
M.p. (oC)
Yield
(%)
References
C12H9N3O2
Pyridine
Reflux, 1.5 h
114-115
(tetrachloromethane)
94
86MI1
C13H11N3O
Pyridine
Reflux, 9 h
164-165 (ClCH2CH2Cl)
71
90IZV2089
C13H11N3O2
Pyridine
Reflux, 1.5 h
134-135 (ethanol)
83
86MI1
C13H12N2
Pyridine
Reflux, 8 h
57-57.5 (petroleum ether)
78
86TH1
C13H13N3
Pyridine
Reflux, 6 h
118.5-119.5 (C6H6)
39
86TH1
C14H13N3O
Pyridine
Reflux, 6 h
148.5-149.5 (benzene)
62
90IZV2089
C14H20N2O2
Pyridine
Reflux, 7 h
33-35 (hexane)
50
2001UP5
C15H14N2O3
Pyridine
Reflux, 5 h
123-124.5 (benzene)
50
2001UP5
C C
Ph
N
1,3-Dimethyl-4-phenylethynyl-1H-pyrazole
N
N
2,5-Dimethyl-4-phenylethynyl-2H-pyrazol-3ylamine
Reaction
conditions
C C Ph
NO 2
1,3-Dimethyl-4-nitro-5-phenylethynyl-1Hpyrazole
Solvent
C C Ph
O
1-Methyl-4-phenylethynyl-1H-pyrazole-3carboxylic acid amide
Formula
index
C C Ph
N
N
C C Ph
NH 2
O
1,5-Dimethyl-3-phenylethynyl-1H-pyrazole4-carboxylic acid amide
NH 2
C C Ph
N N
O
1-Methyl-4-oct-1-ynyl-1H-pyrazole-3carboxylic acid methyl ester
O
N
N
O
4-(4-Methoxy-phenylethynyl)-1-methyl-1Hpyrazole-3-carboxylic acid methyl ester
N
N
C C C6H13
O
C C
O
60
N-(1,3-Dimethyl-4-phenylethynyl-1Hpyrazol-5-yl)-acetamide
N
N
80
83IZV688
C15H15N3O
Pyridine
Reflux, 4 h
189.5-190 (Toluene)
79
99JCS(P1)3713
C15H15N3O
Pyridine
Reflux, 6 h
186-187 (chloroform –
hexane)
82
99JCS(P1)3713
C15H15N3O
Pyridine
Reflux, 4 h
203-204 (benzene –
hexane)
78
99JCS(P1)3713
C15H15N3O2
Pyridine
Reflux, 14 h
131-132 (chloroform –
hexane)
64
99JCS(P1)3713
C15H22N2O2
Pyridine
Reflux, 5 h
27.5-29 (hexane)
50
2001UP5
C15H23N3O
Pyridine
Reflux, 10 h
156-157 (chloroform –
hexane)
74
99JCS(P1)3713
O
O
HN
C C Ph
N N
O
N-(1,5-Dimethyl-3-phenylethynyl-1Hpyrazol-4-yl)-acetamide
HN
C C Ph
N N
O
N-[4-(4-Methoxy-phenylethynyl)-1-methyl1H-pyrazol-3-yl]-acetamide
HN
N
N
C C
O
N N
N-(1,3-Dimethyl-5-oct-1-ynyl-1H-pyrazol-4yl)-acetamide
189.5-190 (toluene)
C C Ph
HN
1,5-Dimethyl-3-oct-1-ynyl-1H-pyrazole-4carboxylic acid methyl ester
Reflux, 4 h
O
N
N
N-(1,3-Dimethyl-5-phenylethynyl-1Hpyrazol-4-yl)-acetamide
Pyridine
C C Ph
HN
N-(2,5-Dimethyl-4-phenylethynyl-2Hpyrazol-3-yl)-acetamide
C15H15N3O
OMe
O
C C C6H13
O
HN
N N
C C C6H13
61
O
N-(1,5-Dimethyl-3-oct-1-ynyl-1H-pyrazol-4yl)-acetamide
O
O
C C
N N
N-(2-Ethyl-5-methyl-4-phenylethynyl-2Hpyrazol-3-yl)-acetamide
N
N
73
99JCS(P1)3713
C16H16N2O3
Pyridine
Reflux, 8 h
129-130 (benzene)
60
2001UP5
C16H17N3O
Pyridine
Reflux, 16 h
161-162 (chloroform –
hexane)
78
99JCS(P1)3713
C16H17N3O2
Pyridine
Reflux, 8 h
143-144 (benzene)
56
99JCS(P1)3713
C16H17N3O2
Pyridine
Reflux, 6 h
168-169 (benzene)
69
99JCS(P1)3713
C16H25N3O
Pyridine
Reflux, 18 h
113-114 (benzene)
81
99JCS(P1)3713
C17H19N3O2
Pyridine
Reflux, 14 h
133-134 (benzene –
hexane)
47
99JCS(P1)3713
O
O
O
C C
OMe
O
HN
C C
N N
N-(2-Ethyl-5-methyl-4-oct-1-ynyl-2Hpyrazol-3-yl)-acetamide
N
N
OMe
C C C6H13
HN
N-[2-Ethyl-4-(4-methoxy-phenylethynyl)-5methyl-2H-pyrazol-3-yl]-acetamide
157.5-158 (chloroform –
hexane)
HN
N N
N-[3-(4-Methoxy-phenylethynyl)-1,5dimethyl-1H-pyrazol-4-yl]-acetamide
Reflux, 8 h
C C Ph
HN
N-[5-(4-Methoxy-phenylethynyl)-1,3dimethyl-1H-pyrazol-4-yl]-acetamide
Pyridine
C C C6H13
N N
3-(4-Methoxy-phenylethynyl)-1,5-dimethyl1H-pyrazole-4-carboxylic acid methyl ester
C15H23N3O
HN
N
N
C C
HN
O
O
OMe
62
TABLE XVI
Acetylenic Derivatives of Annelated Pyrazoles Prepared by Pd/Cu-Catalyzed Couplings between Acetylenes and Hetarylhalides
Alkynylpyrazoles
Structural formula
(4-Amino-7-methyl-8phenylethynyl-pyrazolo[5,1c][1,2,4]triazin-3-yl)-phosphonic
acid diethyl ester
(C 2H5O) 2OP
(4-Amino-7-methyl-8phenylethynyl-pyrazolo[5,1c][1,2,4]triazin-3-yl)-phosphonic
acid diisopropyl ester
(i-C 3H7O)2OP
2-[4-(4-Hydroxy-1H-pyrazolo[3,4d]pyrimidin-3-ylethynyl)benzoylamino]-pentanedioic acid
dimethyl ester
N
Formula
index
Solvent
Catalyst(s)
and
reagent(s)
Reaction
conditions
M.p. (oC)
Yield
(%)
References
C18H20N5O3P
(i-Pr)2NH
Pd(PPh3)4,
CuI, PPh3
Reflux, 4.5 h
75
20
99H513
C20H24N5O3P
(i-Pr)2NH
Pd(PPh3)4,
CuI, PPh3
Reflux, 5 h
207
38
99H513
C21H19N5O6
DMF
Pd(PPh3)4,
CuI, NEt3
85oC, 3 h
105-107
73
92T8089
C21H20N6O6
DMF
Pd(PPh3)4,
CuI, NEt3
105oC, 18 h
258-261
44
92T8089
185-187
47
92T8089
N
H2N
N
N
C C
N
N
H2N
N
N
N
OH
N
O
HN N
C C
NH
MeOOC
2-[4-(6-Amino-4-hydroxy-1Hpyrazolo[3,4-d]pyrimidin-3ylethynyl)-benzoylamino]pentanedioic acid dimethyl ester
H2N
2-[4-(4,6-Diamino-1Hpyrazolo[3,4-d]pyrimidin-3ylethynyl)-benzoylamino]pentanedioic acid dimethyl ester
H2N
C C
N
COOMe
OH
N
O
HN N
C C
NH
MeOOC
N
COOMe
C21H21N7O5
NH 2
N
HN N
(from the
hetarylbromide)
O
C C
NH
MeOOC
COOMe
DMF
Pd(PPh3)4,
CuI, NEt3
100oC, 3 h
(from the
hetarylbromide)
63
Alkynylpyrazoles
2-[4-(4-Hydroxy-6-methyl-1Hpyrazolo[3,4-d]pyrimidin-3ylethynyl)-benzoylamino]pentanedioic acid dimethyl ester
Structural formula
N
OH
N
Catalyst(s)
and
reagent(s)
Reaction
conditions
M.p. (oC)
Yield
(%)
References
C22H21N5O6
DMF
Pd(PPh3)4,
CuI, NEt3
105oC, 3 h
265-257
(aqueous
CH3OH)
62
92T8089
O
HN N
(from the
hetarylbromide)
NH
(C 2H5O) 2OP
COOMe
N
C24H23N4O3P
(i-Pr)2NH
Pd(PPh3)4,
CuI, PPh3
70oC, 4 h
89-90
11
99H513
C15H19N5O4
DMF
Pd(PPh3)4,
CuI, NEt3
-
-
52
99HCA1640
N
Ph
N
N
C C
R
6-Amino-1-(4-hydroxy-5hydroxymethyl-tetrahydro-furan-2yl)-3-R-1,5-dihydro-pyrazolo[3,4d]pyrimidin-4-one
R = pent-1-ynyl
Solvent
C C
MeOOC
(7-Methyl-4-phenyl-8phenylethynyl-pyrazolo[5,1c][1,2,4]triazin-3-yl)-phosphonic
acid diethyl ester
Formula
index
O
C
C
HN
H2N
N
O
N
N
HO
HO
R = C3H7
R = 4-hydroxy-but-1-ynyl
R = CH2CH2OH
C14H17N5O5
DMF
Pd(PPh3)4,
CuI, NEt3
-
-
41
99HCA1640
R = hex-1-ynyl
R = C4H9
C16H21N5O4
DMF
Pd(PPh3)4,
CuI, NEt3
-
-
49
99HCA1640
Pd(PPh3)4,
CuI, NEt3
-
R = hept-1-ynyl
R = C5H11
C17H23N5O4
DMF
97NN821
-
53
99HCA1640
64
Alkynylpyrazoles
Structural formula
R
5-(4-Amino-3-R-pyrazolo[3,4d]pyrimidin-1-yl)-2-hydroxymethyltetrahydro-furan-3-ol
NH 2
C
N
O
Solvent
Catalyst(s) and
reagent(s)
Reaction
conditions
M.p. (oC)
Yield
(%)
References
C16H21N5O3
DMF
Pd(PPh3)4,
CuI, NEt3
Room temp.,
5h
foam
58
99JCS(P1)479
53
99JCS(P1)479
C
N
R = hex-1-ynyl
Formula
index
45oC, 48 ha
N
97NN821
N
HO
HO
R = (CH2)3CH3
R = prop-1-ynyl
R = CH3
C13H15N5O3
DMF
Pd(PPh3)4,
CuI, NEt3
Room temp.,
6h
foam
52
98JCS(P1)3233
R = pent-1-ynyl
R = (CH2)2CH3
C15H19N5O3
DMF
Pd(PPh3)4,
CuI, NEt3
Room temp.,
7h
foam
57
98JCS(P1)3233
R = hept-1-ynyl
R = (CH2)4CH3
C17H23N5O3
DMF
Pd(PPh3)4,
CuI, NEt3
Room temp.,
6h
foam
42
98JCS(P1)3233
R = 2-cyclohexylethynyl
R = cyclohexyl
C18H23N5O3
DMF
Pd(PPh3)4,
CuI, NEt3
Room temp.,
4h
foam
48
98JCS(P1)3233
R = 2-phenylethynyl
R = Ph
C18H17N5O3
DMF
Pd(PPh3)4,
CuI, NEt3
Room temp.,
7h
foam
49
98JCS(P1)3233
45
98JCS(P1)3233
70oC, 6 ha
R = 2-p-tolylethynyl
R = p-CH3-C6H4
C19H19N5O3
DMF
Pd(PPh3)4,
CuI, NEt3
Room temp.,
4h
200-203
(decomp.)
53
98JCS(P1)3233
R = 2-(m-ethynyl)phenylethynyl
R = m-(CCH)-C6H4
C20H17N5O3
DMF
Pd(PPh3)4,
CuI, NEt3
Room temp.,
3h
Foam
44
98JCS(P1)3233
R = 2-(2-pyridyl)ethynyl
R = 2-pyridyl
C20H17N5O3
DMF
Pd(PPh3)4,
CuI, NEt3
Room temp.,
4h
245-248
(decomp.)
52
98JCS(P1)3233
C31H37N5O3
DMF
Pd(PPh3)4,
CuI, NEt3
Room temp.,
6h
210-212
(MeOH,
decomp.)
61
98JCS(P1)3233
R = 2-(17-hydroxy-3-methoxy-1,3,5[10]estratriene-17-yl)ethynyl
HO
~ CH3
R=
OCH 3
a
Prepared from corresponding hetarylbromide.
65
D. Pyrolysis
The pyrolysis of 1-propynoylpyrazoles gives alkynylpyrazoldes (85TL6373, 94AJC991). The
peculiarity of these compounds is that the ethynyl group is bound to nitrogen atoms. Flash
vacuum pyrolysis of 1-propynoylpyrazole at 700-900 oC/ 0.1 torr gives 1-ethynylpyrazole in low
yield.
O
R1
H
C CH 700-900 oC/ 0.1 torr
N
N
R2
R1
N
N
R1
H
C C O -CO R1
R2
C
N
N
N C CH
2
R
N
R2
and other products
R1 = H, Me; R2 = H, Me
Scheme 58
Ring-methylated 1-ethynylpyarzoles were similarly obtained as minor products of the
pyrolysis of the 3,5-dimethyl- and a mixture of 3- and 5-methyl-1-propynoilpyrazoles. Pyrolysis
of the 3-methyl compound gave only pyrazolo[1,5-a]pyridin-5-ol with a trace amount of an Nethynylpyrazole, whereas the 5-methylprecursor gave a mixture of pyrazolo[1,5-a]pyridin-5-ol
(4%), 3-methylpyrazole (19%), 1-ethynyl-3-methylpyrazole (11%) and 1-ethynyl-5methylpyrazole (12%).
66
III. Chemical properties of acetylenylpyrazoles
A. Reactions of terminal acetylenes with participation of C-H bond
The high acidity of ethynylpyrazoles (pKa 24.0-30.4, 92IZV507) determines the high
reactivity of terminal acetylenes and a great number of the functionally substituted
pyrazolylacetylenes produced on their basis.
1. The Favorsky reaction
The Favorsky reaction, the interaction between terminal acetylenes and carbonyl compounds
in the presence of powdered dry KOH is of limited importance for pyrazole series although the
hydroxyacetylenic grouping is one of the most important protecting groups. However, most
often, such an alcoholacetylenic substituent is introduced by direct alkinylation of corresponding
iodopyrazoles with 2-methyl-but-3-yn-2-ol (see, Part II.C).
A typical technique of the Favorsky reaction is the interaction between terminal acetylene
with a 2-3-fold excess of carbonyl compound and a 4-fold excess of dry KOH in ether at 0-20oC.
The Favorsky reaction includes both the nitrogen-nonsubstituted and -substituted
ethynylpyrazoles (68KGS695; 69KGS1055). The interaction of 1-methyl-3-ethynylpyrazole and
1-(N-piperidino)methyl-3-ethynylpyrazole with acetone in the presence of KOH (0-20oC) results
in the corresponding acetylenic alcohols in 62.5 and 68.5% yields. In similar conditions, the
nitrogen-nonsubstituted 3(5)-ethynylpyrazole forms with acetylbenzene the acetylenic alcohol
in 77.5% yield (Scheme 59).
HO
C
CH
C
C
CH 3COCH 3
N
R
N
KOH
N
R
R = H, H2C
N
N
Scheme 59
The same alcohols can be produced using the Iotzich method by boiling the Iotzich complex
(ethynyl magnesium or lithium compound in ether) with a small excess of carbonyl compound.
However, the yields of the alcohols obtained by this method, are somewhat lower (4753%)
(68KGS695) (Scheme 60).
HO
R1
C
C
MgBr
CH
C
C
C
R1COR2
EtMgBr
N
N
H
N
N
BrMg
R1 =R2 = CH3; R1 = CH3, R2 = Ph;
R1 = CH(CH3)2, R2 = H
N
N
H
R2
67
Scheme 60
It is considered that the Favorsky reaction is a general method for producing pyrazolyl-acetylenic alcohols, because even the less reactive 4-ethynyl-1,3,5-trimethylpyrazole,
additionally passivated by three donor methyl groups, reacts with acetone (Scheme 61).
HO
C
CH
C
C
CH 3COCH 3
N
N
N
KOH
N
Scheme 61
In similar conditions, 1-(1-methyl-3-indazolyl)-3-methylbutyne-1-ol-3 (78XGC1535) was
synthesized in 93% yield from 1-methyl-3-ethynylindazole (Scheme 62).
HO
C
CH
C
C
CH 3COCH 3
N
N
KOH
N
N
Scheme 62
Acetylenic alcohols can be obtained using another technique from bromacetylene with
subsequent action of butyllithium and carbonyl compound (Scheme 63).
HO
Br
C
C
R
N
Cl
N
C
N
C
R
1. n-BuLi/THF
2. C4H9CHO
O
C4H9
N
N
Cl
N
O
R = H, Br
Scheme 63
The scheme was used to prepare a number of pyrazolylacetylenic alcohols (Table XVIII).
Note that alcohol protection has lost its significance with the appearance of trimethylsilyl
protection of the terminal acetylenic proton, soft conditions of its removal and the high yields of
the products.
68
TABLE XVII
(Pyrazol-3-yl)-alk-3-yn-2-ols and the (Indazol-3-yl)-alk-3-yn-2-ol Prepared by Favorsky Reaction
Alkynylpyrazoles
Structural formula
OH
2-Methyl-4-(1H-pyrazol-3-yl)-but-3-yn-2-ol
HN N
Formula
index
C8H10N2O
C C
Reagent(s) and reaction conditions
M.p. (oC)
Yield
(%)
References
114.5-115 (CCl4), [153156/2]
77
68KGS695
110-111 (CH2ClCH2Cl)
46
68KGS695
[b.p./ mm Hg]
o
CH3COCH3, KOH, ether, 0 C, 2-3 h
and room temp. 2 days
51
(a) EtMgBr, ether; (b) CH3COCH3
OH
4-Methyl-1-(1H-pyrazol-3-yl)-pent-1-yn-3-ol
HN N
2-Methyl-4-(1-methyl-1H-pyrazol-3-yl)-but3-yn-2-ol
2-Methyl-4-(1,3,5-trimethyl-1H-pyrazol-4yl)-but-3-yn-2-ol
N
N
2-Phenyl-4-(1H-pyrazol-3-yl)-but-3-yn-2-ol
HN N
(a) EtMgBr, ether; (b) (CH3)2CHO
[160-165/1]
OH
N N
C9H12N2O
C C
C9H12N2O
CH3COCH3, KOH, ether, 0-5oC, 4 h
58-59 (CCl4), [162165/1]
62
69IZV2546
C11H16N2O
CH3COCH3, KOH, ether, 0oC, 3 h and
room temp. 10 h
93.5 (petroleum ether)
[118-119/3]
69
69KGS1055
C13H12N2O
(a) EtMgBr, ether; (b) CH3COPh
151-151.5 decomp.
(CCl4)
53
68KGS695
C13H14N2O
CH3COCH3, KOH, ether, 0oC, 1.5 h
oil
93
78KGS1535
C14H21N3O
CH3COCH3, KOH, ether, 0oC, 2-3 h
and room temp. 2 days
84-85 (CCl4 – petroleum
ether)
68
68KGS695
C C
OH
C C
Ph OH
C C
2-Methyl-4-(1-methyl-1H-indazol-3-yl)-but3-yn-2-ol
OH
N N
C C
OH
2-Methyl-4-(1-piperidin-1-ylmethyl-1Hpyrazol-3-yl)-but-3-yn-2-ol
N N
N
C C
69
TABLE XVIII
Examples of Alkynylpyrazoles Prepared from 1-Bromoalkynes (99USP5925769).
HO
R2
Br
C
C
C
1
N
R
N
C
1. n-BuLi/THF
2. R2CHO
O
1
N
N
R
O
Alkynylpyrazoles
Substituents
Formula
index
M.p. (oC)
3-[1-(4-Methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-prop-2yn-1-ol
R1 = Me, R2 = H
C20H18N2O2
150-151
4-[1-(4-Methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-but-3yn-2-ol
R1 = Me, R2 = Me
C21H20N2O2
69-70
decomp.
1-[1-(4-Methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-pent-1yn-3-ol
R1 = Me, R2 = Et
C22H22N2O2
135-137
4-[5-(4-Ethyl-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3yl]-but-3-yn-2-ol
R1 = Et, R2 = Me
C22H22N2O2
Foam
1-[1-(4-Methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-4methyl-pent-1-yn-3-ol
R1 = Me, R2 = i-Pr
C23H24N2O2
157-159
70
2. Homo-coupling
As compared with the ChodkiewiczCadio reaction, the oxidative coupling of
enthynylpyrazoles by the FrankeMeisterHay method (CuCl, pyridinemethanol, 40oC)
(57USP2796442; 60JOC1275) allows one to synthesize symmetric dipyrazolylbutadiynes
(69IZV2546; 69KGS1055). The homo-coupling reaction was used to prepare a number of
di(pyrazolyl)butadiynes (Table XIX). The oxidative condensation runs in a high yield and 3ethynyl-1-methyl- and 4-ethynyl-1,3,5-dimethylpyrazole form dehydrodimers in 70% and 90%
yields (69IZV2546, 69KGS1055) (Scheme 64 and Table XIX).
O2
N
C CH
N
N N
CuCl
C C C C
N N
Scheme 64
It is shown that even the labile monosubstituted butadiynyl derivatives can be used as the
starting terminal alkynes. Thus, the oxidative coupling of 3-butadiynyl-1-methyl, 5-butadiynyl1-methyl and 4-butadiynyl-1,3,5-dimethylpyrazole in pyridine by oxygen in the presence of
CuCl at room temperature leads to conjugate octatetraynes in 75%, 83%, and 84.0% yields
(69IZV2546,69KGS1055) (Scheme 65 and Table XIX).
O2
N
C C C CH
N
CuCl
N N
C C C C C C C C
N N
Scheme 65
Moreover, it has been established that dehydrocondensation can be also applied to 3,5diethynyl-1-methylpyrazole which makes it possible to produce polymer (88%) with an extended
system of conjugate bonds possessing semiconductor properties (UP2).
Existence of the aliphatic amino group complicates the course of reaction. Thus, the
oxidative coupling of 4-ethynyl-1,3-dimethyl-5-aminomethylpyrazole in mild conditions (20oC,
CuCl, pyridine, O2) leads only to 20% of butidiyne. However, the acylic protection removes
these complications and 4-ethynyl-1,3-dimethyl-5-(acetyl)aminomethylpyrazole forms
dehydrodimer in 95% yield (Scheme 66) (86TH1).
N
N
O2
C C C CH
CuCl
N
N
C C C C C C C C
NH
R
NH
R
HN
R
R = H, yield 20%;
R = Ac, yield 95%
Scheme 66
N
N
71
TABLE XIX
Di(pyrazolyl)butadiynes and Di(pyrazolyl)octatetraynes Prepared by Homo-coupling Reactiona
Alkynylpyrazoles
Structural formula
Bis(1-methylprazol4-yl)butadiyne
N
N
Bis(1-methylprazol5-yl)butadiyne
N N
Bis(1-methylprazol4-yl)octatetrayne
N
N
Bis(1-methylprazol5-yl)octatetrayne
N N
C C C C
Bis(5-aminomethyl1,3-dimethylprazol4-yl)butadiyne
N
N
N
N
C C C C
C C C C
N
N
C C C C
NH
Ac
a
C12H10N4
98-99
(tetrachloromethane)
70
69IZV2546
C12H10N4
103-104 (petroleum
ether)
80
69IZV2546
C16H10N4
~180 decomp. with
explosion
(CH2ClCH2Cl)
75
69IZV2546
C16H10N4
~147 temp. of
polymerization
83
69IZV2546
C16H18N4
107.5-108 (benzene
– petroleum ether)
90
69KGS1055
C16H20N6
167-168 (water)
20
86TH1
C20H18N4
179-179.5
(petroleum ether)
84
69KGS1055
C20H24N6O2
293-295 decomp.
(ethanol)
91
86TH1
C8nH4n+2N2n
< 330
88
69KGS1055
N
N
N
N
HN
Ac
H C C
References
H2N
C C C C C C C C
N
N
Yield
(%)
N N
N
N
NH2
Bis(5-(Nacetylamino)methyl1,3-dimethylprazol4-yl)butadiyne
N
N
C C C C C C C C
N
N
M.p. (oC)
N N
C C C C C C C C
Bis(1,3,5trimethylprazol-4yl)butadiyne
Bis(1,3,5trimethylprazol-4yl)octatetrayne
N
N
C C C C
Formula
index
C C
N N
H
n
Typical experimental conditions: O2, CuCl, pyridine (or a mixture of pyridine with methanol), room temperature.
72
3. Cross-coupling
When the cross-coupling is used in the synthesis of alkyl(aryl)acetylenylpyrazoles,
iodopyrazoles act most often as a halide component, because the methods of their production are
well developed (80IZV1071; 85MI1). The number of examples of the "reverse variant" of crosscoupling where ethynylpyrazole acts as an acetylenic component, are rather scarce (96MC98;
2001UP3) (Scheme 67).
O
R
N
O
CH
2
C
N
R1
R3
C
R2
Br
N
Pd(OAC)2, PPh3,
CuI, Et3N, C6H6
C
N
R1
R3
R1 = CH3, CH(CH3)OCH2CH3,
R2 = H, CH3; R3 = H, CH3
Scheme 67
The condensation of 4-ethynyl-1,3-dimethyl-5-aminomethylpyrazole with iodbenzene in the
standard conditions of the HeckSonogashira reaction caused no complications and the yield of
disubstituted acetylene was 87% (86TH1) (Scheme 68).
C
CH
I
C
N
NH 2
C
N
Pd(PPh3)2Cl 2,
CuI, Et 2NH
N
NH 2
N
Scheme 68
Cross-coupling
of
5-ethynyl-4-chloro-1,3-dimethylpyrazole
with
3-iodo-4chloronitrobenzene was carried out in the presence of (PPh3)2PdCl2, CuI and Et3N (66%)
(96MC98) (Scheme 69).
I
Cl
Cl
NO 2
Cl
Cl
N
N
C CH
Pd(PPh3)2Cl 2,
CuI, Et 3N
N
N
C C
NO 2
Scheme 69
The same type of reactions includes the Chodkiewicz-Cadio reaction, i.e., a coupling of
terminal acetylenes with bromacetylenes which is performed in inert atmosphere at 2040 oC in
the presence of CuCl and ethylamine. Thus, 3-ethynyl-1-methyl, 5-ethynyl-1-methyl, and 4ethynyl-1,3,5-trimethylpyrazole were coupled with 1-brom-3-methyl-butyne-1-ol-3 according to
73
the Chodkiewicz-Cadio reaction giving the corresponding diacetylenic alcohols in 76%, 76%
and 75% yields (69IZV2546,69KGS1055) (Scheme 70, Scheme 71).
OH
Br C C
N
N
C CH
N
CuCl, C 2H5NH2,
NH2OH, MeOH
C C
N
C C
OH
Scheme 70
CH
CH
R
N
C
N
R
C
OH
Br C C
CuCl, C 2H5NH2,
NH2OH, MeOH
C
R
N
C
N
R
R = H, CH3
Scheme 71
Concerning mechanism of this reaction little is known; probably intermediates are acetylides.
74
TABLE XX
Alkynylpyrazoles Prepared by Cross-coupling Reactions of Ethynylpyrazoles with sp- and sp2-halides.
Alkynylpyrazoles
2-Methyl-6-(2-methyl-2H-pyrazol-3-yl)-hexa3,5-diyn-2-ol
Structural formula
OH
4-Chloro-5-(2-chloro-4-nitro-phenylethynyl)1,3-dimethyl-1H-pyrazole
Reagents and reaction conditions
M.p. (oC)
Yield
(%)
References
C11H12N2O
CuCl, EtNH2, NH2OH·HCl,
MeOH, 30oC, 3 h
63-63.5
(petroleum ether)
76
69IZV2546
C11H12N2O
CuCl, EtNH2, NH2OH·HCl,
MeOH, 30oC, 3 h
90.5-91 (benzene)
76
69IZV2546
C13H9Cl2N3O2
Pd(PPh3)2Cl2, CuI, NEt3, 80oC, 4
h
188.5-189.5
(benzene)
77
96MC98
C C C C
N N
OH
2-Methyl-6-(1-methyl-1H-pyrazol-3-yl)-hexa3,5-diyn-2-ol
Formula
index
C C C C
N N
Cl
Cl
N
N
2001IZV(ip)
C C
NO 2
4-(2-Methyl-2H-pyrazol-3-ylethynyl)benzaldehyde
2-Methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)hexa-3,5-diyn-2-ol
4-(1,3-Dimethyl-1H-pyrazol-4-ylethynyl)benzaldehyde
4-(1,5-Dimethyl-1H-pyrazol-4-ylethynyl)benzaldehyde
O
N N
N
N
C13H10N2O
Pd(OAc)2, CuI, PPh3, NEt3,
C6H6, 50-60oC, 0.5 h
C13H16N2O
CuCl, EtNH2, NH2OH·HCl,
MeOH, 40oC, 3 h
C14H12N2O
C14H12N2O
C C
OH
C C C C
O
N
N
C C
N
N
C C
O
84
2001UP3
75
69KGS1055
Pd(OAc)2, CuI, PPh3, NEt3,
C6H6, 50-60oC, 1 h
81
2001UP3
Pd(OAc)2, CuI, PPh3, NEt3,
C6H6, 50-60oC, 2 h
76
2001UP3
134.5 (petroleum
ether)
75
Alkynylpyrazoles
Structural formula
C-(2,5-Dimethyl-4-phenylethynyl-2H-pyrazol3-yl)-methylamine
Formula
index
Reagents and reaction conditions
M.p. (oC)
Yield
(%)
References
C14H15N3
Pd(PPh3)2Cl2, CuI, NHEt2, 5055oC, 17 h
56-57 (water)
87
86TH1
C16H16N2O2
Pd(OAc)2, CuI, PPh3, NEt3,
C6H6, 50-60oC, 2 h
68
2001UP3
C
C
N
4-[1-(1-Ethoxy-ethyl)-1H-pyrazol-4-ylethynyl]benzaldehyde
N
N
O
NH 2
N
O
C C
76
4. Aminomethylation
A great series of Mannich bases with secondary amines (69KGS1055; 72IZV2524; 90MIP1)
was obtained using mono-, di, and triethynylpyrazoles. Aminoalkylation of terminal acetylenes
by paraform and secondary amines is performed in argon atmosphere at 50-100oC in dioxane in
the presence of CuCl, as it is known that copper salts activate ethynyl derivatives in this reaction.
Diethylamine, diethanolamine, pyrrollidine, piperidine, and morpholine were used as secondary
amines. The general Scheme 72 was used to prepare a number of Mannich bases (Table XXI).
N
CH
C
N
C
Piperidine, paraform,
CuCl, dioxane
C
N
N
N
Scheme 72
1-(N,N-Diethylaminomethyl)-3-ethynylpyrazole with paraform form diamine in the presence
of CuCl in dioxane (100oC, 3h), in 82% yield. The aminomethylatlon of the 4-ethynyl-l,3,5trimethyl-, 4-butadiynyl-l,3,5-trimethyl-, 3,5-diethynyl-l-methyl-, 3,4-diethynyl-l-methyl-, 4,5diethynyl-l-methylpyrazole and. 4-ethynyl-l-methylpyrazole was run in dioxane in the presence
of CuCl.(72IZV2524) in argon atmosphere. With diethylamlne and piperldlne the reaction was
ended in 7-9 h at 35oC, while 2-3 h at 80oC was sufficient for its total completion with any of the
employed amines.
The differences in the reactivity of the acetylenic groups, occupying different positions in the
pyrazole ring, are slight. This can be followed using pyrazole diethynyl derivatives as an
example. In the case of 4,5-diethynyl- and 3,5-diethynyl-l-methylpyrazole, respectively, the
relative condensation rates (piperidine, 35oC) at 5-CCH are ~4 times higher than at 4-CCH,
and ~1.6 times higher than at 3-CCH.
77
TABLE XXI
Aminomethylethynylpyrazoles Prepared by Mannich Reaction
Alkynylpyrazoles
Structural formula
O
4-[3-(1-Methyl-1H-pyrazol-3-yl)-prop-2ynyl]-morpholine
Yield
(%)
References
C11H15N3O
Morpholine, paraform, CuCl, dioxane,
80oC, 2 h
[164-171/1.5]
91
90MIP1
C12H17N3
Piperidine, paraform, CuCl, dioxane, 35oC,
8h
47-48 (petroleum
ether)
64
72IZV2524
N
N
C13H19N3
Pyrrolidine, paraform, CuCl, dioxane,
35oC, 8 h
[137-138/2]
82
72IZV2524
N
N
C13H19N3O
Morpholine, paraform, CuCl, dioxane,
35oC, 8 h
72.5-73 (petroleum
ether)
85
72IZV2524
C13H21N3
Diethylamine, paraform, CuCl, dioxane,
35oC, 8 h
[136-137/1.5]
86
72IZV2524
Piperidine, paraform, CuCl, dioxane, 35oC,
8 h (or 80oC, (petroleum ether)30 min.)
44-45 (petroleum
ether)
82
72IZV2524
N
N
C C
O
N
N
nD20 1.5135
C C
1-[3-(1,3,5-Trimethyl-1H-pyrazol-4-yl)prop-2-ynyl]-piperidine
C14H21N3
N
N
nD20 1.5345
C C
Diethyl-[3-(1,3,5-trimethyl-1H-pyrazol4-yl)-prop-2-ynyl]-amine
N
N
nD20 1.5458
C C
4-[3-(1,3,5-Trimethyl-1H-pyrazol-4-yl)prop-2-ynyl]-morpholine
N
N
[b.p./ mm Hg]
C C
1-[3-(1-Methyl-1H-pyrazol-4-yl)-prop-2ynyl]-piperidine
1,3,5-Trimethyl-4-(3-pyrrolidin-1-ylprop-1-ynyl)-1H-pyrazole
Reagent(s) and reaction conditions
N
N N
M.p. (oC)
Formula
index
N
C C
78
Alkynylpyrazoles
Structural formula
O
4-[5-(1,3,5-Trimethyl-1H-pyrazol-4-yl)penta-2,4-diynyl]-morpholine
Reagent(s) and reaction conditions
C15H19N3O
Morpholine, paraform, CuCl, dioxane,
35oC, 8 h
C18H24N4O2
M.p. (oC)
Yield
(%)
References
94-95 decomp.
(petroleum ether)
63
72IZV2524
Morpholine, paraform, CuCl, dioxane,
35oC, 8 h
94.5-95.5
(petroleum ether)
65
72IZV2524
C18H24N4O2
Morpholine, paraform, CuCl, dioxane,
35oC, 8 h
79-80 (petroleum
ether)
66
72IZV2524
C18H24N4O2
Morpholine, paraform, CuCl, dioxane,
35oC, 8 h
Viscous liquid
58
73IZV2524
C20H28N4
Piperidine, paraform, CuCl, dioxane, 35oC,
8h
82-83 (petroleum
ether)
66
72IZV2524
N
N
N
1-Methyl-3,5-di[3-(Nmorpholino)propyn-1-yl-1]pyrazole
Formula
index
[b.p./ mm Hg]
C C C C
O
N
O
C
C
N
C C
N N
1-Methyl-3,4-di[3-(Nmorpholino)propyn-1-yl-1]pyrazole
O
N
C
C
O
N
N
N
C C
1-Methyl-4,5-di[3-(Nmorpholino)propyn-1-yl-1]pyrazole
O
N
C
C
O
N
N N
1-Methyl-3,5-di[3-(Npyperidino)propyn-1-yl-1]pyrazole
C C
N
C
C
N
N N
C C
79
Alkynylpyrazoles
Structural formula
1-Methyl-3,4-di[3-(Npyperidino)propyn-1-yl-1]pyrazole
N
C
C
N
N
N
C C
Formula
index
Reagent(s) and reaction conditions
C20H28N4
Piperidine, paraform, CuCl, dioxane, 35oC,
8h
M.p. (oC)
[b.p./ mm Hg]
77-78 (petroleum
ether)
Yield
(%)
References
90
72IZV2524
80
5. Halogenation
The interaction between terminal pyrazolylacetylenes and alkaline solutions of KOHal (Hal =
Cl, Br, I) of alkaline metals gives pyrazolylethynylhalogenides. The chosen method of synthesis
could cause complications due to the low rate of halogenation owing to the low solubility of
ethynylpyrazoles in alkaline solution and the lability of both starting ethynyl derivatives and
final products with respect to the oxidative action of KOHal. To avoid possible complications,
the reaction of halogenation is carried out at room temperature. To increase the reaction rate, the
mixture is taken with about 5-fold excess of KOHal. For liquid ethynylpyrazoles and resulting
halogenethynylpyrazoles these precautions gave good results and the product yields were
9598%. The yields of halogenides were much lower when the crystalline monosubstituted
acetylenes were used as substrates. Probably, this is due to the fact that the resulting
halogenacetylene whose solubility is worse than that of ethynyl derivatives, covered the surface
of starting acetylene thus hampering the access of a reagent. Indeed, the addition of either ether
or dioxane that dissolve a substrate and halogenozole, to the reaction mass, causes an increase in
the yields of the compounds. The action of KOBr and KOI on 4-ethynyl-1,3,5-methylpyrazole
gives 4-bromethynyl- and 4-iodethynylpyrazoles in 73% and 75% yields (76IZV2292;
77IZV2306).
N
H
C C
KOHal
N
N
Hal
C C
N
Hal = Cl, Br, I
Scheme 73
By chlorination of 3-ethynyl-, 4-ethynyl- and 5-ethynyl-l-mechylpyrazole with КОСl were
synthesized corresponding compounds in 98%, 100% and 94% yields.
Typical procedure: to a aqueous solution of KOX (0.64 N) in 12.5% KOH, prepared from
corresponding halogen and potassium hydroxide in water at 5-10oC was added terminal
acetylene and stirred at room temperature up to disappearing of starting material.
81
TABLE XXII
Halogenoethynylpyrazoles Prepared by Reaction of Ethynylpyrazoles with KOHal.
Alkynylpyrazoles
Structural
formula
4-Chloroethynyl-1-methyl1H-pyrazole
N
N
3-Chloroethynyl-1-methyl1H-pyrazole
N N
5-Chloroethynyl-1-methyl1H-pyrazole
4-Bromoethynyl-1,3,5trimethyl-1H-pyrazole
4-Iodoethynyl-1,3,5trimethyl-1H-pyrazole
N N
N
N
N
N
C C Cl
C C Cl
C C Cl
Formula
index
M.p. (oC)
Yield
(%)
References
C6H5ClN2
61-62 (hexane)
98
86TH1
C6H5ClN2
Oil, nD20 = 1.5457
98
77IZV2306
C6H5ClN2
Oil, nD20 = 1.5510
94
77IZV2306
C8H9BrN2
136-137 (benzene –
petroleum ether)
73
76IZV2292
C8H9IN2
178-179 decomp.
(benzene – petroleum
ether)
75
76IZV2292
C C Br
C C I
82
6. Alkylation
A comparatively high acidity of terminal acetylenes allows the alkylation (without isolation
of an intermediate acetylenide) of even less active ethynyl groups occupying position 4 in the
pyrazole cycle. Thus, methylation of 4-ethynyl-1,3-dimethylpyrazole was carried out by
(CH3)2SO4 in presence of sodium amide in liquid NH3 (77IZV2306). The yield of 4-(1propynyl)-1,3-dimethylpyrazole was 71% (Scheme 74).
1. NaNH 2, NH3
N
N
C CH
2. (CH 3)2SO4
N
N
C C
Scheme 74
The chlorine atom does not react in these conditions and 5-chloro-4-(1-propynyl-1,3dimethylpyrazole was prepared similarly from corresponding ethynyl derivative in 75.8% yield.
1. NaNH 2, NH3
N
N
C CH
2. (CH 3)2SO4
N
N
C C
Cl
Cl
Scheme 75
7. Metalation
All above mentioned reactions are likely to result in intermediate organo-metal compounds
and the starting terminal acetylenes can be characterized as the synthetic equivalents of
syntonnucleophiles RCC-.
As an example the reaction of methyl-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4(chloromethoxyphosphinyl)butyrate with lithium pyrazolylalkynide may be cited that is used to
prepare compounds with structure HOP(O)(PzCC)CH2CH(OH)CH2CO2H useful as 3hydroxyl-3-methylglutaryl CoA (HMG CoA) reductase inhibitors (88GEP3817298) (Scheme
76).
O
O
HO
Pz C CLi
Si
O
O
P
Cl
O
O
H+
HO HO P
C
C
Pz
O
Scheme 76
Pyrazolylacetylides are rare in a free form. The only example is the production of
ethynylpyrazole copper salt by means of interaction between terminal acetylene and CuCl
(2001UP1).
83
N
N
C CH
O
N
N
CuCl
NH 3, NH2OH
C C Cu
O
Scheme 77
B. Reactions with participation of CC bond
The triple bond in pyrazole derivatives tends, as in other acetylenic derivatives, to typical
reactions of addition.
1. Halogenation
When 4-ethynyl-3,5-dimethylpyrazole interacts with bromine, only one halogen molecule is
added which is probably to be due to steric hindrance (71TH1).
Br
Br2
N
HN
C C Cl
Cl
N
HN
Br
Scheme 78
2. Hydration
The hydration of pyrazolylacetylenes shows no peculiarities. Ethynylpyrazoles are
hydrogenated in high yields on a Reney nickel catalyst, platinum dioxide or palladium catalyst at
room temperature in alcohol solution to the corresponding ethane derivatives.
Thus, the hydration of isomeric 1-ethynyl-3-methyl- and 1-ethynyl-5-methylpyrazoles by
hydrogen with 10% Pd/C in 1-ethyl-3-methyl- and 1-ethyl-5-methylpyrazoles was used to prove
the structure of N-ethynylpyrazoles forming from pyrolysis of the corresponding Npropinoilazoles (94AJC991).
R1
R1
H2, 10%Pd/C
N C CH
2
R
N
N
2
R
N
R1 = H, R2 = Me; R1 = Me, R2 = H
Scheme 79
[4-(1,3-Bis-{6-[(bis-tert-butoxycarbonylmethyl-amino)-methyl]-pyridin-2-yl}-1H-pyrazol-4ylethynyl)-phenoxy]-acetic acid methyl ester and parent compounds were hydrogenated in dry
methanol in presence of 10% Pd/C for 4h in 70% yield (97EUP770610; 99EUP967205).
84
COO- t-Bu
COO- t-Bu
N
N
COO- t-Bu
N
N
N
N
H2, 10%Pd/C
C C
O
N
N
OMe
O
N
N
COO- t-Bu
O
N
COO- t-Bu
OMe
O
COO- t-Bu
N
COO- t-Bu
COO- t-Bu
Scheme 80
There are other examples of the hydration of 1-(hetaryl)-4-alkynylpyrazole derivatives to the
corresponding alkanes (96EUP703234).
Derivatives of 5-ethynylpyrazolo[3,4-d]pyrimidine in presence of 10% Pd/C) were
hydrogenated at 50 psi for 4 days in 41-78% yields (92T8089).
5-Ethynylpyrazol was hydrogenated in ether with PtO2 at 20oC for 3h (41LA279).
H2, PtO2
C CH
N N
H
N N
H
Scheme 81
Lindler catalyst can be used for hydration of 1-[3-(2- phenylpyrazolo[1.5-a]pyridin-3yl)propioloyl]-2-ethylpiperidine in ethyl acetate (38%) (Scheme 82) (89EUP299209;
92USP5102869) and 1-(hetaryl)-4-alkynylpyrazole derivatives to the corresponding alkenes
(96EUP703234).
O
O
N
N
Linlar catalist,
quinoline
C
C
EtOAc
N N
Ph
N N
Ph
Scheme 82
A scheme of preparation of the series of cyclic urea HIV protease inhibitors containing
alkynyl- and alkynyl-tethered heterocycles in the P2 region includes hydration with LiAlH4 in
THF in 60-80% yields (96BML797) (Scheme 83, Scheme 84).
O
N
N
MEM
C C
Ph
N
O
N
O
C C
Ph
O
LiAlH4/THF
N
N
MEM
N
N
MEM
Ph
Scheme 83
N
N
O
O
N
N
MEM
Ph
85
O
Ph
O
N
N
O
O
C C
N
LiAlH4/THF
N
MEM
Ph
Ph
N
N
O
O
N
N
MEM
Ph
Scheme 84
3. Hydrohalogenation
Example of addition of HCl to triple bond is given in work (93EUP571326). The acetic aсid
esters of formula 44 may be obtained from alkynylpyrazoles 43 by alcoholysis with HCl in the
presence of methanol.
R3
Cl
C
R2
Z
R2
C
HCl, MeOH
N
CN
N
N
R1
43
COOMe
N
R1
44
Scheme 85
2. Hydratation
In the presence of silver oxide and BF3-ether complex, 4-phenylethynylpyrazole forms one
isomer from two possible isomers, i.e., 2-phenyl-1-(4-pyrazolyl)ethanone in 72% yield
(88MOC253).
R
C
N
O
1. HgO, BF 3 Et2O, Cl 3CCO 2H
C
2. 2 N H2SO4
N
H
N
R
N
H
R = H, Ph
Scheme 86
However, in the presence of the electron-withdrowing nitro group, hydratation occurs already
under the conditions of its reduction. In this case, the direction of addition of the water molecule
is preserved. The yield of 1-methyl-4-phenylacetylpyrazole was 90% (99JCS(P1)3713) (Scheme
87).
Ph
O
C
O2N
N
C
SnCl 2, HCl
H2N
N
N
Scheme 87
N
Ph
86
At the same time, the hydratation of 3(5)-phenyl-5(3)-phenylethynylpyrazole 45 in sulfuric
acid in the presence of mercury acetate leads to the formation of two isomeric ketones: 46 (yield
44%) and 47 (yield 3%) (68LA117).
Ph
C
Ph
C
N
O
O
Hg(OAc) 2
N
H
Ph
N
AcOH, H2SO4
45
Ph
+
N
H
N
Ph
46
N
H
47
Ph
Scheme 88
The
hydratation
of
5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4ethynylpyrazole was performed with p-toluenesulphonic acid monohydrate in acetonitrile (2 h,
room temperature) to give corresponding 4-acetyl derivative. An alkyl substituent at triple bond
decreases the rate of hydratation; the conversion of 5-amino-3-cyano-1-(2,6-dichloro-4trifluoromethylphenyl)-4-(prop-1-yn-1-yl)pyrazole to the 4-propanoylpyrazole completes after
18 h (99EUP933363).
4. Hydrazination
Acetylene interacting with hydrazine in absolute ethanol gives the mixture of isomeric
hydrazones in a 3:2 ratio (by NMR spectra) (68LA117).
Ph
C
Ph
C
N
NH2
N
N NH2
N2H4
N
H
N
Ph
Ph
+
N
H
N
Ph
N
H
Ph
Scheme 89
The reaction of the propiolate derivatives with hydrazine monohydrate leads to 5-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2H-pyrazol-3-ol (Scheme 90) (90EUP379979).
O
O
H
N
C
C
OH
N
NH 2NH 2
N N
N N
Scheme 90
5. Oxidation
The presence of triple bond allows one to obtain not only mono but also diketones. Recently,
a new reaction of acetylene oxidation to -diketones with reagent PdCl2DMSO has been
discovered (95S1234). Acetylenic derivatives of pyrazole bearing electron-donating substituents
were oxidized with the reagent PdCl2DMSO to the heterocyclic 1,2-diketones in high yield
(2001UP4) (Scheme 91).
87
R2
R1
N
N
R2
C C
PdCl2 - DMSO
4
R
R1
3
R
O
N
N
R4
3
R
O
R1 = R2 = R3 = R4 = H; R1 = R2 = R3 = H, R4 = NO2;
R1 = R2 = R3 = CH3, R4 = H; R1 = R3 = CH3, R2 = R4 = H;
R1 = CH3, R2 = NH2, R3 = R4 = H
Scheme 91
The oxidation reaction of pyrazole derivative with electron-withdrawing substituents (R1 =
Me, R2, R3 = COOCH3, R4 = CHO; Scheme 91) is failed (2001UP4).
For the same reason the oxidation of triple bond in 4-chloro-5-(2-chloro-5-nitrophenylethynyl)-1,3-dimethyl-1H-pyrazole is failed too.
Cl
N N
NO 2
C C
Cl
B. Reactions with participation of CC bond
The triple bond in pyrazole derivatives tends, as in other acetylenic derivatives, to typical
reactions of addition.
1. Halogenation
When 4-ethynyl-3,5-dimethylpyrazole interacts with bromine, only one halogen molecule is
added which is probably to be due to steric hindrance (71TH1).
Br
N
HN
Br2
C C Cl
N
HN
Cl
Br
Scheme 92
2. Hydration
The hydration of pyrazolylacetylenes shows no peculiarities. Ethynylpyrazoles are
hydrogenated in high yields on a Reney nickel catalyst, platinum dioxide or palladium catalyst at
room temperature in alcohol solution to the corresponding ethane derivatives.
Thus, the hydration of isomeric 1-ethynyl-3-methyl- and 1-ethynyl-5-methylpyrazoles by
hydrogen with 10% Pd/C in 1-ethyl-3-methyl- and 1-ethyl-5-methylpyrazoles was used to prove
the structure of N-ethynylpyrazoles forming from pyrolysis of the corresponding Npropinoilazoles (94AJC991).
88
R1
R1
H2, 10%Pd/C
N C CH
2
R
N
N
N
2
R
R1 = H, R2 = Me; R1 = Me, R2 = H
Scheme 93
[4-(1,3-Bis-{6-[(bis-tert-butoxycarbonylmethyl-amino)-methyl]-pyridin-2-yl}-1H-pyrazol-4ylethynyl)-phenoxy]-acetic acid methyl ester and parent compounds were hydrogenated in dry
methanol in presence of 10% Pd/C for 4h in 70% yield (97EUP770610; 99EUP967205).
COO- t-Bu
COO- t-Bu
N
N
COO- t-Bu
N
N
N
N
H2, 10%Pd/C
C C
O
N
N
OMe
O
N
N
COO- t-Bu
O
N
COO- t-Bu
OMe
O
COO- t-Bu
N
COO- t-Bu
COO- t-Bu
Scheme 94
There are other examples of the hydration of 1-(hetaryl)-4-alkynylpyrazole derivatives to the
corresponding alkanes (96EUP703234).
Derivatives of 5-ethynylpyrazolo[3,4-d]pyrimidine in presence of 10% Pd/C) were
hydrogenated at 50 psi for 4 days in 41-78% yields (92T8089).
5-Ethynylpyrazol was hydrogenated in ether with PtO2 at 20oC for 3h (41LA279).
H2, PtO2
C CH
N N
H
N N
H
Scheme 95
Lindler catalyst can be used for hydration of 1-[3-(2- phenylpyrazolo[1.5-a]pyridin-3yl)propioloyl]-2-ethylpiperidine in ethyl acetate (38%) (Scheme 82) (89EUP299209;
92USP5102869) and 1-(hetaryl)-4-alkynylpyrazole derivatives to the corresponding alkenes
(96EUP703234).
O
O
N
Linlar catalist,
quinoline
C
C
N
EtOAc
N N
Ph
N N
Scheme 96
Ph
89
A scheme of preparation of the series of cyclic urea HIV protease inhibitors containing
alkynyl- and alkynyl-tethered heterocycles in the P2 region includes hydration with LiAlH4 in
THF in 60-80% yields (96BML797) (Scheme 83, Scheme 84).
O
N
N
MEM
C C
Ph
N
O
O
C C
N
LiAlH4/THF
N
N
N
N
MEM
MEM
Ph
O
Ph
N
N
O
O
N
N
MEM
Ph
Scheme 97
O
Ph
O
N
N
O
O
C C
N
LiAlH4/THF
N
MEM
Ph
Ph
N
N
O
O
N
N
MEM
Ph
Scheme 98
3. Hydrohalogenation
Example of addition of HCl to triple bond is given in work (93EUP571326). The acetic aсid
esters of formula 44 may be obtained from alkynylpyrazoles 43 by alcoholysis with HCl in the
presence of methanol.
R3
Cl
C
2
R
Z
R2
C
HCl, MeOH
N
CN
N
N
R1
43
COOMe
N
R1
44
Scheme 99
2. Hydratation
In the presence of silver oxide and BF3-ether complex, 4-phenylethynylpyrazole forms one
isomer from two possible isomers, i.e., 2-phenyl-1-(4-pyrazolyl)ethanone in 72% yield
(88MOC253).
R
C
C
N
N
H
O
1. HgO, BF 3 Et2O, Cl 3CCO 2H
2. 2 N H2SO4
R = H, Ph
N
N
H
R
90
Scheme 100
However, in the presence of the electron-withdrowing nitro group, hydratation occurs already
under the conditions of its reduction. In this case, the direction of addition of the water molecule
is preserved. The yield of 1-methyl-4-phenylacetylpyrazole was 90% (99JCS(P1)3713) (Scheme
87).
Ph
O
C
O2N
N
C
H2N
SnCl 2, HCl
N
N
Ph
N
Scheme 101
At the same time, the hydratation of 3(5)-phenyl-5(3)-phenylethynylpyrazole 45 in sulfuric
acid in the presence of mercury acetate leads to the formation of two isomeric ketones: 46 (yield
44%) and 47 (yield 3%) (68LA117).
Ph
C
Ph
C
N
O
O
Hg(OAc) 2
N
H
Ph
N
AcOH, H2SO4
45
+
N
H
Ph
N
Ph
46
N
H
47
Ph
Scheme 102
The
hydratation
of
5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4ethynylpyrazole was performed with p-toluenesulphonic acid monohydrate in acetonitrile (2 h,
room temperature) to give corresponding 4-acetyl derivative. An alkyl substituent at triple bond
decreases the rate of hydratation; the conversion of 5-amino-3-cyano-1-(2,6-dichloro-4trifluoromethylphenyl)-4-(prop-1-yn-1-yl)pyrazole to the 4-propanoylpyrazole completes after
18 h (99EUP933363).
4. Hydrazination
Acetylene interacting with hydrazine in absolute ethanol gives the mixture of isomeric
hydrazones in a 3:2 ratio (by NMR spectra) (68LA117).
Ph
C
Ph
C
N
NH2
N
N NH2
N2H4
N
H
Ph
N
+
N
H
Ph
Ph
N
N
H
Ph
Scheme 103
The reaction of the propiolate derivatives with hydrazine monohydrate leads to 5-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2H-pyrazol-3-ol (Scheme 90) (90EUP379979).
91
O
O
H
N
C
C
OH
N
NH 2NH 2
N N
N N
Scheme 104
5. Oxidation
The presence of triple bond allows one to obtain not only mono but also diketones. Recently,
a new reaction of acetylene oxidation to -diketones with reagent PdCl2DMSO has been
discovered (95S1234). Acetylenic derivatives of pyrazole bearing electron-donating substituents
were oxidized with the reagent PdCl2DMSO to the heterocyclic 1,2-diketones in high yield
(2001UP4) (Scheme 91).
R2
R1
N
N
R2
C C
PdCl2 - DMSO
R4
R1
3
R
O
N
N
R4
3
R
O
R1 = R2 = R3 = R4 = H; R1 = R2 = R3 = H, R4 = NO2;
R1 = R2 = R3 = CH3, R4 = H; R1 = R3 = CH3, R2 = R4 = H;
R1 = CH3, R2 = NH2, R3 = R4 = H
Scheme 105
The oxidation reaction of pyrazole derivative with electron-withdrawing substituents (R1 =
Me, R2, R3 = COOCH3, R4 = CHO; Scheme 91) is failed (2001UP4).
For the same reason the oxidation of triple bond in 4-chloro-5-(2-chloro-5-nitrophenylethynyl)-1,3-dimethyl-1H-pyrazole is failed too.
Cl
N N
NO 2
C C
Cl
C. Reactions with participation of C-X bond
Synthetically, the most important reactions of this type are the cleavage of C-X bond and
the formation of a new C-H bond.
1. Retro Favorsky reaction
A classical variant of the reverse Favorsky reaction assumes the heating of -acetylenic
alcohol of the aromatic (heteroaromatic) series in a set-up for sublimation in vacuum in the
presence of 0.5-5 weight per cent of powdered KOH in the temperature range of 120-160oC with
simultaneous sublimation of ethynyl derivative and the capture of isolated carbonyl compound
by a nitrogen trap. This method was used to synthesize 1-methyl-3-ethynyl- (yield 62%)
(69IZV2546), 1-methyl-4-ethynyl- (84%) (72IZV2524), 1,3,5-trimethyl-4-ethynyl- (90%)
92
(69KGS1055) from the corresponding (1-methylpyrazolyl)-3-methylbutyne-1-ols-3 (Scheme
106).
OH
N
C C
KOH
N
N
C CH
N
Scheme 106
Of interest is the high stability of terminal acetylenes of the pyrazole series. This allowed the
production of polyethynyl derivatives, 3,4-diethynyl-, 4,5-diethynyl- and even 3,4,5-triethynyl-1methylpyrazole in 64%, 78% and 41% yields, respectively, in these hard conditions
(71IZV1764) (Scheme 107, Scheme 108).
HO
C
N
CH
OH
C
C C
C
KOH
N
N
C CH
N
Scheme 107
OH
HO
C
C
C
N
HC
CH
C
C
KOH
N
C
N
C
C
C CH
N
OH
Scheme 108
The series of 1,3-dimethyle-5-ethynylpyrazoles including the functionally substituted ones,
was obtained at lower temperature (100-105oC, 10 weight per cent of powdered KOH, 1.5-2 mm
Hg) (86TH1).
Decreasing the temperature still further (up to 80-90oC), authors have managed to obtain
even the unstable terminal diacetylene  1,3,5-trimethyl-4-butadiynylpyrazole (yield 45%)
(69KGS1055).
HO
CH
C
C
C
C
C
C
C
N
KOH
N
N
N
Scheme 109
However, more mild conditions are necessary for obtaining less stable 1-methyl-3butadiynyl- and 1-methyl-5-butadiynylpyrazole. The acetylenic alcohols are stirred with KOH at
93
room temperature in acetylenic atmosphere (to bind the isolated carbonyl compound). The
product yields were 68% and 65% (69IZV2546), respectively.
In 1978, the improved technique was proposed for the cleavage of the tertiary acetylenic
alcohols (78MIP1). In the set-up for sublimation in vacuum, the acetylenic alcohols (0.12.0 g)
are mixed up with KOH (2-30% by weight) and 15 ml of m-pentaphenyl ether or another highly
boiling solvent to remove local overheating. This method is used to substantially improve and
stabilize the yields of mono- and polyethynylpyrazoles (78MIP1; 86TH1) as compared with the
"dry method" (71IZV1764).
Later, the method of cleavage of the tertiary acetylenic alcohols in boiling benzene or toluene
in presence of NaOH or KOH was used (88MOC253; 2001UP1).
94
TABLE XXIII
Ethynyl- and Polyethynylpyrazoles Prepared by Retro-Favorsky Reaction.
Alkynylpyrazoles
4-Ethynyl-1H-pyrazole
4-Ethynyl-1-methyl-1H-pyrazole
Structural formula
N
HN
C CH
N
N
C CH
Br
4-Bromo-5-ethynyl-1,3-dimethyl-1Hpyrazole
N
N
N
34
88MOC253
C6H6N2
KOH, an oil for vacuum pump,
100oC, 3 mm Hg
27-28 (petroleum ether)
72
72IZV2524
C7H7BrN2
KOH, an oil for vacuum pump,
105oC, 1.5 mm Hg
99-100 decomp. (hexane)
47
86TH1
C7H7ClN2
KOH, an oil for vacuum pump,
105oC, 1.5 mm Hg
74-75 (hexane)
66
86TH1
C7H7IN2
KOH, an oil for vacuum pump,
105oC, 1.5 mm Hg
125-126 decomp. (hexane)
82
86TH1
C7H8N2
KOH, an oil for vacuum pump,
105oC, 2 mm Hg
56-57 (hexane)
50
86TH1
C7H9N3
KOH, an oil for vacuum pump,
100oC, 1.5 mm Hg
121-122 (benzene – petroleum ether)
84
86TH1
C8H6N2
KOH, 105oC, 1.5 mm Hg
54-55 subl.
64
71IZV1764
C CH
N
C CH
N
CH
C
3,4-Diethynyl-1-methyl-1H-pyrazole
101-103 (subl.)
C CH
NH2
N
NaOH, ethanol, toluol, boiling, 3
h
[b.p./ mm Hg]
N
5-Ethynyl-1,3-dimethyl-1H-pyrazole
4-Amino-5-ethynyl-1,3-dimethyl-1Hpyrazole
References
C CH
I
4-Iodo-5-ethynyl-1,3-dimethyl-1Hpyrazole
N
C5H4N2
M.p. (oC)
Yield
(%)
C CH
N N
N
Reagent(s) and conditions
N
Cl
4-Chloro-5-ethynyl-1,3-dimethyl-1Hpyrazole
Formula
index
C CH
95
Alkynylpyrazoles
Structural formula
4,5-Diethynyl-1-methyl-1H-pyrazole
N
N
C CH
Formula
index
Reagent(s) and conditions
C8H6N2
KOH, 105oC, 1.5 mm Hg
C8H6N2
M.p. (oC)
Yield
(%)
References
65-66 subl.
73
71IZV1764
KOH, ether, acetylene,
room.temp., 3 h
43-45
65
69IZV2546
C8H6N2
KOH, ether, acetylene,
room.temp., 3 h
Unstable
68
69IZV2546
C8H10N2
KOH, 100oC, 3.5 mm Hg
78 (petroleum ether)
90
69KGS1055
95
86TH1
[b.p./ mm Hg]
C
CH
3-Buta-1,3-diynyl-1-methyl-1Hpyrazole
5-Buta-1,3-diynyl-1-methyl-1Hpyrazole
N N
N N
4-Ethynyl-1,3,5-trimethyl-1Hpyrazole
C C C CH
C C C CH
N
N
CH
C
3,4-Diethynyl-1,5-dimethyl-1Hpyrazole
N
N
4-Buta-1,3-diynyl-1,3,5-trimethyl1H-pyrazole
N
N
KOH, m-pentaphenyl ether,
100oC, 4 mm Hg
C CH
C9H8N2
KOH, an oil for vacuum pump,
105oC, 1.5 mm Hg
69-70 subl.
85
86TH1
C10H10N2
KOH, 80-90oC, 2.5 mm Hg
109-110 subl.
36
69KGS1055
85
86TH1
41
71IZV1764
85
86TH1
C CH
KOH, m-pentaphenyl ether,
100oC, 1 mm Hg
C C C CH
CH
C
3,4,5-Triethynyl-1-methyl-1Hpyrazole
N
N
C CH
C
CH
C10H6N2
KOH, 105oC, 1.5 mm Hg
KOH, m-pentaphenyl ether,
120oC, 1 mm Hg
Polymerized without melting (C6H6 –
petroleum ether 1:5)
96
Alkynylpyrazoles
5-Ethynyl-1,3-dimethyl-4phenylethynyl-1H-pyrazole
Structural formula
Ph
C
C
N N
C CH
Formula
index
Reagent(s) and conditions
C15H12N2
KOH, an oil for vacuum pump,
100oC, 1.5 mm Hg
M.p. (oC)
[b.p./ mm Hg]
89-90 (hexane)
Yield
(%)
References
65
86TH1
97
2. Desilylation
In the recent years, trimethylsilyl protection is often used for the methine proton of the
acetylenic group because of the mild reaction conditions. As a rule, the starting pyrazole
trimethylsilyl derivative is mixed up, at room temperature, with the aqueous solution of 2N
NaOH water solution, potash or methanol solution of ammonia.
In (73S47) the cleavage of the trimethylsilyl protector is used to prepare the nitrogennonsubstituted 3-aryl-5-ethynylpyrazoles (Scheme 110).
Ar
Ar
NaOH
N
C
N
H
C
N
SiMe3
C CH
N
H
Ar = Ph, 4-Cl-C6H4, 4-MeO-C6H4
Scheme 110
4-Ethynylpyrazole was produced in similar conditions in 46% yield (88MOC253). There are
other examples of the trimethylsilyl cleavage with aqueous solution of potassium hydroxide for
1-(hetaryl)-4-(trimethylsilylethynyl)pyrazole derivatives (96EUP703234).
4-Ethynyl-1--D-ribofuranosylpyrazole-3-carboxamide was obtained in good yield by
treatment of compound 48 with methanolic ammonia (96BML1279).
O
C
N
BzO
O
C
O
BzO
SiMe3
CH
C
H2N
NH 3
N
N
HO
MeOH
HO
OBz
N
OH
48
49
Scheme 111
The ethynyl derivative 50 was prepared by interaction of potassium carbonate with 5-amino3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trimethylsilylethynylpyrazole in methanol
for 10 min (99EUP933363).
C
NC
N
SiMe3
CH
NC
C
N
Cl
CF 3
NH 2
K2CO 3
Cl
MeOH
N
C
N
Cl
Cl
CF 3
50
NH 2
51
Scheme 112
4-Trimethylsilylethynylpyrazole was deprotected by treatment with tetrabuthyl ammonium
fluoride (TBAF) to give monosubstituted acetylene in 90% yield. (96ADD193). The same
98
conditions were used to cleavage trimethylsilyl group in 1-tetrahydropyranyl-3-carboxyethyl-4[2-(trimethylsilyl)ethynyl]pyrazole (96INP9640704).
3. Destannylation
As compared with the alkaline conditions used in the above methods, the removal of the
triethylstannylic group (triethyltin) occurs for 3(5)-triethylstannylethynylpyrazole at room
temperature in the CCl4 solution in the presence of acetic acid (71ZOB2230) (Scheme 113).
AcOH
N
C
N
H
C
SnEt3
CCl 4
N
N
H
C CH
Scheme 113
4. Decarboxylation
The terminal acetylenes can be obtained from the corresponding propylcaboxylic acids by
their thermal decomposition. Thus, 1-methyl-3-ethynyl- and 2-methyl-3-ethynylindazole were
obtained by thermolysis of indazolylpropiolic acids at 150-160oC. The yields of ethynyl
derivatives were 65 and 60%, respectively (75KGS1678) (Scheme 114, Table XXIV).
COOH
C
C
N
CH
C
termolysis
N
N
Scheme 114
N
99
TABLE XXIV
Ethynyl- and Polyethynylpyrazoles Prepared by Desilylation, Destannylation and
Decarboxylation Reaction.
Alkynylpyrazoles
Structural formula
Formula
index
Reagent(s)
and
conditions
C5H4N2
M NaOH,
MeOH,
room
temp., 48
h
C11H7ClN2
M.p. (oC)
Yield (%)
References
101-103
(subl.)
46
88MOC253
0.2 M
NaOH,
MeOH, 20
o
C, 20 min
134135.5
(aqueous
methanol)
Quantitative
73S47
C11H8N2
0.2 M
NaOH,
MeOH, 20
o
C, 20 min
109110.5
(aqueous
methanol)
Quantitative
73S47
C11H13N3O5
NH3,
MeOH, 4
o
C, 24 h
Syrup
82
96BML1279
C12H10N2O
0.2 M
NaOH,
MeOH, 20
o
C, 20 min
165165.5
(aqueous
methanol)
Quantitative
73S47
C5H4N2
AcOH,
CCl4,
room
temp.
-
c
71ZOB2230
[b.p./ mm
Hg]
Desililation (protecting group – SiMe3)
4-Ethynyl-1Hpyrazolea
3-(4-Chlorophenyl)-5ethynyl-1Hpyrazole
N
HN
Cl
5-Ethynyl-3-(4methoxyphenyl)-1Hpyrazole
C CH
N N
H
Ph
5-Ethynyl-3phenyl-1Hpyrazole
1-(3,4Dihydroxy-5hydroxymethyltetrahydrofuran2-yl)-4-ethynyl1H-pyrazole-3carboxylic acid
amideb
C CH
C CH
N N
H
O
CH
C
H2N
N
HO
N
O
HO
96MCR293
OH
O
N N
H
C CH
Destannilation (protecting group – SnEt3)
5-Ethynyl-1Hpyrazole
C CH
N N
H
Decarboxylation (protecting group – COOH)
3-Ethynyl-1methyl-1Hindazole
N
3-Ethynyl-2methyl-2Hindazole
C10H8N2
150-160
45-46
(sublim.)
65
75KGS1678
CH
C10H8N2
150-160
122-124
(sublim.)
60
75KGS1678
N
C
N
a
CH
C
N
Prepared from phenyl-(4-trimethylsilanylethynyl-pyrazol-1-yl)-methanone.
Prepared from 1-(3,4-bis-benzoyloxy-5-benzoyloxymethyl-tetrahydro-furan-2-yl)-4-trimethylsilanylethynyl-1Hpyrazole-3-carboxylic acid methyl ester.
c
The authors cannot be able to purify the 3(5)-ethynylpyrazole from triethylstannylacetate.
b
100
5. Cineamination
In 1973 was found unexpected transformation of 4-chloroethynyl-1,3,5-trimethylpyrazole
under action of sodium amide in liquid ammonia into 5-aminomethyl-4-ethynyl-1,3dimethylpyrazole in 85 % yield (73IZV2166). In this connection authors investigated the
reaction of NaNH2 with certain chloro-, bromo- and iodoacetylenylpyrazoles (76IZV2292)
(Scheme 115).
Cl
C
R
N
CH
R
C
C
1. NaNH 2, NH 3
N
2. H2O
N
52
R = H, CH3
NH 2
N
53
Scheme 115
The chemical shift of the protons of the C-methyl for compounds 53 changes much less than
the shift of the protons of the methylene group in the transition from a nonpolar to an aromatic
solvent. The shift induced by benzene on account of the solvent (CDCl3  C6H6) is a quantity
in the order of 0.5 ppm for 5-CH3 in substituted pyrazoles and 0.1 ppm for 3-CH3 (66BSF293;
66JPB1242; 66BSF3727). Thus, the aminomethyl group in the ethynylpyrazoles 53 is proved to
be at position 5 of the heterocycle. The formation of the rearranged substitution product involves
participation of the CH3 group at position 5 but not position 3. Indeed, in accordance with this 4chloroethynyl-l,5-dimethylpyrazole is readily converted into 4-ethynyl-5-aminomethyl-lmetbylpyrazole in 81% yield.
Necessary to emphasize that the direct aminaton of the methyl group at position 5 of
pyrazoles is impossible. Neither 1,3,5-trimethyl- nor 4-ethynyl-l,3,5-trimethylpyrazole undergo
such transformations under the reaction conditions and starting material were returned near to
quantity yield. Moreover, 4-bromoethynyl-l,3,5-trlmethyl- and 4-iodoethynyl-l,3,5trlmethylpyrazole with sodium amide in ammonia exchange the halogen for metal almost
quantltatlvely and in this respect are similar to phenylchloroacetylene (Scheme 116).
Hal
C
C
N
N
CH
C
1. NaNH2, NH3
2. H2O
N
N
Hal = Br, I
Scheme 116
A scheme of mechanism was proposed to involve successive or synchronous elimination of a
proton and chloride ion from the 5-methyl and from the chloroethynyl group attached to it,
followed by addition of the nucleophile (NH3) to the intermediate bipolar carbene ion stabilized
by conjugation (Scheme 117).
101
Cl
Cl
C
R
N
C
R
NH 2-
N
N
R
C
-Cl -
CH 2-
N
N
C-
C
C
C
N
R
N
CH 2
C
CH 2+
N
CH
R
NH 3
C
NH 2
N
N
Scheme 117
It should be noticed that N-unsubstituted 4-chloroethynyl-3,5-dimethylpyrazole under action
of both NaNH2 and n-butyllithium leads only to 4-ethynyl-3,5-dimethylpyrazole (69IZV927).
Cl
C
C
N
CH
1. NaNH 2
N
2. H2O
N
H
C
N
H
Scheme 118
6. Transhalogenation
By another pathway occurs the reaction of NaNH2 with pyrazolylchloroacetylenes in the
absence of methyl group in 5 position of ring. The 4- and the 3-chloroethynyl-1-methylpyrazoles
in the absence of 5-CH3 undergo isomerization with migration of the halogen atom to position 5
of the pyrazole ring under action of NaNH2 in liquid NH3. Rearrangement of 3-chloroethynyl-1methylpyrazole 54 gives 3-ethynyl-5-chloro-l-methylpyrazole 55 in 70% yield and about 25% of
3-ethynyl-1-methylpyrazole 56 (76IZV2148) (Scheme 119).
Cl
C
CH
C
1. NaNH 2, NH 3
N
N
2. H2O
CH
C
Cl
54
N
55
N
C
+
N
N
56
Scheme 119
From 4-chloroethynyl-l,3-dimethylpyrazole was obtained 80% of 4-ethynyl-5-chloro-l,3dimethylpyrazole. There is simultaneous formation about of 10% of 4-ethynyl-l,3dimethylpyrazole (76IZV2148, 77IZV2306) (Scheme 120).
102
Cl
C
R
N
CH
R
C
1. NaNH2, NH3
N
2. H2O
N
57, 58
CH
R
C
+
N
Cl
C
N
57, 59, 61 R = H,
58, 60, 62 R = CH3
N
61, 62
59, 60
Scheme 120
In order to establish the nature of the chlorine migration (intramolecular or intermolecular)
rearrangement of 54 was carried out in the presence of 4-(phenylethynyl)-l,3-dimethylpyrazole
55 (molar ratio of 54:55 = 2). About 40% of the chlorine migrates to 5 position of the acceptor
molecule 55.
Cl
Ph
C
C
N
C
+
N
58
Ph
C
N
N
C
1. NaNH 2, NH 3
2. H2O
63
CH
C
N
C
+
N
64
Cl
N
N
Cl
60
and dehalogenation products
Scheme 121
It means this rearrangement is intermolecular and reminds the base-induced halogen
migration in aromatic rings known in the halobenzene as the halogen dance (72ACR139;
73RTC245). Authors supposed the next mechanism (77IZV2306) (Scheme 122). The 4(chloroethynyl)-5-chloro-1-dimethylpyrazole 65 is the key intermediate. It is generated by
nucleophilic attack by pyrazolyl anion 58a on the positive halogen atom of the starting chloride
58. Interaction between dicloride 65 and anion 58a, leads to exchanges halogen from the side
chain for metal and formation of the final reaction product as acatylide 60a. At the same time
halogenation of 58a regenerates 65, therefore the rearrangement is a chain reaction in which the
reaction of 65 with 58a represents chain propagation. Chain is interrupting by the reaction of 65
with NaNH2.
103
Cl
Cl
C
C
C
C
NaNH 2
N
N
N
NH 3
58
58a
Cl
Cl
C
+
N
58a
N
58
C
C
C
Cl
N
65
N
58a
+
N
Cl
N
Cl
C
Na +
C
NaNH 2
Cl
N
65
C
65
Cl
C
60a
C
N
Na +
C
Cl
N
N
C
Na +
N
N
62a
Cl
+
N
+
Cl
N
Na +
C
65
Cl
C
C
C
N
C
N
C
C
Na +
N
Cl
C
C
N
Na +
N
+
N
N
ClNH 2
Cl
60a
Scheme 122
Next experiment supports this mechanism. The interaction of 58 in presence of 5-chloro-4chloroethynylpyrazole 65 (8 mol %) containing a 36Cl radiolabel in CCCl gives the product 60
containing 84% of 36Cl. Taking into account that a small amount of the 36Cl is lost in the
dechlorination of 65 by NaNH2, it indubitably confirms that diclhoride 65 is the intermediacy in
the rearrangement. Thus, the reaction occurs by a chain heterolytic mechanism and accompanied
by partial dehalogenation of the starting chloroacetylene to yield corresponding
ethynylpyrazole(77IZV2306).
The halogen migration is completely suppressed by halogen-metal exchange when the
chloroethynyl group is in position 5 of the pyrazole ring. The concentrations of 3-pyrazolyl- and
4-pyrazolyl anions are probably small, and they cannot compete with NH2 anions for chlorine
bonded to the acecylenic carbon.
4-Iodoethynyl and 4-bromoethynyl-1,3-dimethylpyrazole were tested later for comparison of
the migratory capacity of halogens in this transformation. This investigation showed that the
tendency of these halogeno derivatives towards isomerization decreases in going from chloro to
iodo compounds (79IZV2306).
104
TABLE XXV
Reactions of Halogenoethynyl-1-methyl-pyrazoles with NaNH2.
Starting
compound
Alkynylpyrazoles
Structural
formula
M.p. (oC)
Yield
(%)
References
71-72
(petroleum
ether)
68a
76IZV2148
51.5-52
(petroleum
ether)
80b
C7H7BrN2
78-79
(subl.)
17c
77IZV2306
C7H9N3
47-47.5
(petroleum
ether)
80
76IZV2292
C8H11N3
76-76.5
(petroleum
ether)
80
76IZV2292
85
73IZV2166
C6H6N2
d
76
77IZV2306
C7H8N2
e
-
77IZV2306
C8H10N2
f
83
X = Br
76IZV2292
Formula
index
Transhalogenation
N N
N
N
C C Cl
C C Cl
5-Chloro-3-ethynyl-1methyl-1H-pyrazole
5-Chloro-4-ethynyl1,3-dimethyl-1Hpyrazole
Cl
C6H5ClN2
N N
C CH
C7H7ClN2
N
N
C CH
77IZV2306
76IZV2148
77IZV2306
Cl
N
N
C C Br
5-Bromo-4-ethynyl1,3-dimethyl-1Hpyrazole
N
N
C CH
Br
Cineamination
N
N
N
N
C C Cl
C C Cl
C-(4-Ethynyl-2methyl-2H-pyrazol-3yl)-methylamine
C-(4-Ethynyl-2,5dimethyl-2H-pyrazol3-yl)-methylamine
N
N
C CH
NH 2
N
N
C CH
NH2
Halogen-metal exchange
N N
N
N
N
N
a
C C Cl
C C I
C C X
5-Ethynyl-1-methyl1H-pyrazole
4-Ethynyl-1,3dimethyl-1H-pyrazole
4-Ethynyl-1,3,5trimethyl-1H-pyrazole
N N
N
N
N
N
C CH
C CH
C CH
Together with 26% of 3-ethynyl-1-methylpyrazole.
There is simultaneous formation of 8% of 4-ethynyl-1,3-dimethylpyrazole.
c
Major product is 4-ethynyl-1,3-dimethylpyrazole.
d
Described in 69IZV2546.
e
Described in 76IZV2292.
f
Described in 69KGS1055.
b
88
X=I
105
D. Heterocyclizations of vicinal functionally substituted pyrazolylacetylenes
Castro et al. (63JOC3313) in 1963 has first studied the intramolecular O-H and N-H addition
via triple bond in the aromatic series. Russian researchers in the 70s-90s (81IZV902;
85IZV1367; 86TH1; 99JCS(P1)3721) performed the systematic study of the regularities of the
intramolecular heterocyclization of functionally substituted compounds using pyrazole
acetylenic derivatives as an example. These studies revealed substantial differences in both the
easiness and direction of isomerization in the series of benzene and pyrazole. Since this
comparative study allows one to estimate the specificity or general features in the behavior of
five- and six-membered substrates in reactions of heterocyclization, we have used this approach
to write this part.
1. Aminopyrazolylacetylenes
Intramolecular cyclization via addition of amino group to the triple bond in oacetylenylanilines is a method for synthesizing substituted indoles. Castro et al. have established
that the products of either substitution (acetylenylanilines) or cyclization (indoles) can be
obtained from o-halogenanilines and copper acetylenides (63JOC2163; 69JAC6464;
66JOC4071).
R1
N
R2
Cu C C R1
DMF
I
NHR 2
Cu C C R1
pyridine
C
C
R1
NHR 2
Scheme 123
In (83IZV688), the cyclocondensation of iodaminopyrazole with copper acetylides and the
cyclization of aminopyrazolelylacetylene with different mutual arrangement in the ring of
interacting groups have been studied.
It has been revealed that the annelation of the pyrazole with pyrrole ring is difficult,
probably, for steric reasons. All attempts to cyclize 3-amino- and 5-amino-4-acetylenylpyrazole
have failed. For example, upon long heating of 5-amino-4-acetylenylpyrazole 68 in DMF in the
presence of CuI and (or) CuCCPh a side transformations and resinification occur. The side
processes were suppressed by acylation of aminogroup and substitution of DMF by indifferent
cyclohexane. However, 80-90% of starting compounds returned after the heating of acylamine
67 in the presence of CuI in DMF at 110-145oC for 15 h or amine 68 in cyclohexane at 80oC (30
h). However, cross-coupling of iodopyrazole 36 with copper p-phenylbenzoylacetylide 41 gave
pyrrolo[2,3-c]pyrazole 42 directly; presumably, cyclisation is aided by the ketone group.
106
Ph
C
I
C
no cyclization
Cu C C Ph
N
N
Alk
NHAc
36 Alk = Et,
66 Alk = Me
N
pyridine
N
Me
NHR 1
67 R1 = Ac
68 R1 = H
O
Cu C C
pyridine
Ph
41
O
N
N
Et
N
Ac
Ph
42
Scheme 124
The authors assumed that the failure of cyclization of 3-amino- and 5-amino-4acetylenylpyrazole derivatives is due to both the decreased nucleophility of amino-groups in
acceptors positions 3 and 5 of the pyrazole ring and the smallest electrophility of triple bond
carbons in position 4 of the cycle.
As a substrate, it was chosen 4-amino-5-acetylenylpyrazole 71, the position of interacting
groups in which is most favorable for intramolecular cyclization. Indeed, 4-amino-1,3-dimethyl5-phenylethynylpyrazole 71 isomerized into 1,3-dimethyl-5-phenylpyrrolo[3,2-c]pyrazole 70 in
65% yield under heating in DMF for 4 h in the presence of CuI (83IZV688). The authors have
noticed that the cyclization of 71 is accelerated by the addition of CuCCPh.
Pyrrolopyrazole 70 can be also produced by direct cyclocondensation of iodide 69 with
acetylide CuCCPh (2 h, yield 38%).
NH2
N
N
69
I
H
N
Cu C C Ph
DMF
N
Ph
NH 2
Cu C C Ph (cat.)
DMF
N
70
N
N
C C
Ph
71
Scheme 125
Attempts were made to perform heterocyclization with 4-phenylethynyl- and 4-ethynyl-5aminomethyl-1,3-dimethylpyrazole where, on the one side, a strained six-membered cycle can
form, and, on the other side, the aliphatic amino-group is more nucleophilic than the aromatic
(Scheme 124). However, all attempts to cyclize the ethynylpyrazole and its phenyl analog have
failed (86TH1).
107
R
C
C
N
CuI
no cyclization
NH 2
DMF
N
Me
R = H, Ph
Scheme 126
2. Nitroacetylenylpyrazoles
Cyclization of o-nitroacetylenylbenzenes and cyclocondensation of o-iodnitrobenzene with
copper acetylides are widely used to produce isatogens (69JCS2453, 69MI2; 79JHC221). The
nitro-group can be either in the acetylide or halide components.
Iodoarenes and acetylides can bear substituents both electron-releasing and withdrawing
character. Using reaction between copper o-nitrophenylacetylide and aryliodide in pyridine it is
shown that depending on the structure of arylhalide and the process duration, one can obtain
tolanes, isatogens or their mixture (69MI2).
In the case of noncyclized derivatives of the aromatic series (nitrotolanes), isotagen is
obtained by either the longer heating of a substrate in pyridine, or photochemical (sun rays) or
catalytic action (69MI2).
O
I
2
R
Cu C C R1
Cu(I)
2
1
R
NO2
pyridine
N
R1
2
R
R
pyridine
C
C
NO2
O
Scheme 127
However, all attempts to isomerize vic-alkynylnitropyrazole into N-oxide in conditions of
thermal, catalytic or photochemical cyclization, have failed (86MI1).
NO2
R
C
C
N
no cyclization
N
Scheme 128
Since it is known that the ability of nitrotolane cyclization can depend on electron factors
(69MI2), 1,3-dimethyl-4-nitro-5-phenylethynylpyrazole whose acetylenic grouping is in the
most electronacceptor position of the pyrazole ring, i.e., favourable for nucleophilic addition,
was introduced into reaction of cyclization. Thus, 3-nitro-4-phenylethynyl- and 4-nitro-5phenylethynylpyrazoles as compared with o-nitrophenylethynylbenzene are incapable of
photochemical, thermal, or catalytic cyclization resulting in N-oxides. The inability of both
nitropyrazolylacetylenes and aminopyrazolylacetylenes to cyclize is caused by the great tension
of the condensed system consisting of two five-membered cycles.
3. Acetylenylpyrazolcarboxylic acids
The cyclization of o-halogenbenzoic acids with copper acetylides mainly leads to the
formation of five-membered lactones (66JOC4071; 69JAC6464) (Scheme 129). Only in the case
108
of the reaction of o-iodobenzoic with CuCCn-C3H7 the formation of a mixture of - and lactones is occurs (Scheme 130).
Ph
R
I
R
Cu C C Ph
O
COOH
O
Scheme 129
n-C3H7
I
n-C3H7
Cu C C n-C3H7
+
O
O
COOH
O
O
Scheme 130
Similar reactions in the pyrazole series occur by other way (86TH1). The iodine derivatives
of pyrazolecarboxylic acids were introduced into the reaction of cyclocondensation with all
possible variants of the combination of COOH group and halide and i.e. involved acetylenic
substituent. The existence of substrates with all possible variants of the arrangement of
interacting groups is necessary, because positions in the pyrazole cycle are non equivalent: 4 is
most nucleophilic, 5 is most electrophilic. This can affect the degree or even direction of the
polarization of the involved acetylenic group.
Since substituents at triple bond also determine its polarization, the copper acetylides
containing both electron-releasing and electron-withdrawing groups were introduced into
reaction of cyclocondensation (78IZV1175; 81IZV902).
The interaction between 4-iodpyrazole-3-carbocylic acid and copper acetylenides having
both donor and acceptor substituents at triple bond caused six- rather than five-membered
lactones as in the aromatic series (Scheme 131).
R1
O
HOOC
N
I
N
Cu C C R1
O
pyridine
N
N
R1 = Ph, n-Pr, CH2OMe
Scheme 131
The isomeric 4-iodpyrazole-5-carboxylic acid is cyclocondensed in a similar way.
Introduction of the additional methyl group into the cycle has no effect on the direction of
cycloaddition: 4-iod-1,3-dimethylpyrazole-5-carboxylic acid forms only -lactones (Scheme
132).
109
R2
I
N
Cu C C R1
COOH
N
pyridine
R1
R2
O
N
N
O
R1 = Ph, CH2OMe
R2 = H, Me
Scheme 132
Iodpyrazoles with the "reversed" arrangement of I and COOH, 5-iod-1,3-dimethylpyrazole-4carboxylic acid were also introduced into reaction of condensation with copper acetylides to give
the bicycles 79% and 66% yields, respectively (Scheme 133, Table XXVI).
O
COOH
O
Cu C C R
N
I
N
pyridine
R
N
N
R = Ph, n-Pr
Scheme 133
The reaction of the isomeric 3-iodo-1-methylpyrazole-4-carboxylic acid with copper phenyland p-amylacetylide also leads to the closure in the pyranopyrazole system, i.e., the direction of
lactonization differs from that of cyclocondensation of o-halogenobenzoic acids.
To verify the generality of cyclization of iodpyrazolecarboxylic acids, copper pphenylbenzoylacetylenide was involved in the reaction with 3-iodo-1-methylpyrazole-4carboxylic acid. The assumed intermediate alkynylpyrazolylcarboxilic acid has distribution of
the electron density, which is most favorable for closure in the five-membered cyclic ether. But
the reaction leads only to the -lactone close.
R
I
O
COOH
Cu C C R
N
N
pyridine
O
N
N
R = Ph, n-Pr, C(=O)C6H4Ph
Scheme 134
Thus, the cross-coupling of different iod-N-methylpyrazolecarboxylic acids with copper
acetylides leads to the closure of the six-membered ring.
Information on the mechanism of cyclocondensation is rather contradictory. According to
one of the hypotheses, both the condensation of arylhalides with copper acetylenides and the
cyclization occur in the same copper complex (63JOC2163, 63JOC3313). An alternative twostage reaction route has also been considered: condensation followed by cyclization
(66JOC4071; 69JAC6464). However, in the literature there are no rigid evidence for this
assumption and information on the reaction of acetylenylsubstituted acids in conditions of
acetylenide synthesis of feasible intermediates.
For this reason the heterocyclization of acetylenic derivatives of pyrazolecarboxylic acids
with different mutual arrangement in the cycle of interacting groups was studied. The reaction is
110
carried out in boiling pyridine in the presence of catalytic amounts of PhCCCu (81IZV1342). 4Acetylenyl-1-methylpyrazole-5-carboxylic acids (Scheme 135) are fully isomerized during 20
min. into the pyranopyrazoles in 62-84% yields, respectively.
The cyclocondensation of 4-iod-1-methylpyrazole-5-carboxylic acid with PhCCCu under
similar conditions is over only in 1.5 h. Thus, the cyclization of the 4-phenylethynyl-1methylpyrazole-5-carboxylic acids and the cyclocondensation of the iodine acid with PhCCCu
give the same products: pyranopyrazoles. However, the formation rate of the first reaction is
much higher.
R
C
R
C
N
Cu C C Ph (cat.)
COOH
N
pyridine
R = Ph, CH2OMe, H, H2C N
N
O
N
O
O
Scheme 135
The regularities of heterocyclization for 4-acetylenyl-1-methylpyrazole-3-carboxylic acids
and 4-acetylenyl-1-methylpyrazole-5-acrboxylic acids are the same. Isomeric 1-methyl-4phenylethynylpyrazole-3-carboxylic acid forms -lactone  2-methyl-oxo-5-phenylpyrano[3,4c]pyrazole in 71% yield (20 min) (Scheme 136). The same ester is obtained by acetylenic
condensation (3 h) of 4-iodo-1-methylpyrazole-3-carboxylic with copper phenylacetylide.
Ph
Ph
C
HOOC
C
N
O
Cu C C Ph (cat.)
O
N
pyridine
N
N
Scheme 136
3-Acetylenyl-1,5-dimethylpyrazole-4-carbocylic acids (Scheme 137) are isomerized in a
similar way. The yield of 6-substituted 2,3-dimethyl-4-oxopyrano[4,3-c]pyrazoles is more than
80% (0.5 h).
R
R
C
C
N
COOH
N
O
O
Cu C C Ph (cat.)
N
pyridine
R = Ph, CH2OMe, H2C N
N
O
Scheme 137
Thus, the vic-acetylenylpyrazolcarboxylic acids are isomerized into pyranoazoles in boiling
pyridine (2030 min) with catalytic amounts of copper acetylide. The acetylide condensation of
corresponding iodpyrazolocarboxylic acids is followed by cyclization into the same -lactones
but with a lower rate (2-8 h).
111
The obtained results, i.e., agreement between the directions of cyclization and acetylenic
cyclocondensation of iodazolecarboxylic acids and much shorter duration of the first reaction,
confirm the assumption of the two-stage mechanism of cyclocondensation (66JOC4071;
69JAC6464).
Using of a suspension of silver salts in alcohol or acetonitrile for isomerization of tolane-2carboxylic acid leads to changing of the ratio between the resulting - and -lactones to
preferable formation of the five-membered cyclic ester (65JACS742). However, the
heterocyclization of 4-phenylethynylpyrazole-3- and 4-phenylethynylpyrazole-5-carboxylic acid
in alcohol or acetonitrile solutions in the presence of AgNO3 caused once again the closure of the
six-membeterd lactones.
112
TABLE XXVI
Pyranopyrazoles Prepared by Cyclocondensation of vic-Iodopyrazolecarboxylic Acid with
Copper(I) Acetylides.
Pyranopyrazoles
5-Methoxymethyl-2methyl-2H-pyrano[3,4c]pyrazol-7-one
5-Methoxymethyl-1methyl-1H-pyrano[3,4c]pyrazol-7-onea
Formula
index
M.p. (oC)
Yield
(%)
References
C9H10N2O3
115.5-116.5
(benzene)
58
78IZV1175
O
C9H10N2O3
110-111
(benzene –
petroleum
ether)
75
81IZV1342
n-Pr
C10H12N2O2
64-65 (benzene
- hexane)
58
78IZV1175
C10H12N2O3
119.5-120
(benzene)
60
78IZV1175
C11H14N2O2
75-76
(petroleum
ether)
61
78IZV1175
C11H14N2O2
104-105
(hexane)
66
81IZV902
C13H10N2O2
174-175
(EtOH)
61
78IZV1175
C13H10N2O2
150.5-151.5
(EtOH)
75
78IZV1175
C13H18N2O2
53-54
(petroleum
ether)
67
81IZV902
C14H12N2O2
149.5-150.5
(benzene –
petroleum
ether)
58
78IZV1175
C14H12N2O2
217-218
(EtOH)
78
81IZV902
Structural formula
O
N
O
N
O
N
O
N
O
2-Methyl-5-propyl-2Hpyrano[3,4-c]pyrazol-7one
N
O
N
O
5-Methoxymethyl-1,3dimethyl-1H-pyrano[3,4c]pyrazol-7-one
O
N
O
N
O
1,3-Dimethyl-5-propyl1H-pyrano[3,4-c]pyrazol7-one
n-Pr
N
O
N
O
1,3-Dimethyl-6-propyl1H-pyrano[4,3-c]pyrazol4-one
O
O
N
N
2-Methyl-5-phenyl-2Hpyrano[3,4-c]pyrazol-7oneb
n-Pr
N
O
N
O
1-Methyl-5-phenyl-1Hpyrano[3,4-c]pyrazol-7onec
N
O
N
O
2,3-Dimethyl-6-propyl2H-pyrano[4,3-c]pyrazol4-one
n-Pr
N
N
O
O
1,3-Dimethyl-5-phenyl1H-pyrano[3,4-c]pyrazol7-one
N
O
N
O
1,3-Dimethyl-6-phenyl1H-pyrano[4,3-c]pyrazol4-one
O
O
N
N
113
Pyranopyrazoles
Structural formula
2,3-Dimethyl-6-phenyl2H-pyrano[4,3-c]pyrazol4-oned
Formula
index
M.p. (oC)
Yield
(%)
References
C14H12N2O2
210-211
(EtOH)
66
81IZV902
C21H16N2O3
184-185
(EtOH)
30
86TH1
N
N
O
O
6-(Biphenyl-4-carbonyl)2,3-dimethyl-2Hpyrano[4,3-c]pyrazol-4one
O
N
N
O
O
a
The pyranopyrazole was also prepared by cyclization of 4-(3-methoxy-prop-1-ynyl)-2-methyl-2H-pyrazole-3carboxylic acid (CuCCPh as cat., pyridine, boiling) in 84% yield (81IZV1342).
b
The pyranopyrazole was also prepared by cyclization of 1-methyl-4-phenylethynyl-1H-pyrazole-3-carboxylic acid
(CuCCPh as cat., pyridine, boiling, yield 70%; AgNO3, EtOH or MeCN, 60 oC, yields 80-85%) (81IZV1342).
c
The pyranopyrazole was also prepared by cyclization of 2-methyl-4-phenylethynyl-2H-pyrazole-3-carboxylic acid
(CuCCPh as cat., pyridine, boiling, yield 70%; AgNO3, EtOH or MeCN, 60 oC, yields 80-85%) (81IZV1342).
d
The pyranopyrazole was also prepared by cyclization of 1,5-dimethyl-3-phenylethynyl-1H-pyrazole-4-carboxylic
acid (CuCCPh as cat., pyridine, boiling) in 100% yield (81IZV1342).
114
TABLE XXVII
Pyranopyrazoles Prepared by Cyclization of Vicinal (Alkyn-1-yl)pyrazolecarboxylic acid.a
Pyranopyrazoles
Structural formula
1-Methyl-1H-pyrano[3,4c]pyrazol-7-one
N
Formula
index
M.p. (oC)
Yield
(%)
References
C7H6N2O2
126-127 (benzene
– petroleum
ether)
62
81IZV1342
C10H12N2O3
119-120 (hexane)
96
81IZV1342
C12H15N3O3
136.5-137.5
(benzene –
petroleum ether)
79
81IZV1342
C13H17N3O3
153-154
(dioxane)
80
81IZV1342
O
N
O
N
6-Methoxymethyl-2,3dimethyl-2H-pyrano[4,3c]pyrazol-4-one
O
N
O
O
1-Methyl-5-morpholin-4ylmethyl-1H-pyrano[3,4c]pyrazol-7-one
2,3-Dimethyl-6-morpholin-4ylmethyl-2H-pyrano[4,3c]pyrazol-4-one
N
N
O
N
O
O
N
N
N
O
O
O
a
Reaction conditions: CuCCPh as cat., pyridine, boiling.
115
4. Amides of acetylenylpyrazolcarboxylic acids
An unusual cyclization, which results in carbocycles rather than the hetero ones, was
described in (69JCS2453). The reaction between o-iodbenzamides and copper phenylacetylides
in pyridine leads to indenone (74%) rather than to tolane (Scheme 138).
O
I
Cu C C Ph
Ph
O
pyridine
NH2
NH2
Scheme 138
Moreover, when carbamino- and nitro-groups are simultaneously in the ortho-position to
triple bond, isomerization occurs only with participation of the amide group.
O2N
Cu C C
I
C
O
O
C
NO 2
NO 2
Cu(I)
O
pyridine
NH 2
NH 2
NH 2
Scheme 139
Such an easy isomerization of acetylenylbenzoic acid amides assumed the production of the
five-membered nonaromatic cycle condensed with the pyrazole ring. However, the pyrazole
analog of o-iodbenzamide (amide of 4-iod-1-methylpyrazole-3-cacrboxylic acid) formed under
the heating with CuCCPh in pyridine for 9 h, only the disubstituted acetylene in 71% yield. It
coincided in its physical and spectroscopic data with the compound obtained from the
corresponding acid by a successive action of SOCL2 and NH3 (90IZV2089) (Scheme 140).
Ph
H2NOC
N
C
I
Cu C C Ph
N
pyridine
H2NOC
N
C
N
Ph
1. SOCl 2
2. NH 3
C
HOOC
N
C
N
Scheme 140
Interaction between CuCCPh and iodamide with the "reverse" arrangement of the functions
(amide of 3-iod-1,5-dimethylpyrazole-4-carboxylic acid) gave a similar result. Formation of the
bicyclic compound was not observed. The yield of the acetylenylpyrazole was 62% (Scheme
141).
116
Ph
I
CONH 2
N
Cu C C Ph
C
C
N
pyridine
N
CONH 2
N
Scheme 141
The unusual character of cyclization (69JCS2453) and the results obtained by other authors
(66JOC4071) for condensation of o-iodbenzamide with CuCCPh has made the author (86TH1)
reproduces this reaction. When repeating the Bond and Huper (69JCS2453) synthesis, it was
found no traces of the described high-melting dark red substance and obtained only tolane-2carboxilic acid amide (yield 65%), the white crystals with a melting temperature of 156-157oC
which coincided with the results of Castro et al. (66JOC4071). Thus, in conditions of acetylide
synthesis, o-iodbenzamide forms no bicyclic product.
Nevertheless, the adjacent position of amide and acetylenic groups was used in another type
of heterocyclization. The nitrogen atom in the amide group is a weak nucleophil. Therefore, the
N-anion should be generated by potassium ethylate. There are two possible variants of
nucleophilic addition to triple bond. Only one is realized, i.e., the formation of -lactame. Under
7-h heating in EtOH in the presence of KOH, amide 72 isomerized into the known isoindoline 73
in 80% yield.
I
C
Cu C C Ph
C
Ph
Ph
KOH
NH
pyridine
CONH 2
EtOH
CONH 2
O
72
73
Scheme 142
Intramolecular addition of the amide group to the triple bond in pyrazoles is more difficult,
and results in closure of the -lactam rather than the -lactam ring. The reaction time of the 4phenylethynylpyrazole-3-carboxylic acid amide under the same is extended to 42 h (Scheme
143).
Ph
C
C
Ph
CONH 2
NH
O
KOH
N
N
EtOH
N
N
Scheme 143
The cyclization of 1-methyl-4-phenylethynyl-1H-pyrazole-3-carboxylic acid amide, in which
the acetylenic substituent is located in the -electron-rich position of the heterocycle, is the only
complete after 107 h (Scheme 144) (90IZV2089).
117
Ph
Ph
C
H2NOC
N
NH
C
O
KOH
N
EtOH
Scheme 144
N
N
118
TABLE XXVIII
1-Methyl-1,6-dihydro-pyrazolo[3,4-c]pyridin-7-ones Prepared by Cyclization of Vicinal 4(Alkyn-1-yl)pyrazole-5-carboxylic acid Amides.a
Alkynylpyrazoles
Structural formula
2,3-Dimethyl-6-phenyl-2,5dihydro-pyrazolo[4,3-c]pyridin4-one
Formula
index
M.p. (oC)
Yield
(%)
References
C14H13N3O
227-228 (ethanol)
70
90IZV2089
C13H11N3O
312-313 (ethanol)
75
90IZV2089
C15H15N3O2
229-230 (ethanol
 ethylacetate)
85
90IZV2089
N
N
NH
O
2-Methyl-5-phenyl-2,6-dihydropyrazolo[3,4-c]pyridin-7-one
N
NH
N
O
1,3-Dimethyl-6-phenoxymethyl1,5-dihydro-pyrazolo[4,3c]pyridin-4-one
a
O
NH
N
N
Reaction conditions: KOH, ethanol, boiling.
O
Ph
119
5. Hydrazides of acetylenylpyrazolcarboxylic acids
Hydrazides of vicinal acetylene-substituted derivatives of benzoic and azolcarboxylic acids
are the promising intermediate compounds because they allow one to realize cyclization via both
- and -carbon atoms of a multiple bond involving both amine and amide nitrogen atoms.
Besides, the hydrazides of aromatic and heteroaromatic acids are convenient objects for testing
the proposal of the advantageous formation of a five-membered cycle condensed with a benzene
nucleus and the six-membered one condensed the five-membered azoles.
The cyclization of hydrazides of aromatic and heteroaromatic acids is likely to give four most
probable products: diazepines, diazines, -N-aminoalactames and -N-aminolactames.
R
R
N
NH
N
NH
O
C
C
R
O
NHNH 2
R
O
R
N
N NH 2
NH 2
O
O
Scheme 145
The hydrazides of acetylenylbenzoic acids are heterocyclized under standard conditions for
producing them from corresponding esters. The hydrazide of tolane-2-carboxylic acid resulting
from the boiling of ester 74 (R = Ph) with excess NH2NH2·H2O in ethanol was then cyclized in
70% yield into 2-amino-3-benzylidene-2,3-dihydro-isoindol-1-one 75. In condensation of
methylbenzoate 74 with hydrazine-hydrate in ethyl alcohol even at 20oC, -N-aminolactame is
the main reaction product (yield 50%). The easiness of heterocyclization and the attack of the C atom of CC by amide nitrogen whose nucleophility is smaller than the amine one, is,
probably, caused by the fact that hydrazine-hydrate acts in this case as a base generating the
NH2-N-CO anion. Indeed, in the alcohol KOH solution the rate increases and the isomerization
direction remains the same.
Another direction is realized upon cyclization of hydrazides of benzenecarboxylic acids in
the presence of CuCl in inert atmosphere in DMF. But only the cyclization of hydrazide 76 (R =
H) in conditions of copper catalysis makes it possible to isolate compound 77 (yield 20%). Other
hydrazides of acetylenylbenzoic acids react unambiguously giving a complex mixture of
products (Scheme 146) (85IZV1367, 85MI2).
120
C
R
R
C
N2H4
N NH 2
EtOH
COOMe
O
R = Ph, CH2OPh
74
75
CuCl,
DMF
C
C
R
R
CuCl
N
NH
DMF
CONHNH 2
O
R=H
76
77
Scheme 146
In conditions of base catalysis, the acetylenylpyrazolecarboxylic acid hydrazides as opposite
to benzene derivatives are more difficult to cyclize as compared with the benzoic acid
derivatives and are isomerized only after the heating in alcohol in the presence of KOH forming
not five- but six-membered lactames. The yields of pyridopyrazoles were 8090% (Scheme 147)
(85IZV1367, 85MI2).
R
C
R
C
N
KOH
NHNH 2
EtOH
N
N
N NH 2
N
O
O
R = Ph, CH2OPh, H2C N
O
Scheme 147
Another direction is realized upon cyclization of hydrazides pyrazolcarboxylic acids in the
presence of CuCl in inert atmosphere in DMF. When acetylenylcarbocylic acids are heated in the
presence of CuCl in DMF, the orientation of cycloaddition of hydrazide group differs from that
observed for cyclization in basic conditions. The cycloisomerization of hydrazides 78 in boiling
DMF lead to corresponding pyrazolopyridazines 79 in 60-71% yields. (Scheme 148)
(85IZV1367, 85MI2).
R
R
C
C
N
N
NH
CuCl
NHNH 2
N
DMF
N
N
O
78
79
R = Ph, CH2OPh
Scheme 148
O
121
The cycloisomerization of hydrazide 80, catalyzed by CuCl, gives the diazine 81 and -Naminolactame 82 and unexpected 6,7-dihydro-4-vinyl-1-methylpyrazolo/3.4-d/pyridazine-7 83
(85MI2).
N
C
C
N
N
O
N
NH
CuCl
NHNH 2
N
DMF
N
N
O
80
O
N
+
O
81
N
N NH2
N
82
O
O
+
N
N
NH
N
O
83
Scheme 149
The data obtained allow us to make some generalizations for the heterocyclization of
hydrazides of the vicinal acetylenic derivatives of pyrazolecarboxylic acids. Under the action of
bases, these compounds cyclize into - and -N-aminolactames, i.e. always form a bicyclic
system consisting of five- and six-membered cycles.
122
TABLE XXIX
6-Amino-1-methyl-1,6-dihydro-pyrazolo[3,4-c]pyridin-7-ones Prepared by Cyclization of 4(Alkyn-1-yl)pyrazole-5-carboxylic acid Hydrazides.a
Alkynylpyrazoles
Structural formula
O
6-Amino-1-methyl-5-morpholin-4ylmethyl-1,6-dihydropyrazolo[3,4-c]pyridin-7-one
Formula
index
M.p. (oC)
Yield
(%)
References
C12H17N5O2
148-149
(EtOH)
90
85MI2
C13H12N4O
129.5-130.5
(EtOH)
80
85IZV1367
C14H14N4O2
183-184
(EtOH)
90
85MI2
N
N
N
N
NH 2
O
6-Amino-1-methyl-5-phenyl-1,6dihydro-pyrazolo[3,4-c]pyridin-7one
N
N
N
NH 2
O
6-Amino-1-methyl-5phenoxymethyl-1,6-dihydropyrazolo[3,4-c]pyridin-7-one
O
N
N
N
NH 2
O
a
Reaction conditions: KOH, ethanol, boiling.
TABLE XXX
1-Methyl-1,6-dihydro-pyrazolo[3,4-d]pyridazin-7-ones Prepared by Cyclization of 4-(Alkyn1-yl)pyrazole-5-carboxylic acid Hydrazides.a
Alkynylpyrazoles
1-Methyl-4-(2-morpholin-4-yl-ethyl)1,6-dihydro-pyrazolo[3,4-d]pyridazin7-oneb
Structural formula
N
N
NH
N
N
Formula
index
M.p. (oC)
Yield
(%)
References
C12H17N5O2
193-194
(ethanol)
18
85MI2
C13H12N4O
197-198
(ethanol)
70
85IZV1367
C14H14N4O2
153-154
(ethanol)
60
85MI2
O
O
4-Benzyl-1-methyl-1,6-dihydropyrazolo[3,4-d]pyridazin-7-one
N
NH
N
N
O
1-Methyl-4-(2-phenoxy-ethyl)-1,6dihydro-pyrazolo[3,4-d]pyridazin-7one
O
N
NH
N
N
O
a
Reaction conditions: CuCCPh as cat., DMF, 150-155oC.
b
Other compounds isolated were 1-methyl-4-vinyl-1,6-dihydro-pyrazolo[3,4-d]pyridazin-7-one (C8H8N4O, yield
11%, m.p. 172-173oC (from ethanol)).
123
6. Diazonium salts of acetylenylpyrazoles
Vasilevsky et al (94SC1733) have demonstrated that the classical Richter reaction (79MI1),
the intramolecular cyclisation of 2-alkynylaryldiazonium salts to give cinnolines, can be applied
to the synthesis of not only 4-hydroxy- but also 4-bromo- and 4-chlorocinnolines. By attempting
to extend the applicability of this reaction, it was found that the behavior of
alkynylpyrazolediazonium chlorides differs from that of their benzene analogues. Thus,
cyclisation of 1,3-dimethyl-5-phenylethynylpyrazole-4-diazonium salts does not lead to the
expected 4-hydroxydiazines (95LA775) and, under similar conditions, the isomeric 1,5dimethyl-3-phenyl-ethynylpyrazole-4-diazonium chloride does not even react via a Richter
mechanism (96MC190).
In general, it is difficult to predict the outcome of cyclisations of alkynylpyrazolediazonium
salts, even with closely related arrangements of functional groups since reaction can occur at
both the a- and -carbon atoms of the acetylenic substituent. Moreover, it is known that the
electrophilicity of the diazo group and the nucleophilicity of a triple bond depend markedly on
their positions in the pyrazole ring and that this can affect both the course and ease of cyclisation
and even its viability (83IZV688).
In the first examples, diazotization of the 4-alkynyl-5-amino-3-methyl-l-alkylpyrazoles 84 in
hydrochloric or hydrobromic acid at 15°C led to the corresponding alkynylpyrazolediazonium
salts which underwent facile cyclisation upon warming to 25-30°C to give fair to good yields of
the 4-chloro-1-alkyl-1H-pyrazolo[3,4-c]pyridazines or the corresponding 4-bromo derivative
respectively (95LA775; 98HC519; 99JCS(P1)3721).
R
Hal
C
C
N
R = Ph, 4-CH 3O-C6H4, (CH 2)5CH 3
HNO 2
NH 2
N
Alk
R
HHal
N
N
N
Alk
84
N
Hal = Cl, Br
Alk = Me, Et
85
Scheme 150
In contrast, the isomeric 5-alkynylpyrazole-4-diazonium chlorides cyclized only after heating
to 100105°C for 2 hours, to give good yields of the 1,3-dimethyl-7-chloro-lH-pyrazolo[4,3c]pyridazines 87 (98HC519; 99JCS(P1)3721) (Scheme 151).
NH 2
N
N
86
N
N Cl
HNO2
C C
HCl
R
N
N
C C
R
R = Ph, 4-CH3O-C6H4
N N
110 oC
N
R
N
Cl
87
Scheme 151
3-Alkynylpyrazole-4-diazonium chlorides derived from the corresponding aminopyrazoles
88 underwent cyclisation much more slowly than the isomeric derivatives (diazonium salt from
86) (concentrated HCl, 100105°C, 6 h). Surprisingly, the reaction products were identical to
compounds 87 formed by cyclisation of diazotized amines 86. Thus, the cyclisation of the
pyrazole-4-diazonium chlorides causes methyl group migration to the neighboring nitrogen atom
(98HC519; 99JCS(P1)3721) (Scheme 152).
124
R
C
Cl
110 oC
C
C
NH 2
C
N
N
N
N
C
HNO 2, HCl
N
N
-15 oC
N
N
R
R
N N
N
C
R
N
N
Cl
87
Cl
N
R = Ph, 4-CH3O-C6H4
NaHCO 3
R
88
N
C
Et3N
EtOH, 80 oC
R
C
H
N
C
N
N
N
N
N
C
N
N N
N
89
N
C
C
R
R
C
C
N N
N
N
R = Ph, 4-NO2-C6H4
90
Scheme 152
The behavior of aminopyrazole 88 (R = 4-NO2-C6H4) under these conditions was quite
different; diazotization using nitrous acid in concentrated hydrochloric acid gave rise to an
alkynylpyrazolediazonium chloride, which did not participate in the Richter reaction, probably
due to the electron-withdrawing effect of the nitro group. Instead, after neutralization of the
hydrochloric acid with sodium hydrogen carbonate, the methyl group at position 5 of the
pyrazole added to the diazonium group of a second molecule of the diazotized pyrazole. The
resulting diazonium chloride 89 (R = 4-NO2-C6H4) was cyclized in pyridine at 110°C to give the
pyrazolo[4,3-c]pyrazole 90 (R = 4-NO2-C6H4) (99JCS(P1)3721).
Because of the much lower reactivity of the diazonium salt, with respect to Richter
cyclisation, the same sequence could also be carried out starting with aminopyrazole 88 (R =
Ph). The azodiazonium salt 89 (R = Ph) was thus obtained by sequential diazotization and
neutralization of the diazotizing mixture at 5-10°C. The salt 89 (R = Ph) could be smoothly
cyclized in boiling ethanol in the presence of triethylamine to give the pyrazolo[4,3-c]pyrazole
90 (R = Ph) (96MC190; 99JCS(P1)3721).
To create a complete pattern of transformations of amino-acetylenes of the pyrazole series in
the Richter reaction, it was studied the cyclisations of 4-alkynylpyrazole-3-diazonium salts
containing no methyl groups at position 5 of the heterocycle, thus excluding the possibility of
intermolecular condensations between these and the diazonium functions. 4-Alkynyl-3aminopyrazoles 91 were diazotized under standard conditions. Heating the resulting
alkynylpyrazole-diazonium salts in the diazotization solution at 50-60°C caused cyclisation, to
give mainly the 5-substituted-4-hydroxy-2-methyl-2H-pyrazolo[3,4-c]pyridazines 92 together
with the 4-chloro or 4-bromo derivatives 93 as minor components (99JCS(P1)3721).
125
R
H2N
C
N
N
R
R
C
HNO 2, HHal
-15 oC to reflux
N
N
N
N
OH
N
N
N
91
R = Ph, 4-MeOC6H4
Hal
+
N
93
92
Hal = Cl, Br
Scheme 153
The difference in behaviour of 3-alkynylpyrazole-4- and 4-alkynylpyrazole-3-diazonium salts
[la and Ib respectively] upon Richter synthesis may be explained as follows (Scheme 154). The
cyclisation is assumed to be favoured by the aromaticity inherent in the newly-formed pyridazine
ring. In some cases, however, as for example upon cyclisation of vic-alkenyldiazonium salts, the
cyclic conjugated polyene is not formed at the initial stage of the reaction. In these cases, the
aromaticity (75MI1) of the transition state, arising from disrotatory electrocyclic cyclisation may
compensate for the energy losses upon approach of the reaction centres. Obviously, these
considerations may be extended to the cyclisation of vic-alkynyl-arenediazonium salts because in
the disrotatory process, the overlapping of orbitals in the ring plane is reached earlier than the overlapping of p-orbitals of both the -nitrogen atom of the diazonium group and the -carbon
atom of the triple bond. At the same time, the electrocyclic reactions of vic-acetylenic derivatives
of monocyclic arenediazonium salts may formally be realised by a second mechanism, via the 6electron 1,6-electrocyclic mechanism involving the entire aromatic cycle system. In the former
case, the energy of the transition state must be lower due to a higher level of aromaticity. In
examples of the cyclisation of 3-alkynylpyrazole-4- and 4-alkynylpyrazole-3-diazonium salts Ib,
a peculiarity of these substrates is the possibility that cyclisation via a 1,6-electrocyclic reaction,
depends upon the degree of double-bond character of the bond between carbon atoms in
positions 3 and 4 which, in turn, is determined by the contribution of resonance structures IIIa,b
to the true structure of the pyrazolediazonium salts. Due to the introduction of an electronacceptor diazonium group into position 4 of the ring, the contribution of resonance structures IIa
and IIIa is large, when compared to the contribution of structures IIb and IIIb to the true
structure of the corresponding diazonium salts. The difference is, probably, in the fact that in the
first case, the distribution of electron density favours the methyl cation migration towards the
neighboring nitrogen atom.
R1
N
N2
N
CH 3
Ia
R1
N
R1
N2
N
CH 3
N2
N
N
R1 =
N2
R
1
R
N2
N
N
Ib
N
II b
N
Cl
C C R2
R2
1
R
N2
10p-ER
N
R2
N
III a
II a
1
N N
6p-ER,
1,2~Me
N
N
III b
Scheme 154
N
N
N
N
OH
126
Thus, the Richter reaction of the series of alkynyl-aminopyrazoles opens up a route to haloderivatives of 1H-pyrazolo[3,4-c]pyridazines, 2H-pyrazolo[3,4-c]pyridazines and lHpyrazolo[4,3-c]pyridazines.
127
TABLE XXXI
Pyrazolopyridazines Prepared by Cyclization Followed by Diazotization of Vicinal (Alkyn-1yl)aminopyrazoles.
Alkynylpyrazoles
Structural formula
OH
2-Methyl-5-phenyl-2Hpyrazolo[3,4-c]pyridazin4-ol
Formula
index
M.p. (oC)
Yield
(%)
References
C12H10N4O
273-274
(dioxane)
91
99JCS(P1)3721
C12H9BrN4
256-257
(chloroform)
8.4
99JCS(P1)3721
C12H9ClN4
247-248
(chloroform)
1.9a
99JCS(P1)3721
C13H11BrN4
97-98 (benzene
- hexane)
77
95LA775
C13H11ClN4
111-113
(benzene hexane)
65
95LA775
C13H11ClN4
175-176 (1:1
benzene hexane)
82
99JCS(P1)3721
C13H12N4O2
284-285
(dioxane)
84
99JCS(P1)3721
C14H13BrN4
97-98 (1:1
benzene hexane)
77
99JCS(P1)3721
C14H13ClN4
88-89 (benzene
- hexane)
64
99JCS(P1)3721
C14H13ClN4O
186-187
(benzene hexane)
76
99JCS(P1)3721
oil
82
Ph
N
N
N
N
Br
4-Bromo-2-methyl-5phenyl-2H-pyrazolo[3,4c]pyridazine
Ph
N
N
N
N
Cl
4-Chloro-2-methyl-5phenyl-2H-pyrazolo[3,4c]pyridazine
Ph
N
N
N
N
Br
4-Bromo-1,3-dimethyl-5phenyl-1H-pyrazolo[3,4c]pyridazine
Ph
N
N
N
N
Cl
4-Chloro-1,3-dimethyl-5phenyl-1H-pyrazolo[3,4c]pyridazine
Ph
N
N
7-Chloro-1,3-dimethyl-6phenyl-1H-pyrazolo[4,3c]pyridazine
N
N
N
N
N
N
Ph
98519
Cl
5-(4-Methoxy-phenyl)-2methyl-2H-pyrazolo[3,4c]pyridazin-4-ol
N
N
N
N
Br
4-Bromo-1-ethyl-3methyl-5-phenyl-1Hpyrazolo[3,4-c]pyridazine
Ph
N
N
N
Ph
N
N
N
N
N
N
N
N
Cl
4-Chloro-1-ethyl-5-hexyl3-methyl-1Hpyrazolo[3,4-c]pyridazine
N
Cl
4-Chloro-1-ethyl-3methyl-5-phenyl-1Hpyrazolo[3,4-c]pyridazine
7-Chloro-6-(4-methoxyphenyl)-1,3-dimethyl-1Hpyrazolo[4,3-c]pyridazine
O
OH
O
Cl
C14H21ClN4
C6H13
N
N
98519
N
N
99JCS(P1)3721
128
Alkynylpyrazoles
4-Chloro-1-ethyl-5-(4methoxy-phenyl)-3methyl-1H-pyrazolo[3,4c]pyridazine
a
Structural formula
O
Cl
N
N
N
Formula
index
M.p. (oC)
Yield
(%)
References
C15H15ClN4O
106-107
(benzene hexane)
47
99JCS(P1)3721
N
Also prepared from 2-methyl-5-phenyl-2H-pyrazolo[3,4-c]pyridazin-4-ol with yield 79%.
129
The data obtained allow us to make some generalizations for the heterocyclization of the
functionally substituted acetylenic derivatives of the benzene and pyrazole series. Studies of the
heterocyclization of the functionally substituted acetylenic derivatives of substituted benzenes
and pyrazoles reveals noticeable differences in their reactivities.
Whereas the condensation of o-iodonitrobenzene with copper acetylenides is accompanied by
cyclization into isatogens, neither 4-iod-3-nitro- nor 5-iod-4-nitro-1,3-dimethylpyrazole give
cyclized products in conditions of acetylide synthesis. Moreover, nitropyrazolylphenylacetylene,
as compared with o-nitrotolane, is not undergone to thermal, catalytic or photochemical
isomerization to give to annelated five-membered cycles.
The intramolecular nucleophilic addition of amino group is typical for o-acetylenylanilines
that are readily cyclized into 2-substituted indoles. On contrary, 4-acetylenyl-3-amino- and -5aminopyrazoles are not able to be cyclized. However, when amino-groups are in position 4 of the
pyrazole cycle where their nucleophility is much higher, the formation of pyrrole ring occurs to
give the condensed system of two five-membered heterocycles. The decreased tendency of the
vicinal functionally substituted pyrazole acetylenic derivatives to cyclization with the closure of
the five-membered cycle is likely to depend on the higher strength of the annealed system of two
five-membered rings as compared with the system of five- and six-membered ring.
This tendency is especially manifested in compounds containing functional groups capable of
addition with the formation of both five- and six-membered cycles. It was shown that for amides
and hydrazides of azolcarboxylic acids, selectively, and for the acids with any arrangement of a
function and triple bond, properly, heterocyclization always leads to the closure of the sixmembered ring. Similar reactions in the benzoic series mainly lead to the formation of fivemembered cycles.
The intramolecular cyclisation of 2-alkynylaryldiazonium salts (Richter reaction) leads not
only to 4-hydroxy- but also 4-bromo- and 4-chlorocinnolines. The behavior of
alkynylpyrazolediazonium chlorides differs from that of their benzene analogues. The Richter
reaction of the series of alkynylaminopyrazoles gives only 4-halo-derivatives of 1Hpyrazolo[3,4-c]pyridazines and lH-pyrazolo[4,3-c]pyridazines, and mainly hydroxy derivatives
of 2H-pyrazolo[3,4-c]pyridazines.
Synthetically, the vicinal functionally substituted aryl- and hetarylacetylenes are the
promising intermediates for producing the different condensed heterocyclic compounds if taking
into account the fact that the polyfunctional groups can be involved in cyclization selectively.
IV. Structure, Spectra and Properties of Acetylenylpyrazoles
A. Molecular Dimensions
Molecular structure study has so far been published only for 3-(pyrazol-4-yl)propargyl
alcohole (98MO76) and 5-trimethylsilanyl-4-trimethylsilanylethynyl-1H-pyrazole-3-carboxylic
acid ethyl ester (88JOM247).
The X-ray crystal structure of 3-(pyrazol-4-yl)propargyl alcohole, R = 0.042, shows that the
N and O atoms are involved in chains of hydrogen bonds, running through the whole crystal,
which show proton disorder in a 1:1 ratio. The bond lengths and angles in the pyrazole moiety
display a quite symmetric pattern due to the proton disorder observed between both nitrogen
atoms. The ring is not significantly planar and the carbon atoms of the substituent deviate
progressively from its least-square plane. The CC bond length is slightly elongated (1.193(2)
Å) compared for the triple bond in organic compounds. Selected geometrical parameters (Å, o):
N(1)-N(2) 1.345(2), N(1)-C(5) 1.323(3), N(2)-C(3) 1.321(2), C(3)-C(4) 1.387(2), C(4)-C(5)
1.385(2); N(2)-N(1)-C(5) 108.6(2), N(1)-N(2)-C(3) 108.4(2), N(2)-C(3)-C(4) 109.7(1), C(3)C(4)-C(5) 103.9(1), N(1)-C(5)-C(4) 109.5(2); C(4)-C(alkyne) 1.425(2) (98MO76).
130
The X-ray crystal analysis of 5-trimethylsilanyl-4-trimethylsilanylethynyl-1H-pyrazole-3carboxylic acid ethyl ester was made only with R = 0.17 because of the crystals of the molecule
diffracted extremely weakly, and only a very limited data set were available. This means that
although the gross stereochemistry of the molecule has been determined, individual bond lengths
are not reliable (88JOM247).
C. IR Spectra
Parameters of IR spectra (in solutions, films or KBr) of acetylenylpyrazoles are close to those
in the arylacetylene series. The values of the characteristic frequencies of the stretching
vibrations of a disubstituted triple bond are in the range 21602260 cm1, those of the
monosubstituted CC-H bond are in the range 21002160 cm1 and those of the C-H bond are in
the range 32753325 cm1 (86TH1).
For example, 3-ethynylpyrazole shows bands: 2120 cm1, 3275 cm1. 5-Ethynyl-1methylpyrazole shows bands: 3290 cm1 and 2120 cm1 (68LA113).
1-Ethynylpyrazole shows a sharp peak at 2170 cm1 (CC) and 3300 cm1 (C-H); the
corresponding bands for 1-ethynyl-3,5-dimethylpyrazole appear 2160 cm1 and 3300 cm1
(94AJC991).
Only in one work (69KGS1055) was made attempt to interpret the main IR spectrum
parameters (in the region of stretching vibrations of triple bonds) of the synthesized
pyrazolylacetylenes considering a mechanical model and using the results of calculation analysis
but doing no calculations. The IR spectra of all produced acetylenylpyrazoles manifest in the
range 2100-2200 cm1 the stretching vibrations of the CC bond. Below (Table XXXII), we are
giving the corresponding frequencies.
131
TABLE XXXII
Frequencies of vibrations of the CC and CH bonds of the acetylenylpyrazoles.
N
N
Compound
C CH
OH
N
N
N
N
C C
C C C CH
OH
C C C C
96
95
94
N
N
97
CC
2112
2228
2212
2150, 2232
CH
3315

3310

H
C
Compound
N
N
C C
C C
N
N
N
N
C C C C C C C C
99
98
N
N
C
N
N
C
C
H
100
CC
2147, 2215
2078, 2125, 2195
2122
CH


3313
Popov and Lubuzh (66ZPS498) using a mechanical model and a set of force constants have
calculated vibration frequencies for polyacetylenic groupings. But these calculations are rather
complex and the data on the IR spectra of acetylenic compounds are given, as a rule, at a purely
descriptive level without any attempts to interpret them. At the same time, a simple qualitative
method for relating the structure of such a compound to the number and arrangement of bands in
its spectrum would be highly helpful.
Considering a diatomic oscillator model shows that an increase in mass x strengthens the
fastening of a C2 atom and thus, increases the frequency of its own vibrations.
C1
C2
X
Indeed, in the ethynylpyrazole 94 spectrum, the triple bond manifests itself at 2112 cm1, and
then in the spectrum of carbinol 95 as in other disubstituted acetylenes its frequency increases by
about 100 cm1. Note that the high intensity of the band 2112 cm1 of compound 94 is likely to
result from the elevated electron density at position 4 of pyrazole cycle and the resulting increase
in the dipole moment of the triple bond conjugate to the nucleus.
Vibrations of diacetylenic grouping in pyrazole 96 split into symmetric and antisymmetric. In
this case, according to the linear model of two oscillators with an elastic bond, the former must
have a higher frequency due to the rigidity of the C1C2 bond.
For acetylenes close in structure, the values of the characteristic frequencies of the triple
bond change negligibly. Thus, 3,4-diethynyl-, 4,5-diethynyl-, and 3,4,5-triethynyl-1methylpyrazoles have the following values for the CC bond frequencies: 2132, 2135, and 2138
cm1, respectively, and the band typical of the C-H bond has the same value for all three
polyethynylpyrazoles (3320 cm1) (71IZV1764).
B. UV spectra
The ultraviolet absorption spectra of most alkynylpyrazoles are quite similar to those of the
corresponding pyrazoles. In general, they show a shift towards the visible (See as examples
(76T1293; 98JCS(P1)3233)).
The electronic spectra of radical 101 and 102 have two sets of absorption bands in the visible
and near UV spectrum regions (Figure 1, Table XXXIII).
132
O
N
C C
N
O
O
N
N
N
C C
N
N
N
102
101
30
in Benzene
Radical 101
Radical 10120
Radical 102
Radical 10220
-3
-1
*10 , M cm
-1
20
102
10
0

35
102
101
30
25
-3
101
20
15
-1
*10 , cm
Figure 1. Electronic absorption spectra of the 101, and 102 nitroxylic radicals in benzene.
133
TABLE XXXIII
Data on the optical absorption spectra of radical 101 and 102.
, cm-1 (, M-1cm-1)
Radical
Visible spectrum region (sh-shoulder)
101
13900 sh (120)
15200 (295)
16500 (310)
17700 sh (210)
20000 (145)
21500 (135)
102
18900 (340)
20300 (600)
21300 (610)
22800 sh (485)
24000 (515)
25500 sh (540)
Near-UV spectrum region (sh-shoulder)
101
26100 (9800)
29300 (25600)
30500 (29900)
102
29100 sh (6600)
30900 (27400)
32500 (28000)
34850 (13300)
34900 sh (20200)
The splitting of both groups (visible and UV spectrum regions) is related to a vibrational
structure of electron transitions (characteristic frequencies being 1200-1500 cm1). For radical
102, the absorption bands are shifted towards a short-wave region, which changes the colour of
this radical.
7-Alkynylated 7-deazaadenine (pyrrolo[2,3-d]pyrimidin-4-amine) 2’-deoxyribonucleosides
show strong fluorescence which is induced by the 7- alkynyl side chain A large stokes shift with
an emission around 400 nm is observed when the compound is irradiated at 280 nm. The solvent
dependence indicates the formation of a charged transition state the fluorescence appears when
the triple bond is in conjugation with the heterocyclyc base. Electron donating substituents at
triple bond increase the fluorescence, while electron – withdrawing residues reduce it. In
comparison, the 7-alkynylated 8-aza-7-deazaadenine (pyrrolo[3,4-d] pyrimidin-4-amine) 2’deoxyribonucleosides are rather weakly fluorescence (2000HCA910).
D. 1H-NMR spectra
The NMR parameters of the spectra of methyne protons for the simplest
monoethynylpyrazoles vary even in different solvents within 1.0 ppm (from 2.7 to 3.7 ppm) and
are close to those for the monosubstituted aromatic derivatives (71IZV1764; 76IZV2292;
72IZV2524). The values of the chemical shifts of acetylenic protons for 3 and 4-CC groups are
close to one another even in different solvents and the signal of ethynyl protons of 5-CCH is
noticeably shifted to the weak field. Thus, C-H in 3-ethynyl-1-methylpyrazole has 2.89 ppm
(CCl4); in 5-ethynyl-1-methylpyrazole  3.49 ppm (CCl4) (69IZV2546); in 4-ethynyl-1methylpyrazole  2.88 ppm (CCl4) (72IZV2524). Introduction of each additional methyl group
lead to its chemical shift moves to a higher field.
For 1-ethynylpyrazole the chemical shift of methyne protone is 3.14 ppm (CDC1 3). For 1ethynyl-3,5-dimethylpyrazole the chemical shift of methyne protone is 3.22 ppm (CDC13); 1ethynyl-3-methylpyrazole - 3.05 ppm; 1-ethynyl-5-methylpyrazol – 3.21 ppm. (94AJC991).
The same regularities are observed for polyethynylpyrazoles. Thus, for 3,5-diethynyl-1methylpyrazole the chemical shifts (in CCl4) are 3-CCH 2.95, 5-CCH 3.52 ppm
(69KGS1055), for 3,4-diethynyl-1-methylpyrazole (in CC14) 3-CCH 3.09, 4-CCH 3.01 ppm,
for 4,5-diethynyl-1-methylpyrazole (in CDC13) 4-CCH 3.02, 5-CCH 3.62 ppm and for 3,4,5triethynyl-1-methylpyrazole (CD3COCD3) 4-CCH 3.64, 3-CCH 3.72, 5-CCH 4.36 ppm
(71IZV1764). Note that the chemical shifts of the 5-ethynyl groups of pyrazoles are weakly
dependent on the nature of substituents in the conjugate position 4 of the cycle. The difference in
the chemical shifts of acetylenic protons in 4-chlor-, 4-brom, 4-iod-, 4-amino-, and 4phenylethynyl-1,3-dimethyl-5-ethynylpyrazoles lies in the narrow range 3.61-3.66 (CDCl3)
(86TH1).
134
E. 13C NMR spectra
The 13C-NMR spectra for several alkynylpyrazoles have been measured, and selected data is
presented in this part.
The signals of the CC atoms in the 13C-NMR spectra are manifested in the range 70-95
ppm. For 1-ethynyl-3-methylpyrazole the chemical shift of CCH atom is 58.3; the chemical
shift of CCH atom is 61.7. For 1-ethynyl-5-methylpyrazole the chemical shift of CCH atom is
58.3; the chemical shift of CCH atom is 61.7 (94AJC991). A direct constant of the spin-spin
coupling of 13C13C (1JCC) is 179.9 Hz for 5-ethynyl-1-methylpyrazole (88ZOR1595).
For 4-phenyl-3(5)-phenylethynylpyrazole in DMSO the chemical shifts of CC carbon atoms
are 83.0 and 90.4 ppm (93ZOB1107).
For 4-phenylethynylpyrazoles the chemical shift (DMCO-D6) -C is 82.09 ppm, and -C 
89.49 ppm. For 4-ethynylpyrazole these signals are shifted towards higher field, 76.06 ppm and
80.55 ppm respectively (78MOC253).
Using NMR spectra of 13C, one can unambiguously estimate the direction and the degree of
triple bond as is demonstrated using 7-alkynyl-8-aza-7-deazaadenines as an example
(99JCS(P1)479). The phenyl substituent at triple bond has a weak -I and -M-effect and causes
polarization upon which the triple bond carbon atom closest to the benzene nucleus obtains a
negative charge. In this case, the difference in the chemical shifts between - and -C is not
large and amounts to 10-13 ppm. At the same time, the butyl group having the +I-effect causes an
opposite shift of electrons. In this case, the difference in the chemical shifts between - and -C
is 20-25 ppm (possibly, there appears a push-pull system). The absolute values for -C with an
alkyl substituent are 71.973.6 ppm and for -C, they are 93.896.9, for -C with an aromatic
substituent they are 91.893.5 and for -C, these are 80.782.5 ppm.
The 13C- NMR spectra for phenylethynyl-3H-pyrazoles have also been measured
(91ZOB2286).
F. Thermodynamic CH-acidity of ethynylpyrazoles
The high reactivity of monosubstituted acetylenes in many reactions (acetylenic
condensation, Favorsky, Mannich, oxidative coupling, etc.) is determined by their acidity
(71MI1; 83MI1). The literature data on the equilibrium CH-acidity of these compounds are
rather scarce.
The equilibrium CH-acidity of terminal acetylenes in the series of N-alkylpyrazoles was
studied (83IZV466). The equilibrium CH-acidity measurements were performed in DMSO by
the method of remetallation (75ZOB1529). It was revealed some regularities in the influence of
cycle structure, the nature of other substituents and the position of ethynyl group in a heterocycle
on the acidity of ethynyl pyrazoles.
H
H
C
C
C
N
N
C C
H
pK = 26.9
N
C
N
pK = 29.0
N
N
pK = 30.4
The acidity of ethynylpyrazoles, free of other substituents, increases with ethynyl group
transfer from position 4 to position 3 and then in 5 for pyrazole. The observed order of changes
in equilibrium CH-acidity values is in agreement with a change in the different positions of azole
reactivity in reactions of electrophilic substitution (66MI1; 67MI1).
135
A comparison between the values of the acidity of ethynylpyrazoles and the energies of
heterocyclic break of C-H bond calculated by the CNDO-2 method (75KGS821) has revealed a
symbatic change in these values (Figure 2.).
35
2-
- ethynylimidazoles
30
H
C C
N
- E
kKal/mole
5-
5-
25
N
20
4-
= ethynylpyrazoles
15
N
10
3-
H
C C
N
45
26
27
28
pK
29
30
31
Figure 2. Values of the acidity of ethynylpyrazoles and the energies of heterocyclic break of
CH bond calculated by the CNDO-2 method (75KGS821).
The obtained data experimentally confirm the order of pK values of ethynyl proton 4 > 3 > 5
for pyrazoles predicted in (75KGS821) on a basis of calculations of the energy of CH bonds
break.
Of interest is also a tendency of a "pyrrole" nitrogen to increase the acidity of ethynyl group
compounds as compared with a "pyridine" nitrogen. The difference in the activity of "pyrrole"
and "piridine" nitrogen is about 2 log units.
The acidity of 4-ethynyl-1-methylpyrazole is lower than that of phenylacetylene (pK = 29.1)
(75IZV2351, 79JCS(PII)726, 84IZV923). Ethynyl group in other positions of pyrazoles has
smaller pK values, i.e., 4-pyrazolyl-radicals have a weaker electron-acceptor characteristic than
the phenyl ring.
H
H
C
C
N
N
pK = 30.7
N
pK = 30.6
C
C
C
N
H
H
C
C
C
N
N
N
N
pK = 30.5
pK = 30.4
4-Ethynylpyrazoles are less acid than other CH-acids in the series of both alkyl- and
arylacetylenes (great value of pK). In this case, the values of equilibrium CH-acidity determined
in the aproton solvent DMSO, agree with those of the "eigen" aciditiy obtained on a basis of
quantum-chemical calculations on determination of deprotonation energy of terminal acetylenes
136
(92ZOB2757). Indeed, among 27 monosubstituted acetylenes the value of deprotonation energy
(1550 kJ/mole) calculated by the MNDO/3 method for 1-methyl-4-ethynylpyrazole is second
only to acetylene and methylacetylene (92ZOB2757).
The effect of substituents in the cycle on the mobility of a methyne proton can be followed
from the series of 5-substituted 1-methyl-4-ethynylpyrazoles and 1,3-dimethyl-4ethynylpyrazoles. In both structural series, the acidity of compounds increases with a change in
the character of substituents in the following order: CH3 < H < CH2NH2 < Cl.
H
N
C
pK = +0.1
N
N
pK = 30.5
N
pK = 30.4
pK = 29.7
pK = +0.2
H
N
N
N
pK = 30.7
Cl
N
pK = 28.7
H
C
N
pK = +0.6
pK = +0.4
H
C
pK = +0.1
C
pK = +1.0
NH 2
N
C
C
C
pK = -0.7
N
pK = +0.2
C
C
C
C
H
H
H
C
H
C
C
pK = -0.3
N
N
pK = 30.6
C
C
pK = +1.2
NH 2
N
N
pK = 30.3
N
Cl
pK = 29.1
The scheme shows that the influence of substituents on CH-acidity in ethynylpyrazoles is not
additive as compared with benzene derivatives (84IZV923) and its value depends, for each
substituent, on the nature of other groups in the different positions of azole.
The CH3 group in position 5 displays weak electron-donor properties by decreasing acidity
by 0.1 log unit. The methyl group in position 3 causes a slightly greater decrease in ethynyl
group acidity. If there are acidifying groups in pyrazole position 5, the donor properties of 3-Me
increase and pK is 0.4 and even 0.6 unit of equilibrium CH-acidity.
The acidity of 4-acetylenenylpyrazoles increases by 0.3-0.7 log units with introducing
CH2NH2 group into position 5 of the cycle. Chlorine atoms have the greatest acidifying effect.
Chlorine atom in position 5 increases the acidity of 1-methyl-3-ethynylpyrazole.
In the 4-substituted 1,3-dimethylpyrazoles with ethynyl group fixed in position 5 the acidity
increases with a change in the character of substituents in the series: H = NH2 < CCPh < J < Br
= Cl.
X
N
X
pK
H
27.0
NH2
27.0
N
CCPh
26.1
C C
H
I
26.0
Br
25.5
Cl
25.5
The order of effects of substituents on ethynyl group acidity in acetylenylpyrazoles is likely
to reflect the advantageous inductive nature of this influence. Although the data are rather scarce,
137
some symbacity is observed between the ethynyl group pK values and I-constants of
substituents in heterocycles (Figure 3).
31
CH3
H
CH2NH2
30
Cl
X
29
=
N
H
C C
H
N
C
C
28
pK
H
=
NH2
N
X
N
27
CCPh
I
26
25
-0,1
Br Cl
0,0
0,1
0,2
0,3
0,4
0,5
I
Figure 3. The ethynyl group pK values and I-constants of substituents in ethynylpyrazoles.
It is known that diacetylenes in, e.g. Favorsky's reaction, are 1000-fold more active than
monoacetylenes. It is of interest to consider how the accumulation of triple bonds will affect the
compound acidity. However, in the literature there are no data on the CH-acidity of diacetylenic
compounds. We were the first to estimate pK of monosubstituted diacetylene  4-butadinyl1,3,5-trimethylpyrazole to be about 24-26 log units. Unfortunately, authors (83IZV466) have
failed to determine the acidity of the diyne more accurately due to the side processes of
remetallization that complicate control over reaction.
N
N
C C C C H
pK ~ 24-26
N
N
C C H
pK = 30.7
The acidity of the diacetylene is by 5-6 orders of magnitude higher than that of
monoacetylenic analog.
G. Magnetic properties of spin-labelled alkynylpyrazoles
138
The structure of spin-labelled acetylenes includes -electron rich pyrazole and 4,4,5,5tetramethylimidazoline-3-oxide-1-oxyl (nitronylnitroxyl radicals, NN radicals) or 4,4,5,5tetramethylimidazoline-1-oxyl (iminonitroxyl radicals, IN radicals) fragment bound by a stable
phenylacetylene bridge included in the general conjugation system of a molecule. Such
compounds are rather promising for the practical solution of a problem of creation of new classes
of optical and magnetic materials. The use of acetylene fragment in molecule structure allows
one to reach definite distances between the coordination and the paramagnetic centers that is
very desirable in design of n- dimensional molecular systems (98MC216, 99MC92).
O
N
C C
N
O
N
N
C C
N
O
N
C C
N
103
N
N
102
101
O
N
O
O
N
N N
C C
N
O
N
N
104
Pyrazolylethynylphenylnitroxides 101-104 are quite stable in solid and in solution at ambient
temperature. They have intrinsic to 2-imidazoline nitroxides EPR spectra. Figures exemplify
EPR spectra for nitroxides 101 and 102.
0.1 mT
Figure 4 Central component of EPR spectrum of radical 101.
139
The spectrum of radical 101 is quintet (1:2:3:2:1), caused by hyperfine interaction with two
equivalent nitroxide nitrogen nuclei (аN= 0.74 mT), each line of quintet being additionally
splitted due to hyperfine interaction with 12 protons of -methyl groups (aH(CH3) = 0.021 mT)
and with ortho-protons of benzene ring (aortho= 0.054 mT). Figure illustrates this, where a central
component of quintet is depicted. EPR spectrum of radical 102 presented in Figure is caused by
HFI with two non-equivalent nitrogen of imidazoline moiety, hyperfine coupling constants
differing about 2 times (aN1= 0.907 mT and aN3= 0.432 mT).
1 mT
Figure 5 EPR spectrum of radical 102 (510-5 M) in oxygen-free hexane solution at room
temperature.
g-Factors of radicals 101 and 102 are 2.0065 and 2.0059, respectively. The
pyrazolylnitroxides have effective magnetic moments at room temperature corresponding to
usual for one unpaired electron per molecule values (1.71  0.05 B.M.). The values of effective
magnetic moments of the niroxyls practically do not change in the temperature range 5-300 K.
A fundamental parameter characterising the EPR signals of radicals is a g-tensor, which
depends on the electron structure of a radical, and the influence of medium in which it is located.
A conventional X-band technique (wavelength being 3 cm, frequency being 9.6 GHz) of
determination of g-tensor is, in this case, ineffective, because for most organic radicals the
anisotropy and mean values of g-tensor give the spacing between the lines of different
components of about several Gauss which is comparable with a linewidth. The use of a 2mm
wave allows one to get a g-factor resolution of up to 105 by increasing the value of Zeeman
interaction by order of magnitude. This accuracy makes it possible to determine all g-tensor
components, which become the individual parameters of radicals.
Figure 6 shows the ESR spectra with defined g-tensor and HFI components for radicals 101
and 102.
140
gx
gy
101
gx
gy
102
gz
I II III IIA2zzI
IA1zzI I
gz
+2
Mn
I I II I II IA2Izz
I A1zzI I
4600
4610
4620
4630
4640
H0, mT
Figure 6 2mm-band EPR spectra of radical 101 and 102 (5105 M) in oxygen-free toluene at
130-140 К.
The spectra display three lines whose positions are determined by orientations of magnetic
field along each of the own axes of the g-tensor. The positions of the centres of three
components allow one to determine the main values of g-tensor (gxx, gyy, gzz). Hyperfine
interaction with one or two nitrogen nuclei leads to additional splitting of components. In most
cases, it is possible to record the splitting of Z-component into five lines upon interaction with
two equivalent nitrogen nuclei (Figure 6, radical 101). If two nitrogen nuclei are non-equivalent,
the Z-component splits into seven components (Figure 6, radical 102) owing to the overlapping
of two pairs of the lines. Table XXXIV shows the magneto-resonance parameters of radicals 101
and 102 obtained by analysing line positions in the 2 mm-band EPR spectra.
TABLE XXXIV
The values of g-factor and HFI constants of radicals 101 and 102.
Radical
gxx
gyy
gzz
Azz(1)
Azz(2)
101
2.0110
2.00660
2.00210
18.9
18.9
102
2.00980
2.00607
2.00186
23.0
12.1
141
V. Biological properties of acetylenylpyrazoles
In the last years, interest in the medicine and agriculture of alkynylpyrazoles has greatly
increased. Izyumov (74MI1) (Department of Pharmacology of the Novosibirsk Medical Institute)
have studied an influence alkynylpyrazoles injected to rats for the different types of extreme
action on an organism (hypoxy, overheating, poisoning by copper salts, etc.).
One of the most important problems in the sphere of industrial activity is the high ambient
temperature control. Therefore, the search is on for substances that could increase organism
resistance to the dangerous action of overheating. Experiments on white rats show that substance
103 called “azomopine”, has the screening effect at different temperature regimes.
O
N
C
C
C
N
O
C
N
N
O
C C
N
103
Depending on the dose and temperature regime, the screening effect of “azomopine” is
manifested upon intoxication by chlorophos. The survival of white rats injected with this
preparation is by 50% higher than that of the rats under control. When toxic doses of copper
sulphate have been injectd for 7 days, 70 and 36% of white rats survived. After the simultaneous
injection of “azomopine”, their survival increased up to 100 and 70% (74MI1).
An intensive search for pharmacological means decreasing the demand for oxygen is one of
the effective methods for controlling diseases, many of which are caused by oxygen
insufficiency. The influence of a number of aminoacetylenes with different number of
morpholinopropynyl group on the hypoxic and tissue hypoxy of animals (white rats) has been
studied. Hypoxic hypoxy was caused by lifting white mice at a height of 9000 m in a pressure
chamber. It appeared that the survival of animals injected with “asomopine” is 4-6 times higher
than that of the mice in the control group. In conditions of hystoxic (tissue) hypoxy caused by
injection of KCN, the lifetime of white mice in the control group is 3-4 times shorter than that of
the mice injected with the “azomopine” (74MI1).
Among aminoacetylenes with different number of morpholinopropynyl group, the substance
has been revealed which displays antihypotoxic, thermoprotecting properties increasing the
stability of animals to intoxication by phosphor organic compounds and the salts of toxic metals,
which in its action exceeds the efficiency of “azomopine” 103. It is nontoxic and could be of
interest to clinical medicine after additional studies.
Following the action of extraordinary stimulants (hypoxic hypoxia, hypoxia+hyperoxia,
hypodynamia+hyperthermy) animals demonstrate accumulation of malonic dialdehyde with a
simultaneous fall of antiradical activity of the liver tissue. A preliminary introduction to rats of
acetylene amines 3,4,5-tris(morpholinopropynyl)-1-methylpyrazole 103 and also of tocopherol
antioxidant and gutumine antihypoxant averts activation of the lipids peroxidation processes.
The inhibition of peroxidation with the studied agent is attended by stabilization of lyzosomal
and mitochondria membranes. Unsaturated amines prevent destruction the organelles membranes
provoked by the UV-irradiation and incubation at 37 oC (pH-4.7) (78MI1).
The study acetylene aminopyrazole 103 was capable of inhibiting the processes of lipids
peroxidation both in the enzymatic and non- enzymatic peroxidation system (76MI2).
4-[3-(1-Methyl-1H-pyrazol-3-yl)-prop-2-ynyl]-morpholine hydrochloride was patented as the
compound with high hypoxic activity (93MIP1).
142
O
N
C C
N N
Acetylenylpyrazoles were tested on antyarrhythmia activity (84MI1). Using 5 mg/kg of
compound 104 inhibited the development of aconitine arrhythmia of 50% of animals. However,
it failed to prevent the heart arrhythmia. A dose of 15mg/kg prevented or substantially inhibited
the break of arrhythmic activity of about 75% of white rats.
O
N
N
O
O
HN
N
C C
O
104
Compounds 105 and 106 have the pronounced anti-inflammatory effect. 100 mg/kg of these
compounds suppress the development of edema by 69 and 45%, respectively. Compound 107
whose activity is 4-times higher than that of amidopyrine, has a stronger effect (87MI2).
O2N
O
O
O
O
HN
N
O
C C
HN
N
O
O
O
C C
O
O
105
Br
O
106
HN
N
O2N
C C
O
O
107
O
Br
The compounds of formula 26, 27 were shown to be effective against phytopathogens
(93EUP571326).
R3
C
R1
C
O
N
N
R2
O
A
O
26 A = CH; R4 = H
27 A = N; R4 = Me
R4
R1 = H, alkyl, substituted aryl, CF3; R2 = alkyl, substituted aryl;
R3 = substituted hydrocarbyl or heteroaryl
Their advantageous fungicidal activity is established by in vivo tests with test concentrations
from 0.5 to 500 mg. a.i./l against Uromyces appendiculatus on pole beans, against Puccinia
triticina on wheat, against Sphaerotheca fuliginea on cucumber, against Erysiphe graminis on
wheat and barley, against Podosphaera leucotricha on apple, against Uncinula necator on grape
143
vine, against Leptosphaeria nodorum on wheat, against Phytophthora infestans on tomato and
against Plasmopara viticola on grape vine. Many of the compounds of formula 26, 27 have an
excellent plant tolerance and a systemic action. The compounds of the invention are therefore
indicated for treatment of plant, seeds and soil to combat phytopathogenic fungi, e.g.
Basidiomycetes of the order Uredinales (rusts) such as Puccinia spp, Hemileia spp, Uromyces
spp; and Ascomycetes of the order Erysiphales (powdery mildew) such as Erysiphe ssp,
Podosphaera spp, Uncinula spp, Sphaerofheca spp; as well as Cochliobolus; Pyrenophora spp;
Venturia spp; Mycosphaerella spp; Leptosphaeria; Deuteromycetes such as Pyricularia
(Corticium), Botrytis; and Comycetes such as Phytophthora spp, Plasmopara spp. The
compounds of formula 26, 27 are particularly effective against powdery mildew and rust fungi,
in particular against pathogens of monocotyledonous plants such as cereals, including wheat.
Tolf et al. prepared 4-alkynylpyrazoles and its saturated analogs and assayed its for in vitro
inhibition of horse lover alc. dehydrogenase (LADH). It was shown that the saturated
substituents displayed increased inhibitory activity (84BAP265).
In patent (95JAP07196655) the preparation of 2H-indazole derivative of a specific formula
108 useful as a therapeutic agent for a circulatory disease such as hypertension, having
angiotensin II antagonism and antihypertensive action was described. The derivative of formula
108 [R1 are a lower alkyl or an alkenyl; R2 and R3 each are H, a halogen, a lower alkyl, (CH2)nR9
(R9 are hydroxyl or alkoxy; n are 1-4); R4 are aryl; R5 are COOH or C-bonded tetrazoline; R6
and R7 are H, F, Cl, a lower alkyl, etc.].
R3 R2
1
R
N
N
R4
C
C
R5
N
R6
R7
N
108
A new triazole derivative free from phytotoxicity to crops and exhibiting excellent herbicidal
effect on weeds of paddy field, especially echinochloa, which is a harmful paddy field, weed at a
low rate of application were described (93JAP5255314). The compound of formula 109 [A is
(branched) lower alkylene or lower alkylene containing N atom in the C chain; R1 is lower
alkynyl; R2 and R3 are lower alkyl or lower alkenyl or R2 and R3 are lower alkenylene groups
together form a ring).
A
N
N
O2
S
R1
109
N
O
N
N
N R2
R3
Different heterocyclic acetylenes including pyrazolyl derivatives 110 are useful in treating
hypertension and / or angina (87USP4663334).
144
N
HN
C C
O
NH
OH
110
Quinoline derivatives of the formula 111 are outstandingly active as microbicides and can be
preferably used as agricultural fungicides and bactericides, for the control of undesired plant
pathogens (96EUP703234).
R2
N
N
C C R1
N
111
Compounds (112) having structural features of the dual COX/5-LO inhibitor tepoxalin and
the 5-LO inhibitor ABT-761 were prepared. Many of these hybrid compounds are potent COX
and 50LO inhibitors; two compounds (112 R1 = MeO; R2 = R4 = R5 = H; R3 = NH2; R6 = Me and
R1 = MeO; R2 = R3 = Me; R4 = R5 = H; R6 = Cl) inhibit eicosanoid biosynthesis in an ex vivo
assay, but neither improved on the main deficiency of tepoxalin, duration of 50LO inhibitory
activity (99BMC979). The compounds 112 inhibit the production of arachidinic acid products
associated with 5-lipoxygenase and cyclooxygenase and are useful in the treatment of
inflammatory disorders (99USP5925769).
R6
R5
N N
R4 O
N
C C
R2
O
R3
112
R1
A number of compounds of invention (95EUP658547) include the next derivatives 113 have
an excellent fungicidal activity. They exert excellent preventive effect on various
phytopathogenic fungi, which makes them useful as an agricultural/horticultural fungicide.
CF 3
C
C
N
N
O
N
R
O
113
A series of Seela’s papers (97NN821; 98JCS(P1)3233; 99JCS(P1)479, 99HCA1640)
described the synthesis of 7-alkynylated 8-aza-7-deazaadenine (pyrazolo[3,4-d]pyrimidine) 2’-
145
deoxyribonucleosides 114 and 115. The 7-alkynylated nucleosides show a more stable glycosylic
bond than does 8-aza-7-deaza-2’-deoxyadenosine.
R
NH 2
C
N
N
O
R
O
C
N
C
C
HN
H2N
N
HO
N
O
N
N
HO
HO
HO
114
115
The compounds represented by general formula 116 are useful as an insecticide, acaricide,
and bactericide (99INP9946247).
R3
C
R2
N
C
N
R1
R4
N
R5
O
116
Structure-activity relationship studies of alkynylated 1--D-ribofuranosil-pyrazoles were
tested (96ADD193, 96BML1279, 96INP9640704, 96MCR293) but they proved inactive.
Acknowledgment
We thank Dr. I. V. Zibareva very much for a great deal of help with our Chemical Abstracts search.
The authors are grateful to the Russian Foundation for Basic Research for an access to the STN
International databases (grant 00-03-32721) via STN Center at the Institute of Organic Chemistry, Russian
Academy of Sciences, 630090 Novosibirsk, Russia.
VI. Conclusions
We believed that the present review would stimulate a novel developing of the
acetylenylpyrazole area and further extension of the preparative possibilities of the high reactive
acetylene derivatives of pyrazole.
146
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T. Metler, A. Uchida, and S.I. Miller, Tetrahedron 24, 4285 (1968).
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E. E. Zaev, V. K. Voronov, M. S. Shvartsberg, S. F. Vasilevsky, Yu. N.
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69IZV927
M. S. Shvartsberg, S. F. Vasilevsky, R. Z. Sagdeev, and I. L.
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69JAC6464
C. E. Castro, R. Havlin, V. K. Honvad, A. Malte, and S. Moje, J. Amer.
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C. C. Bond and M. Hooper, J. Chem Soc. (C) 18, 2453 (1969).
69JHC545
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69IZV2546
M. S. Shvartsberg, A. A. Demeneva, R. Z. Sagdeev, and I. L.
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69KGS1055
M. S. Shvartsberg, S. F. Vasilevsky, V. G. Kostrovskii, and I. L.
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69LA117
H. Reimlinger and J. J. M. Vandewalle, Justus Liebigs Ann. Chem. 720,
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69MI1
“The Chemistry of Alkenes” (S. Patai ed.), Interscience Publishers a
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69MI2
“Chemistry of Acetylenes” (H. G. Viehe ed.), Marcel Dekker, New
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69MIP1
V. N. Andrievskii, M. S. Shvartsberg, and I. L. Kotlyarevskii, U.S.S.R.
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M. E. Stephan, M. L. Vo-Quang, and M. Y. Vo-Quang, C. R. Acad. Sci.,
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S. F. Vasilevsky, M. S. Shvartsberg, and I. L. Kotlyarevskii, Izv. Akad.
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71MI1
L. Brandsma in “Preparative Acetylenic Chemistry”, Amsterdam,
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71TH1
S. F. Vasilevsky, Thesis for Candidate of Chemical Sciences (in
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71ZOB2230
V. S. Zhagorodnii, A. I. Maleeva, and A. A. Petrov, Zh. Obshch. Khim.
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72ACR139
J. F. Bunnet, Accounts Chem. Res. 5, 139 (1972).
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S. F. Vasilevsky, P. A. Slabuka, E. G. Izyumov, M. S. Shvartsberg, and
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A. V. Fokin, A. F. Kolomiets, and V. S. Shchennikov, Zh. Obshch.
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M. S. Shvartsberg and S. F. Vasilevsky, Izv. Akad. Nauk SSSR, Ser.
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D. A. De Bia, H. C. Van der Plas, G. Geurtsen, and K. Nijdam, Rec.
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M. F. Ford and D. R. M. Walton, Synthesis, 47 (1973).
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R. L. Bol’shedvorskaya and L. I. Vereshchagin, Uspekhi Khim. 42, 511
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74JOC843
K. G. Migliorese and S. I. Miller, J. Org. Chem. 39, 843 (1974).
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A. A. Avetisyan, A. N. Dzhandzhapanyan, L. E. Astsatryan, and M. T.
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74MI1
“Acetylenic Compounds and its Pharmacology Properties” (E. G.
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V. N. Yandovskii and T. K. Klindukhova, Zh. Org. Khim. 10, 136 (1974)
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74ZOR1510
V. N. Yandovskii and T. K. Klindukhova, Zh. Org. Khim. 10, 1510
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74ZOR730
V. N. Yandovskii and T. K. Klindukhova, Zh. Org. Khim. 10, 730 (1974)
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75IZV2351
E. S. Petrov, M. I. Terekhova, A. I. Shatenshtein, R. G. Mirskov, N. P.
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75JOM253
L. Cassar, J. Organometal. Chem. 93, 253 (1975).
75KGS1678
I. I. Popov, A. A. Zubenko, A. M. Simonov, B. A. Tertov, and P. P.
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75KGS821
P. V. Schastnev and M. S. Shvartsberg, Khim. Geterotsikl. Soedin., 821
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75MI1
M. J. S. Dewar and R. C. Dougherty in “The PMO Theory of OrganicChemistry.” Plenum Press, New York, 1975.
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M. I. Terekhova, E. S. Petrov, S. P. Mesyats, and A. I. Shatenshtein, Zh.
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75ZOR47
L. I. Vereshchagin, L. D. Gavrilov, E. I. Titova, S. R. Buzilova, N. V.
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76IZV2148
A. N. Sinyakov, S. F. Vasilevsky, and M. S. Shvartsberg, Izv. Akad.
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76IZV2288
S. F. Vasilevsky, A. N. Sinyakov, M. S. Shvartsberg, and I. L.
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76IZV2292
M. S. Shvartsberg, S. F. Vasilevsky, and A. N. Sinyakov, Izv. Akad.
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76MI1
H. P. Ibragimov, A. G. Makhsumov, A. D. Dzhuraev, and N.
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76MI2
O. P. Grek, E. G. Izyumov, A. G. Styuklyaev, and V. M. Mishin,
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H. Hauptmann, Tetrahedron 32, 1293 (1976).
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C. Simionescu, E. Comanita, M. Vata, and M. Daranga, Angew.
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77IZV2306
A. N. Sinyakov, S. F. Vasilevsky, and M. S. Shvartsberg, Izv. Akad.
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77MI1
A. G. Makhsumov, H. P. Ibragimov, and A. D. Dzhuraev, Dokl. Akad.
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78IZV1175
S. F. Vasilevsky, E. M. Rubinshteyn, and M. S. Shvartsberg, Izv. Akad.
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78KGS1535
I. I. Popov, A. A. Zubenko, and A. M. Simonov, Khim. Geterotsikl.
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78MI1
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78MI2
K. Abdullaev in “Farmakol. Prir. Veshestv” (B. S. Sadritdinov ed.), p.
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78MI3
A. G. Makhsumov, H. P. Ibragimov, A. D. Dzhuraev, P.
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78MIP1
S. F. Vasilevsky, M. S. Shvartsberg, I. L. Kotlyarevskii, and A. N.
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L. G. Fedenok, V. M. Berdnikov, and M. S. Shvartsberg, Zh. Org. Khim.
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79MI1
A. E. A. Porter in “Comprehensive Organic Chemistry” (D. Barton and
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S. F. Vasilevsky and M. S. Shvartsberg, Izv. Akad. Nauk SSSR, Ser.
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81IZV1342
M. S. Shvartsberg, S. F. Vasilevsky, T. V. Anisimova, and V. A.
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81IZV902
S. F. Vasilevsky, V. A. Gerasimov, and M. S. Shvartsberg, Izv. Akad.
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Acta Chem. Scand. B36, 101 (1982).
83IZV1686
S. F. Vasilevsky and M. S. Shvartsberg, Izv. Akad. Nauk SSSR, Ser.
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83IZV466
M. I. Terekhova, S. F. Vasilevsky, E. S. Petrov, and M. S. Shvartsberg,
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S. F. Vasilevsky, T. V. Anisimova, and M. S. Shvartsberg, Izv. Akad.
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83MI1
M. S. Shvartsberg, Izv. Sibirsk. Otdeleniya Akad. Nauk Ser. Khim. Nauk,
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B. R. Tolf, R. Dahlbom, A. Akeson, and H. Theorell, Biol. Act. Princ.
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84IZV923
M. I. Terekhova, E. S. Petrov, S. F. Vasilevsky, V. F. Ivanov, and M. S.
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84MI1
A. G. Makxsumov, U. B. Zakirov, A. D. Dzhuraev, N. Madikhanov, M.
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85IZV1367
S. F. Vasilevsky, A. V. Pozdnyakov, and M. S. Shvartsberg, Izv. Akad.
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85MI1
S. F. Vasilevsky, A. I. Belov, and M. S. Shvartsberg, Izv. Sibirsk.
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85MI2
S. F. Vasilevsky, A. V. Pozdnyakov, and M. S. Shvartsberg, Izv. Sibirsk.
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R. F. C. Brown, P. D. Godfrey, and S. C. Lee, Tetrahedron Lett. 26,
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86MI1
S. F. Vasilevsky, Izv. Sibirsk. Otdeleniya Akad. Nauk Ser. Khim. Nauk,
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86MI2
A. G. Makxsumov, A. D. Dzhuraev, G. Kilichev, and A. T. Nikbaev,
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86PM458
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86TH1
S. F. Vasilevsky, Thesis of Doctor of Chemical Sciences (in Russian),
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87KGS787
T. Akhmedov, N. S. Sadykhov, V. M. Ismailov, M. A. Akhundova, M.
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87KGS915
N. M. Przhiyalgovskaya, L. I. Kon’kov, D. L. Tarshits, S. V. Salmina, N.
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A. D. Dzhuraev, A. G. Makxsumov, and U. Tadzhibaev, Uzb. Khim. Zh.
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87MI2
A. D. Dzhuraev, A. G. Makhsumov, U. B. Zakirov, and A. T. Nikbaev,
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T. Kusumi, I. Ohtani, K. Nishiyama, and H. Kakisawa, Tetrahedron
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S. F. Vasilevsky and M. S. Shvartsberg, Izv. Akad. Nauk SSSR, Ser.
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A. G. Proydakov, G. A. Kalabin, and S. F. Vasilevsky, Uspekhi Khimii,
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К. Sonogashira, Сотр. Org. Synth. 3, 521 (1991).
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A. I. Belov, M. I. Terekhova, E. S. Petrov, S. F. Vasilevsky, and M. S.
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S. F. Vasilevsky, E. V. Tretyakov, H. D. Verkruijsse, Synth. Commun.,
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M. Yamaguchi, H.-J. Park, S. Ishizuka, K. Omata, and M. Hirama, J.
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S. F. Vasilevsky and E. V. Tretyakov, Liebigs Ann. Chem., 775 (1995).
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E. V. Tretyakov and S. F. Vasilevsky, Mendeleev Commun., 233 (1995).
95S1234
M. S. Yusubov, V. D. Filimonov, V. P. Vasilyeva, and Chi Ki-Whan,
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E. V. Tretyakov and S. F. Vasilevsky, Mendeleev Commun., 190 (1996).
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S. F. Vasilevsky and T. A. Prikhodko, Mendeleev Commun., 98 (1996).
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A. G. Malkina, L. Brandsma, S. F. Vasilevsky, and B. A. Trofimov,
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E. V. Tretyakov, Thesis of Candidate of Chemical Sciences (in Russian),
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