Abstract
The thesis entitled “ZrCl4 in organic synthesis: synthesis of α-amino nitriles, azadisaccharides, un-natural amino acids, homoallylic amines, β-amino ketones and
desilylations” is divided into two chapters.
Chapter I: Zirconium(IV) chloride mediated synthesis α-amino nitriles
and their applications
Section A: A mild and rapid synthesis of α-amino nitriles and amino
acid glyco-conjugates
This section deals with the synthesis of α-amino nitriles and amino acid glyco-conjugates
by the one-pot three component reaction of aldehyde, amine and trimethylsilyl cyanide by
using 10 mol% ZrCl4 as catalyst at ambient temperature under solvent free conditions.
The Strecker reaction1 between an aldehyde, an amine and hydrogen cyanide,
widely regarded as the first multicomponent reaction, provides the most efficient method
for the synthesis of α-amino nitriles. Several modifications of Strecker reaction have been
reported by using a variety of cyanating2,3,4 agents such as HCN, KCN, TMSCN,
(EtO)2P(O)CN, Et2AlCN, Bu3SnCN, which often involve harsh reaction conditions.
Among them TMSCN is a safer and more easily handled reagent for the nitrilation.
α-Amino nitriles have proven to be versatile intermediates for a large number of
synthetic applications.5,6 Though there exist many methodologies for the synthesis of
amino nitriles, still there is a need for the development of milder and better methods to
overcome the drawbacks associated with reported methods.7,8 Nucleophilic addition of
cyanide anion to imines by using TMSCN in the presence of catalytic amount of an acid
under nearly neutral conditions would be a very fascinating and ideal C-C bond forming
protocol to generate amino nitriles. A mild and efficient protocol for the synthesis of αamino nitriles using trimethylsilyl cyanide and 10 mol% ZrCl4 as catalyst under solvent
free conditions at room temperature is developed (Equation 1).
Equation 1
R1CHO + R2NH2
TMSCN
CN
R1
NHR 2
10 mol% ZrCl4, RT
R1 = phenyl, aryl, alkyl, heteroaryl, glycosyl
R2 = phenyl, aryl, alkyl, cycloalkyl, acrolyl, Cbz, amino acid
1
Abstract
To test the nature of the carbon-carbon bond formation in the presence of ZrCl4
(10 mol%), initially benzaldehyde 1 was treated with aniline and TMSCN at room
temperature under solvent free conditions. It underwent a facile Strecker reaction and
formed α-amino nitrile 1a (Scheme 1) in 10 min in 93% yield.
Scheme 1
CN
TMSCN
PhCHO + PhNH2
Ph
10 mol% ZrCl4, RT
1
NHPh
1a
To extend the new method, a variety of aldehydes were subjected to Strecker
reaction under the new conditions. Accordingly, aromatic aldehyde 2, aliphatic aldehyde
3 and hetero aromatic aldehydes 4, 5 and 6 were treated with aniline under the above
reaction conditions to give corresponding α-amino nitriles 2a to 6a in 7-12 min (Scheme
2).
Scheme 2
CN
TMSCN
R1CHO + R2NH2
10 mol% ZrCl4, RT
F
(2) R =
1
;
(4) R1 =
;
F
(2a) R1 =
R2 = Ph
(3a) R1 =
R = Ph
;
(3) R1 =
2
R2 = Ph
R1
;
R2 = Ph
R2 = Ph
7 min, 88%
;
9 min, 90%
R2 = Ph
;
R2 = Ph
5 min, 87%
;
R2 = Ph
12 min, 82%
N
(5a) R1 =
O
O
;
(6) R1 =
;
(4a) R1 =
N
(5) R1 =
NHR 2
R2 = Bn
;
(6a) R1 =
O
R2 = Bn
10 min, 85%
O
Further study on the chiral aldehydes, such as 7, 8, 9 and 10 (Scheme 3) with
aniline and TMSCN in presence of ZrCl4 (10 mol%) afforded nitriles 7a-10a with good
yields.
Scheme 3
R1CHO + PhNH2
CN
TMSCN
10 mol% ZrCl4, RT
2
R1
NHPh
Abstract
OBn
OBn
1
(7) R =
1
(7a) R =
12 min, 88%
O
O
(8a) R1 = O
O
11 min, 72%
O
1
(9) R =
O
O
1
(9a) R =
O
13 min, 65%
(10) R1 = O
N
(10a) R1 = O
N
(8) R1 =
15 min, 69%
In continuation of our work on C-nucleosides9 and new glyco-substances10, the
present study was extended to sugar aldehydes. Accordingly, furanoside aldehydes 11
and 12 (Scheme 4) under the above reaction conditions, gave corresponding nitriles 11a,
11b and 12a as inseperable diastereomeric mixtures.
Scheme 4
NHR 2
O
OHC
O
+ R NH2
O
R1O
TMSCN
2
O
NC
10 mol% ZrCl4, RT
O
O
R 1O
(11) R1 = Me
R2 = Ph
1
2
(11a) R = Me, R = Ph
23 min, 81%
(11) R1 = Me
R2 = Bn
(11b) R1 = Me, R2 = Bn
20 min, 80%
(12) R1 = Bn
R2 = Bn
(12a) R1 = Bn, R2 = Bn
18 min, 83%
A similar study on aldehyde 13 gave corresponding amino nitriles as
inseparable diastereomeric mixtures of 13a and 13b (Scheme 5).
Scheme 5
NHR
OHC
O
O
OMe
TMSCN
+ RNH2 10 mol% ZrCl , RT
4
O
O
(13)
O
NC
R = Ph
OMe
O
(13a) R = Ph 23 min, 79%
(13b) R = Bn 18 min, 81%
R = Bn
3
Abstract
A further study on pyranoside aldehyde 14 using aniline and benzyl amine
(Scheme 6) under the above reaction conditions afforded nitriles 14a, 14b as a separable
diastereomeric mixture and 14c as single S-isomer.
Scheme 6
O
NHR
O
H
O
TMSCN
+ RNH2 10 mol% ZrCl , RT
4
O
O
NHR
O
NC
O
+
O
O
O
O
Minor
Major
R = Ph
R = Bn
O
O
O
O
(14)
O
NC
14b R = Ph (25%)
14a R = Ph (59%)
14c R = Bn (55%)
Encouraged by the above results, aldehyde 14 was treated with alkyl amines such
as isopropyl amine and cyclopropyl amine to give the corresponding nitriles 14d and 14e
as inseparable diastereomeric mixtures (Scheme 7).
Scheme 7
NHR
O
O
H
O
+
O
O
RNH2
TMSCN
10 mol% ZrCl4, RT
O
NC
O
O
O
O
O
(14)
(14d) R =
35 min, 80%
(14e) R =
27 min, 88%
Having successfully achieved the synthesis of α-amino nitriles using different
amines, we explored our study to continue the synthesis of α-amido nitriles. Accordingly,
benzaldehyde 1 was treated with acryl amide using TMSCN and 10 mol% ZrCl4 to give
amido nitrile 15 in 15 min (entry 1, table 1). The successful incorporation of acryl amide
in Strecker reaction in place of an amine for the first time prompted us to undertake the
study onto more useful sugar aldehydes. Accordingly, glycosyl aldehydes 11, 13 and 14
(entries 2, 3 and 4, table 1) were treated with acryl amide to afford nitriles 16, 17 and 18
respectively as inseparable diastereomeric mixtures in good yields.
4
Abstract
Table 1: ZrCl4 mediated synthesis of α-amido nitriles
Product
Amine
Aldehyde
S.No
O
O
OHC
1
O
OHC
O
O
O
2
O
O
OHC
OMe
O
OHC
NH 2
13
O
O
O
82
27
90
32
87
29
77
16
OMe
17
O
CN
14
O
O
O
O
N
H
NH 2
O
H3CO
CN
O
4
O
O
O
O
O
15
CN
N
H
3
O
15
N
H
NH 2
O
11
H3CO
Yield
(%)
CN
N
H
NH 2
1
Time
(min)
O
O
O
18
O
The study on the formation of α-amido nitriles was further extended to benzyl
carbamate. Accordingly, 4-fluoro benzaldehyde 2 (entry 1, table 2) was treated with
benzyl carbamate under the preceding reaction conditions to give nitrile 19 in 81% yield.
Similar study on 11, 13 and 14 (enries 2, 3 and 4, table 2) under the above reaction
conditions was found to be facile and afforded the expected products 20-22 respectively
as inseparable diastereomeric mixtures.
Table 2: ZrCl4 mediated synthesis of α-amido nitrile
S.No
Amine
Aldehyde
Product
Time
(min)
Yield
(%)
10
81
37
74
NHCb z
1
OHC
CbzNH2
2
2
OHC
O
H3CO 11
NC
19
F
F
O
CbzNH2
NC
O
NHCb z
O
H3CO
5
O
O
20
Abstract
Aldehyde
S.No
O
OHC
OMe
CbzNH2
3
O
OHC
O
Product
Amine
NC
NHCb z
O
O
13
O
O
O
O
14
4
CbzNH2
NC
Time
(min)
Yield
(%)
35
70
OMe
21
O
NHCb z
O
O
O
O
27
O
78
22
O
Having observed ZrCl4 as a facile Lewis acid for the Strecker reaction with
different amines and amides, the study was extended to the addition of amino acids,
which in turn would result in the amino acid glyco-conjugates. Accordingly, aldehyde 14
Table 3: ZrCl4 mediated synthesis of amino acid glyco-conjugates
S.No
Aldehyde
O
1
O
H
O
H3CO 2C
H3CO 2C
NH 2
Ph
H3CO 2C
NH 2
H3CO 2C
4
OHC
NHCb z
NH 2
O
N
H
O
H3CO
5
11
11
40
77
36
65
36
58
O
24
Ph
O
N
H
O
25
O
CN
O
H3CO 2C
NH 2
O
O
O
O
H3CO 2C
81
CN
H3CO 2C
CH2Ph
H3CO 2C
35
CN
CbzHN
O
79
23
O
14
30
O
O
3
Yield
(%)
O
O
H3CO 2C
14
O
N
H
O
14
CH2Ph
2
Time
(min)
CH3 CN
CH3
O
O
O
Product
Ester
N
H
H3CO
O
O
26
CN
NHCb z
NH 2
H3CO 2C
CbzHN
6
N
H
O
H3CO 27
O
O
Abstract
was treated with TMSCN and L-alanine methyl ester in presence of ZrCl4 (10 mol%) to
give the glyco-conjugate 23 as single S-isomer (entry 1, Table 3) in 79% yield. Aldehyde
14 was further treated with different α-amino acids to give 24 as single S-isomer and 25
as an inseparable diastereomeric mixture (entries 2, 3, Table 3). A similar study on
aldehyde 11 (entries 1, 2, table 3) gave the expected amino acid glyco-conjugates 26 and
27 as inseparable diastereomeric mixtures.
Thus, the present study with ZrCl4 (10 mol%) has evolved into an efficient
protocol for the synthesis of α-amino nitriles, α-amido nitriles and amino acid glycoconjugates by the reaction of various aldehydes with TMSCN and various amines,
amides and amino acids
under conditions at ambient temperature. The reaction
conditions are mild, well adoptable for large scale synthesis. Shorter duration of time and
higher yields of the products in pure form are the attractive features of the present
protocol.
Section B: Applications of α-amino nitriles
Part-I: Synthesis of β3-,γ4- and δ5-amino acids from α-amino nitriles
This part deals with the synthesis of alkyl, benzyl and Cbz protected β3-amino acids and
alkylated γ4- and δ5- amino acids from α-amino nitriles by using Reformasky reaction as
key step.
Peptides play an important role in many physiological processes,11 hence, their de
novo design has emerged as a valuable tool to critically evaluate the rules of folding and
structural stabilization. A variety of secondary structures have been found in - as well as
in homologous - and -peptides derived from unnatural amino acids,12 providing a
promising class of peptidomimetics. In recent years, our group developed C-linked carbo-amino acids (3-Caas) as a new class of -amino acids and utilized them to prepare peptides13 with helical diversity and robustness.
Having synthesized the α-amino nitriles of glycosyl compounds from glycosyl
aldehydes by using ZrCl4 as Lewis acid, flexible protocols for the preparation of a variety
of Caa monomers were proposed from α-amino nitriles. Thus, the main strategy would be
7
Abstract
to replace the nitrile group for the introduction of acid group, through Reformatsky
reaction to result in β3-, γ4- and δ5-amino acids.
Accordingly, glycosyl aldehydes 11, 13 and 14 (from preceding section) were
treated with isopropyl amine and TMSCN in presence of 10 mol% ZrCl4 to afford nitriles
1, 2 and 14d respectively as inseparable diastereomeric mixtures. Further, the nitriles 1, 2
and 14d on treatment with ethyl bromoacetate and activated Zn-AcOH (5 mol%) in THF
at room temperature (Reformatsky reaction) gave the β3-amino acid esters 1a and 1b, 2a
and 2b and 3a and 3b respectively (Scheme 8) as diastereomeric pairs (3:1) which were
easily separated and characterized.
Scheme 8
NH
O
OHC
H3CO
11
O
a
O
NH
O
NC
O
EtO2C
b
O
H3CO
H3CO
1
O
OHC
O
O
OM e
NC
O
O
O
O
O
O
14
O
1b (Major)
14%
H3CO
b
NH
O
EtO2C
O
O
2
OM e
O
EtO2C
a
O
OM e
O
b
NH
O
EtO2C
O
O
14d
O
O
O
O
O
O
2b (Minor)
15%
NH
O
NC
O
2a (Major)
44%
NH
O
O
1a (Major)
42%
O
+
13
OHC
O
EtO2C
+
O
NH
NH
OM e a
NH
O
EtO2C
+
O
O
O
3a (Major)
51%
O
O
3b (Minor)
14%
Reagents and conditions: a) Isopropyl amine, TMSCN, 10 mol% ZrCl4, RT b) BrCH2CO2Et,
Zn-AcOH, THF, RT
Similarly, the α-amido nitriles 4, 5 and 6 (table 4) were further treated with ethyl
bromoacetate and Zn-AcOH to give Cbz protected β3-amino acids 4a-6a respectively as
inseparable diastereomeric mixtures.
8
Abstract
Table 4: Synthesis of Cbz protected β3-amino esters
S.No
Time Yield
(min) (%)
Aldehyde
Nitrile
O
NHCb z
O
OHC
O
NC
O
37
74
Time Yield
(min) (%)
Ester
Et O2CH 2C
NHCb z
O
O
1
O
H3CO
H3CO
11
O
OHC
OMe
NC
4
NHCb z
O
OMe
2
35
70
NHCb z
O
Et O2CH 2C
OHC
O
O 13
O
O
NC
O
O
O
NHCb z
O
O
78
27
O
OMe
4
52
3
53
5a
O
NHCb z
O
O
O
O
Et O2CH 2C
O
6
O
14
O
O
54
O
4a
H3CO
5
O
3
O
3
O
6a
To ascertain the absolute stereochemistry at the new stereocentre in the esters, a
fused lactone 7 was prepared from aldehyde 12 (preceding section). Accordingly,
aldehyde 12 on reaction with isopropyl amine, TMSCN-ZrCl4 furnished nitrile 8 as an
inseparable diastereomeric mixture, which on further treatment with ethyl bromoacetate
gave 8a (major) and 8b (minor) as separable diastereomers (3:1). Hydrogenetion of 8b
with Pd-C (10%) in EtOAc was facile to undergo debenzylation along with concomitant
cyclisation to give (Scheme 9) the lactone 7.
Scheme 9
NH
OHC
O
O
O
BnO
a
O
NC
O
b
O
EtO2C
O
O
BnO
12
NH
NH
O
BnO
O
EtO2C
BnO
major
8a
8
c
NH
O
O
8b
O
O
7
O
Reagents and conditions:a) Isopropyl amine, TMSCN, 10 mol% ZrCl4, RT, 28 min, 68% b) BrCH2CO2Et,
Zn-AcOH, THF, RT, 3 h, 42%+21% c) 10% Pd-C, H2, EtOH, RT, 12 h, 86%
9
O
+
O
minor
8b
Abstract
The structure and the stereochemistry at the C-5 stereo centre was unambiguously
assigned through NMR studies. The analytical data confirmed that the absolute
configuration at C5 is R. The structure was further supported from the energy
minimization calculations (Figure 1) obtained from SYBYL 6.8 programme.14
Figure1
Further the study was extended for the synthesis of γ4-amino acids. Accordingly,
nitrile 14d was treated with allyl bromide and Zn-AcOH in dry THF at room temperature
to give olefin 9. Treatment of 9 with Borane-DMS gave alcohol 10, which on further
oxidation furnished acid 11. Finally, esterification of 11 with diazomethane afforded a
novel γ4-amino ester 12 (Scheme 10) as a single major isomer.
Scheme 10
NH
14d
O
a
NH
NH
O
b
HO
O
O
O
O
O
O
O
c,d
O
R
O
O
O
O
10
9
O
11 R = COOH
12 R = CO2Me
Reagents and conditions: a) allyl bromide, Zn-AcOH/THF, RT, 4 h b) BH3.DMS, THF:H2O, 0
o
C-RT, 3 h c) RuCl3, CCl4:CH3CN:H2O, 7-8 h d) CH2N2, Ether
Likewise, in a further study the synthesis of δ5-amino acid was performed.
Accordingly, olefin 9 was subjected to ozonalysis at –78 C to give aldehyde 13, in 85%
yield (Scheme 11). The aldehyde 13 on Wittig reaction in CH2Cl2 at room temperature
10
Abstract
gave α, β-unsaturated ester 14 in 82% yield, which was subjected to hydrogenation with
Pd-C (10%) in EtOAc under hydrogen atmosphere to give the C-linked carbo δ5-amino
ester 15 (Scheme 11) in 82% yield as single S-isomer.
Scheme 11
NH
O
O
O
O
H
O
O
O
O
a
HN
O
O
NH
O
EtO
O
O
9
O
c
13
NH
O
EtO
O
O
O
O
O
b
O
O
O
15
14
Reagents and conditions: a) O3, CH2Cl2:MeOH, -78oC to RT, 85% b) PPh3=CHCO2Et, CH2Cl2, RT
3 h, 82% c) 10% Pd-C/H2, EtOAc, RT, 12h, 82%
Thus, this study demonstrated that the α-amino nitriles made by Strecker reaction
were directly substituted by ester and allyl functionalities and have been effectively
utilized to result in 3-, 4- and 5- Caas of significant current interest. The use of such
monomers not only creates an opportunity for the design diversity, but also the structural
diversity, leading to the development of peptidomimetics and peptide based drugs.
Part-II: Stereoselective synthesis of aza-disaccharide from α-amino
nitriles
This part deals with the synthesis of new aza-disaccharides from α-amino nitriles
using ring closing metathesis as a key step.
The imino sugars are the non natural analogues of monosaccharides with nitrogen
atom instead of an oxygen atom in the furan / pyarn ring. Polyhydroxylated piperidine
alkoloids manifest great potential therauptic applications as antiviral agents and in
regulation of carbohydrate metabolic disorders. In view of the particular attention on antiHIV, diabetes,15 cancer,16 and antiviral,17 a number of chemical and enzymatic synthesis
of aza sugars have been reported. In continuation of the study on the synthesis of various
11
Abstract
bio-active compounds,18 as well as new glycosubstances,19 it was further aimed at the
synthesis of the carbon linked aza disaccharides, using ring closing metathesis20 as a key
step.
The basic strategy would be to introduce one of the olefins by a Reformasky
reaction in α-amino nitrile, while the second olefinic double bond is introduced as an
acrylate ester. The bis-olefin thus developed, on metathetic ring closure by use of
Grubbs’ reagent would result the target molecule. Accordingly, nitrile 14c (Scheme 12)
on reaction with allyl bromide with Zn-AcOH in THF at room temperature underwent
facile replacement of nitrile group by allyl group and afforded 16 (63%). Treatment of
olefin 16 with acryloyl chloride and Et3N in CH2Cl2 at 0 oC gave bis-olefin 17 (62%),
which on ring closing metathesis with Grubb’ catalyst II and Ti(Oipr)4 in CH2Cl2 for 18 h
at reflux21 afforded cyclic enone 18 in 60% yield. Finally, cis-dihydroxylation of the
olefin 18 with OsO4 in the presence of NMO in acetone-water (3:1) system afforded aza
disaccharide 19.
Scheme 12
O
NHBn
NBn
O
b
O
c
O
14c
O
O
O
d
O
O
16
O
O
17
O
O
HO
NBn
O
O
O
O
18
O
e
NBn
HO
O
O
O
O
19
O
Reagents and conditions: a) BnNH2, TMSCN, ZrCl4, RT b) allyl bromide, Zn-AcOH, THF, 4 h, RT c)
acryloyl chloride, Et3N, CH2Cl2, 3 h d) Grubbs catalyst(c), Ti(OiPr)4, CH2Cl2, reflux, 18 h e) OsO4,
NMO, RT, 12 h
Chapter II: Zirconium(IV) chloride mediated synthetic transformations
Section A: Zirconium(IV) chloride mediated selective desilylations
An efficient ZrCl4 catalysed selective deprotection of t-butyldiphenylsilyl (TPS)
ethers
12
Abstract
This section is dealt with selective deprotection of TPS ethers by use of 20 mol% of ZrCl4
as catalyst
Selective protection and deprotection of polyfunctional molecules present a
critical challenge in organic synthesis. Protecting groups play a key role in the synthesis
of polyfunctional organic molecules. Silyl ethers are among the most frequently used
protecting groups for the alcohol functional groups. In particular, the TBS34 and TPS35
ethers are among the most widely used due to their stability towards many reagents and
reaction conditions. Only few methods are available for the selective deprotection of TPS
ethers.36
In our previous studies on the protection and deprotection37 of alcoholic
functional groups, we have reported efficient protocols by use of a variety of Lewis acids.
In the present study, we report a new protocol that deprotects TPS ethers by use of ZrCl 4
(20 mol%) in nitromethane at ambient temperature (Figure 1).
Figure (1)
ZrCl4 (20 mol%)
R-OH
R-OTPS
CH3NO2, rt, 45-90 min
Initially, TPS ether 1 was subjected to desilylation with ZrCl4 (20 mol%) in
CH3NO2 at room temperature for 50 min to give the alcohol 1a in 94% yield. Similarly,
benzylic and hetero aromatic ethers 2 and 3 when were treated with ZrCl4 at room
temperature gave 2a (88%) in 60 min, while, phenol ether 3 was resistant to desilylation.
The study was then extended to the TPS ethers possessing acid sensitive ethers 5
(TBS) and 6 (THP); base sensitive ethers 7 (Ac) and 8 (Bz); and ethers 9 (Bn) and 10
(allyl) with neutral groups. Except for ether 5, the desilylation was exclusive. Further,
desilylation study on TBS ethers on 11, 12 and 13 was also found to be facile.
In conclusion, our present study demonstrated a facile deprotection of TPS ethers
with ZrCl4 (20 mol%) in nitromethane under mild conditions. This study also
demonstrated that both acid and base sensitive groups and allylic and benzylic groups
were unaffected. Thus, ZrCl4 in nitromethane is an efficient catalyst with simple reaction
13
Abstract
conditions, shorter reaction times, high selectivity and high yields, for the desilylation of
TPS ethers.
Table 1. ZrCl4 (20 mol%) catalysed deprotection of TPS ethers in CH3NO2
ENTRY
STARTING MATERIAL
1.
OTPS
1
2.
Ph
2
PRODUCT
TIME (min)
OH
1a
OTPS
Ph 2a OH
OH
OTPS
3.
YIELD (%)
50
94
3 (h)
79
50
86
18(h)
No Reaction
O 3a
O3
OTPS
OTPS
4.
4a
4
OTPS
RO
OH
RO
5.
5 R = TBS
5a R = H
60
87
6.
6 R = THP
6a R = THP
45
72
7.
7 R = Ac
7a R = Ac
50
93
8 R = Bz
9 R = Bn
8a R = Bz
9a R = Bn
60
91
60
91
10 R = allyl
10a R = allyl
75
92
3 (h)
77
45
88
8.
9.
10.
O
O
TPSO
O
HO
O
11.
MeO
11
O
OTPS
MeO
11a
O
OH
12.
12a
12
7 (h)
85
13.
OH
OTPS
13a
13
Selective deprotection of primary tert.-butyldimethylsilyl (TBS) ethers in presence of
secondary tert.-butyldimethylsilyl (TBS) ethers with ZrCl4
This section is dealt with the selective deprotection of primary tert.-butyldimethylsilyl
(TBS) ethers in presence of secondary tert.-butyldimethylsilyl (TBS) ethers
14
Abstract
Silyl protecting groups are widely used as hydroxyl group protecting agents in
organic synthesis due to their stability towards many reagents and reaction conditions.
Only few methods are available for the selective deprotection of primary TBS ethers in
the presence of secondary TBS ethers.38 To develop practical reaction conditions for
selective deprotection of primary TBS ethers over the secondary TBS ethers, a study was
undertaken on the silyl ethers that are containing both the primary and secondary TBS
groups (Figure 1).
Figure (1)
ZrCl4 (20 mol%)
OTBS
R
OTBS
OTBS
R
OH
OH, RT, 1-2 h
The silyl ether 1 underwent a facile desilylation with ZrCl4 (20 mol%) in
isopropanol at room temperature, and the primary TBS ether was deprotected in 60 min
to give 1a in 92% yield as an exclusive product. The secondary TBS group in 1 remained
unaffected. A similar study on 2 also was found to be very selective to primary TBS
group.
Further study on ethers 3-6 with benzyl, allyl, benzoyl and acetyl groups
respectively also was found to be very facile. As indicated in ether 7 though PMB ether is
prone to ZrCl4 for cleavage, the primary TBS deprotection was found to be very effective
under the present conditions. The primary desilylation in benzylic ether 8, ethers 9 and 10
with acid sensitive groups also was very selective.
Thus this study demonstrates a high selectivity in the deprotection of primary
TBS ethers in presence of secondary TBS ethers with ZrCl4 in isopropanol under mild
conditions. This study also demonstrated that both acid and base sensitive groups and
allylic and benzylic groups were unaffected. Thus, ZrCl4 (20 mol%) in isopropanol is
evaluated as an efficient catalyst with simple reaction conditions, shorter reaction times,
high selectivity and high yields.
15
Abstract
Table 1. ZrCl4 (20 mol%) catalysed deprotection of 10 TBS ethers in IPA
ENTRY STARTING MATERIAL
PRODUCT
OTBS
TIME (min)
YIELD (%)
OTBS
OTBS
1.
OH
1
60
92
1a
OTBS
OTBS
RO
OTBS
TPSO
OH
2
R = TPS
2a
R = TPS
105
89
3.
3
R = Bz
3a
R = Bz
90
91
4.
4
R = Ac
4a
R = Ac
120
88
105
89
2.
OTBS
OTBS
5.
OTBS
Ph
OH
Ph
5a
5
O
6.
O
O
OTBS
OTBS
O
OH
6
O
TBSO
O
7.
TBSO
O
7
110
79
6 (h)
90
OTBS 6a
O
HO
O
TBSO
7a
O
Section B: Zirconium(IV) chloride catalyzed multi-component coupling
reactions
Part-I: A mild and rapid synthesis of protected homoallylic amines
This section deals with the synthesis of protected homoallylic amines catalysed by ZrCl4
as a Lewis acid.
Carbon-carbon bond formation by nucleophilic addition of carbon nucleophiles to
imines is an important tool in organic synthesis.22,23 Most of the previously reported
methods24-26 suffer from several setbacks. Therefore there is a need to develop new
16
Abstract
methods for the synthesis of protected homoallylic amines using commercially available
and pollution preventing green catalysts.
Herein, we introduce ZrCl4 as a new catalyst for the synthesis of homoallylic
amines from one-pot three component condensation reaction of aldehydes, benzyl
carbamate and allyltrimethylsilane using 20 mol% ZrCl4 at room temperature under
solvent free conditions (Equation 1).
Equation 1
R
R-CHO + PhCH2-O-CO-NH2 +
9
10
SiMe3
ZrCl4 (20 mol%)
Solvent free, RT
11
R = aryl, alkyl, heteroayl, unsaturated aryl aldehydes
CbzHN
12
.
Benzaldehyde 1 (entry 1, Table 1) on reaction with benzyl carbamate and
allyltrimethylsilane using 20 mol% ZrCl4 as a catalyst at room temperature under solvent
free conditions furnished 1a in good yield. The study was then extended to different
aromatic aldehydes. Thus, aldehydes 2 and 3 having electron donating (p-methoxy) and
electron-withdrawing (nitro) groups under the above reaction conditions afforded 2a and
3a repectively, while, the other aldehydes 4, 5 and 6 (entries 4, 5 and 6), gave the
respective products 4a, 5a and 6a.
Further, aliphatic aldehydes 7-9 (entries 7, 8 and 9) under the above reaction
conditions gave the corresponding homoallylic amines 7a-9a in good yields. Similarly,
the α, β-unsaturated aldehyde (entry 10) gave homo allylic amine 10a. Likewise, the 1, 4dialdehyde (entriy 11) gave corresponding homoallylic amine 11a. Thus it is pertinent to
mention that, the present reaction conditions are facile and applicable to variety of
substrates. It is noteworthy that all the substrates reacted with equal ease in short times,
furnishing the products in high yields and with no side products.
17
Abstract
Table 1. Synthesis of homoallylic amines using ZrCl4 (20 mol%)
Having synthesized the homoallylic amines successfully, these systems were
envisaged as the precursors for the synthesis of 3-amino acids. Accordingly, the Cbz
protected homoallylic amines 9a and 5a were subjected to oxidation with RuCl3-NaIO4 in
CH3CN:H2O:CCl4 to afford the corresponding acids 12 and 13, which on further reaction
with CH2N2 gave the Cbz protected esters 14 and 15 respectively (Scheme 2).
18
Abstract
Scheme 2
1. RuCl3, NaIO4
CH3CN:H2O:CCl4
R
NHCb z
2. CH2N2, Ether
9a R = isobutyl
5a R = PhCH2
R
CO2R'
NHCb z
12R = isobutyl; R' = H
13 R = PhCH2; R' = H
14R = isobutyl; R' = CH3
15 R = PhCH2; R' = CH3
In summary, a mild and efficient method for the synthesis of homoallylic amines
has been developed using 20 mol% ZrCl4 under solvent free conditions at room
temperature. The salient features of the present protocol are: a) the reagent is catalytic (20
mol%), b) the reaction time is short, c) carried out under solvent free conditions d)
usefulness in the synthesis of amino acids.
Part-II: A direct three component Mannich reaction
This section deals with the synthesis of protected β-amino carbonyl compounds catalyzed
by ZrCl4 as a Lewis acid catalyst.
One-pot multi-component coupling protocols are powerful methodologies for the
synthesis of novel organic nitrogen molecules and challenging goals in organic
chemistry.27 The Mannich reaction is one such multi-component reaction and is widely
used in organic synthesis28 of biologically important nitrogen containing molecules such
as β-amino ketones and other β-amino carbonyl compound libraries.29 β-Amino carbonyl
compounds are important synthetic intermediates for various pharmaceuticals and natural
products.30 Traditionally Mannich reactions have been achieved by using a transition
metal salt31,32 or an organic compounds such as proline as catalysts.
Inspite of the availability of various methods for Mannich reactions, in
continuation of our work we were interested to explore the scope of ZrCl4 as an efficient
acid catalyst.33 Herein, we developed a rapid, efficient and convenient solvent free route
for the synthesis of protected β-amino ketones using 10 mol% ZrCl4 (Equation 1).
19
Abstract
Equation 1
O
O
+
R
H
R'
CbzNH2, 10 mol% ZrCl4
solvent free, RT
R'
O
NHCb z
R
R = aryl, alkyl, hetero aryl
R' = aryl, alkyl
Accordingly, benzaldehyde 1 (entry 1, table 1) on reaction with acetophenone 2
and benzyl carbamate by using 10 mol% ZrCl4 as catalyst at room temperature for 5 min
under solvent free conditions gave the Cbz protected amino ketone 1a in 95% yield. Thus
Table 1: Synthesis of protected β-amino ketones by using ZrCl4 (10 mol%)
Aldehyde
S.No
ketone
Time
(Min)
Product
O
O
Yield
(%)
NHCbz
CHO
1
R
8
90
10
83
5a
15
86
6a
22
75
18
90
20
88
15
85
23
86
25
90
1a R = H
3a R = F
3R=F
2
95
R
2
O
1R=H
5
2
O
O
NHCbz
O
Br
NHCbz
O
CHO
3
4
Br
2
O
4
CHO
O
4a
5
CHO
5
2
O
O
NHCbz
6
Ph
Ph
2
O
O
NHCbz
CHO
6
7a
7
2
O
O
7
NHCbz
1
1b
8
CHO
8
O
O
9
Me
10
Me 9a
O
9
NHCbz
O
5
NHCbz
O
10
5b
O
10
S
CHO
11
O
10
NHCbz
S
11a
20
Abstract
aromatic aldehydes p-fluoro benzaldehyde 3, o-bromo benzaldehyde 4, p-phenyl
benzaldehyde 6 and napthaldehyde 7 (entries 2, 3, 5 and 6, table 1) were subjected to
reaction with acetophenone to furnish amino ketones 3a, 4a, 6a and 7a respectively
within 10-20 min in very good yield. Further, hetero aromatic aldehyde 5 (entry 4, table
1) was treated with acetophenone and benzyl carbamate under the above reaction
conditions to furnish 5a in 15 min.
The study was then extended to aliphatic ketones. Accordingly, reaction of 1 with
ketone 8 gave 1b in 88% yield. Similarly, aromatic and hetero aromatic aldehydes 5, 9
and 11 underwent smooth coupling reaction to give the corresponding carbamates 5b, 9a
and 11a.
Having successfully synthesized the protected amino ketones from various
aldehydes by using aromatic and aliphatic ketones, the study was extended to β-keto
esters to obtain protected amino β-keto esters.
Table 2: Synthesis of Protected β-Amino Ketones by using ZrCl4 (10 mol%)
Keto ester
Aldehyde
S.No
O
CHO
1
Product
1c
Ph
1
OEt
13
O
CHO
Ph
1d
O
H3 C
O
O
CHO
4
OEt H C
3
13
9
14
9b
Ph
92
OEt
13
Ph
21
15
90
25
90
O
NHCb z
CO2Et
O
Ph
20
NHCb z
CO2Et
3
Ph
84
NHCb z
CO2Et
O
CHO
2
25
O
12
O
Yield
(%)
NHCb z
CO2Et
O
OEt
1
Time
(Min)
O
14a
Abstract
Accordingly, benzaldehyde 1 (entry 1, table 2) was treated with ethyl acetoacetate
and Cbz amine under the same reaction conditions to give 1c in 25 min in 84% of yield.
Further, aromatic aldehydes 1 and 9 (entries 2, 3, table 2) and aliphatic aldehyde 14
(entry 4, table 2) by reaction with β-keto ester (entries 2-4, table 2) under the above
reaction conditions gave 1d, 9b and 14a with good yields.
In conclusion, the present protocol using ZrCl4 (10 mol%) describes a simple yet
rapid and efficient means of synthesizing β-amino carbonyl compounds and β-amino
carbonyl esters under mild solvent free conditions in high yields at ambient temperature.
Thus, it would have immense effect for the synthesis of a wide variation of β-amino
carbonyl compounds for varied medical applications.
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25