Abstract
ABSTRACT
The thesis entitled “Novel electrophiles, bases and synthetic utility of Baylis-Hillman
reaction; synthesis of syn, anti, syn stereotetrad building block and TosMIC
mediated synthesis of amides” is divided into three chapters.
Chapter I: Novel electrophiles, bases in Baylis-Hillman reaction and synthetic utility
of Baylis-Hillman adducts.
Section A: This section dealt with the acetylenic aldehydes as electrophiles, NMM and
Urotropine as bases in Baylis-Hillman reaction.
Part I: This part of section exploits the use of acetylenic aldehydes as novel electrophiles
in Baylis-Hillman reaction.
The Baylis–Hillman reaction is one such interesting reaction, which involves the
selective atom-economical construction of a carbon–carbon bond at the -position of an
activated alkene, providing densely functionalized molecules. This reaction has earned
overwhelming synthetic popularity in recent years as evidenced by the publication of
several reviews 1,2 and a large number of research papers.
Although there is considerable progress in designing and synthesizing various
three essential components such as electrophiles, activated olefins and catalysts (bases),
to date there is a challenge to develop the above components for buildup multi
functionalized molecule which are useful and needful either in biological activity systems
or precursors to biological acive complexes in nature. For instance, Bhat and co-workers3
investigated
the
antimalarial
activity
of
3-hydroxy-3-aryl(heteroaryl)-2-
methylenepropanenitriles (Baylis-Hillman adducts derived from acrylonitrile and aryl or
heteroaryl aldehydes) and found that adducts 1-3 (Figure 1) were shown to have
antimalarial activity against P. falciparum in vitro. 2-(hydroxymethyl)cyclohex-2-enone
(the Baylis- Hillman adduct obtained from cyclohex-2-enone and formaldehyde) has been
used in the preparation of 2-crotonyloxymethyl-2-cyclohexenone (COMC) (biologically
active molecule) by Creighton and coworkers.4 They hypothesized that COMC is an
enzyme activated prodrug in which the crotonate ester serves as a leaving group, in a
process triggered by glutathionyl transferase (Scheme 1).
1
Abstract
OH
OH
OH
CN MeO
CN
CN
MeO
O2N
N
OMe
1
3
2
Figure 1
Similarly, Lin et al.5 synthesized a new class of pyrimidinyl agents using the
Baylis-Hillman strategy and studied their in vitro antimalarial activities against
Plasmodium falciparum. Out of all these molecules, the compound 4 exhibits the most
antimalarial activity, which is comparable to that of chloroquine including several works6
has been carried out until now (Figure 2).
O
O
OH
crotonic anhydride
py, DMAP, rt
OCOCH=CH-CH3
GSH
glutathionyltransferase
GS
O
COMC
Scheme 1
N
O
O
Ph
OAc
O
N
H
N
O
N
H
OMe
O
4
Figure 2
In the course of our study on Baylis-Hillman reaction,7 the development of
electrophile such as acetylenic aldehydes has been explored for carbon-carbon bond
formation to construct functionalized molecule (Scheme 2). Accordingly, the acetylenic
aldehydes were prepared by known procedure8 from simple alkynes through formylation.
Initially, we examined Baylis-Hillman reaction of phenyl acetylenic aldehyde 1 with
common known activated alkene ethyl acrylate 4 to afford 7 in 45% yield but the same
reaction was completed within short time in DMSO in the presence of 50 mol% of
DABCO giving a 74% yield of the product 7. Thus obtained product 7 in the above was
confirmed by its spectral data.
2
Abstract
O
R
CHO
+
DABCO, DMSO
R1
R = 1.C6H5, 2. n-C6H13
3. BnO-(CH2)2-
RT, 15 h
58-80%
24 - 44% de
R1 = 4. OEt
5. CH3
6. Sug
O
Sug =
O
O
O
O
O
Scheme 2
OH O
R
R1
7. R = C6H5, R1 = OEt
8. R = C6H5, R1 = CH3
9. R = C6H5, R1 = Sug
10. R = n-C6H13, R1 = OEt
11. R = n-C6H13, R1 = CH3
12. R = n-C6H13, R1 = Sug
13. R = BnO-(CH2)2-, R1 = OEt
14. R = BnO-(CH2)2-, R1 = CH3
15. R = BnO-(CH2)2-, R1 = Sug
In the same way, we performed the Baylis-Hillman reaction of phenyl acetylenic
aldehyde 1 with methylvinyl ketone 5 under optimized reaction conditions to result in 8
(67%). On the other hand, after getting good results with simple and common olefins, our
next aim was to construct the sugar molecule with sugar auxillary as as chiral olefin 6,
which on reaction with the aldehyde 1 gave the desired Baylis-Hillman adduct 9 as a
product in 58% yield and in moderate diastereoselectivity with 30% as determined from
1
H NMR spectrum.
Later, the remaining acetylenic aldehydes such as 2-nonynal 2 and 5-benzyloxy-
2-pentynal 3 have also been used with ethyl acrylate 4, methylvinyl ketone 5, and sugar
acrylate 6, under optimized conditions to afford the product 10 (80%), 11 (59% yield), 12
(61% yield) and in 44% diastereoselectivity obtained, in the case of aldehyde 3 gave
compound 15 with 24% diastereoselectivity of the adduct with sugar acrylate 6, apart
from 13 in 75% yield and 14 in 61% yield respectively.
In conclusion, it has successfully been demonstrated that acetylenic aldehydes can
be used in Baylis-Hillman reaction for the synthesis of allyl propargyl alcohols.
Part II: This part of section exploits the use of NMM and Urotropine as bases in BaylisHillman reaction.
Catalysts used often are very substrate specific9 and the results are also very
sensitive to precise reaction conditions.10 The most common catalyst for Baylis-Hillman
reaction is 1,4-diazabicyclo [2.2.2]octane (DABCO). However, DABCO was found to be
ineffective to many substrates.11 For instance, in the coupling of cyclohexenone with
3
Abstract
formaldehyde12 DABCO is not a reagent of choice. Though DMAP, 13 DBU,14 and
tetramethylguanidine9 (TMG) are known in literature as catalysts for Baylis-Hillman
reaction. It is very challenging task to identified and build up various inexpensive bases
(catalysts) in Bayli-Hillman reaction.
Thus, N-Methylmorpholine ( C5H11NO, NMM) is a inexpensive flammable liquid
chemical with a pungent smell and, is a commercially available milder base and, has been
isolated15 from the seeds of Cassia occidentalis L. (coffee senna) belonging to
leguminacae family. It is widely useful solvent16 for resins, waxes, dyes, casein, and used
in peptide synthesis17 to minimize racemization as a base, as a deprotecting agent18 for
Fmoc, in heterocyclization of thiosemicarbazides.
Similarly, Urotropine (C6H12N4), is flammable white crystalline solid and is
commercially
very
inexpensive
chemical,
and
is
also
called
as
hexamine/hexamethylinetetraamine. It can be easily prepared from the condensation19 of
ammonia and formaldehyde. It is used as a reagent in ring-closure reaction, synthesis of
triaza-, tetraaza- heterocyclic derivatives,19,20 and has been used as a base in BaylisHillman reaction,21 in α-methylation of aryl alkyl ketones,22 and mostly used in the
preparation of trimethylenetrinitramine (RDX).23
Consequently, the Baylis-Hillman reaction was performed for standardization of
reaction conditions between 4-nitrobenzaldehyde 17 and ethyl acrylate 4 in different
solvents such as THF (0% yield with NMM and urotropine), DMF (39% yield with
NMM and 56% with urotropine), DMSO (48% yield with NMM and 69% with
urotropine), sulpholane (0% yield with NMM and 80% with urotropine) and dioxanewater (1:1) using stoichiometric amounts of NMM and urotropine at ambient
temperature. An optimum yield of adduct 22 73% with NMM and 95% with urotropine
was obtained when the reaction was run for 24 h in a 1:1 mixture of 1, 4-dioxane-water.24
However, when the catalyst loading was decreased to 50 mol% or 25 mol% there was
significant reduction of the yields This amply demonstrates the necessity of
stoichiometric amounts of NMM and urotropine for catalyzing Baylis-Hillman reaction.
Subsequently, ethyl acrylate was also treated with other aldehydes (Scheme 3).
Accordingly, 2-nitrobenzaldehyde 18 and phenyl acetylenic aldehyde 19 reacts with ethyl
4
Abstract
acrylate 4 to result in the adducts 25 in 62% and 92% with NMM and urotropine and 29
in 69 and 76% yields respectively.
R CHO
+
17. R = 4-NO2-Ph,
OH
NMM or Urotropine
EWG
EWG
R
Dioxane: H2O (1:1)
or, DMSO, r.t., 16-48 h
22. R = 4-NO2-Ph, EWG = CO2Et
23. R = 4-NO2-Ph, EWG = COCH3
EWG = 4. CO2Et,
24. R = 4-NO2-Ph, EWG = CN
18.
2-NO2-Ph,
5. COCH3,
25. R = 2-NO2-Ph, EWG = CO2Et
19.
Ph
16. CN
26. R = 2-NO2-Ph, EWG = COCH3
20.
Ph
27. R = 2-NO2-Ph, EWG = CN
28. R = Ph, EWG = CN
O
R CHO
OH
O
NMM or Urotropine
+
R
Dioxane: H2O (1:1)
r.t., 20-36 h
R = 17, 18 and
21 (H)
22
29. R = Ph
EWG = CO2Et
30. R = Ph
EWG = COCH3
31.R = Ph
EWG = CN
32. R = H
33. R = 17
34. R = 18
Scheme 3
Table 1: Reactions of various aldehydes with olefins by using NMM and Urotropine
Urotropine
Time (h)
Entry
Aldehyde
Alkene
Solvent
NMM
Time (h)
1
17
4
Dioxane-H2O
24
22, 73
24
22, 95
2
18
4
Dioxane-H2O
36
25, 62
34
25, 92
3
20
4
Dioxane-H2O
24
29, 69
24
29, 76
4
17
5
DMSO
24
23, 68
20
23, 85
5
18
5
DMSO
36
26, 62
28
26, 73
6
20
5
DMSO
24
30, 72
16
30, 84
7
17
16
Dioxane-H2O
24
24, 98
20
24, 99
8
18
16
Dioxane-H2O
36
27, 96
24
27, 99
9
20
16
Dioxane-H2O
24
31, 88
18
31, 91
10
19
16
Dioxane-H2O
48
28, 64
35
28, 71
11
17
22
Dioxane-H2O
24
32, 71
20
32, 83
12
18
22
Dioxane-H2O
36
33, 63
24
33, 68
13
21
22
Dioxane-H2O
36
34, 60
32
34, 62
5
Yield (%)
Yield
(%)
Abstract
Simultaneously, the other activate olefins such as methylvinyl ketone 5 and
acrylonitrile 16 also reacted with the above aldehydes 4-nitrobenzaldehyde 17, 2nitrobenzaldehyde 18 and phenyl acetylenic aldehyde 19 under this reaction conditions to
afford corresponding Baylis-Hillman adducts in moderate to good yields (Table 1). In the
case of acrylonitrile 16, simple benzaldehyde 20 was also gave a desired product in good
yields with NMM (64%) as well as urotropine (71%).
Likewise, aldehydes 4-nitrobenzaldehyde 17, 2-nitrobenzaldehyde 18 including
simple formaldehyde 21 under went Baylis-Hillman reaction under the present reaction
conditions with cyclohex-2-enone 22 to produce the adducts 33 (63 and 68% yields), 34
(60 and 62% yields), 32 (71 and 83% yields) respectively.
In conclusion, we have successfully introduced inexpensive and comercially
available N-methylmorpholine (NMM) and urotropine as new base catalysts for the
Baylis-Hillman reaction at ambient temperature in aqueous dioaxne (1:1) to afford
adducts in reasonably good yields.
Section B: Lewis Acid and/or Lewis Base catalyzed [3+2] cycloaddition reaction:
Synthesis of pyrazoles and pyrazolines
This section dealt with the utility of Baylis-Hillman adducts including simple activated
olefins in [3+2] cycloaddition reactions in the presence of Lewis acid (InCl3) and Lewis
base (DABCO).
Cycloadditions of nitrogen-containing dipoles with olefinic dipolarophiles
continue to be attractive for the synthesis of a variety of heterocycles.25 Synthesis of
pyrazolines has been stimulated by the fact that some of their derivatives were found to
possess important bioactivities. Especially their antimicrobial,26 immunosuppressive27
and central nervous system activity28 should be emphasized. Although pyrazolines are
useful substances in drug research and are well-known five-membered nitrogencontaining heterocyclic compounds, a comprehensive review on their synthesis was
published thirty years ago.29 However, the pyrazole substructure appears in small
6
Abstract
molecules which possess a wide range of biological activities, and accordingly represents
a valuable target for organic synthesis.30
Owing to the importance of the five membered carbocyclic or heterocyclic
molecules, and, in the continuation of our work on Baylis-Hillman reaction and utility of
their adducts, we envisaged a development of [3+2] cycloaddition reaction with BaylisHillman adducts including some commercially available olefins (Scheme 4).
R
EWG
R = H, CH2OH, alkyl, aryl
EWG = CO2Et, CN, etc
CO2Et
N2CHCOOEt 35
EWG
DABCO (Method A)/
InCl3 (Method B)
neat, rt
Scheme 4
R
N
H
N
.
Accordingly, in our initial study, we found that DABCO effectively catalyzes
pyrazoline formation from simple Michael acceptor/electron poor olefin 4 ethyl acrylate
and ethyl diazoacetate 35 in 97% yield in 2 h at ambient temperature (Scheme 5). For this
protocol various solvents were examined and the maximum yield was obtained under
neat conditions at short time. Subsequent to these preliminary investigations, the effects
of different Lewis acids/and bases on the [3+2] cycloaddition reaction was examined and
concluded that InCl3 and DABCO act as best Lewis acid and base respectively for
cycloaddition reactions.
Further, known olefin, ethyl acrylate 4 undergoes a facile [3+2] cycloaddition
with ethyl diazoacetate 35 in the presence of DABCO (Method A) and Lewis acid InCl3
(Method B) independently to result in which substituted pyrazoline derivative 43 in 97%
yield with DABCO as well as 80% yield with InCl3 respectively. In similar manner, the
other olefins such as acrylonitrile 16, N,N-dibenzyl acrylamide 36 and 4acryloylmorpholine 37 underwent reaction to afford the pyrazoline ring systems like 44
(52 and 46% yields), 45 (69 and 56% yields), 46 (58 and 49% yields) respectively with
both the methods absolutely (Table 2).
Our next aim was to construct the heterocyclic rings with different types of
Baylis-Hillman adducts (Table 3). Accordingly, ethyl 2-[hydroxy(phenyl)methyl]acrylate
38 with ethyl diazoacetate 35 gave substituted pyrazoline derivatives by both the methods
in 75 and 60% yields respectively. In the same manner, the other adducts such as ethyl 2-
7
Abstract
[hydroxy(4-nitrophenyl)methyl]acrylate 39, 2-[hydroxy(2-nitrophenyl)methyl]acrylate
40, diethyl 5-(1-hydroxyhexyl)-4,5-dihydro-1H-3,5- pyrazoledicarboxylate 41, ethyl 2(hydroxymethyl) acrylate 42 were also reacted to result in corresponding pyrazoline
Table 2: Ethyl diazoacetate reaction with simple olefins with InCl3 and DABCO.
Dipolarophile
Entry
Method
Product
CO2Et
CO2Et
1
EtO2C
4
N
H
N
CN
NC
16
N
H
O
NBn 2
3
N
Bn 2N
36
N
H
N
O
N
4
37
N
O
N
H
2
97
B
4
80
A
6
52
B
10
46
A
4
69
B
8
56
A
5
58
B
7
49
45
CO2Et
O
A
44
CO2Et
O
Yield (%)
43
CO2Et
2
Time [h]
N
46
O
Table 3: Ethyl diazoacetate reaction with Baylis-Hillman adducts with InCl3 and DABCO.
Entry
Dipolarophile
Product
Method
OH
OH
CO2Et
CO2Et
Time [h]
Yield (%)
A
6
75
B
8
60
A
2
95
B
5
78
A
2
86
B
5
66
A
3
85
B
7
61
A
4
B
7
N
1
N
EtO2C H 47
38
OH
OH
CO2Et
CO2Et
2
N
O2N
N
EtO2C H 48
39
O2N
OH
OH
CO2Et
CO2Et
3
NO 2
40
N
NO 2
N
EtO2C H 49
OH
H3C
4
4
CO2Et
41
OH
CO2Et
5
42
CO2Et
OH
H3C
N
4
N
EtO2C H 50
CO2Et
OH
EtO2C
N
N
H 51
8
82
71
Abstract
derivatives like 48 (95 and 78% yields), 49 (86 and 66% yields), 50 (85 and 61% yields),
51 (82 and 71% yields) respectively by both the methods A and B respectively.
Thus, obtained results motivated us to be apply this reaction on simple alkynes
such as phenyl acetylene 52 and activated alkyne 53 with ethyl diazoacetate 35 to
construct pyrazoles in moderate to good yields (Scheme 5).
O
CO2Et
EtO
OEt
56
O
N2CHCO2Et
Method A
neat, rt
N2CHCO2Et
Method B
neat, rt
EtO2C
53
EtO2C
N
N
H 55
CO2Et
N2CHCO2Et
Ph
52
Method A or B
neat, rt
Ph
N
H
N
54
Scheme 5
As illustrated in the above scheme ethyl diazoacetate 35 when react with phenyl
acetylene 52 in both the reaction conditions to afford the pyrazole 54 in 64% and 53%
yields with DABCO and InCl3 respectively, in the case of ethyl propiolate 53 on reaction
with ethyl diazoacetate 35 resulted the pyrazole 55 in 66% yield only in the presence of
Lewis acid InCl3, but resulted the dimer 56 of ethyl propiolate in the presence of
DABCO.
In conclusion, a simple, general one-pot protocol for the synthesis of heterocyclic
3,5-disubstituted pyrazolines and pyrazoles was developed under mild conditions in good
to excellent yields from Baylis-Hillman adducts including different type of electron poor
and simple alkynes are also tolerated in this reaction.
Chapter II: Synthesis of syn, anti, syn stereotetrad building block
This chapter dealt with the linear synthesis of syn, anti, syn stereotetrad from simple
homopropargylic alcohol as a useful building block in the synthesis of biologically active
systems such as pironetin
The polyketides constitute an important family of natural products having a broad
spectrum of biological activity such as antibiotic, antitumor, antifungal, antiparasitic, or
9
Abstract
immunomodulatory action.31 Many of these compounds are referred to as
polypropionates32 (systems possessing units with alternating hydroxyl and methyl
groups), reflecting their common biosynthesis from propionate and, to a lesser extent,
acetate units.33 The importance of these natural products as therapeutic agents and as
biomedical tools together with their structural complexity has made these molecules
attractive targets for synthetic organic chemists for over two decades.34 The key to
construct these systems, which possess a high level of stereochemical information, is the
O
OMe OPG O
O
II
OMe OH
O
Evan's aldol
O
O
Et
OMe OR 1
RCM
Et
+
N
Bn
Et
I
O
R2
III
IV
R1 = MOM
R2 = CHO
OMe OR 1 O
TBDPSO
OEt
OH
67
3-Butyn-1-ol 57
Aldol
OR 1
TBDPSO
R2
O
OH
TBDPSO
R1 = H
66
60
OR 1
OR 1
TBDPSO
R1 = PMB
R2 = CH2OH 63
+
CH3CO2Et
R1 = PMB
R2 = CHO
Hydroboration
TBDPSO
R2
65
Grignard
reaction
Epoxide ringopening
Tebbe's reaction
Scheme 6
control of the absolute and relative stereochemistry. Towards this goal and an attempt to
total synthesis of pironetin35 (PA-48153C) we approached linear synthetic method that
included the key steps such Sharpless asymmetric epoxidation, stereo- and regioselective
ring-opening of epoxide and hydroboration of the olefin which was accessed through
Tebbe’s reaction as a key steps including an EtOAc addition on the stereotriad to obtain
an advanced intermediate.
10
Abstract
The retrosynthetic analysis, as depicted in Scheme 6, reveals that the stereotetrad
67 can be accessible from ethyl acetate and triad 66 by aldol reaction selectively with
LiHMDS. Meanwhile, the triad 66 can be achieved from formylation of simple terminal
alkyne 57 following Lindlar’s catalytic cis-olefination, Sharpless asymmetric
epoxidation, stereo- and regioselective ring-opening of epoxide and hydroboration of the
olefin that was earlier accessed through Tebbe’s reaction as some of the key steps.
Accordingly (Scheme 7), homo propargylic alcohol 57 was converted to TBDPS
ether which was further subjected to produce propargylic alcohol 58 by formylation. 60
in turn was obtained from the compound 58 on reaction of selective catalytic reduction in
the presence of 5% Pd/BaSO4 and quinoline (5 wt%), which on asymmetric Sharpless
epoxidation of cis-olefin resulted in hydroxyl epoxide 60 in 94% yield (92% ee). Then
the resulting hydroxyl epoxide 60 was subjected to oxidation with NaIO4 in the presence
of catalytic amounts of RuCl3 in CCl4:CH3CN:H2O (1:1:1.5) at ambient temperature to
furnish carboxylic acid,36 which further underwent highly regioselective and efficient,
incorporation of the methyl group stereoselectively to afford 61 (80%).
Thus obtained hydroxyl acid 61 was converted into methyl ester and the ester was
reduced to give diol 62 under known conditions. Later this diol 62 was converted into
dioxalane derivative with anisaldehyde dimethyl acetal in the presence of cat. PTSA
followed by a regioselective reductive ring-opening to give PMB ether 63 in good yields.
Compound 63 on oxidation followed by Grignard reaction with CH3MgI yielded
secondary alcohol 64. The stereotriad 66
was obtained by oxidation of 64, and
converting thus obtained ketone into olefin 65 with Tebbe’s reagent in good yield, which
then prompted to hydroboration with dicyclohexylborane resulted in stereotriad 66 as a
exclusively product with a free primary alcohol. This alcohol 66 on further oxidation with
IBX resulted an aldehyde which in turn formed a stereotetrad 67 by addition of EtOAc to
aldehyde in the presence of LiHMDS with good yield as an exclusive Felkin product.37
The exclusive formation of 1,3-anti and 1,2-syn product in the EtOAc addition to
afford product 67 in Scheme 7 can be explained by presuming both the Felkin-Anh rule
and the Zimmerman-Traxler model.37 In the case of Z(O)-enolates, the Felkin-type
transition states leading to 67 suffer from severe 1,3-syn-pentane (cf. I) or gauche (cf. II)
interactions. In contrast, the anti-Felkin transition state III minimizes both 1,3-syn-pen-
11
Abstract
OH
OTBDPS
a, b
c
57
d
OTBDPS
HO
HO
59
58
O
e, f
OTBDPS
HO
g, h
HO
O
OTBDPS
OH
60
HO
OTBDPS
OH
61
62
OH
k, l
i, j
HO
m, n
OTBDPS
H3C
OPMB
OTBDPS
o
64
65
p, q
HO
OTBDPS
r, s
EtO2C
OTBDPS
OH
OPMB
OPMB
66
EtO2C
OTBDPS
OPMB
OPMB
63
H3C
67
OTBDPS
OH
OMOM
68
Scheme 7
Reagents: (a) TBDPSCl (1.1 equiv), imidazole (2.2 equiv), CH 2Cl2, 25 °C, 16 h, 99%; (b) EtMgBr (3
equiv), p-formaldehyde (3 equiv), THF 0oC-25 °C, 18 h, 71%; (c) H2 (1 atm), 5% Pd/BaSO4 (7 wt %),
quinoline (5 wt %), MeOH, 25 °C, overnighht, 98%; (d) Ti(OiPr)4 (0.1 equiv), L-DIPT (0.2 equiv), CHP
(1.0 equiv), MS (4 Å), CH2Cl2, -20 °C, 24 h, 99%, 92% ee ; (e) NaIO4 (4.1 equiv), RuCl33H2O (2.2 mol
%), CCl4/CH3CN/H2O (1:1:1.5), 25 °C, 4 h, 80%; (f) AlMe3 (3.0 equiv), hexane, 25 °C, 40 h, 75%; (g) MeI
(1.3 equiv), K2CO3 (1.0 equiv), acetone, 25 °C, 18 h, 90%; (h) LAH (1.2 equiv), THF, 0 oC, 1h, 84%; (i)
Anisaldehyde dimethyl acetal (1 equiv), PTSA (cat), CH2Cl2, 98%; (j) DIBAL (1.5 equiv), CH2Cl2, 0 oC-25
o
C, 98%; (k) DMSO (4 equiv), (COCl)2 (2 equiv), Et3N (8 equiv), CH2Cl2, -78 oC, 30 min, >99% (crude
oil); (l) MeMgI (3 equiv), ether, 0 oC-25 oC, 3 h, 94 %; (m) Dess-Martin periodinane (1.5 equiv), solid
NaHCO3 (1.2 equiv), CH2Cl2, 0 oC, 4 h, 96%; (n) Tebbe reagent (1.1 equiv), THF, 0 oC, 2 h, 88%; (o)
BH3DMS (3 equiv), cyclohexene (6 equiv), THF, 0 oC-25 oC, 4 h, 86%; (p) IBX (1.5 equiv), DMSO, 0 oCrt, 4 h, 76%; (q) HMDS (4.2 equiv), n-BuLi (4.2 equiv), EtOAc (4 equiv), THF, -78 oC, 2 h, 74%; (r)
MOMCl (2 x 2 equiv), DIPEA (5 equiv), CH 2Cl2, 0 oC-reflux, 2-4 h, 82%; (s) DDQ (1.2 equiv),
CH2Cl2:H2O (8:0.4 mL), 25 oC, 40 min, 91%.
tane and gauche interactions, leading to anti, anti aldol product as anti-Felkin product
predominantly (Figure 4).
In contrast, E(O)-enolates, should preferentially give rise to the Felkin adduct 67
The transition state V leading to the anti-Felkin product, which suffers from a gauche
interaction between R and L compared to the Felkin transition state IV, in which only a
gauche interaction between R and M is evident (Figure 5).
On the other hand, during the addition of EtOAc to aldehyde the experience of all
the interactions are suppressed because herein R group is a simple hydrogen therefore the
transition states III and V are ruled out. However, the transition state II has some of
12
Abstract
X
Lig
Met
H
O
H
H
L
O
X
Lig
Lig
Met
H
O
H
L
M
R
Lig
O
R
M
H
1,3-syn-pentane interaction
gauche interaction
I
II
L
M
Lig
Met
X
O
H
Lig
O
H
R
anti-Felkin transitionstate
III
Figure 4
the Gauche interactions between H and L groups and hence this transition state also not
suitable when compared to transition states I and IV where all the interactions are absent
except in the transition state I which shows 1,3-syn-pentane interactions between
hydrogen, H and M is negligible to form Felkin product predominantly and exlusively.
Hence, of the two I and IV, the later transition state is more preferred to invoke and
explain the anti, syn aldol product formation in the above reaction.
X
Lig
Met
H
O
R
H
L
O
M
H
Lig
Lig
Met
X
O
R
O
Lig
L
H
H
M
gauche interaction unfavorable
leads to Felkin product
IV
V
Figure 5
Thus, resulted alcohol 67 undergo protection with MOM-Cl in the presence of
DIPEA in CH2Cl2 to afford MOM ether which then deblocking of PMB with DDQ
afforded 68 in good yield. Thus, it is clearly demonstrated that the two hydroxyl groups
are differently protected and can be discriminated. Also interestingly both the ends of the
carbon chain is decorated with different functional groups for convenient manipulationt.
13
Abstract
In conclusion, the stereotetrad is a common substructure in polypropionate natural
products. Four stereogenic centers next to each other result in eight possible
diastereomeric combinations of this structure. Thus, an asymmetric synthesis of each of
these combinations (anti, anti, anti; anti, anti, syn; anti, syn, anti; syn, anti, anti; syn, syn,
anti; syn, anti, syn; anti, syn, syn and syn, syn, syn) demands accurate planning and
careful realization in the laboratory. When the synthesis of a stereotetrad is a part of a
total synthesis of a more complex molecule the situation becomes even more
complicated. If the stereotetrad fragment can be cleaved retro synthetically into an
independent sub-goal, its synthesis is often more straightforward than in the case where
the stereochemistry of the stereotetrad is created by a linear approach. In the latter
situation, the stereochemistry and structure of the remaining molecule has to be
considered and it usually limits the possible strategies to a minimum.
Chapter III: TosMIC mediated synthesis of Amides
Section A: InCl3 catalyzed C-C coupling of aryl alcohols with TosMIC
This section dealt with the synthesis of amides through InCl3 catalyzed carbon-carbon
bond formation of aryl alcohols with TosMIC.
To construct C-C bonds, coupling reactions between reactive nucleophiles such as
organometallic compounds (R1M) and halides or a related species (RX) are undoubtedly
a useful process. The species RX and R1M are often prepared from alcohols (ROH) and
active methylenes (R1H), respectively. However, the coupling reaction intrinsically
produces a salt (MX) alongside the desired product (R-R1). The direct reaction between
ROH and R1H would be an ideal process for C-C bond formation because preparation of
the reactive materials would not be required and only H2O would be generated as a side
product. This process would significantly save energy during multistep transformations
and separation of the product from the salt. Thus, a catalyst for the reaction is required
that activates either ROH or R1H and has low oxophilicity and insensitivity to water.
14
Abstract
Catalytic activation of alcohols is generally difficult because of the inefficient
leaving-group ability of the hydroxyl group. On the otherhand p-toluenesulfonylmethyl
isocyanide38 TosMIC a versatile, widely applicable reagent that constitutes a densely funC-nucleosides
(Ref. 49b)
R'
R
O
R
Tos
'R
NC
OH
R
'R
C
N
Passerini
(Ref. 49d, 49f)
S
O
O
TosMIC
Figure 6
ctionalized building block bearing an active methylene group. a Lewis acid mediated
direct C-C coupling was envisaged between TosMIC and aryl alcohols which would
result in α-alkylated TosMIC as products (Figure 6),39 however an N-substituted amide
was obtained instead (Scheme 7). To the best of our knowledge, this is the first report on
the use of isonitrile in such a mechanistic pathway.40
OH
+ TosMIC
R'
78
69-77
R = R1 = alkyl, aryl, heteroaryl etc
R
O
NH
InCl3 (5 mol%)
o
CH3CN, 80 C
R
R'
79-87
Tos
+
R
R'
O
'R
R
by product
Scheme 7
Accordingly the coupling reaction was performed between, benzhydrol 69 and
TosMIC 78 in the presence of FeCl3 (5 mol%) at 80 oC in acetonitrile as solvent to afford
amide 79 in 73% yield along with the corresponding dimeric ether (9%) as a byproduct.
In order to minimize byproduct formation, different Lewis acids such as BF3.OEt2, ZrCl4,
Sc(OTf)3 and InCl3 were screened under similar reaction conditions to afford 79 and the
dimeric ether in varying yields. It was found that when the reaction was carried out using
InCl3 as the catalyst the amide 79 (92%) was formed in a shorter reaction time. Amide 79
was identified from its 1H NMR spectral data. Further the versatility of the methodology
was studied with various substrates. Thus, alcohols 70-77, including an α,β-unsaturated
alcohol 70, a tertiary alcohol 72, bicyclic benzylalcohol 73, and heteroaryl benzylalcohol
74 afforded the corresponding amides 80-87 under standard reaction conditions in good
to high yields (75-88%) (Table 3).
15
Abstract
In conclusion, we have reported a new InCl3 mediated C-C coupling reaction
between aryl alcohols and TosMIC to afford the corresponding amides in good to high
yields. This reaction besides being atom economical in nature is also a novel protocol that
paves way for further exploitation of TosMIC.
Table 3 Coupling reaction between various alcohols and TosMIC under optimized conditions
Entry
Productb
Alcohol
OH
1
Ph
Yield (%)c
79
2
92
80
4
87
81
8
76
82
4
85
83
3
88
84
4
80
85
4
76
86
3
78
87
6
75
Ph
69
2
Time [h]
OH
Ph
Ph
70
OH
3
Ph
CH3
71
OH
4
Ph
72
Ph
CH 3
OH
5
73
OH
6
S
74
Ph
OH
Ph
7
HO
75
OH
Ph
8
76
9
OH
77
Section B: Indium mediated synthesis of -keto-(E)-enamino esters through C-H
activation of 1,3-dicarbonyl compounds
This section dealt with the Synthesis of -keto-(E)-enamino esters through InCl3
catalyzed carbon-carbon bond formation of 1,3-dicarbonyl compounds with TosMIC.
16
Abstract
Enamination of -dicarbonylcompounds forming β-enamino ketones and esters, is
an important and widely used transformation.41 The latter compounds are highly versatile
class of intermediates for the synthesis of heterocycles and biologically active
compounds.42 In particular, the enamino ketone moiety has attracted much interest
because it is a basic and versatile structure for the synthesis of natural therapeutic and
biologically active analogues including taxo,43 anticonvulsivant,44 anti-inflammatory,45
and antitumor agents,46 as well as quinolone antibacterials47 and quinoline antimalarials
and also such as β-enamino acids, -enamino alcohols or β-enamino esters.48
Because of this usefulness and in continuation of our effort to expand the utility of
p-toluenesulfonylmethyl isocyanide (TosMIC) as an isonitrile component49 we intended
to develop a novel protocol of accessing -keto-(E)-enamino esters by considering the
fact that 1, 3-dicarbonyl compound(s) can be activated by the Lewis acids50 and the
ensuing enolate could be trapped, in situ, with TosMIC as a worthwhile proposition
(Scheme 8).
Tos
O
R1
O
O
R2 +
TosMIC
InCl3
CH3CN, 80 0C
78
R1 = CH3, Cl-CH2, 4-NO2-Ph etc
R2 = CH3, OEt
R1
NH
O
R2
Scheme 8
Accordingly, we first screened various commercially available isonitriles such as
tert-butyl isocyanide, cyclohexyl isocyanide and TosMIC 78 with ethyl acetoacetate 88 in
the presence of InCl3 (5 mol%) as the Lewis acid catalyst in acetonitrile as a solvent at 80
C in a bid to access the respective -keto-(E)-enamino ester. Gratifyingly, TosMIC was
o
the only isonitrile to have reacted under the said reaction conditions to afford -keto-(E)enamino esters 95 (91%) mainly due to the multiple reactivity of TosMIC that emerges
from it’s densely functionalization while the other isonitriles were inactive. Also we
screened several Lewis acids, namely FeCl3 (20%), BF3.OEt2 (15%) and ZrCl4 (30%) for
the same transformation but found InCl3 the best yielding. This behavior maybe
attributed to the fast decomposition of TosMIC.
17
Abstract
Table 4 C-C Coupling between carbonyl compound and TosMIC under optimized conditionsa
Entry
Productb
Carbonyl compd.
Time [h]
O
O
1
H3C
O
H3C
O
OEt
HN
95
CH2Tos
OEt
88
O
2
96
89
O
3
O
H3C
O
O
91
O
H3C
R
OEt
OBn
HN
CH2Tos
92
O
94
6
82
O
H3C
OBn
6
4
HN
98
CH2Tos
O
OEt
86
OEt
R = 4-NO2
O
10
O
OEt
R R = 4-NO2
5
CH3
HN
97
CH2Tos
90
4
88
O
H3C
CH3
O
5
HN
CH2Tos
OEt
O
91
OEt
O
Cl
3
O
Cl
O
Yield (%)c
99
O
EtO
no reaction
OEt
93
O
7
H3C
H3C
H
N
O
Tos
OEt
CN
CH3
94
Tos
100
-keto-(E)-enamino ester 91 was identified from its 1H NMR spectrum, 13C NMR
spectrum, IR spectrum revealed the characteristic peaks and stretching frequencies
18
Abstract
respectively, ofcourse, ESIMS spectrum show the corresponding product. On the
otherhand, the geometry was unambiguously proved experimentally by 1D nOe study of
-keto-(E)-enamino ester 95, which reveals the characteristic olefin proton was in cis
position to ester, as well as amine derivative was in trans to ester due to correlation of
O
O
H3C
CH3
H
O
HN
H
CH2 Tos
Figure 7
olefin proton with methylene of ester group has been observed (Figure 7). Further it was
supported by HB values of eanaminones and enamino esters studied independently from
17
O NMR.51Accordingy, formation of the compound showed in structure B has been
believed strongly because it is well known that ester carbonyl groups are less basic than
O
OEt
H3C
CH3 O
O
H
A
O
H
N
CH2Tos
OEt
N
CH2Tos
B
Figure 8
ketone carbonyls, and consequently ester carbonyls are expected to be poorer hydrogen
bond acceptors than ketone carbonyls (Figure 8).
Subsequently, in an effort to generalize the synthetic methodology, we studied
various 1,3-dicarbonyl compounds, 89-92, possessing different functional groups and
substituents (Table 4), including the -chiral 1,3-dicarbonyl compound 92 under the
standardized reaction conditions to afford corresponding β-keto-(E)-enamino esters 96-99
in good yields except in the case of di ketone 90, where the product obtained is β-keto
enaminone 97 (Table 4). Similarly there was determined no such product of desired and
un desired new prodct 100 in the case of ethyl malonate 93 with TosMIC 78.
Interestingly, self coupling of TosMIC to result undesired new product 100
(Scheme 9) has been observed first time during the reaction between 94 with TosMIC 78
19
Abstract
because of unsuitable di ketone system, but it could be act as chelating ligand52 in the
presence of InCl3 to afford undesired new compound 100.
H
N
94
TosMIC 78
InCl3, CH3CN
CN
Tos
Tos
100
Scheme 9
In conclusion, we have reported a new protocol for the synthesis of -keto-(E)enamino esters and -keto enaminone in good yields by the C-C coupling between 1,3dicarbonyl compounds and TosMIC via Lewis acid catalyzed enolization pathway.
20