Synopsis
SYNOPSIS
The Thesis entitled “Stereoselective Synthesis of Functionalized Trisubstituted Olefins
Including Some Insects Pheromones and Bioactive Molecules Using Baylis-Hillman
Protocol and Development of New Synthetic Methodologies.” consists of four chapters.
CHAPTER I
The Baylis-Hillman Reaction: An Overview
The Baylis-Hillman reaction including its application to the synthesis of trisubstituted
olefins is briefly reviewed.
Introduction
Construction of a C–C bond is most fundamental requirement in the synthetic organic
chemistry from its origin. The well-known C–C bond forming reactions are
Aldol condensation reaction (1872), Friedel-Craft reaction (1877), Diels-Alder reaction
(1928), Wittig reaction (1954) and Heck reaction (1968).
Recently, Baylis-Hillman reaction got serious attention as a novel and versatile C–C
bond forming protocol after its discovery by two German scientists, A. B. Baylis and M.
E. D. Hillman in 1972.
Baylis-Hillman Reaction:
This is a two component coupling reaction involving the -position of an activated
alkenes with carbon electrophiles under the catalytic influence of a tertiary amine
providing a simple process for synthesis of densely functionalized molecules known as
X
EWG
+
R1
R
tert. amine
R
XH
EWG
R1
Baylis-Hillman adduct
R = alkyl, aryl, heteroaryl; R1 = H, COOR, Alkyl; X = O, NCOOR, NTS, NSO2Ph
EWG = Electron withdrawing group; COR, CHO, CN, COOR, PO(OEt) 2 SO2Ph, SO3Ph, SOPh
tertamine =
N
N
,
1
N
,
OH
N
,
3
2
i
O
N
,
4
N
5
Synopsis
Baylis-Hillman adducts.
Components of Baylis-Hillman Reaction
The Baylis-Hillman reaction requires three essential components, that is, the activated
alkene, electrophile and the catalyst.
1) Activated alkenes: The most commonly used activated alkenes in Baylis-Hillman
reaction are alkyl vinyl ketones, alkyl (aryl) acrylates, acylonitrile, acrylamides, vinyl
sulfonates and vinyl phosphonates.
2) Electrophiles: Various aliphatic, aromatic and hetero-aromatic aldehydes have been
used as a primary source of electrophiles in obtaining interesting Baylis-Hillman adducts.
Also -keto esters, non enolizable 1,2-diketones, aldimine derivatives and activated
alkenes have been employed as electrophilies in this reaction.
3) Catalysts: The most commonly used catalyst is DABCO (1). The other tertiary amine
catalysts such as quinuclidine (2), 3-HQD (3), 3-quinuclidone (4) and indolizine (5) were
also used to perform the Baylis-Hillman reaction.
Application of Baylis-Hillman Reaction
The Baylis-Hillman adduct is densely functionalized with several groups in close
proximity. A hydroxyl or amino group, a highly activated double bond, an electron
withdrawing group ranging from –CHO, -COR, -COOR, -CN, -PO(OR)2 to -SO2Ph are
the core functionalities. Normally the adduct is having an allyl alcohol moiety, a chiral
center and a Michael acceptor. Applications of this adduct need proper tuning of the
functional groups.
OH
R'
Addition
EWG
reaction
OH
R'
EWG
R
R
Nu
R'
Substitution
Nu
Nu
EWG
R'
reaction
R
+
EWG
R
Baylis-Hillman
adducts are mostly exploited for nucleophilic
substitution
(SN2 and SN2’)
Nu
Nu = H, C, N, O, S and X (halogen)
atoms as nucleophilic centre
Trisubstituted Olefins
and addition reactions. Nucleophilic substitution
reactions of Baylis-Hillman adducts are
commonly associated with the concomitant allylic rearrangement of the double bond
which led to the formation of a variety of trisubstituted olefins stereoselectively. Various
adducts have been employed for the stereoselective synthesis of different naturally
occurring bioactive compounds including several alkaloids, terpenoids, macrolides and
ii
Synopsis
pheromones. All of these molecules contain a stereodefined trisubstituted olefin moiety
as the central structural unit, which have been well documented in the literature.
A brief review on the Baylis-Hillman reaction and its application to the synthesis of
functionalized trisubstituted olefins has been presented.
CHAPTER II
Stereoselective Synthesis of Functionalized Trisubstituted Olefins by the
Metal-mediated Reduction of Baylis-Hillman Adducts
This chapter is divided into two sections.
SECTION A: Stereoselective Synthesis of [2E]-2-Methylalk-2-enoates and [2Z]-2Methylalk-2-enenitriles and Its Applications
[2E]-2-Methylalk-2-enoates and [2E]-2-methylalk-2-enoic acids (or its other
derivatives) are the important skeletons present in a wide range of biologically active
molecules. We have visualized that the acetate derivatives of Baylis-Hillman adducts 6,
derived from acrylic ester and 7, derived from acrylonitrile could be easily transformed
into
the
desired
[2E]-2-methylalk-2-enoates
and
[2Z]-2-methylalk-2-enenitriles
respectively. Accordingly, we have treated methyl 3-acetoxy-2-methylene-alkanoates 6
or 3-acetoxy-2-methylenealkanenitriles 7 with Zn powder in saturated aqueous
NH4Cl solution under reflux condition. The resulting trisubstituted alkenes (14
examples) 8 or 9 were obtained in high yields and in good stereoselectivity (Scheme 1).
Scheme 1
OAc
Zn / aq. sat. NH4Cl
reflux, 1 - 4.5 h
EWG = COOMe
R
H
EWG
R = aryl, alkyl
Zn / aq. sat. NH4Cl
reflux, 2.5 - 5 h
EWG = CN
6: EWG = COOMe
R
CN
9 [Z]- Major (78-91%)
+
7: EWG = CN
H
H
COOMe
CN
R
R
8 [E]- 100%
10 [E]- Minor (9-22%)
75-96% (Yield)
71-86% (Combined yield)
The regioselective reduction of 6 into 8 can possibly be explained by proposing the
reaction to proceed via the formation of the intermediate A (Figure 1). This intermediate
iii
Synopsis
may arise by an initial SET to the conjugated enone moiety of 6 followed by protonation
and the second SET process. A similar mechanism of the regioselective reduction of 7
into 9 can be proposed by involving the intermediate B (Figure 1). This mechanism
explains the (E)- selectivity with ester (forming a chelated reaction intermediate, A) and
(Z)- selectivity with nitriles (forming a nonchelated intermediate, B).
Cl
O
O
Zn
O
O
O
N
ZnCl
C
R'
R'
OR
A
B
Figure 1. Possible intermediates to account for the observed stereoselectivity.
With a view to prove the efficacy of this ecofriendly protocol we have undertaken the
practical synthesis of three insect pheromones. (+)-(S)-1-methylbutyl (E)-2-methyl-2pentenoate (dominicalure-I) 11 and (+)-(S)-1-methylbutyl (E)-2,4-dimethyl-2-pentenoate
(dominicalure-II) 12, the aggregation pheromones of lesser grain borer Rhyzopertha
dominica (F) and 1-methylethyl (E)-2-methyl-2-pentenoate (trunc-call-I) 13, an important
aggregation pheromone of the insect species Prostephanus truncatus have been
synthesized here.
H
H
O
O
O
O
H
H
(+)-(S)-Dominicalure-II
(+)-(S)-Dominicalure-I
12
11
H
O
O
Trunc-call-I
13
iv
Synopsis
We have undertaken the synthesis of pheromones 11 and 12 starting from n-propanal
and 2-methylpropanal respectively according to the procedure presented in Scheme 2.
Scheme 2
OH
O
OMe
R-CHO +
O
AcCl, Py
DABCO
OMe
R
Dioxane:H2O (1:1)
14 R = Et, 85%
15 R = i-Pr, 81%
OAc
R
O
OMe
H
Zn/ aq. NH4Cl (saturated)
R
reflux, 4.5 h
O
18 R = Et
OMe
19 R = i-Pr
16 R = Et, 87%
[E]-2-Methylalk-2-enoates
17 R = i-Pr, 84%
H
1. NaOH/MeOH
18, 19
2. aq. HCl
R
O
H
OH
1. SOCl2
2. (+)-(S)-2-pentanol
20 R = Et, 69%
21 R = i-Pr, 64%
v
R
O
O
H
11 R = Et, 74% (+)-(S)-Dominicalure-I
12 R = i-Pr, 71%(+)-(S)-Dominicalure- II
Synopsis
We have synthesized molecule 13 starting from n-propanal according to procedure
presented in Scheme 3.
Scheme 3
O
CHO +
OH
OMe
O
DABCO
OMe
Dioxane:H2O (1:1), 85%
AcCl
Py, 87%
14
OAc
O
H
OMe
O
Zn/ aq. NH4Cl (saturated)
1. NaOH/MeOH
OMe
reflux, 4.5 h
2. aq. HCl, 69%
16
[E]-2-Methylalk-2-enoates
H
O
H
OH
O
1. SOCl2
O
2. 1-methylethanol, 41%
20
13, Trunc-call-I
Thus, we have successfully utilized the potential of our developed methodology for the
practical synthesis of three important insects pheromones.
SECTION B: Stereoselective Synthesis of [E]-α-Methylcinnamic and [2E]-2Methylalk-2-enoic Acids and Its Applications
[E]--Methyl cinnamic and [E]-2-methylalk-2-enoic acid moieties are central structural
unit
present
in
various
biologically
active
molecules.
1-[p-(Myristyloxy)--
methylcinnamoyl]glycerol (LK-903) 22 is a very active hypolipidemic agent. N-Allyl-N-[4{(4-amidinophenoxy)-carbonyl}--methyl cinnamoyl]glycine methanesulfonate 23 and its
analogues are potent orally active serine protease inhibitors. [E]-2-Methyl-3-(4(myristyloxy)-phenyl)prop-2-enoic acid 24 itself also shows good hypolipidemic activity.
[E]-2-Methyl-3-(4-carbomethoxyphenyl)-prop-2-enoic acid 25 is a valuable synthon for
the synthesis of serine protease inhibitor 23. On the other hand, (+)-(S)-manicone 26
and (+)-(S)-normanicone 27, are the mandibular gland alarm pheromone components of
the ants in the genus Manica. (4S, 2E)-2,4-Dimethyl-2-hexenoic acid 28 is a caste-
vi
Synopsis
specific substance present in the mandibular glands of the male carpenter ants in the
genus Camponotus.
OH
O
O
O C
H2N
H
O
OH
n-H29C14O
H
O
HN
MeSO3H
N
22
CO2H
23
LK-903
O
O
H
H
OH
OH
MeO2C
n-H29C14O
25
24
O
O
H
H
27
(+)-(S)-Normanicone
26
(+)-(S)-Manicone
O
H
OH
28
(S, E)-2,4-Dimethyl-2-hexenoic acid
We have realized that the unactivated Baylis-Hillman adducts derived from methyl
acrylate could be transformed into the desired [E]--methyl cinnamic and [E]-2methylalk-2-enoic acid moiety. We observed that the treatment of Baylis-Hillman
adducts,
methyl-3-hydroxy-3-aryl-2-methylenepropanoates
29
with
Al-NiCl2.6H2O
reagent in methanol at room temperature, followed by hydrolysis with KOH/MeOH and
crystallization or chromatography afforded the corresponding [E]--methylcinnamic acids
vii
Synopsis
and [E]-2-methylalk-2-enoic acids 31 (10 examples) in high yields via the formation of
the intermediates 30 (Scheme 4).
Scheme 4
OH
OMe
R
O
O
O
Al-NiCl2.6H2O
MeOH
OMe
R
R
ii) crystallization
or
chromatography
r.t., 1-2h
30
29
i) KOH MeOH
r. t., 2 h
OH
31
71-88% (overall yield)
R = aryl, alkyl
100% E
The stereochemistry of products was solely [E]- which can possibly be explained
by considering the transition state models C and D (Figure 2). Transition state C is more
favored than D due to steric demand and the R group (alkyl, aryl) prefers to stay trans to
the –COOMe group. Thus, [E]- products are formed solely.
Figure 2.
OH
R
O
Me
H
COOMe
Me
COOMe
H
OH
O
R
D
C
Encouraged by this observation, we have then synthesized a series of (E)--methyl
cinnamic and [E]-2-methylalk-2-enoic acids directly from various adducts without
isolating the intermediates 30. The used reagents i.e. Al-NiCl2.6H2O in MeOH is useful
for the synthetic purposes as per as the operational simplicities, overall yields and
stereoselectivities are concerned. We have presented the synthetic applications of AlNiCl2.6H2O in MeOH using Baylis-Hillman adducts. Infact, the efficiency of the protocol
have been proved by the practical synthesis of compound 22, 24, 25, 26, 27 and 28
which have been discussed below.
viii
Synopsis
Potent
anti-cholesterolemic
drug
LK-903
(22)
was
synthesized
starting
from
4-hydroxybenzaldehyde in six steps via the formation of p-myristyloxy-[E]--methyl
cinnamic acid 24 which also showed good hypolipidemic activity (Scheme 5).
Scheme 5
CHO
CHO
O
1) C14H29Br
OH
2) K2CO3 / Acetone
2h, reflux, 93%
+
OMe
DABCO
Dioxane /water (1:1)
r.t., 8 days, 76%
OR
32
OH O
OMe
H
Al-NiCl2.6H2O
MeOH
r. t., 2 h
O
1) KOH / MeOH, 2h
OMe
RO
RO
2) aq. HCl
3) crystalisation
78%
34
33
O
H
O
HO
O
H
O
35
O
OH
BOC2O, DMAP, THF, r.t.,
14h, 89%
RO
O
O
RO
36
24
NaHSO4.SiO2
DCM:iso-propanol (4:1)
r.t., 4h, 85%
H
O
OH
O
OH
RO
22
R = n-C14H29
We have undertaken the synthesis of 25 starting from 4-carboxybenzaldehyde in four
steps (Scheme 6).
ix
Synopsis
Scheme 6
CHO
CHO
O
MeOH/H2SO4
DABCO
t
O BU
+
Dioxane /water (1:1)
48 h, 84%
2h, reflux
92%
CO2H
CO2Me
37
H
OH O
OtBU
O
Al-NiCl2.6H2O
OtBU
MeOH, r.t., 2 h.
MeOOC
MeOOC
39
38
Amberlyst-15
CH3CN, r. t., 3 h
62%
H
O
OH
MeOOC
25
Thus, we have utilized the potential of our developed methodology for the practical
synthesis of two hypolipidemic agents LK 903 22 and 24, and of 25 which is a valuable
synthon for the synthesis of serine protease inhibitor, N-allyl-N-[4-{(4-amidino phenoxy)carbonyl}--methylcinnamoyl] glycine methane sulfonate 23.
We have given a modern and improved approach in every step during the synthesis of
these molecules, unlike the classical approach, to enhance the overall yield and
stereoselectivity of the target molecule.
We have synthesized the pheromone 28 starting from (S)-2-methyl butanol via the
Baylis-Hillman adduct 41 according to the Scheme 7.
x
Synopsis
Scheme 7
OH
CH2OH
H
O
CHO
+
K2Cr2O7 / H2SO4.H2O
OMe
OMe
H
70 0 C, distillation, 54%
H
0°C, 20 h, 71%
41
40
(S)-2-Methylbutanol
(S)-2-Methylbutanal
H
Baylis-Hillman adduct
H
O
O
1. KOH, MeOH/H2O
Al-NiCl2.6H2O
OMe
H
O
DABCO, Dioxane
OH
H
2. aq. HCl, 73%
MeOH, r. t., 2 h
28
42
(4S, 2E)-2,4-Dimethyl-2-hexenoic acid
The pheromones 26 and 27 have been synthesized through a common sequential route
of six steps via the compound 28 according to Scheme 8.
Scheme 8
H
O
SOCl2
H
OH
H
benzene
H
O
Cl
43
28
H
O
Et2CuLi / Et2O
(S, E)-2,4-Dimethyl-2-hexenoic acid
- 78° C
84%
Me2CuLi / Et2O
26
H
(+)-(S)-Manicone
H
27
- 78° C
H
80%
O
(+)-(S)-Normanicone
Thus, we have successfully utilized the potential of Baylis-Hillman chemistry for the
practical synthesis of three important pheromones, (+)-(S)-manicone (26), (+)-(S)normanicone (27) and (4S, 2E)-2,4-dimethyl-2-hexenoic acid (28). In most of the
previous reports, controlling of two stereoselective factors, the [E]- configuration of the
double bond and the absolute (S)- configuration of the chiral center consist of multistep
sequences with low global yields or have a moderate optical purity. In the present case,
we could overcome those difficulties successfully and established an improved protocol.
xi
Synopsis
CHAPTER III
Stereoselective
Synthesis
of
Functionalized
Trisubstituted
Olefins
Introducing Heteroatom Nuclephiles (S, O, Br, Cl) to the Baylis-Hillman
Adducts
This chapter is divided into three sections.
SECTION A: Stereoselective Synthesis of [Z]- and [E]-Allylsulfides introducing
Sulfur Nucleophile to the Baylis-Hillman Adducts and Its Applications
In continuation of our work on the streoselective synthesis of functionalized
trisubstituted alkenes using Baylis-Hillman protocol and its applications, we would like to
synthesize different stereodefined trisubstituted allyl sulfides of synthetic need. Herein,
we have reported an efficient stereoselective synthesis of [Z]- and [E]- allyl sulfides (16
examples) from Baylis-Hillman acetates in one-pot by treatment with benzenethiol in the
presence of catalytic amounts of 15% aqueous NaOH and TBAI in DMSO at room
temperature (Scheme 9).
Scheme 9
OAc
PhSH
15% aq. NaOH/ TBAI
EWG
R
EWG
R
DMSO, r.t., 30 60 min.
SPh
R= aryl or alkyl
6. EWG=
COOMe,
7. EWG=
CN
71- 92 %
COOt-Bu
44. EWG=
COOMe,
45. EWG=
CN
COOt-Bu
During the studies, several 3-acetoxy-2-methylene-alkanoates (6) and 3-acetoxy-2methylene-alkannitriles (7) were treated with benzenethiol in the presence of catalytic
amounts of 15% aqueous NaOH and TBAI in DMSO at room temperature to generate
different trisubstituted allyl sulfides.
The electron withdrawing groups present in the adducts direct the stereochemistry of the
products which is a well known fact in the Baylis-Hillman chemistry. In the present case,
when the –COOMe or –COOt-Bu group (as EWG) was present in the adducts (6) the
conversion afforded the olefins (44) with 100% trans– stereoselectivity while when the –
CN group was present (as EWG) in the adducts (7) the olefins (45) were formed with
high cis– stereoselectivity along with minor trans-isomer. The stereochemistry of 44 and
45 can possibly be explained by considering the transition state models E, F and G
xii
Synopsis
(Figure 3). Transition state E is more favored than F due to steric demand when EWG is
an ester and the R group (alkyl, aryl) prefers to stay trans to the ester group. Hence, [Z]products are formed exclusively. On the other hand, model G is more favored than E
when the EWG is a nitrile as –CN is linear and hence the [E]- products are formed
predominantly.
OAc
OAc
O
H
R
EWG
PhS
COOMe
PhS
C
N
PhS
H
OAc
E
R
H
R
O
O
F
G
Figure 3. Possible TS models to account for the observed stereoselectivity.
Synthetic Application of Stereodefined Trisubstituted [Z]-Allyl Sulfides: A New
Protocol for the Synthesis of (Z)-3-Benzylidenethiochroman-4-one
The (Z)-3-benzylidenethiochroman-4-one moiety occupies a special place in the field of
heterocycles as this skeleton is an integral part of many biologically active molecules.
For example, the (Z)-3-benzylidenethiochroman-4-ones 46 & 47 displayed significant
antifungal activity against pathogenic fungi Candida albicans and Toru-lopsis glabrata
(MIC = 6 µg/mL). On the other hand, compounds 48 and 49 displayed useful activity
against Cryptococcus neoformans. The (Z)-3-benzylidenethiochroman-4-one moieties
are important synthons for the synthesis of novel tricyclic heterocycles having anticancer
activity.
O
O
O
S
O
S
MeO
47
46
O
O
Cl
Cl
MeO
S
S
49
48
xiii
Synopsis
Thus, the development of new protocol for synthesis of (Z)-3-benzylidenethiochroman-4one is highly desirable. During our efforts, we envisaged that [Z]- allyl sulfides could be
used
as
valuable
synthons
benzylidenethiochroman-4-one.
for
With
the
this
synthesis
of
conception,
we
stereodefined
have
(Z)-3-
delineated
the
retrosynthetic analysis for (Z)-3-benzylidenethiochroman-4-one moiety (Scheme 10).
Scheme 10
O
COOH
I. F. A
F. G. I
S
S
R1
R1
OAc
COOR
Nucleophilic
Substitution
S
R1
COOR
+
HS
Reaction
R1
Benzene thiol
Baylis-Hillman acetate
From retrosynthetic analysis it was cleared that (Z)-3-benzylidenethiochroman-4-one
moieties could be obtained from [Z]- allyl sulfides via their corresponding (Z)-3-phenyl-2(phenylthiomethyl)acrylic acids. Accordingly, the [Z]-allyl sulfides 44a-e containing –
COOMe group were converted into their corresponding acids 50 (5 examples) by base
hydrolysis, followed by acidification (Scheme 11).
Scheme 11
COOMe
Ar
KOH, H2O
Acetone
COOH
Ar
Ar
CH3CN, reflux, 3 h
r.t., 20 h
SPh
SPh
44 a-e
COOt-Bu
Amberlyst-15
50
SPh
44 f-i
Alternatively, the allyl sulfides 44f-i containing tert-butyl ester group were converted into
their corresponding acids 50 (4 examples) by acid hydrolysis, treating with
heterogeneous solid acid catalyst, Amberlyst-15 in CH3CN at reflux temperature.
After successful transformation of [Z]- allyl sulfides 44a-e or 44f-i into their
corresponding acids 50, we proposed to synthesize (Z)-3-benzylidenethiochroman-4-
xiv
Synopsis
ones by developing a method of intramolecular Friedel-Crafts cyclization using (Z)-3aryl-2-(phenylthiomethyl)acrylic acids as starting materials. For this purposes we used
TFAA (trifluro acetic anhydride) as a promoter.
We have first attempted to synthesize (Z)-3-(4-methoxybenzylidene)thiochroman-4-
one (46) from (Z)-3-(4-methoxyphenyl)-2-(phenylthiomethyl)acrylic acid 50e by treating
with TFAA (1 eq.) in anhydrous DCM at reflux temperature for 1 h (Scheme 12).
Scheme 12
O
COOH
TFAA, DCM
S
MeO
reflux, 1 h, 92 %
MeO
S
46
50e
After successful synthesis of (Z)-3-(4-methoxybenzylidene)thiochroman-4-one (46), a
potent antifungal agent, we have prepared a series of (Z)-3-benzylidenethiochroman-4one (5 examples) by treating the acids 50 with TFAA in anhydrous DCM at reflux
temperature for 1 h.
Thus first time we have demonstrated a stereoselective synthesis [Z]- and [E]trisubstituted allylsulfides from Baylis-Hillman acetates under mild conditions. The
method is associated with simple and inexpensive reagents. The high yields, short
reaction time and excellent stereoselectivity are the other advantages of our
methodology, which provides a convenient route to the synthesis of [Z]- and [E]trisubstituted allylsulfides.
With a view to prove the efficacy and urgency of this protocol we have
successfully applied the present protocol for the synthesis of some bioactive
benzylidenethiochroman-4-ones.
SECTION B: Stereoselective Synthesis of [E]-Allylethers Introducing Oxygen
Nucleophiles to the Baylis-Hillman Adducts and Its Applications.
After successful synthesis of trisubstituted [Z]- and [E]- allylsulfides, we proposed to
synthesize trisubstituted [E]-allyethers by introducing oxygen nucleophile into the BaylisHillman adducts. Accordingly, we have treated Baylis-Hillman acetates 6, derived from
acrylic esters with phenol in the presence of catalytic amounts of 15% aqueous NaOH
xv
Synopsis
and TBAI (tetrabutyl ammonium iodide) in DMSO at room temperature to afford [E]trisubstituted allyl ethers 51 (9 examples) in an one-pot (Scheme 13).
Scheme 13
OAc
COOR
Ar
PhOH
15% aq. NaOH/ TBAI
COOR
Ar
DMSO, r.t., 1 h
OPh
55-70% 100% E
R= Me or t-Bu
51
6
The stereochemistry of the products 51 can possibly be explained by considering the
transition state models as discussed in the chapter-II, section B. Transion state H is
more favored than I due to steric demand and the aryl group (Ar) prefers to stay trans to
the ester group (Figure 4). Hence, (E)-products are formed exclusively.
_
O
Ar
OAc
H
PhO
COOR
COOR
PhO
H
OAc
H
_
O
Ar
I
Figure 4. Possible TS models to account for the observed stereoselectivity.
This demonstrates a stereoselective synthesis of [E]- trisubstituted allylethers from
Baylis-Hillman acetates under mild condition using inexpensive reagents. Although the
yields are moderate but sole stereoselectivity is impressive fact of this methodology.
To prove the efficacy and necessity of the present method we have applied this
method for the synthesis of methyl ether derivative of bonducelline, a recently isolated
bioactive natural product.
Synthetic Application of [E]- Trisubstituted Allylethers: An Alternative Protocol for
the Synthesis of Methyl Ether of Bonducelline, a (E)-3-Benzylidenechroman-4-one
Heterocycle.
The (E)-3-benzylidenechroman-4-one moiety occupies a special place in the field
of heterocycles as this skeleton is an integral part of many biologically active molecules
and natural products. For example, bonducelline 52 is an important natural product
occurring in Caesalpinia bonducella and Caesalpinia pulcherrima. Methyl ether derivative
xvi
Synopsis
O
MeO
O
O
OH
MeO
Bonducelline 52
O
OMe
Methyl ether of Bonducelline 53
of bonducelline 53 is a recently isolated natural product from Caesalpinia pulcherrima
which have antimicrobial activity.
Hence, we realized that there is a need to develop the synthesis of (E)-3benzylidenechroman-4-one skeleton. We have synthesized methyl ether of bonducelline
53 using the present protocol (Scheme 14).
Scheme 14
OAc
m-MeOC6H4OH
COOt-Bu
COOt-Bu 15% aq. NaOH/TBAI
r. t., 2 h, 54 %
O
MeO
MeO
55
54
OMe
Amberlyst-15/ CH3CN
reflux, 3 h, 91%
O
COOH
TFAA, DCM
MeO
O
OMe
reflux, 1 h, 89 %
O
MeO
56
53
OMe
.
SECTION C: Stereoselective Synthesis of [2Z]-2-(Halomethyl)alk-2-enoates and
[2E]-2-(Halomethyl)alk-2-enenitriles
[2Z]-2-(Halomethylalk-2-enoates have been used as valuable synthons in the
synthesis of a variety of important molecules such as micanecic acid, kijanolide, rennin
inhibitor A-72517, and β-lactams. Similarly others bioactive molecules like, α-metyleneγ-butyrolactones and flavonoids have also been synthesized using [Z]-allyl halides
derived from Baylis-Hillman adducts.
xvii
Synopsis
The importance of [Z]- and [E]-allyl halides in the synthesis of several natural products
deserved our attention.
Introduction of Br¯ Nucleophile:
We thought to synthesize [2Z]- and [2E]- allyl bromides directly from unmodified BaylisHillman adducts using MgBr2 or LiBr as a halides donor in the presence of HClO4.SiO2, a
heterogeneous Lewis acid catalyst of current interest.
Stereoselective synthesis of these important class of synthons have been achieved by
the treatment of Baylis-Hillman adducts (12 examples) with MgBr2 or LiBr in presence of
HClO4.SiO2 as the heterogeneous catalyst according to Schemes 15 and 16
respectively.
Scheme 15
HClO4.SiO2
OH
H
MgBr2 or LiBr
COOR'
COOR'
R
R
CH2Cl2, r. t.
82-94%
Br
100 % [Z]
57
29
R'= Me, Et
Scheme 16
HClO4.SiO2
OH
CN
R
H
H
MgBr2 or LiBr
Br
R
CH2Cl2, r. t
CN
+
R
CN
74-86 %
84-95 % E
58
Br
5-16 % Z
59
The stereochemistry of products was exclusively [Z]- when EWG = -COOMe, whereas
[E]- was the major isomer (84-95%) when EWG = -CN.
In conclusion, we have prepared the [Z]- and [E]- allyl bromides by treatment of
Baylis-Hillman adducts with magnesium or lithium bromides in CH2Cl2 using HClO4.SiO2
as a heterogeneous catalyst at room temperature. The mild reaction condition, shorter
reaction times, convenient experimental procedure and inexpensive catalyst are the
great advantages associated with this method.
xviii
Synopsis
Introduction of Cl¯ ion Nucleophile:
We wanted to synthesize allyl chloride moieties under mild and acid free conditions. It
was observed that the Baylis-Hillman adduct 29 could efficiently be transformed into
[2Z]-2-(chloromethyl)alk-2-enoates 60 (15 examples) using Cl3CCONH2 in combination
with PPh3 in CH2Cl2 at room temperature (Scheme 17).
Scheme 17
PPh3 (2 eq.)
OH
COOR'
R
H
COOR'
Cl3CCONH2 (2 eq.)
R
CH2Cl2, r. t.
3 - 4 h, 74 - 89%
Cl
R' = Me, Et
94 - 100% [Z].
60
29
The EWG present in the adducts directed the stereochemistry of the allyl halides
which can be explained by transition state models (Figure 5) J, K and L. Model J is
favored compared to K when EWG = -COOR’ and thus [Z]-alkenes are formed
exclusively whereas, model L is favored when the EWG = -CN as it is not facing any
steric boundary due to its linear disposition.
H
R
R'O2 C
OH2
+
R
R'O2 C
X
-
H
+
OH2
R
N
C
X
+ OH2
K
J
H
X
L
Figure 5. Possible TS models to account for the observed stereoselectivity.
In conclusion, we have accomplished a simple and efficient one-pot synthesis of
[2Z]-2-(chloromethyl)alk-2-enoates
in
high
yields
using
the
readily
available
Cl3CCONH2/Ph3P under mild conditions, in CH2Cl2 at room temperature. The reaction
conditions are compatible with several functional groups. The method is highly
stereoselective. We feel the present procedure will find important synthetic applications.
xix
Synopsis
CHAPTER IV
Development of New Synthetic Methodologies
This chapter is divided into three sections
SECTION A: NaHSO4.SiO2-catalysed Highly Efficient Conjugate Addition of Indoles
with Electron Deficient Olefins
Recently, heterogeneous catalysts have gained much importance due to enviroeconomic factors. In connection to our work on the development of useful synthetic
methodologies we have observed that silica supported sodium hydrogen sulfate
(NaHSO4.SiO2) can catalyze efficiently the conjugate addition of indoles with electron
deficient olefins to form the corresponding Michael adducts at room temperature
(Scheme 18).
Scheme 18
R1
NaHSO4.SiO2
CH3CN
O
N
H
61
R2
R + R1
R
r.t, 2 35 min.
62
O
R2
N
H
63
67 98%
%
A variety of indoles and activated olefins were used for the above reaction to prepare
a series of 3-substituted indoles (18 examples) in high yields. Unsubstituted indole as
well as indoles having substituent at C-2, C-3 or in the aromatic ring worked well.
However, with 3-methyl indole C-2 substituent products were obtained and the yields
were somewhat low. Several α,β-unsaturated ketones and nitro compounds were used
here as activated olefins.
The catalyst, NaHSO4.SiO2 works under heterogeneous conditions. This catalyst has
been found to be highly efficient for the present conversion. It can conveniently be
removed from the reaction mixture by simple filtration.
SECTION B: Iodine-catalyzed Efficient Conjugate Addition of Pyrroles to α,βUnsaturated Ketones
In recent years, iodine has emerged as a very effective catalyst for various organic
transformations. We have developed a highly convenient method for conjugate addition
xx
Synopsis
of pyrroles to α,β-unsaturated ketones under the catalytic influence of molecular iodine
(Scheme 19).
Scheme 19
I2 (5 mol%)
CH3CN
O
R2
+ R1
N
R
64
r.t., 3-12 min.
R2 + R2
N
65
O
O
R1
R
66
R2
N
R1
R
67
R1
O
73-95% (Combined yields)
Both 2-Alkyl pyrroles, 66 and 2,5-dialkyl pyrroles, 67, were obtained in different ratios in
73-95% yields (Scheme 19) when equimolar ratio of α,β-unsaturated ketones were taken
with pyrrole (14 examples) at room temperature under the influence of 5 mol% of iodine.
Dialkylated pyrroles were obtained solely by increasing the molar ratio of the
reactants. The reaction of pyrroles with α,β-unsaturated ketones (1:3) in the presence of
5 mol% of iodine in CH3CN afforded only 2,5-dialkylated pyrroles, 67 (9 examples) in 7491% yields within short reaction time at room temperature.
In conclusion, we have employed molecular iodine as an effective catalyst for the
alkylation of pyrrole with α,β- unsaturated ketones. The procedure has the advantages of
short reaction times, high yields, mildness and operational simplicity which make it a
useful and attractive process for the synthesis of C-alkylated pyrroles.
SECTION C: Application of Heterogeneous Solid Acid Catalysts for Friedlander
Synthesis of Quinolines
We attempted the Friedlander annulation for synthesis of substituted quinolines in the
presence of heterogeneous solid acid catalysts including NaHSO4-SiO2, H2SO4-SiO2,
Amberlyst-15 and HClO4-SiO2 in ethanol under reflux. Considering the reaction time and
yield Amberlyst-15 was found to be most effective. Subsequently a series of substituted
quinolines (18 examples) were prepared following the same method using Amberlyst-15
as a catalyst (Scheme 20).
Scheme 20
R1
R1
O
R3
R3
O
+
R2
NH2
R
68
Amberlyst-15
EtOH, reflux
2.0
xxi
69
3.5 h
N
R
69
93%
70
R2
Synopsis
The catalyst, Amberlyst-15 is commercially available, inexpensive and non-hazardous. It
works under heterogeneous conditions and conveniently be handled and removed from
the reaction mixture by simple filtration. The recovered catalyst was reused three times
consecutively showing almost equal catalytic activity.
In conclusion, the application of various heterogeneous solid acid catalysts for the
preparation of quinolines via Friedlander annulation has been studied. Amberlyst-15 has
been demonstrated here as the most effective catalyst for this synthesis. The simple
experimental procedure and impressive yields by applying this inexpensive reusable
catalyst have made this protocol practically useful for the synthesis of quinolines.
xxii