Abstract
ABSTRACT
The Thesis entitled “Advanced Synthetic Applications of Baylis-Hillman Chemistry:
Stereoselective Synthesis of Functionalized Trisubstituted Olefins Including Some
Insects Pheromones and Potent Pharmaceutical Agents” consists of four chapters.
CHAPTER I
The Baylis-Hillman Reaction: An Overview
This Chapter is divided into two sections.
SECTION A: 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).
Very recently Baylis-Hillman reaction got serious attention as a novel and versatile C–C
bond forming protocol after it’s discovery by two German scientists A. B. Baylis and M.
E. D. Hillman in 1972.
Baylis-Hillman Reaction:
This is essentially the coupling of the -position of activated alkenes with carbon
electrophiles under the catalytic influence of a tertiary amine providing a simple process
for synthesis of densely functionalized molecules (Eq.1).
Equation. 1
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
Abstract
Essential Components
1) Activated alkenes: A variety of activated alkenes such as alkyl vinyl ketones, alkyl
(aryl) acrylates, acylonitrile, vinyl sulfones, acrylamides, allenic esters, vinyl sulfonates,
vinyl phosphonates and acrolien couple with a number of carbon electrophiles to provide
a wide range of multifunctional molecules.
2) Electrophiles: Aldehydes have been primary source of electrophiles. Tthus, various
aliphatic, aromatic and hetero-aromatic aldehydes have been extensively employed in
obtaining various 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) Catalyst: Although DABCO (1) has been the catalyst of choice, various other tertiary
amine catalysts such as quinuclidine (2), 3-HQD (3), 3-quinuclidone (4) and indolizine
(5) were also employed to perform the Baylis-Hillman reaction (Eq. 1).
SECTION B: Synthesis of Functionalized Trisubstituted Olefins and BaylisHillman Chemistry
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 needs 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
+
Nu
Trisubstituted Olefins
Nu = H, C, N, O, S and X (halogen)
atoms as nucleophilic centre
EWG
R
Baylis-Hillman adducts are mostly exploited for nucleophilic substitution (SN2 and SN2’)
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
ii
Abstract
occurring bioactive compounds including several alkaloids, terpenoids, macrolides and
pheromones. All of these molecules contain a stereodefined trisubstituted olefin moiety
as the central structural unit which have been well documented in the literature.
CHAPTER II
Stereoselective
Synthesis
of
Functionalized
Trisubstituted
Olefins
Introducing Hydride Nucleophile to the Baylis-Hillman Adducts
This chapter is divided into three sections.
SECTION A: Stereoselective Synthesis of [2E]-2-Methylalk-2-enoates 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. The presence of [2E]-2-methylalk-2-enoates and [2E]-2-methylalk-2-enoic
acids moieties in various biologically active molecules has attracted our attention. We
have visualized that the Baylis-Hillman adduct derived from methyl acrylate could be
easily transformed into the desired [2E]-2-methylalk-2-enoates. Accordingly, we have
treated methyl 3-hydroxy-2-methylene-alkanoate 1 with NaBH4 in the presence of a
series of metallic chlorides. Using NaBH4/CuCl2.2H2O in MeOH at room temperature, the
resulting trisubstituted alkene 2 was obtained in high yield and in 100% [E]-selectivity
(Scheme 1).
Scheme 1
OH
O
R
OMe
H
NaBH4/CuCl2.2H2O
MeOH, r.t., 15min.
O
R
OMe
1
2
R = alkyl, aryl
71-86%
[E]-100%
The sole [E]-stereoselectivity of the reaction can possibly be explained by
considering the transition state models A & B (Figure 1). The transition state A is more
Figure 1
H
R
Me
R
H
Me
COOMe
OH
A
COOMe
OH
B
iii
Abstract
favoured than B due to steric demand and the R group (alkyl, aryl) prefers to stay trans
to the –COOMe group. Thus, [E]-products were formed exclusively.
With a view to prove the efficacy of this methodology, we have undertaken the practical
synthesis of five insect pheromones. (4S, 2E)-2,4-dimethyl-2-hexenoic acid 3, a castespecific substance present in the mandibular glands of the male carpenter ants in the
genus Camponotus, (+)-(S)-manicone 4 and (+)-(S)-normanicone 5, the mandibular
gland alarm pheromone components of the ants in the genus Manica, and (+)-(S)-1methylbutyl (E)-2-methyl-2-pentenoate (dominicalure-I) 6 and (+)-(S)-1-methylbutyl (E)2,4-dimethyl-2-pentenoate (dominicalure-II) 7, the aggregation pheromones of lesser
grain borer Rhyzopertha dominica (F) have been synthesized here.
H
H
O
H
O
OH
(S, E)-2,4-Dimethyl-2-hexenoic acid
(+)-(S)-Manicone
(+)-(S)-Normanicone
4
5
3
H
H
H
H
O
H
O
O
O
O
H
H
(+)-(S)-Dominicalure-II
(+)-(S)-Dominicalure-I
7
6
We have synthesized the pheromone 3 starting from (S)-2-methyl butanol via the BaylisHillman adduct 9 according to the Scheme 2.
Scheme 2
OH
CH2OH
H
K2Cr2O7 / H2SO4.H2O
H
700C, distillation, 66%
DABCO, Dioxane
OMe
OMe
H
0°C, 20 h, 71%
9
(S)-2-Methylbutanal
H
Baylis-Hillman adduct
H
O
O
1. NaOH, MeOH/H2O
MeOH, r. t
OMe
H
O
O
8
(S)-2-Methylbutanol
NaBH4 / CuCl2. 2H2O
CHO
+
OH
H
2. aq. HCl, 78%
3
10
(4S, 2E)-2,4-Dimethyl-2-hexenoic acid
The pheromones 4 and 5 have been synthesized through a common sequential route of
six steps via the compound 3 according to Scheme 3.
iv
Abstract
Scheme 3
H
O
H
OH
H
O
SOCl2
11
Cl
H
benzene
H
3
O
Et2CuLi / Et2O
(S, E)-2,4-Dimethyl-2-hexenoic acid
4
H
- 78° C
85%
(+)-(S)-Manicone
H
Me2CuLi / Et2O
O
5
- 78° C
H
(+)-(S)-Normanicone
82%
We have undertaken the synthesis of pheromones 6 and 7 starting from n-propanal and
2-methylpropanal respectively according to the procedure presented in Scheme 4.
Scheme 4
OH
O
O
DABCO
R-CHO +
12 R = Et, 83%
OMe
OMe
R
Dioxane:H2O (1:1)
13 R = i-Pr, 78%
1. NaBH4 / CuCl2. 2 H2O
H
O
14 R = Et
MeOH, r. t.
12, 13
15 R = i-Pr
OMe
R
[E]-2-Methylalk-2-enoates
H
H
O
1. NaOH/MeOH
O
R
OH
R
O
1. SOCl2
2. (+)-(S)-2-pentanol
2. aq. HCl
H
16 R = Et, 76%
6 R = Et, 68% (+)-(S)-Dominicalure-I
17 R = i-Pr, 75%
7 R = i-Pr, 69% (+)-(S)-Dominicalure- II
Thus, we have successfully utilized the potential of Baylis-Hillman chemistry for the
practical synthesis of five important insects pheromones.
SECTION B: Stereoselective Synthesis of [E]-α-Methylcinnamic Acids and Its
Applications
[E]--Methyl cinnamic acids moiety is an important and central structural unit present in
various
biologically
methylcinnamoyl]glycerol
active
molecules,
(LK-903)
1
is
v
for
a
very
example,
active
1-[p-(myristyloxy)-hypolipidemic
agent.
Abstract
N-Allyl-N-[4-{(4-amidinophenoxy)carbonyl}--methylcinnamoyl]
glycine
methane
sulfonate 2 and its analogues are potent orally active serine protease inhibitors. Also
[E]-2-methyl-3-(4-(myristyloxy)-phenyl)prop-2-enoic
acid
3
itself
shows
good
hypolipidemic activity. [E]-2-Methyl-3-(4-carbomethoxyphenyl)-prop-2-enoic acid 4 is a
valuable synthon for the synthesis of serine protease inhibitor 2.
OH
O
O
O C
H2N
H
O
H
O
HN
MeSO3H
OH
n-H29C14O
N
1
CO 2H
2
LK-903
H
O
O
H
OH
OH
n-H29C14O
MeO 2C
3
4
The presence of [E]--methyl cinnamic acid moiety (or derivatives) in various biologically
active molecules has attracted our attention. We observed that, the treatment of BaylisHillman
adduct,
methyl-3-hydroxy-3-aryl-2-methylene
propanoates
5
with
NaBH4/CuCl2.2H2O in methanol or NaBH4 in combination with molecular I2 in THF at
room temperature, followed by hydrolysis with KOH/MeOH and crystallization afforded
the corresponding [E]--methylcinnamic acids 7 in high yields via the formation of the
intermediates 6 (Scheme 1).
Scheme 1
OH
Ar
H
NaBH4/CuCl2.2H2O
MeOH or
O
OMe
Ar
OMe
I2/NaBH4
6
THF, r.t. 2-3h
5
H
1) KOH/MeOH
r.t. 2h
O
2) aq. HCl
3) crystallisation
O
Ar
OH
7
74-81% over all yield
100% [E]-selectivity
The stereochemistry of products was solely [E]- as evident by considering the
same transition state models described in Section A (Fig. 1). Encouraged by this
observations, we have then synthesized a series of (E)--methyl cinnamic acids directly
from various adducts without isolating the intermediates 6. The used reagents i.e.
NaBH4/CuCl2.2H2O or I2/NaBH4 are comparably useful for the synthetic purposes as per
vi
Abstract
as the operational simplicities, overall yields and stereoselectivies are concerned. Here,
we presented NaBH4/CuCl2.2H2O reagent system in synthetic applications. Infact, the
efficiency of the protocol have been proved by the practical synthesis of compound 1, 3,
& 4 which have been discussed below.
We have undertaken the synthesis of synthon 4 starting from 4-carboxybenzaldehyde in
four steps (Scheme 2).
Scheme 2
CHO
CHO
O
MeOH/H2SO4
+
95%
OtBU
Dioxane /water (1:1)
48h, 80%
MeOOC
CO 2Me
9
8
H
O
NaBH4/CuCl2.2H2O
MeOH, r.t. 30min.
H
O BU
anti-cholesterol
OH
CH3CN, reflux
MeOOC
drug
MeOOC
3 h, 66%
LK-903
O
KSF-clay
t
10
Potent
O
O BU
2h, reflux
CO 2H
OH
DABCO
t
(1)
was
4
synthesized
starting
from
4-hydroxybenzaldehyde in six steps via the p-myristyloxy)-[E]--methyl cinnamic acid 3
which also showed good hypolipidemic activity (Scheme 3).
Scheme 3
CHO
CHO
1) C14H29Br
2) K2CO3 / Acetone
2h, reflux 95%
OH
O
+
OMe
DABCO
Dioxane /water (1:1)
OH O
OMe
r.t., 7 days, 73%
RO
OR
12
11
H
O
OMe
RO
13
2) aq. HCl
3) crystalisation
75%
OH
RO
3
O
HO
O
R = n-C14H29
O
1) KOH / MeOH, 2h
NaBH4/CuCl2.2H2O
MeOH, r.t. 20min.
H
H
H
14
O
BOC2O, DMAP, THF, r.t.,
16h, 92%
O
O
O
O
RO
15
vii
OH
O
Amberlyst-15
OH
MeOH, r.t., 2h, 94% RO
1
Abstract
SECTION C: Stereoselective Synthesis of Trisubstituted [E]-Alkenones From
Unmodified Baylis-Hillman Adducts: Improved Synthesis of (+)-(S)-Manicone and
(+)-(S)-Normanicone
Trisubstituted alkenone is an important and key structural unit present in various
biologically active molecules and is a versatile intermediate for the synthesis of various
natural products. α, β-Unsaturated ketones are enormously useful synthons in organic
synthesis. 3-Alkenyl–2-ketones as well as 4-alkenyl-3-ketones are common metabolites
in insects and other arthropods where they serve a range of communicatory and
ecological functions. As For examples, (+)-(S)-manicone (1) and (+)-(S)-normanicone (2)
are the two mandibular gland alarm pheromones of Manica ants. (+)-(S)-homomanicone
(3) is another alarm pheromone found in the mandibular gland secretions of two
sympatric harvester ants, Pogonomyrmex salinus and Messor lobognathus.
H
H
O
H
O
H
H
H
2
1
3
(+)-(S)-Normanicone
(+)-(S)-Manicone
O
(+)-(S)-Homomanicone
In the section-A of this chapter, we have already discussed the six steps synthetic
procedures for both the pheromones 1 and 2. Though, those were simple and practically
useful, we were still in search for the shorter routes applying Baylis-Hillman chemistry for
their synthesis. We envisaged that a chemoselective reduction of B-H adduct (4) derived
from an aldehyde and vinyl ketone would lead to the formation of a trisubstituted
alkenone (5) what we required for the synthesis of the pheromones. After several
attempts, it was observed that sodium borohydride in presence of catalytic amount of
indium chloride in acetonitrile acted as the best catalyst to afford the desired product in
high yield within 3 hours (Scheme 1).
Scheme 1
OH
H
O
1
3
R
R
R2
4
NaBH4 - InCl3
MeCN, r. t
3 - 3.5 h
R1 = aryl, alkyl
2
O
1
R3
R
R2
5 54 - 84%
3
R = H, alkyl, R = alkyl
100 % [E] selectivity
viii
Abstract
The stereochemistry of the products was found to be solely [E]. The formation of
stereodefined [E]-alkenones in the present reaction can possibly be explained by
considering the transition state models I and II. The transition state I is more favored
than II since –COR3 is bulkier than –CH2R2 group and causing more steric crowding to
R1 group.
R1
H
H
-
R1
-
COR3
COR3
R2
R2
OH
OH
II
I
Exclusive chemoselectivity and [E]-stereochemistry of the products enabled us to
synthesize (+)-(S)-manicone (1) and (+)-(S)-normanicone (2) applying our methodology
according to Scheme 2.
Scheme 2
H
O
CHO
OH K2Cr2O7, H2SO4, H2O
H
700C, 205 Torr
DABCO
R
+
6
OH
NaBH4 - InCl3
O
R
H
H
dioxane/water (1:1)
18 h,
O
MeCN, r. t
R
H
3h
7 R = Et, 68%
1 R = Et, 77%
8 R = Me, 65%
2 R = Me, 73%
The synthetic routes demonstrated here are simple, convenient, shorter and more
improved compared to the previously described methods in section-A of this chapter.
CHAPTER III
Stereoselective
Synthesis
of
Functionalized
Trisubstituted
Olefins
Introducing Carbon Nucleophiles to the Baylis-Hillman Adducts
This chapter is divided into two sections. Section A is further divided into two parts.
SECTION A/PART I: Zn-Mediated Alkylation of Baylis-Hillman Adducts in
Aqueous Media: Introduction of Alkyl Nucleophiles
ix
Abstract
In continuation of work for the synthetic applications of B-H chemistry, we wanted to
synthesize different stereodefined trisubstituted oefins of synthetic need. Herein we have
reported an efficient alkylation on activated Baylis-Hillman adducts to produce
trisubstituted alkenes in water. In the presence of zinc and saturated aqueous NH4Cl,
simple alkyl iodides reacted with activated Baylis-Hillman adducts at room temperature
to yield [E] and [Z] trisubstituted alkenes with moderate to high yield and excellent
stereoselectivity (Scheme 1).
Scheme 1
OAc
R2 I
R1
r. t., 10 - 14 h
EWG = COOMe
H
R2 I
Zn / aq. sat. NH4Cl
EWG
Zn / aq. sat. NH4Cl
R2
R1
r. t., 10 - 14 h
EWG = CN
CN
4
1: EWG = COOMe
2: EWG = CN
+
H
H
COOMe
CN
R1
R1
R2
3
[Z]- Major
R2
5
[E]- 100%
[E]- Minor
During the studies, several 3-acetoxy-2-methylene-alkanoates (1) and 3-acetoxy-2methylene-alkannitriles (2) were treated with various alkyl iodides in the presence of zinc
in saturated aqueous NH4Cl solution at room temperature to generate different
trisubstituted alkenes. The electron withdrawing groups present in the adducts directed
the stereochemistry of the products which is a well known fact in in the B-H chemistry.
When EWG = -COOMe (1) the conversion afforded the olefins (3) with [E]–
stereoselectivity exclusively while when EWG = -CN (2) the olefins (4) were formed with
high [Z]– stereoselectivity. The regioselective alkylation could be explained by a 1,4
addition type mechanism involving a -acetoxy elimination. This mechanism explained
the [E]– selectivity with ester (forming a chelated reaction intermediate, A, Figure 1) and
[Z]– selectivity with nitriles (forming a non-chelated intermediate, B, Fig. 1).
Figure 1.
I
Zn
O
1
O
O
O
O
R1
OR
A
ZnI
C N
R1
R2
R2
B
x
Abstract
PART II: Friedel-Crafts Reaction of Baylis-Hillman Adducts: Introduction of Aryl
Nucleophiles
Stereoselective synthesis of [2E] and [2Z]-2-benzyl substituted trisubstituted alkenes (7,
8) has been achieved by employing Friedel-Craft reaction of benzene with unactivated
Baylis-Hillman adducts (6) in the presence of HClO4.SiO2 as a heterogeneous catalyst.
When EWG = -COOMe, [E]- alkene was the major product whereas [Z]- alkene was
obtained as the major product when EWG = -CN (Scheme 2).
Scheme 2
OH
H
EWG
R
Benzene
HClO4.SiO2
EWG
R
reflux, 2 h
Ph
.
6
7 [E] when EWG = -COOMe
R = alkyl, aryl
8
[Z] when EWG = - CN
SECTION B: Applications of Alkylation of Baylis-Hillman Adducts in
Aqueous Media: Stereoselective Synthesis of Biologically Active Molecules
We have already demonstrated a novel Zn-mediated alkylation of the B-H adducts in
aqueous medium for the synthesis of methyl [2E]-2-alkylalkenoates. With a view to prove
the efficacy of our above mentioned methodology, we have undertaken the synthesis of
some biologically active molecules. Synthesis of [2E]-2-butyloct-2-enal, an alarm
pheromone component of the African weaver ant, Oecophylla longinoda (1), [2E]-2tridecylheptadec-2-enal (2), an unusual metabolite from the red alga Laurencia species
and a potent anti alzheimer’s drug (R)-2-propyloctanoic acid (3) have been
demonstrated here.
1
CHO
H
CHO
H
2
O
OH
H
3
xi
Abstract
Accordingly, we have synthesized the alarm pheromone [2E]-2-butyloct-2-enal (1)
by preparing the B-H adduct 3-hydroxy-2-methyleneoctanoate (4) starting from
commercially available n-hexanal and methyl acrylate as per the procedure described in
Scheme 1.
Scheme 1
O
CHO
OH
DABCO
OMe
+
COOMe
AcCl, Py
Dioxane/ water (1:1)
r.t., 85%
4
OAc
COOMe
COOMe
H
Zn/aq. NH4Cl(sat.)
+
LiAlH4-AlCl3
I
r.t., 14 h, 63%
Dry THF
5
6
CH2OH
H
CHO
H
PDC/Cat.Ac2O
r.t., 2h, 92%
DCM
r.t., 3h, 87%
7
1
[2E]-2-tridecylheptadec-2-enal (2), the unusual metabolite of red algae was synthesized
in six steps starting from n-pentadecanol according to the route depicted in Scheme 2.
Scheme 2
O
PDC/Cat.Ac2O
DCM
n-C15H31OH
n-C14H29CHO
OMe
+
r.t., 3 days, 85%
reflux, 2 h, 94%
OH
DABCO
Dioxane/ water (1:1)
n-C14H29
9
8
n-Pentadecanol
OAc
AcCl, Py
H
COOMe
+ n-C12H25 -I
n-C14H29
r.t., 14 h, 66%
Dry THF
00-r.t.,
2h, 86%
n-C12H25
n-C14H29
n-C12H25
n-C14H29
11
CH 2OH
H
COOMe
Zn/aq. NH4Cl (sat.)
10
LiAlH4-AlCl3
COOMe
PDC/Cat.Ac2O
DCM
H
CHO
r.t., 3h, 65%
2
12
xii
Abstract
Synthesis of potent Anti-Alzheimer Drug, (R)-2-Propylocta-noicacid (3):
Alzheimer’s disease (AD) is the most common form of dementia in the elderly. It is a
fatal disorder that robs its victims of their most precious organ, the brain by slowly
destroying the complex web of neuronal connections that support cognitive processes
such as thought and memory. Thus, research into fighting this ever-growing disease is
directed towards new therapeutic agents, such as neuroprotective agents or
antioxidents. One novel emerging compound is (R)-arundic acid (3), a neuroprotective
agent, which modulates astrocytic activation by inhibiting the enhanced astrocytic
synthesis of S-100β, responsible for inducing neuronal death.
We envisaged a synthetic route for compound 3 applying our ecofriendly
alkylation protocol of preparing [2E]-2-alkylalkenoates as the key step. We thought to
generate the desired configuration of the chiral center (‘R’ at C-2 position) by asymmetric
hydrogenetion of double bond of the trisubstituted alkene. Noyori reported that [2E]-2alkylalk-2-enoic acids upon hydrogenation by (R)-BINAP-Ru (II) dicarboxylate complex
(16) as catalyst, affords (R)- configurated 2-alkylalkanoic acid. This prompted us to think
for the asymmetric hydrogenation as our target molecule is having the chiral center with
‘R’-configuration. In this case, we have started with the B-H adduct (4) prepared from the
commercially available n-hexanal (Scheme 3).
Scheme 3
OH O
DABCO
O
AcCl, Py
Dioxane/ water (1:1)
CHO
OMe
OMe
+
r.t., 85%
4
O
OAc O
Zn/aq. NH4Cl(sat.)
OMe
+
H
OMe
r.t., 14 h, 55%
92%
5
13
O
H
OH
Ru [(R)- BINAP] (OCOCH3)2
15
O
H2 (4 atm), 12 h
OH
H
Argon
88%, 84% ee
14
(R)-2-Propyloctanoic
Ph2
3
O
O
P
15
Ru
P
Ph2
KOH / MeOH
aq. HCl
I
O
O
xiii
Abstract
The key intermediate, [2E]-2-propyloct-2-enoate (13) was synthesized by the alkylation
of B-H acetate (5) with ethyl iodide in presence of zinc in saturated aqueous NH4Cl
solution. Finally asymmetric hydrogenation by Ru (II) [(R)-BINAP] dicarboxylate catatlyst
(15) furnished the target molecule (R)-2-propyloctanoic acid (3) in 88% yield and
84%optical purity.
CHAPTER IV
Stereoselective
Synthesis
of
Functionalized
Trisubstituted
Olefins
Introducing Heteroatoms (Cl, Br, I and O) as Nucleophiles to the BaylisHillman Adducts.
This chapter is divided into two sections.
SECTION A: 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-metylene-γbutyrolactones and flavonoids have also been synthesized using [Z]-allyl halides derived
from Baylis-Hillman adducts.
The importance of [Z]- and [E]-allyl halides in the synthesis of several natural products
deserved our attention. We thought to synthesize these important class of synthons
directly from unmodified B-H adducts using metal-halides in the presence of some
heterogeneous Lewis acid catalysts.
Introduction of Br¯ and I¯ Nucleophiles:
Stereoselective synthesis of [2Z]- and [2E]- allyl bromides and iodides have been
achieved by the treatment of LiBr and LiI with Baylis-Hillman adducts in presence of
NaHSO4. SiO2 as the heterogeneous catalyst according to Scheme 1 and 2 respectively.
Scheme 1
H
LiBr / NaHSO4.SiO2
OH
100 % [Z]
CH2Cl2, r. t.
COOR'
R
COOR'
R
Br
80 - 98%
2a-h
H
LiI / NaHSO4.SiO2
1a-h
R' = Me, Et
CH2Cl2, r. t.
81 - 98%
COOR'
R
100 % [Z]
I
xiv
3a-h
Abstract
Scheme 2
H
H
Br
LiBr / NaHSO4.SiO2
R
3 - 6 % [Z]
2i-k
H
H
LiI / NaHSO4.SiO2
1i-k
Br
94 - 97 % [E]
CN
R
R
CN
CH2Cl2, r. t.
OH
CN
+
I
CH2Cl2, r. t.
+
R
CN
R
CN
I
94 - 97 % [E]
3 - 6 % [Z]
3i-k
The stereochemistry of products was exclusively [Z]- when EWG = -COOMe, whereas
[E]- was the major isomer (94-97%) when EWG = -CN.
Introduction of Cl¯ ion Nucleophile:
We wanted to synthesize allyl chloride moieties under heterogeneous conditions. It was
observed that the Baylis-Hillman adduct 1 could efficiently be transformed into [2Z]-2(chloromethyl)alk-2-enoates (4) using InCl3 in CH2Cl2 at room temperature (Scheme 3).
Scheme 3
OH
COOR'
R
H
InCl3
Dry DCM
COOR
R
r.t, 3-4 h
Cl
1a-m
4a-m
R= alkyl, aryl
R'= alkyl
[Z]- allyl chloride
Here InCl3 worked under heterogeneous condotion as it was poorly soluble in CH2Cl2.
The EWG present in the adduct directed the stereochemistry of the allyl halides
which can be explained by transition state models A, B and C. Model A is favored
compared to B when EWG = -COOR’ and thus [Z]-alkenes are formed exclusively
whereas, Model C is favored when the EWG = -CN as it is not facing any steric
boundary due to its linear disposition.
xv
Abstract
H
R
R'O2 C
OH2
+
R
-
H
R
R'O2 C
X
+
N
OH2
H
C
X
+ OH2
B
A
X
C
SECTION B: Stereoselective Synthesis of [E]-Cinnamyl Alcohol Derivatives
Introducing Oxygen Nucleophile to The Baylis-Hillman Adducts
The Baylis-Hillman adducts, 3-aryl-3-hydroxy-2-methylene-alkanoates and 3-aryl-3hydroxy-2-methylene-alkanenitriles
have
been
efficiently
isomerized
to
the
corresponding [E]-cinnamyl alcohols by treatment of the adducts with Ac2O in the
presence of HClO4.SiO2 followed by hydrolysis of the intermediate acetates with
K2CO3/MeOH. The first step occurs under solvent-free conditions and the catalyst has
been found to be reusable (Scheme 1).
Scheme 1
H
H
COOMe
EWG= -COOMe Ar
K2CO
MeOH
3
COOMe
Ar
r. t. 1 hr
OH
EWG
Ac2O
HClO4.SiO2
2a-e
OH
OAC
3a-e
Ar
Solvent free
400C
2 hr
1a-i
H
EWG= -CN
H
K2CO3
OAc
Ar
MeOH
r. t. 1 hr
OH
Ar
CN
2f-i
CN
3f-i
The stereochemistry of the conversion can possibly be explained by considering the
favourable transition state models A and B, which suggest the formation of [E]-cinnamyl
alcohols predominantly in the present reaction.
xvi
Abstract
H
Ar
MeO2C
+
OH
O
A
Ar
H
C
CH3
+
OH
O
N
B
CH3
In conclusion, we have developed a simple and efficient protocol for stereoselective
synthesis of [E]- cinnamyl alcohols starting from Baylis-Hillman adducts containing both
ester and nitrile moieties. The simple experimental procedure, utilization of a
heterogeneous recyclable catalyst and high yields and stereoselectivity of the products
are the advantages associated with the protocol.
xvii