High-yielding sequential one-pot synthesis of chiral and achiral α-substituted acrylates via a metal-free reductive coupling reaction

Article abstract of DOI:10.1039/c4ob00667d

A general process for the high-yielding synthesis of substituted chiral and achiral α-substituted acrylates was achieved through the sequential one-pot combination of a metal-free reductive coupling reaction followed by an Eschenmoser methylenation. The proline catalyzed reaction of Meldrum's acid, aldehydes and Hantzsch ester followed by methylenation was successful with Eschenmoser's salt in the presence of an alcohol solvent. Herein, we have shown the high-yielding synthesis of privileged building blocks from chiral/achiral α-substituted acrylates and shown them to be very good intermediates in the pharmaceuticals and natural products synthesis. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00667d

Organic &
Biomolecular Chemistry
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PAPER
High-yielding sequential one-pot synthesis of
chiral and achiral α-substituted acrylates via a
metal-free reductive coupling reaction†
Cite this: Org. Biomol. Chem., 2014,
12, 5400
Dhevalapally B. Ramachary,* Chintalapudi Venkaiah and Y. Vijayendar Reddy
A general process for the high-yielding synthesis of substituted chiral and achiral α-substituted acrylates
was achieved through the sequential one-pot combination of a metal-free reductive coupling reaction
followed by an Eschenmoser methylenation. The proline catalyzed reaction of Meldrum’s acid, aldehydes
and Hantzsch ester followed by methylenation was successful with Eschenmoser’s salt in the presence of
an alcohol solvent. Herein, we have shown the high-yielding synthesis of privileged building blocks from
chiral/achiral α-substituted acrylates and shown them to be very good intermediates in the pharmaceuti-
cals and natural products synthesis.
Received 29th March 2014,
Accepted 30th May 2014
DOI: 10.1039/c4ob00667d
www.rsc.org/obc
Introduction
Much of the current research on organic synthesis is focused
on the economy and efficiency of chemical reaction
a
sequence.1 The efficiency of a synthetic process depends not
only on parameters such as selectivity and reactivity, but also
on the overall yield and the number of purification steps. The
challenge for synthetic chemists is to synthesize complex
target compounds in both high yield and selectivity, and to
reduce the number of unit operations, isolations and purifi-
cation without compromising multi-step one-pot synthesis. In
this context, sequential one-pot combination of multi-com-
ponent and multi-catalysis cascade reactions offers significant
advantages over classical linear syntheses by combining a
number of sequential reactions in one pot from easily available
precursors and catalysts.1 This concept has become an impor-
tant tool for organic, medicinal and combinatorial chemists to
make high-yielding drugs/natural products and their building
blocks with minimum wastage and unit operations.1
α-Substituted acrylates are found in many biologically active
compounds, pharmaceuticals, and polymer precursors and are
also used as key intermediates for the synthesis of α-methylene
lactones and lactams, which are found in many natural pro-
ducts and medicinally important molecules (see Fig. 1).2
Catalysis Laboratory, School of Chemistry, University of Hyderabad, Hyderabad-
500 046, India. E-mail: ramsc@uohyd.ernet.in, ramchary.db@gmail.com;
Fax: +91-40-23012460
†Electronic supplementary information (ESI) available: Experimental procedures
and analytical data (1H NMR, 13C NMR, HRMS and HPLC) for all new com-
pounds. See DOI: 10.1039/c4ob00667d
Fig. 1 Medicinal application of methyl α-substituted acrylates.
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Although many classical synthetic methods (Mannich, Baylis–
Hillman, Horner–Wittig and metal catalyzed cross-couplings)
have been developed for their synthesis,3 the development of
mild and efficient protocols for the one-pot synthesis of these
Results and discussion
Preliminary optimization of the sequential one-pot TCRA/A/M
reaction
compounds remains a challenge in modern organic chemistry. The initial investigation looked into the TCRA/A/M between
In 2002, Tsukamoto et al. reported the synthesis of α-substi- Meldrum’s acid 1a and benzaldehyde 3a in methanol 5a. A
tuted acrylates from the corresponding carboxylic acids via number of substrates were screened using the proline catalyst
5-monosubstituted Meldrum’s acids.4a Frost et al. reported the including Meldrum’s acids 1a–b, organic-hydrides 2a–c and
synthesis of α-substituted tert-butyl acrylates starting from the Eschenmoser’s salts 7a–b for TCRA/A/M reaction with benz-
commercially available aldehydes and Meldrum’s acids.4b,c aldehyde 3a in methanol 5a (Table 1). The metal-free reductive
These two methods suffer from tedious and repetitive work-up coupling or TCRA reaction of Meldrum’s acid 1a, Hantzsch
and purification steps coupled with unselective NaBH4- ester 2a and benzaldehyde 3a under the L-proline 4-catalysis in
mediated olefinic reduction, limited substrate scope and low methanol 5a at 25 °C was complete after 2 h and was then
yields (Scheme 1). To the best of our knowledge, there is no in situ treated with 2.5 equivalents of N,N-dimethyl-methylenei-
sequential one-pot process for the high-yielding synthesis of minium chloride 7a at 65 °C for 12 h to furnish the methyl
chiral and achiral α-substituted acrylates starting from com- 2-benzylacrylate 8aa in 82% yield (Table 1, entry 1). In a
mercially available simple materials. Therefore, the develop- similar manner, a TCRA/A/M reaction of 1a, 2a, 3a, and 4 with
ment of a high-yielding sequential one-pot procedure for the N,N-dimethyl-methyleneiminium iodide 7b in methanol 5a at
synthesis of a variety of α-substituted acrylates is of significant 65 °C for 12 h furnished the expected methyl 2-benzyl acrylate
interest (see Scheme 1).
8aa in 85% yield (Table 1, entry 2). When the sequential one-
Recently, we have discovered the chemoselective C-alkyl- pot TCRA/A/M reaction was carried out with other substrates
ation of 1,3-diketones with a variety of aldehydes and organic like 1b or 2b–c, the expected product 8aa was furnished in
hydrides under amino acid-catalysis through a three-com- poorer yields (Table 1, entries 3–5). From these preliminary
ponent reductive alkylation (TCRA) reaction.5 Since the report results we came to the conclusion that 1a, 2a and 7b were
of this metal-free reductive coupling or TCRA reaction, many optimal substrates for the TCRA/A/M reaction (Table 1, entry 2).
research groups have used this protocol to synthesize high-
yielding 2-alkyl-1,3-diketones as a key reaction in their method
development towards the total synthesis of natural products
and drug molecules.6,7 Herein, we envisioned that the TCRA
reaction of Meldrum’s acids 1, organic hydrides 2 and alde-
hyde 3 in the presence of a catalytic amount of L-proline 4
would provide the reductive alkylation products 6 at 25 °C,
which on further in situ treatment with Eschenmoser’s salt
(N,N-dimethylmethyleneiminium iodide) 7 in alcohol 5 would
provide the α-substituted acrylates 8 in very good yields via a
domino TCRA/alkylation/methylenation (TCRA/A/M) reaction
sequence in a one-pot manner (Scheme 1).
Solvent effect on the sequential TCRA/A/M reaction
After this preliminary understanding, we proceeded to investi-
gate the scope of the sequential TCRA/A/M reaction of 1a, 2a,
Table 1 Reaction preliminary optimizationa
a Reactions were carried out in solvent (0.5 M) with 0.5 mmol of 1a
relative to the 2a (0.5 mmol) and 3a (0.5 mmol) in the presence of
20 mol% of L-proline 4 followed by a one-pot alkylation/methylenation
(A/M) reaction with 2.5 equiv. of 7 in MeOH 5a (0.5 M) at 65 °C. b Yield
refers to the column-purified product.
Scheme 1 Synthesis of alkyl α-substituted acrylates through a domino
metal-free reductive coupling reaction (TCRA) and Eschenmoser
methylenation.
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3a and 7b in various alcoholic solvents 5b–k under the Scope of the sequential one-pot TCRA/A/M reaction with
proline-catalysis at 65 °C in order to permit control of the final achiral aldehydes
ester product (Table 2). Sequential one-pot products 8ab–ai
With optimised conditions in hand, we explored the scope of
were obtained in moderate to good yields by using alcohols
the sequential one-pot TCRA/A/M reaction for the synthesis
5b–i as solvents (Table 2, entries 2–9). Reaction in t-BuOH 5f
of methyl α-substituted acrylates 8ba–pa by using a variety of
furnished the expected one-pot product 8af in low yield when
aldehydes 3b–p under the proline-catalysis (Table 3). We found
compared to other larger alkyl alcohols (Table 2, entry 6).
that both aryl and alkyl aldehydes proceeded smoothly to
Interestingly, a sequential TCRA/A/M reaction of 1a, 2a, 3a and
afford the expected products 8ba–pa in moderate to very good
7b in (S)-ethyl lactate 5j as the solvent furnished the desired
yields. Interestingly, many of the α-substituted acrylates 8 are
not known and this methodology is the first one to prepare
them with good yields. For instance, a domino reaction of
optically pure product 8aj in low yield (Table 2, entry 10). This
may be due to the moderate steric hindrance of the alkyl
portion of (S)-ethyl lactate. Surprisingly, a sequential TCRA/
4-methylbenzaldehyde 3b with 1a and 2a in methanol 5a
A/M reaction of 1a, 2a, 3a and 7b in water furnished the 2-ben-
under the catalytic amount of proline 4 furnished the TCRA
zylacrylic acid 8ak in 68% yield, which is a better yield com-
product 6ba, which on in situ treatment with 7b gave the
corresponding methyl 2-(4-methylbenzyl)acrylate 8ba in 80%
yield (Table 3). In a similar manner, products 8ca–ea were
obtained in good yields when 4-halobenzaldehydes 3c–e were
employed as reactants. A sequential one-pot TCRA/A/M reac-
tion of 2-substituted-benzaldehydes 3f–i also furnished the pro-
ducts 8fa–ia in good yields, despite the steric encumbrance of the
pared to the alcoholic solvents investigated excepting the
optimal conditions with methanol (Table 2, entries 1 and 11).
To further improve the yield of 8aa, we also tested the sequen-
tial one-pot TCRA/A/M reaction in a 1 : 1 mixture of MeOH–
THF, but the yield did not improve compared to the reaction
performed in neat methanol (Table 2, entry 12). Sequential
one-pot TCRA/A/M products 8aa–ak are useful intermediates
ortho-substituents (Table 3). The dialdehydes 3j–k were success-
in the synthesis of several biologically important molecules;2
fully utilized as the substrates in this one-pot reaction to deliver
especially 2-benzylacrylic acid (8ak) is an intermediate for the
the TCRA/A/M products 8ja–ka in good yields. In addition, the
industrial scale synthesis of an anti-diarrheal drug (racecado-
tril N), a neutral endopeptidase inhibitor (ecadotril M), an
HIV-1 protease inhibitor (L) and an enkephalinase inhibitor
Table 3 Scope of the sequential one-pot TCRA/A/M reaction with
different achiral aldehydesa
(RB-101), highlighting the importance of the TCRA/A/M
one-pot approach. The structures of all these one-pot products
8 were confirmed by NMR and mass analysis.
Table 2 Solvent effect on the sequential TCRA/A/M reaction
a Yield refers to the column-purified product. b Reaction performed
using (S)-ethyl lactate 5j (0.5 M) as a solvent.
a Yield refers to the column-purified product.
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sequential one-pot TCRA/A/M reaction of 1a, 2a with aliphatic
aldehydes 3l–p followed by treatment with 7b in methanol furn-
ished the desired methyl α-substituted acrylates 8la–pa in good
yields (Table 3). Finally, compound 8oa is an important precur-
sor for the synthesis of the hypoglycemic agent etomoxir (B).
Table 4 Scope of the sequential one-pot TCRA/A/M reaction with
different chiral aldehydesa
Scope of the sequential one-pot TCRA/A/M reaction with
chiral aldehydes
Entry
1
Chiral aldehyde 3
Product 8–10
Chiral methyl α-substituted acrylates are important building
blocks for the synthesis of medicinally important molecules
and also used as attractive intermediates in the total synthesis
of natural products and pharmaceuticals.8 As such the devel-
opment of mild and simple procedures for the synthesis of
these compounds is of significant interest in organic syn-
thesis, and to the best of our knowledge, there is no one-pot
procedure for the synthesis of chiral methyl α-substituted acry-
lates. This methodology may provide a new class of chiral
α-substituted methyl acrylates with high enantiomeric purity
by employing chiral aldehydes as starting materials.
2
3
4
First, we investigated the sequential one-pot reaction of
Meldrum’s acid 1a, organic hydride 2a, and Eschenmoser’s
salt 7b with (R)-(+)-glyceraldehyde acetonide 3q under the opti-
mized conditions. Interestingly, we observed the formation of
unexpected products (S)-methyl 4,5-dihydroxy-2-methylenepen-
tanoate 9qa and (S)-5-(hydroxymethyl)-3-methylenedihydro-
furan-2(3H)-one 10qa in 32% and 58% yields respectively
instead of the expected product 8qa (Table 4, entry 1). In a
similar manner, the sequential one-pot TCRA/A/M reaction of
1a, 2a, 7b with (R)-2,3-cyclohexylideneglyceraldehyde 3r under
the optimized conditions furnished the desired product 8ra in
only 10% yield, which is accompanied by unexpected products
9qa and 10qa in 28% and 40% yields, respectively (Table 4,
entry 2). The formation of the unexpected products 9qa and
10qa can be explained through the in situ hydrolysis of the
ketal group followed by intramolecular lactonization of 8ra or
8qa in the presence of acidic HI, which is in situ generated
from the reaction. In addition, we performed a sequential one-
pot TCRA/A/M reaction of 1a, 2a, 7b with butane-2,3-diacetals
of (R)-glyceraldehyde and (S)-glyceraldehydes (3s, 3t) under the
optimized conditions to furnish the desired products 8sa and
8ta in 78% and 53% yields, respectively (Table 4, entries 3 and
4).9 In a similar manner, we have investigated the sequential
one-pot reactions by employing a series of chiral aldehydes
3u–3z under the optimized conditions, and we are happy to
find that all reactions proceeded well and the desired products
8ua–8za were obtained in good yields (Table 4, entries 5–10).
All these obtained chiral products 8 have direct applications in
medicinal chemistry and natural product synthesis.2,8
5
6
7
8
9
10
a Yield refers to the column-purified product.
have been developed for their synthesis, most of them are
lengthy or complicated procedures with harsh reaction con-
ditions.3,4 Herein, we further utilized the one-pot TCRA/A/M
products in the synthesis of biologically important α-methylene-
lactones, α-methylenelactams and their precursors under suit-
able reaction conditions (Table 5).
First we focused on the synthesis of 3-methylene-3,4-di-
hydroquinolin-2(1H)-one 11ha by using methyl 2-(2-nitro-
benzyl)acrylate 8ha as the starting material through
a
Synthetic applications of methyl α-substituted acrylates
reduction–lactamization sequence in one pot. Nitro group
reduction of 8ha with six equivalents of Fe in CH3CO2H at
120 °C for 1 h directly furnished the 3-methylene-3,4-dihydro-
quinolin-2(1H)-one 11ha in 65% yield (Table 5, entry 1). In a
similar manner, reaction of methyl 2-methylene-5-(2-nitrophe-
nyl)pentanoate 8na under the same reductive lactamization
conditions (Fe/CH3CO2H) furnished only the corresponding
α-Methylenelactones and α-methylenelactams are important
classes of compounds and have received great attention over
the past decade in medicinal and synthetic chemistry. Many of
the natural and synthetic α-methylenelactones, α-methylene-
lactams and their analogues have displayed important biologi-
cal activities (Fig. 1).2 Although different synthetic methods
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Table 5 Synthetic applications of methyl α-substituted acrylatesa
suitable precursor for the synthesis of 3-methyldihydrofuran-2
(3H)-one (Table 5, entry 5).
Entry
1
Substrate 8
Conditions
Products (9–15)
With the inspiration of these results, we were further inter-
ested in the synthesis of chiral α-methylene lactones, lactams
and their precursors using chiral TCRA/A/M products 8 as
shown in Table 5, entries 6–9. Reaction of TCRA/A/M chiral
product 8ua with CH3COCl in MeOH at 70 °C for 2 h furnished
the (R)-methyl 4-amino-5-hydroxy-2-methylenepentanoate 9ua
in 90% yield (Table 5, entry 6). Interestingly, treatment of the
same substrate 8ua with 30% p-TSA in MeOH at 25 °C for 2 h
furnished the (R)-methyl 4-((tert-butoxycarbonyl)amino)-5-
hydroxy-2-methylenepentanoate 15ua in 75% yield (Table 5,
entry 7). Chiral compounds 9ua and 15ua could be used as
chiral precursors for the asymmetric synthesis of medicinally
important five- and six-membered lactams and lactones,
respectively. Treatment of TCRA/A/M chiral product 8wa with
conc. HCl in MeOH at 70 °C for 1 h furnished (S)-5-methyl-3-
methylenedihydrofuran-2(3H)-one 10wa in 72% yield (Table 5,
entry 8). Reaction of (S)-methyl 4-(benzyloxy)-2-methylene-
pentanoate 8xa with H2 under the Pd-catalysis in EtOAc at
25 °C for 2 h furnished (4S)-methyl 4-hydroxy-2-methyl-
pentanoate 14xa in 60% yield (Table 5, entry 9).
Fe/CH3CO2H,
120 °C, 1 h
2
(i) Fe/CH3CO2H,
120 °C, 1 h
(ii) tBuOK, Dry THF,
RT, 8 h
3
4
10% HCl
iPrOH : THF, 50 °C,
12 h
(i) 10% NaOH,
MeOH, 70 °C, 7 h
(ii) 10% HCl
iPrOH : THF, 50 °C,
12 h
5
6
7
8
Pd/C (10%)
H2, EtOAc, RT, 2 h
MeCOCl
MeOH, 70 °C, 2 h
p-TSA (30%)
MeOH, RT, 2 h
Conc. HCl
MeOH, 70 °C, 1 h
Conclusions
In summary, we have developed a general process for the high-
yielding synthesis of substituted chiral and achiral α-substi-
tuted acrylates through a sequential one-pot combination of a
reductive coupling reaction followed by alkylation and methy-
lenation reactions of Meldrum’s acid, Hantzsch ester, alde-
hydes with Eschenmoser’s salt in the presence of a catalytic
amount of L-proline. In this manuscript, we have shown the
high-yielding synthesis of privileged building blocks from
chiral/achiral α-substituted acrylates and have shown them to
be useful intermediates in the synthesis of pharmaceuticals
and natural products.
9
Pd/C (10%)
H2, EtOAc, RT, 2 h
a Yield refers to the column-purified product.
amine product in 66% yield, which on further treatment with
1.2 equiv. of KOtBu in dry THF at 25 °C for 8 h furnished the
cyclized 3-methylene-3,4,5,6-tetrahydrobenzo[b]azocin-2(1H)-
one 11na in 87% yield for an overall yield of 57% (Table 5,
entry 2). For the high-yielding synthesis of 3-methylene-
chroman-2-one in mind, we prepared two suitable precursors
from TCRA/A/M compound 8ga. Treatment of 8ga with 10%
aqueous HCl in a mixture of i-PrOH : THF at 50 °C for 12 h
furnished the corresponding methyl 2-(2-hydroxybenzyl)acry-
late 12ga in 85% yield (Table 5, entry 3). In another route,
ester hydrolysis of 8ga with 10% aqueous NaOH in MeOH at
70 °C for 7 h followed by deprotection of MOM with 10%
aqueous HCl in i-PrOH : THF at 50 °C for 12 h furnished the
corresponding 2-(2-hydroxybenzyl)acrylic acid 13ga in 77%
yield (Table 5, entry 4). Both the compounds 12ga and 13ga
are important precursors for the Hutchinson synthesis of
3-methylenechroman-2-one.10a Our methodology is simple and
mild when compared with the reported Hutchinson protocol
for the synthesis of 3-methylenechroman-2-one.10a In a similar
manner, methyl 4-hydroxy-2-methylbutanoate 14pa was syn-
thesized in 95% yield using TCRA/A/M product 8pa via a
deprotection–reduction sequence under the Pd-mediated
hydrogenation with H2 in EtOAc at 25 °C for 2 h, which is a
Acknowledgements
This work was made possible by a grant from the Department
of Science and Technology (DST), New Delhi [grant no. DST/
SR/S1/OC-65/2008]. Ch.V. and Y.V.R. thank the Council of
Scientific and Industrial Research (CSIR), New Delhi for their
research fellowships.
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