Organocatalyzed Baylis-Hillman reaction: An enantioselective approach

Article abstract of DOI:10.1016/j.tetasy.2012.08.013

A convenient protocol has been developed for the synthesis of Baylis-Hillman adducts in the presence of a base and an organocatalyst. We have designed and synthesized organocatalysts based on hydrogen bonding using a pyrrolidine ring as the backbone and applied them to Baylis-Hillman transformations. This method provides products in good to high yields (73-90%) and with excellent enantiomeric excesses (up to 96%) and reasonable reaction times.

Full text of DOI:10.1016/j.tetasy.2012.08.013

Tetrahedron: Asymmetry 23 (2012) 1320–1325
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Organocatalyzed Baylis–Hillman reaction: an enantioselective approach
⇑
Prashant B. Thorat, Santosh V. Goswami, Bhimrao C. Khade, Sudhakar R. Bhusare
Department of Chemistry, Dnyanopasak College, Parbhani 431401, MS, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2012
Accepted 14 August 2012
Available online 14 September 2012
A convenient protocol has been developed for the synthesis of Baylis–Hillman adducts in the presence of
a base and an organocatalyst. We have designed and synthesized organocatalysts based on hydrogen
bonding using a pyrrolidine ring as the backbone and applied them to Baylis–Hillman transformations.
This method provides products in good to high yields (73–90%) and with excellent enantiomeric excesses
(up to 96%) and reasonable reaction times.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
such as DABCO. It has also been reported that LiClO4 is an excellent
additive,17 while the combination of an acid and a base such as
Carbon–carbon bond formation is the essence of organic syn-
thesis and provides the foundation for generating more compli-
cated organic compounds from simpler ones. Many classical
carbon–carbon bond forming reactions have been well docu-
mented; for example the aldol, Friedel–Crafts, Reformatsky, and
Grignard reactions. More recently the Baylis–Hillman reaction,
which involves the coupling of activated vinylic systems with elec-
trophiles under the catalytic influence of a tertiary amine and gives
rise to Baylis–Hillman adducts with a new stereocenter, has proven
to be a very useful carbon–carbon bond forming method in the
synthesis of highly functionalized molecules.1,2
La(OTf)3 and N(CH2CH2OH)3,18 or 1,10-bi-2-naphthol and tributyl-
phosphine19 promotes the reaction efficiently. Davies et al. have
reported the asymmetric synthesis of Baylis–Hillman products
employing (R)-N-methyl-N-a
-methylbenzyl amide as a catalyst.20
The solvent also has a significant effect on the reaction rate, and
it has been reported that the reaction proceeds smoothly in a mix-
ture of 1,4-dioxane and water.21 Ultrasound22 and microwaves23
have been reported to be effective for the Baylis–Hillman reaction.
High pressure is also a useful method for the acceleration of many
organic transformations,24–26 and has been effectively applied to
the Baylis–Hillman reaction15 because of its large negative volume
of activation.27
The Baylis–Hillman reaction is a simple and straightforward
alternative to generate a new C–C
r
bond. Over the last few years,
A general inspection of successful asymmetric catalysts28 re-
vealed that the catalysts all bear a common structural motif with
a ‘proton’-donating moiety, which may be viewed as a critical
determinant for chiral induction.29 A recent finding that a protic
additive could mediate intramolecular proton transfer, rather than
enolate–aldehyde coupling, as the rate determining step in the ini-
tial stage of a Baylis–Hillman reaction,30 is clearly in agreement
with this proposal.
this reaction has attracted the attention of many organic chemists,
since this efficient reaction produces polyfunctional chiral mole-
cules in a single step. Various efforts seeking to develop asymmet-
ric versions of this reaction to afford allylic alcohols in
enantiomerically enriched form have been reported, for example,
utilizing chiral acrylates,3–6 chiral aldehydes,7–11 chiral amines,12–
and chiral phosphines.15 Although efficient, these approaches
14
are restricted to the use of acrylate components, generating
methylene-b-hydroxy compounds. Methods for the preparation
of -alkylidene-b-hydroxycarboxylic acid derivatives (b-substi-
tuted Baylis–Hillman products) have been also reported, although
examples are limited.
Although the Baylis–Hillman reaction is synthetically useful,
one disadvantage of the reaction is the low reaction rate, thus
requiring a long reaction time. Recently, several methods have
been developed to overcome this problem; DBU has been reported
to be a better accelerator16 than a conventional nucleophilic base
a
-
Worch and Bolm recently reported the replacement of carbox-
ylic acid with a chiral sulfonimidamide, in this catalyst the sulfinyl
N–H is postulated to activate the substrates by the formation of
key hydrogen bonding interactions.31 The inductive electron-with-
drawing effect of sulfinyl group acidifies this N–H bond, which
serves to modulate hydrogen bonding interactions. Furthermore,
the close proximity of stereogenic sulfur to the active site of the
catalyst contributes to high levels of stereocontrol in these reac-
tions. Finally, the sulfinyl group enhances the solubility of the cat-
alyst in organic solvents.
a
The Baylis–Hillman organocatalyzed reaction proceeds via
reversible condensation of the catalytic amine with a ketone to
provide a nucleophilic enamine intermediate. However, proline is
⇑
Corresponding author.
E-mail address: bhusare71@yahoo.com (S.R. Bhusare).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.08.013

P. B. Thorat et al. / Tetrahedron: Asymmetry 23 (2012) 1320–1325
1321
not an effective catalyst for all aldol reactions; for example, high
proline catalyst loading is required.32 Many researchers have
therefore investigated the replacement of the carboxylic acid of
proline with other H-bond donors with the goal of improving cat-
alyst solubility, activity, stability, and levels of asymmetric induc-
tion including achiral acid replacements.
In our initial studies, a set of experiments were performed with
the model reaction of p-flurobenzaldehyde 4a with methyl acrylate
5 in the presence of triethylamine using various solvents in the
presence of organocatalysts to give the product methyl 2-[(4-fluo-
rophenyl) (hydroxy) methyl] acrylate 6a. The chiral organic mole-
cules were evaluated as organocatalysts for the Baylis–Hillman
reactions using different sets of reaction conditions.
In L-proline (and its derivatives) catalyzed reactions, the nitro-
gen on the pyrrolidine ring forms imine or enamine. Based on
our hypothesis that the hydrogen bonding assists in catalyzing
the reaction, we designed a catalyst that kept the pyrrolidine ring
as the backbone of the organocatalyst. We restricted the imine for-
mation by introducing an acetyl group on active nitrogen site in
pyrrolidine ring and replaced the carboxylic group by amide group.
The Baylis–Hillman reaction has many advantages with regard
to atom economy, non-metal catalysis, mild conditions, as well
as the promising utility of the multifunctional products. Recent ef-
forts in this area have largely been focused on developing efficient
reaction systems and exploring asymmetric Baylis–Hillman reac-
tions. Taking into account all of the aspects discussed above, we
herein report on sulfinyl based chiral catalyst in the asymmetric
Baylis–Hillman reaction.
The results obtained are shown in Table 1. We started our inves-
tigation using water as the solvent. In the presence of catalyst 3a,
the reaction was completed in 48 h to give 49% isolated yield with
poor enantiomeric excess (Table 1, entry 1). When catalysts 3b and
3c were used, the same reaction in water gave yields of 48% and
57% respectively after stirring for 48 h (Table 1, entries 2 and 3).
The reaction in dioxane as the solvent improved the performance
to some extent as did stirring of 40 h for the reaction with in-
creased yields and enhanced enantioselectivities for all catalysts
(Table 1, entries 4–6). Ethanol as a solvent was found to be suitable
for all experiments. The reaction was reported to be faster in eth-
anol compared to other solvents tested. When the reaction was
carried out using catalyst 3a, the reaction was completed in 24 h
and gave 68% yield and 65% ee (Table 1, entry 7). Good results were
obtained with catalyst 3b with the reaction completed in 18 h with
a good yield of 79% and with 73% ee (Table 1, entry 8). When using
catalyst 3c, the reaction was completed in 22 h to give 63% yield
and 58% ee (Table 1, entry 9).
2. Result and discussion
Catalysts 3a–c were prepared from the commercially available
Next we performed the optimization of the reaction using eth-
anol as the solvent and varied the amount of organocatalyst 3b. A
decrease in the catalytic quantity showed an adverse effect on the
reaction, affording low product yield and long reaction time
(Table 1, entry 10). Interestingly 12 mol % of catalyst was able to
catalyze the corresponding transformation smoothly; the reaction
was completed in just 12 h and we obtained the desired product in
the best yield (83%) and enantioselectivity (84%) under room
L
-proline and the corresponding methane sulfonamide, p-toluene
sulfonamide, and p-nitro benzenesulfonamide according to the
known synthetic routes (Scheme 1).33 Pyrrole N-sulfonamides
have already been used in some catalytic asymmetric reactions.34
Other catalysts were also synthesized and compared for their reac-
tivities and efficiencies. These compounds were purified by column
chromatography and characterized by 1H NMR, 13C NMR, and mass
spectrometry.
O
R:
O
S
(c)
(a)
(b)
84%
87%
88%
3a =
CH3
COOH
CONH2
COOH
N
N
N
N
H
HN
R
O
O
O
O
O
1
2
3a-c
S
3b =
3c =
O
O
S
NO2
O
Scheme 1. Reagents and conditions: (a) acetyl chloride, THF, reflux; (b) (i) DCC, DCM, 15 °C, 1 h; (ii) NH4HCO3, rt, 1 h; (c) pyridine, sulfonyl chloride, 14 h.
Table 1
Effect of catalyst, solvent, and catalyst loading on the Baylis–Hillman reaction
Entry
Catalyst
Catalyst loading (mol %)
Solvent
Time (h)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3a
3b
3c
3a
3b
3c
3b
3b
3b
10
10
10
10
10
10
10
10
10
7.5
12
15
Water
Water
Water
48c
48
49
48
57
58
59
54
68
79
63
58
83
64
33
38
40
51
61
57
65
73
58
55
84
53
48
Dioxane
Dioxane
Dioxane
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
40c
40
40
24c
18c
22c
26c
12c
19c
9
10
11
12
a
b
c
Isolated yields.
Determined by chiral HPLC.
Reaction conversion was monitored by thin layer chromatography.

1322
P. B. Thorat et al. / Tetrahedron: Asymmetry 23 (2012) 1320–1325
temperature conditions (Table 1, entry 11). When the catalyst
loading was elevated from 12 mol % to 15 mol %, there was no sig-
nificant improvement in the results (Table 1, entry 12).
increased to 94% (Table 1, entry 6). At lower temperatures there
was not much significant change (Table 1, entry 7).
Thus, the optimized conditions for the Baylis–Hillman reaction
were obtained in ethanol as the solvent with catalyst 3b at 0 °C in
the presence of triethylamine as the base. Upon extending this pro-
tocol to other aldehydes we observed that the reaction proceeded
smoothly. The results are summarized in Table 3. Various alde-
hydes were reacted with methyl acrylate in the presence of trieth-
ylamine under the optimized conditions to give the corresponding
Baylis–Hillman adducts in good to moderate yield. However, the
nature of the substituents on the phenyl ring had a profound effect
on the reaction. When electron-withdrawing substituents were
used as the substrates, the Baylis–Hillman reaction was completed
within 12–14 h giving high yields, which should be attributed to
the strong electron-withdrawing ability of the functional group
on the phenyl ring, whereas an electron-donating substituent de-
creased the yield and increased the reaction time. It should be
emphasized that hydroxy, methoxy, and methyl groups, which
are electron-donating groups on a phenyl ring, provided lower
yields for the corresponding product with 16–20 h reaction time.
After studying the effect of the solvent and the catalyst loading,
we next studied the effect of bases on the reaction. The reaction re-
sults in the presence of different bases and catalyst 3b are shown in
Table 2. The use of a strong base, such as piperidine (5 mol %) as an
additive gave the corresponding Baylis–Hillman adduct 6c in 83%
yield in just 10 h, but the enantioselectivity obtained was very poor
(Table 1, entry 1). Triethylamine appears to be suitable for the Bay-
lis–Hillman reaction since the best results obtained were with this
compound as the base (83% yield and 84% ee) (Table 1, entry 2). The
aromatic compound pyridine as a base gave the corresponding Bay-
lis–Hillman adducts 6c in 15 h and the yield obtained was 74% yield
with only 43% ee (Table 1, entry 3). When DMAP was used as a base,
the product was obtained in good yield (78%) but enantioselectivity
was only 51% (Table 1, entry 4). Using morpholine as a base, no
reaction occurred under the same reaction conditions due to its
low catalytic ability to initiate the Baylis–Hillman reaction (Table 1,
entry 5). Thus, triethylamine was the best base for Baylis–Hillman
reaction. In order to achieve higher levels of enantioselectivity,
we carried out the reaction at 0 °C. The corresponding reaction
proceeded smoothly in 11 h to give 90% yield while the ee value
3. Conclusion
In conclusion, we have synthesized organocatalysts and studied
their applications in the Baylis–Hillman reaction for the first time.
The reaction proceeded smoothly for various aldehydes, giving the
products in good to high yields and with excellent enantioselectiv-
ity. Our results also demonstrate that hydrogen bonding and van
der Waal’s interaction are very important in the catalytic field
and are capable of stabilizing the intermediate. Our studies clearly
demonstrate the diversity and the power of hydrogen bonding and
van der Waal’s interactions in the field of synthetic organic
chemistry.
Table 2
Effect of base and temperature on the Baylis–Hillman reactionc
Entry Base
Mol % Temp (°C) Time (h) Yielda (%) eeb (%)
1
2
3
4
5
Piperidine
Triethylamine
Pyridine
DMAP
Morpholine
5
5
5
5
5
rt
rt
rt
rt
rt
10
12
15
13
48
83 37
83 84
74 43
78 51
No
—
reaction
6
7
Triethylamine
Triethylamine
5
5
0
ꢀ20
11
14
90 94
76 82
4. Experimental
4.1. General
rt Reaction was performed at 27 °C.
a
Isolated yields.
Determined by chiral HPLC.
Reaction conversion was monitored by thin layer chromatography.
b
c
All solvents were used as commercial anhydrous grade without
further purification. Column chromatography was carried out over
silica gel (100–120 mesh). Optical rotations were measured on a
Polax-2L digital polarimeter. Melting points were determined in
an open capillary tube and are uncorrected. 1H and 13C NMR
spectra were recorded on a Bruker 300 MHz spectrometer in CDCl3
solvent. Mass spectra were taken on Polaris-Q Thermoscientific
GC–MS. Enantiomeric purity is determined on PerkinElmer Series
200 HPLC Systems.
Table 3
Synthesis of a
-methylene-b-hydroxy compounds using the Baylis–Hillman reactiond
CHO
OH
O
O
OMe
organocatalyst 3b
OMe
+
ethanol
R
R
4.2. Typical procedure for the acetylation of
L-proline
4a-j
5
6a-j 73-90 %, 77-96 % ee
To a suspension of -proline (4.34 mmol, 500 mg) in tetrahydro-
L
furan was added acetyl chloride (20 mL) at room temperature and
the reaction mixture was refluxed for 2 h. After completion of the
reaction, the mixture was cooled to room temperature, diluted
with water, and stirred for 20 min. Saturated brine and ethyl ace-
tate were added and the organic layer was collected. The aqueous
layer was re-extracted with ethyl acetate. The combined organic
extracts were dried over anhydrous Na2SO4 and concentrated un-
der vacuum. The semisolid residue was stirred in diisopropyl ether
for 0.5 h at room temperature and the mixture was then cooled to
0 °C for 1 h. The precipitated crystalline solid was filtered, washed
with cold diisopropyl ether, and dried under vacuum to afford
compound (S)-1-acetylpyrrolidine-2-carboxylic acid 1. White solid
(573 mg, 84%). Mp 75–77 °C, 1H NMR (300 MHz, CDCl3): d 11.18 (s,
1H, OH), 3.96 (t, 1H, J = 9.3 Hz, 6.0 Hz), 3.53 (t, 2H, J = 10.1 Hz,
c
Entry
R
Time (h)
Product
Yielda (%)
eeb (%)
[a]
D
1
2
3
4
5
6
7
8
9
10
4-F
11.00
10.00
11.30
12.30
13.00
14.30
16.00
17.00
18.00
20.00
6a
6b
6c
6d
6e
6f
6g
6h
6i
90
85
84
88
82
79
78
77
73
79
94
96
90
89
87
81
76
83
78
77
ꢀ53.2
ꢀ15.5
ꢀ61.3
ꢀ58.4
ꢀ10.2
+11.7
ꢀ44.6
ꢀ09.4
ꢀ12.3
+31.2
4-NO2
3-NO2
4-CN
4-Cl
2-Cl
H
4-OH
4-OMe
4-Me
6j
a
Isolated yields.
Determined by chiral HPLC.
b

P. B. Thorat et al. / Tetrahedron: Asymmetry 23 (2012) 1320–1325
1323
5.8 Hz), 3.05 (q, 2H, J = 11.2 Hz, 6.7 Hz, 4.4 Hz), 2.39 (s, 3H), 2.12–
2.26 (m, 2H); 13C NMR (300 MHz, CDCl3): d 178.32, 172.12,
59.46, 52.09, 26.71, 21.45; GC–MS m/z 157.10 (M+); Elemental
Analysis: Calcd C7H11NO3 C, 53.49; H, 7.05; N, 8.91; O, 30.54. Found
C, 53.46; H, 7.03; N, 8.93; O, 30.52.
7.32 (m, 4H), 4.55 (t, 1H, J = 8.7 Hz, 6.1 Hz), 3.22 (t, 2H, J = 10.1 Hz,
5.9 Hz), 3.31 (s, 3H), 2.29 (q, 2H, J = 11.7 Hz, 7.4 Hz, 5.0 Hz), 1.63–
1.77 (m, 2H), 1.53 (s, 3H); 13C NMR (300 MHz, CDCl3): d 173.72,
172.49, 140.03, 139.72, 129.26, 128.00, 61.83, 47.04, 36.64, 29.56,
27.29, 24.51; GC–MS m/z 310.34 (M+); Elemental Analysis: Calcd
C14H18N2O4S: C, 54.18; H, 5.85; N, 9.03; O, 20.62; S, 10.33. Found
4.3. Typical procedure for the preparation of (S)-1-acetylpyrrol-
idine-2-carboxamide 2
C, 54.16; H, 5.86; N, 9.01; O, 20.65; S, 10.31. HPLC: Enantiomeric
purity was determined by chiral HPLC using Whelk-O1
(25 cm ꢂ 4.6 nm), hexane/ethanol (75/25) + 15 mM ammonium
acetate, flow rate 1.5 mL/min, k = 254 nm; tR (minor) = 9.6 min, tR
(major) = 12.9 min, ee % 98.89.
To a solution of compound 1 (3.18 mmol, 500 mg) in dichloro-
methane was slowly added a solution of dicyclohexylcarbodiimide
(6.37 mmol, 656 mg) in dichloromethane at 10–15 °C (duration
5.0 min) and the mixture was stirred at room temperature for
1 h. To this, ammonium bicarbonate (3.18 mmol, 305 mg) was
added and the mixture was stirred for 1 h. The reaction was mon-
itored by TLC. After completion of the reaction, the mixture was fil-
tered and the residue was washed with dichloromethane. The
filtrates were collected, combined, and concentrated under vac-
uum. The resulting gummy mass was suspended in tetrahydrofu-
ran under stirring and diisopropyl ether was slowly added
dropwise over 15 min. The mixture was then cooled to 0 °C and al-
lowed to stand at this temperature for 1 h. The resulting crystalline
white solid was filtered, washed with diisopropyl ether, and dried
under vacuum to afford the crude product 2. This was then purified
by column chromatography to obtain (S)-1-acetylpyrrolidine-2-
carboxamide 2. White solid (392 mg, 79%), mp 115 to 117 °C, 1H
NMR (300 MHz, CDCl3): d 8.18 (s, 2H NH), 4.16 (t, 1H, J = 9.5 Hz,
6.1 Hz), 3.63 (t, 2H, J = 9.5 Hz, 6.0 Hz), 3.24 (q, 2H, J = 11.1 Hz,
7.1 Hz, 6.4 Hz), 2.48 (s, 3H), 2.19–2.26 (m, 2H); 13C NMR
(300 MHz, CDCl3): d 179.12, 175.54, 61.87, 50.07, 29.93, 24.32,
21.12; GC–MS m/z 156.20 (M+); Elemental Analysis: Calcd
C7H12N2O2: C, 53.83; H, 7.74; N, 17.94; O, 20.49. Found C, 53.82;
H, 7.76; N, 17.91; O, 20.48.
4.7. Characterization of compound 3c
White solid (385 mg, 88%), mp 102 to 104 °C, ½a D27
¼ ꢀ112:5 (c
ꢁ
0.5, ethyl acetate); 1H NMR (300 MHz, CDCl3): d 9.11 (s, 1H, NH),
8.34–8.37 (m, 2H), 8.43–8.57, (m, 2H), 4.36 (t, 1H, J = 9.2 Hz,
5.8 Hz), 3.51 (t, 2H, J = 10.1 Hz, 6.1 Hz), 2.99 (s, 3H), 2.43 (q, 2H,
J = 11.4 Hz, 7.1 Hz, 5.3 Hz), 1.87–2.14 (m, 2H); 13C NMR
(300 MHz, CDCl3): d 178.0, 174.1, 153.7, 147.4, 129.3, 125.7, 61.2,
47.1, 30.4, 25.7, 21.4; GC–MS m/z 341.06 (M+); Elemental Analysis:
Calcd C13H15N3O6S: C, 45.74; H, 4.43; N, 12.31; O, 28.12; S, 9.39.
Found C, 45.71; H, 4.40; N, 12.32; O, 28.14; S, 9.41.
4.8. General procedure for the Baylis–Hillman reaction
To a stirred mixture of the substrate aldehyde (1.0 mmol) and
methyl acrylate (1.2 mmol) were added triethylamine (5 mol %)
and organocatalyst (12 mol %) using ethanol as the solvent. The
homogeneous reaction mixture was stirred at 0 °C for the appro-
priate time (Table 3). The progress of the reaction was monitored
by thin layer chromatography. After the completion of reaction
as indicated by TLC, the reaction mixture was allowed to return
to room temperature. The solvent was evaporated, dichlorometh-
ane was added, and dried over anhydrous sodium sulfate. The ob-
tained organic layer was filtered and then concentrated in vacuo.
The resulting crude oil was further purified by column chromatog-
raphy using silica gel (mesh 80–120), with ethyl acetate and
hexane as the eluent to give the desired products 6a–j as the
Baylis–Hillman adduct. The absolute configuration was deter-
mined by resolution methods35 using chiral compound (ꢀ)-(R,R)-
2-amino-l-(4-nltrophenyl) propan-l,3-diol.
4.4. General procedure for the synthesis of pyrrolidine sulfon-
amide organocatalysts 3a–c
Compound 2 (4.43 mmol, 500 mg) was dissolved in a much
smaller amount of pyridine; to this solution was added methane-
sulfonamide/p-toluenesulfonamide/p-nitrobenzenesulfonamide.
This mixture was stirred for 1–2 h and then left overnight without
stirring. After completion of the reaction, crushed ice was added to
this mixture and the mixture was stirred again to obtain a solid
crude product; if the mixture was slightly acidified, we did not ob-
tain any product. This crude product was washed with dichloro-
methane and ice cold water. The product was further purified
using column chromatography to obtain crystals of compounds
3a–c.
4.9. (R)-Methyl 2-[(4-fluorophenyl) (hydroxy) methyl] acrylate
6a
The product was characterized by comparing the spectroscopic
data with those reported in the literature.36 Colorless oil,
½
a 2D7
ꢁ
¼ ꢀ53:2 (c 0.5, ethyl acetate); 1H NMR (300 MHz, CDCl3): d
4.5. Characterization of compound 3a
8.21–8.34 (m, 2H), 7.67–7.81 (m, 2H), 6.58 (s,1H), 5.87 (s, 1H),
5.24 (s, 1H), 3.58 (s, 3H), 2.49 (br s, 1H, OH); 13C NMR (300 MHz,
CDCl3): d 171.89, 163.78, 144.22, 140.00, 124.96, 120.08, 116.16,
77.27, 55.86; GC–MS: m/z 210 (M+); Elemental Analysis:
White solid (352 mg, 84%), mp 132 to 134 °C, ½a D27
¼ ꢀ89:5 (c
ꢁ
0.5, ethyl acetate); 1H NMR (300 MHz, CDCl3): d 8.67 (s, 1H, NH),
4.65 (t, 1H, J = 10.2 Hz, 6.0 Hz), 3.86 (t, 2H, J = 9.5 Hz, 5.8 Hz),
3.11 (s, 3H), 2.74 (q, 2H, J = 11.6 Hz, 6.8 Hz, 4.9 Hz), 2.14–2.22 (m,
2H), 2.06 (s, 3H); 13C NMR (300 MHz, CDCl3): d 174.20, 169.78,
71.49, 49.18, 43.47, 30.61, 25.01, 19.98; GC–MS m/z 234.05 (M+);
Elemental Analysis: Calcd C8H14N2O4S: C, 41.01; H, 6.02; N,
11.96; O, 27.32; S, 13.69. Found C, 41.03; H, 5.99; N, 12.01; O,
27.35; S, 13.72.
C11H11FO3: C, 62.85; H, 5.27; F, 9.04; O, 22.83. Found C, 62.87; H,
5.274; F, 9.05; O, 22.81. HPLC: 94% ee. [Determined by chiral
HPLC with Whelk-O1 (25 cm ꢂ 4.6 mm), 2% IPA/hexane, Flow
rate
1.0 mL/min,
k = 254 nm;
tR
(major) = 14.4 min,
tR
(minor) = 18.2 min.]
4.10. (R)-Methyl 2-[(4-nitrophenyl) (hydroxy) methyl] acrylate
6b
4.6. Characterization of compound 3b
The product was characterized by comparing the spectroscopic
data with those reported in the literature.37 Yellowish oil,
White solid (397 mg, 87%), mp 88 to 90 °C, ½a D27
¼ ꢀ125:7 (c 0.5,
ꢁ
ethyl acetate); 1H NMR (300 MHz, CDCl3): d 8.34 (s, 1H, NH), 7.18–
½
a 2D7
ꢁ
¼ ꢀ15:5 (c 0.5, ethyl acetate); 1H NMR (300 MHz, CDCl3): d

1324
P. B. Thorat et al. / Tetrahedron: Asymmetry 23 (2012) 1320–1325
7.71–7.87 (m, 2H), 7.31–7.46 (m, 2H), 6.89 (s, 1H), 6.31 (s, 1H), 5.80
(s, 1H), 3.55 (s, 3H), 2.29 (br s, 1H, OH); 13C NMR (300 MHz, CDCl3):
d 176.03, 151.37, 149.11, 138.28, 129.14, 123.05, 122.24, 78.89,
50.04; GC–MS: m/z 237 (M+); Elemental Analysis: C11H11NO5: C,
55.70; H, 4.67; N, 5.90; O, 33.72. Found C, 55.72; H, 4.69; N,
5.90; 88, 33.74. HPLC: 96% ee. [Determined by chiral HPLC with
Whelk-O1 (25 cm ꢂ 4.6 mm), 2% IPA/hexane, Flow rate 1.0 mL/
min, k = 254 nm; tR (major) = 15.5 min, tR (minor) = 20.1 min.]
(M+); Elemental Analysis: C11H11ClO3: C, 58.29; H, 4.89; Cl,
15.64; O, 21.18. Found, C, 58.27; H, 4.87; Cl, 15.63; O, 21.19. HPLC:
81% ee. [Determined by chiral HPLC with Whelk-O1
(25 cm ꢂ 4.6 mm), 2% IPA/Hexane, Flow rate 1.0 mL/min,
k = 254 nm; tR (major) = 16.5 min, tR (minor) = 19.5 min.]
4.15. (R)-Methyl 2-[hydroxy(phenyl) methyl] acrylate 6g
The product was characterized by comparing the spectroscopic
data with those reported in the literature.36 Colorless oil,
4.11. (R)-Methyl 2-[hydroxy(3-nitrophenyl) methyl]) acrylate 6c
½
a 2D7
ꢁ
¼ ꢀ44:6 (c 0.5, ethyl acetate); 1H NMR (300 MHz, CDCl3): d
The product was characterized by comparing the spectroscopic
data with those reported in the literature.38 Yellowish oil,
6.89–7.02 (m, 4H), 7.05–7.10 (m, 1H), 6.55 (s, 1H), 6.29 (s, 1H),
5.43 (s, 1H), 3.61 (s, 3H), 2.30 (br s, 1H, OH); 13C NMR (300 MHz,
CDCl3): d 170.25, 143.18, 141.89, 128.76, 127.34, 126.91, 126.11,
70.36, 51.20; GC–MS: m/z 192 (M+); Elemental Analysis:
½
a 2D7
ꢁ
¼ ꢀ61:3 (c 0.5, ethyl acetate); 1H NMR (300 MHz, CDCl3): d
7.67–7.82 (m, 2H), 7.21–7.33 (m, 1H), 7.04–7.12 (m, 1H), 6.82 (s,
1H), 6.34 (s, 1H), 5.74 (s, 1H), 3.61 (s, 3H), 2.33 (br s, 1H, OH);
13C NMR (300 MHz, CDCl3): d 170.23, 151.44, 144.49, 139.17,
135.29, 131.36, 128.81, 125.71, 123.42, 70.61, 50.55; GC–MS: m/z
237 (M+); Elemental Analysis: C11H11NO5: C, 55.70; H, 4.67; N,
5.90; O, 33.72. Found, 55.71; H, 4.65; N, 5.88; O, 33.73. HPLC:
90% ee. [Determined by chiral HPLC with Whelk-O1
(25 cm ꢂ 4.6 mm), 2% IPA/hexane, Flow rate 1.0 mL/min,
k = 254 nm; tR (major) = 12.7 min, tR (minor) = 18.4 min.]
C11H12O3: C, 68.74; H, 6.29; O, 24.97. Found, C, 68.73; H, 6.31; O,
25.00. HPLC: 76% ee. [Determined by chiral HPLC with Whelk-O1
(25 cm ꢂ 4.6 mm), 2% IPA/hexane, Flow rate 1.0 mL/min,
k = 254 nm; tR (major) = 12.9 min, tR (minor) = 18.4 min.]
4.16. (R)-Methyl 2-[hydroxy(4-hydroxyphenyl) methyl] acrylate
6h
The product was characterized by comparing the spectroscopic
data with those reported in the literature.36 Blackish viscous mass,
4.12. (R)-Methyl 2-[(4-cyanophenyl) (hydroxy) methyl] acrylate
6d
½
a 2D7
ꢁ
¼ ꢀ9:4 (c 0.5, ethyl acetate); 1H NMR (300 MHz, CDCl3): d 8.93
(br s, 1H, OH), 7.91–8.09 (m, 1H), 7.61–7.78 (m, 2H), 6.33 (s, 1H),
5.71 (s, 1H), 4.51 (s, 1H), 3.22 (s, 3H), 2.29 (br s, 1H, OH); 13C
NMR (300 MHz, CDCl3): d 167.57, 157.33, 144.36, 137.27, 129.60,
125.01, 118.21, 79.18, 50.37; GC–MS: m/z 208 (M+); Elemental
Analysis: C11H12O4: C, 63.45; H, 5.81; O, 30.74. Found C, 63.48;
H, 5.79; O, 30.73. HPLC: 83% ee. [Determined by chiral HPLC with
Whelk-O1 (25 cm ꢂ 4.6 mm), 2% IPA/hexane, Flow rate 1.0 mL/
min, k = 254 nm; tR (major) = 15.4 min, tR (minor) = 18.2 min.]
Colorless oil, ½a D27
ꢁ
¼ ꢀ58:4 (c 0.5, ethyl acetate); 1H NMR
(300 MHz, CDCl3): d 7.17–7.52 (m, 4H), 6.87 (s, 1H), 6.43 (s, 1H),
5.79 (s, 1H), 3.69 (s, 3H), 2.41 (br s, 1H, OH); 13C NMR (300 MHz,
CDCl3): d 169.87, 148.72, 142.54, 131.66, 128.71, 127.59, 119.48,
113.92, 73.73, 53.83; GC–MS: m/z 217 (M+); Elemental Analysis:
C
12H11NO3: C, 66.35; H, 5.10; N, 6.45; O, 22.10. Found, C,
66.33; H, 5.07; N, 6.44; O, 22.13. HPLC: 89% ee. [Determined by chi-
ral HPLC with Whelk-O1 (25 cm ꢂ 4.6 mm), 2% IPA/hexane, Flow
rate
1.0 mL/min,
k = 254 nm;
tR
(major) = 17.4 min,
tR
4.17. (R)-Methyl 2-[hydroxy(4-methoxyphenyl) methyl] acrylate
(minor) = 22.4 min.]
6i
4.13. (R)-Methyl 2-[(4-chlorophenyl) (hydroxy) methyl] acrylate
6e
The product was characterized by comparing the spectroscopic
data with those reported in the literature.36 Colorless oil,
½
a 2D7
ꢁ
¼ ꢀ12:3 (c 0.5, ethyl acetate); 1H NMR (300 MHz, CDCl3): d
The product was characterized by comparing the spectroscopic
data with those reported in the literature.36 Colorless oil,
7.57–7.86 (m, 4H), 6.41 (s, 1H), 5.88 (s, 1H), 4.49 (s, 1H), 3.01 (s,
3H), 2.66 (s, 3H), 2.10 (br s, 1H, OH); 13C NMR (300 MHz, CDCl3):
d 168.74, 154.00, 143.19, 132.22, 128.41, 118.05, 117.36, 79.71,
59.41, 54.71; GC–MS: m/z 222 (M+); Elemental Analysis:
½
a 2D7
ꢁ
¼ ꢀ10:2 (c 0.5, ethyl acetate); 1H NMR (300 MHz, CDCl3): d
7.25–7.41 (m, 2H), 7.08–7.20 (m, 2H), 6.77 (s, 1H), 6.34 (s, 1H),
5.23 (s, 1H), 3.75 (s, 3H), 2.37 (br s, 1H, OH); 13C NMR (300 MHz,
CDCl3): d 163.44, 143.05, 140.12, 134.65, 130.83, 128.90, 126.00,
71.96, 49.87; GC–MS: m/z 226 (M+); Elemental Analysis:
C11H12O4: C, 63.45; H, 5.81; O, 30.74. Found C, 63.48; H, 5.79; O,
30.73. HPLC: 78% ee. [Determined by chiral HPLC with Whelk-O1
(25 cm ꢂ 4.6 mm), 2% IPA/hexane, Flow rate 1.0 mL/min,
k = 254 nm; tR (major) = 11.3 min, tR (minor) = 19.5 min.]
C11H11ClO3: C, 58.29; H, 4.89; Cl, 15.64; O, 21.18. Found, C,
58.26; H, 4.92; Cl, 15.66; O, 21.21. HPLC: 87% ee. [Determined by
chiral HPLC with Whelk-O1 (25 cm ꢂ 4.6 mm), 2% IPA/Hexane,
Flow rate 1.0 mL/min, k = 254 nm; tR (major) = 14.3 min, tR
(minor) = 20.1 min.]
4.18. (R)-Methyl 2-[hydroxy(p-tolyl) methyl] acrylate 6j
The product was characterized by comparing the spectroscopic
data with those reported in the literature.36 Colorless oil,
4.14. (R)-Methyl 2-[(2-chlorophenyl) (hydroxy) methyl] acrylate
6f
½
a 2D7
ꢁ
¼ þ31:2 (c 0.5, ethyl acetate); 1H NMR (300 MHz, CDCl3): d
7.11–7.25 (m, 2H), 6.87–6.98 (m, 2H), 6.46 (s, 1H), 5.81 (s, 1H),
4.89 (s, 1H), 3.44 (s, 3H), 2.29 (s, 3H), 2.18 (br s, 1H, OH); 13C
NMR (300 MHz, CDCl3): d 168.74, 154.00, 143.19, 132.22, 128.41,
118.05, 117.36, 79.71, 59.41, 54.71; GC–MS: m/z 206 (M+); Ele-
mental Analysis: C12H14O3: C, 69.88; H, 6.84; O, 23.27. Found C,
69.90; H, 6.81; O, 23.29. HPLC: 77% ee. [Determined by chiral HPLC
with Whelk-O1 (25 cm ꢂ 4.6 mm), 2% IPA/hexane, Flow rate
1.0 mL/min, k = 254 nm; tR (major) = 14.2 min, tR (minor) =
21.4 min.]
The product was characterized by comparing the spectroscopic
data with those reported in the literature.36 Colorless oil,
½
a 2D7
ꢁ
¼ þ11:7 (c 0.5, ethyl acetate); 1H NMR (300 MHz, CDCl3): d
7.32–7.49 (m, 2H), 7.18–7.27 (m, 1H), 6.97–7.05 (m, 1H), 6.69 (s,
1H), 6.40 (s, 1H), 5.31 (s, 1H), 3.70 (s, 3H), 2.33 (br s, 1H, OH);
13C NMR (300 MHz, CDCl3): d 168.30, 144.00, 142.45, 130.61,
129.71, 128.10, 127.43, 117.27, 68.71, 50.84; GC–MS: m/z 226

P. B. Thorat et al. / Tetrahedron: Asymmetry 23 (2012) 1320–1325
19. Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41, 2165.
1325
Acknowledgments
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