Stereoselective synthesis of vic-halohydrins and an unusual Knoevenagel product from an organocatalyzed aldol reaction: A non-enamine mode

Article abstract of DOI:10.1016/S1872-2067(14)60317-X

Stereoselective synthesis by an aldol reaction between chloroacetone and aldehyde was studied using a synthesized chiral organocatalyst and triethylamine. The reaction gave α-chloro-β-hydroxy ketones in excellent yield with high anti selectivity and enantioselectivity. The chiral organocatalyst was also used in the Knoevenagel reaction, which gave α-cyano-β-hydroxy ketones at a low temperature and the usual Knoevenagel product at a high temperature. Both products were obtained in good to moderate yield with good anti selectivity in the case of α-cyano-β-hydroxy ketone derivatives.

Full text of DOI:10.1016/S1872-2067(14)60317-X

Chinese Journal of Catalysis 36 (2015) 1093–1100
a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / c h n j c
Article
Stereoselective synthesis of vic-halohydrins and an unusual
Knoevenagel product from an organocatalyzed aldol reaction:
A non-enamine mode
P. B. Thorat, S. V. Goswami, V. P. Sondankar, S. 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:
Stereoselective synthesis by an aldol reaction between chloroacetone and aldehyde was studied
using a synthesized chiral organocatalyst and triethylamine. The reaction gave α-chloro-β-hydroxy
ketones in excellent yield with high anti selectivity and enantioselectivity. The chiral organocatalyst
was also used in the Knoevenagel reaction, which gave α-cyano-β-hydroxy ketones at a low tem-
perature and the usual Knoevenagel product at a high temperature. Both products were obtained in
good to moderate yield with good anti selectivity in the case of α-cyano-β-hydroxy ketone deriva-
tives.
Received 5 January 2015
Accepted 10 February 2015
Published 20 July 2015
Keywords:
Aldol reaction
Asymmetric synthesis
Chloroacetone
© 2015, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
Published by Elsevier B.V. All rights reserved.
Diastereoselectivity
Hydroxy propanoate
Knoevenagel reaction
Pyrrolidine derivative
1. Introduction
active methylene compound in the presence of a base is known
as Knoevenagel condensation [8]. The Knoevenagel reaction is
Vic-halohydrins are important intermediates for the synthe-
sis of biologically active compounds and natural products such
as bagonists [1], substituted pyrrolidines [2], polychlorosul-
folipid [3], and insect sex pheromones [4]. These molecules are
building blocks for various bioactive products and natural
compounds. Thus efforts have been made to develop effective
techniques to synthesize these compounds. The ring opening of
enantiomerically pure epoxides is one of the most popular
process [5] but suffers from the disadvantage of the formation
of regioisomers. The asymmetric reduction of prochiral α-halo
ketones by chiral catalysts such as oxazaborolidine with borane
[1–2,6], Ru [1,7], or Rh [7,8] by asymmetric hydrogenation has
shown good enantioselectivity.
an important C–C bond forming reaction because the synthe-
sized alkenes are very useful intermediates in organic synthesis
[9]. For example, Knoevenagel condensation has been success-
fully combined with hetero-Diels-Alder reactions, Michael ad-
dition reactions, ene reactions, and sigmatropic rearrangement
for the synthesis of highly functionalized molecules [10–13].
Asymmetric organocatalysis has become an important area
of research in organic synthesis. The development of organo-
catalyzed reactions for the stereoselective construction of C–C
bonds has been intensively investigated. Since the discovery by
List et al. [14] that L-proline can mimic enantioselectively cata-
lyzed intermolecular aldol reactions, many organocatalysts
have been synthesized with the aim of increasing their activity
and stereoselectivity [15–17]. These reactions are typical of
The condensation reaction of carbonyl compounds with an
* Corresponding author. Tel: +91-2452-242411; Fax: +91-2452-242493; E-mail: bhusare71@yahoo.com
DOI: 10.1016/S1872-2067(14)60317-X | http://www.sciencedirect.com/science/journal/18722067 | Chin. J. Catal., Vol. 36, No. 7, July 2015

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P. B. Thorat et al. / Chinese Journal of Catalysis 36 (2015) 1093–1100
enamine based organocatalysis and proceeds via the reversible
condensation of the catalytic amine with a ketone to provide a
nucleophilic enamine intermediate. In these reactions, the car-
boxylic acid functionality on proline is important, and it is pos-
tulated that it activates and orients the aldehyde acceptor via a
hydrogen bonding interaction.
2.2. Preparation of organocatalysts 1–4
The synthesis and characterization of the organocatalyst
was described in our previous communication [23].
2.3. General procedure for the aldol reaction for the synthesis of
Alternatively, the utility of a N-sulfinyl group [18–22] as
both a chiral directing group and acidifying element in hydro-
gen-bonded organocatalysts has been demonstrated. In these
reactions, the sulfinyl N–H bond is postulated to activate the
substrate by the formation of a key hydrogen bonding interac-
tion. The inductive electron-withdrawing effect of the sulfinyl
group acidifies the N–H bond, which serves to modulate the
hydrogen bonding interaction. In addition, the close proximity
of the stereogenic sulfur to the active site of the catalyst con-
tributes to high stereoselectivity control in these reactions. On
the basis of the success of hydrogen bonding organocatalysis,
we studied pyrrolidine based organocatalysis in the absence of
a Lewis basic primary or secondary amine functionality, which
occurs exclusively via hydrogen bonding and van der Waals
interactions.
7a–7f
To a solution of chloroacetone 6 (1.5 eq.) dissolved in etha-
nol, a few drops of triethylamine (3–4 drops) was added and
the reaction mixture was stirred for 15–20 min. To this stirred
solution, an aromatic aldehyde 5(a–f) (1.0 eq.) and a catalytic
amount of the organocatalyst (S)-1-acetyl-N-tosylpyrrolidine-
2-carboxamide 3 was added and reacted and stirred for an
appropriate time (Table 2). The progress of reaction was mon-
itored by thin layer chromatography. After completion of the
reaction, the solvent was evaporated under vacuum. The crude
product was partitioned between ethyl acetate and water. The
organic layer was collected, and the aqueous phase was ex-
tracted with ethyl acetate. The collected organic layer was
washed with saturated brine solution, and the product was
purified using column chromatography using silica gel (80–120
mesh).
3-Chloro-4-hydroxy-4-(4-nitrophenyl)butan-2-one (7a).
Light yellow solid (182 mg, 90%), M.P. 142–144 °C [19]; 1H
NMR (300 MHz, CDCl3): δ 7.40–7.52 (m, 2H), 7.12–7.28 (m, 2H),
6.01 and 5.76 (bs, 1H, OH for syn and anti), 5.21 (s, 1H) syn,
4.96 (d, 1H, J = 8.7 Hz) anti, 4.29 (s, 1H) anti, 3.95 (s, 1H) syn,
2.08 (s, 3H); 13C NMR (300 MHz, CDCl3): δ 209.9, 154.5, 149.8,
129.7, 123.2, 68.9, 59.1, 28.1; GC-MS m/z 243 (M+); Elemental
analysis: Anal. Calcd for C10H10ClNO4: C, 49.30; H, 4.14; Cl,
14.55; N, 5.75; O, 26.27; Found C, 49.31; H, 4.17; Cl, 14.57; N,
5.76; O, 26.29. Enantiomeric purity was determined by chiral
HPLC using Whelk-O1 (25 cm  4.6 mm), 20:80:0.5 IPA/hex-
ane/HOAc, flow rate 1.0 mL/min,  = 254 nm; tR(major) = 17.2
min, tR(minor) = 25.5 min, ee = 92%.
We restricted enamine/imine formation by introducing an
acetyl group onto the active nitrogen site in the pyrrolidine ring
and replaced the carboxylic group by an amide and sulfinyl
group. To perform hydrogen bonding organocatalysis, we syn-
thesized the organocatalysts shown in Fig. 1. Earlier results
have been reported in a previous communication [23].
2. Experimental
2.1. General details
All solvents used were commercial anhydrous grade used
without further purification. Aluminium sheets 20 cm  20 cm,
silica gel 60 F254, Merck grade was used for thin layer chroma-
tography to determine the progress of the reaction. Column
chromatography was carried out over silica gel (80–120 mesh).
The optical rotation was measured on a Polax-2L digital po-
larimeter. The melting point was determined in an open capil-
3-Chloro-4-(4-fluorophenyl)-4-hydroxybutan-2-one (7b).
Colorless solid, (158 mg, 92%), M.P. 77–79 °C; 1H NMR (300
MHz, CDCl3): δ 7.56–7.66 (m, 2H), 7.23–7.34 (m, 2H), 5.79 and
5.46 (bs, 1H, OH for syn and anti), 5.21 (s, 1H) syn, 4.88 (d, 1H, J
1
lary tube and was uncorrected. H and 13C NMR spectra were
recorded on an Avance 300 MHz spectrometer using CDCl3
solvent. Mass spectra were obtained on a Polaris-Q Thermo-
scientific GC-MS. Elemental analyses were obtained using a
flash EA 1112. Enantiomeric purity was determined on a
PerkinElmer Series 200 HPLC System.
= 8.2 Hz) anti, 4.33 (s, 1H) anti, 3.89 (s, 1H) syn, 1.98 (s, 3H); 13
C
NMR (300 MHz, CDCl3): δ 208.4, 151.8, 147.6, 128.9, 124.5,
70.4, 57.9, 29.1; GC-MS m/z 246 (M+); Elemental analysis: Anal.
Calcd for C11H12ClFO3: C, 53.56; H, 4.90; Cl, 14.37; F, 7.70; O,
19.46; Found C, 53.54; H, 4.91; Cl, 14.40; F, 7.73; O, 19.44. En-
antiomeric purity was determined by chiral HPLC using
Whelk-O1 (25 cm  4.6 mm), 20:80:0.5 IPA/hexane/HOAc, flow
rate 1.0 mL/min,  = 254 nm; tR(major) = 23.2 min, tR(minor) =
27.1 min, ee = 92%.
4-(2-Chloro-1-hydroxy-3-oxobutyl)benzonitrile (7c). Vis-
cous oil (171 mg, 88%) [19]; 1H NMR (300 MHz, CDCl3): δ
7.56–7.94 (m, 4H), 6.14 and 5.82 (bs, 1H, OH for syn and anti),
5.61 (s, 1H) syn, 4.37 (d, 1H, J = 9.3 Hz) anti, 4.45 (s, 1H) anti,
3.95 (s, 1H) syn, 2.17 (s, 3H); 13C NMR (300 MHz, CDCl3): δ
205.1, 149.1, 132.7, 128.3, 112.2, 106.6, 81.1, 64.4, 23.4; GC-MS
m/z 223 (M+); Elemental analysis: Anal. Calcd for C11H10ClNO2:
C, 59.07; H, 4.51; Cl, 15.85; N, 6.26; O, 14.31; Found C, 59.10; H,
O
O
CONH
2
N
N
HN S Me
O
O
O
1
2
O
O
O
O
N
HN
S
Me
N
HN
S
NO
2
O
O
O
O
3
4
Fig. 1. Pyrrolidine based organocatalysts.

P. B. Thorat et al. / Chinese Journal of Catalysis 36 (2015) 1093–1100
1095
4.55; Cl, 15.87; N, 6.29; O, 14.33. Enantiomeric purity was de-
termined by chiral HPLC using Whelk-O1 (25 cm  4.6 mm),
20:80:0.5 IPA/hexane/HOAc, flow rate 1.0 mL/min,  = 254
nm; tR(major) = 24.2 min, tR(minor) = 31.4 min, ee = 90%.
3-Chloro-4-(4-chlorophenyl)-4-hydroxybutan-2-one (7d).
White sticky solid (165 mg, 85%); 1H NMR (300 MHz, CDCl3): δ
7.26–7.36 (m, 4H), 6.03 and 5.79 (bs, 1H, OH for syn and anti),
5.34 (s, 1H) syn, 4.41 (d, 1H, J = 8.4 Hz) anti, 4.36 (s, 1H) anti,
4.03 (s, 1H) syn, 2.14 (s, 3H); 13C NMR (300 MHz, CDCl3): δ
203.4, 153.3, 147.1, 129.2, 126.7, 71.0, 59.8, 29.5; GC-MS m/z
263 (M+); Elemental analysis: Anal. Calcd for C11H12Cl2O3: C,
50.21; H, 4.60; Cl, 26.95; O, 18.24; Found C, 50.24; H, 4.63; Cl,
26.91; O, 18.22. Enantiomeric purity was determined by chiral
HPLC using Whelk-O1 (25 cm  4.6 mm), 20:80:0.5 IPA/hex-
ane/HOAc, flow rate 1.0 mL/min,  = 254 nm; tR(major) = 20.2
min, tR(minor) = 27.3 min, ee = 88%.
4-(2-Bromophenyl)-3-chloro-4-hydroxybutan-2-one (7e).
Brownish oil (178 mg, 77%) [24]; 1H NMR (300 MHz, CDCl3): δ
7.26–7.35 (m, 2H), 7.19–7.25 (m, 1H), 7.05–7.12 (m, 1H), 5.74
and 5.51 (bs, 1H, OH for syn and anti), 5.19 (s, 1H) syn, 4.93 (d,
1H, J = 7.2 Hz) anti, 4.40 (s, 1H) anti, 3.85 (s, 1H) syn, 2.11 (s,
3H); 13C NMR (300 MHz, CDCl3): δ 210.3, 153.6, 148.3, 127.2,
126.5, 71.8, 59.4, 30.4; GC-MS m/z 307 (M+); Elemental analy-
sis: Anal. Calcd for C11H12BrClO3: C, 42.96; H, 3.93; Br, 25.98; Cl,
11.53; O, 15.61; Found C, 42.96; H, 3.93; Br, 25.98; Cl, 11.53; O,
15.61. Enantiomeric purity was determined by chiral HPLC
using Whelk-O1 (25 cm  4.6 mm), 20:80:0.5 IPA/hexane/
HOAc, flow rate 1.0 mL/min,  = 254 nm; tR(major) = 23.4 min,
tR(minor) = 25.1 min, ee = 84%.
3-Chloro-4-hydroxy-4-phenylbutan-2-one (7f). Colorless
solid (120 mg, 73%), M.P. 110–112 °C [24]; 1H NMR (300 MHz,
CDCl3): δ 6.97–7.43 (m, 4H), 5.84 and 5.51 (bs, 1H, OH for syn
and anti), 5.17 (s, 1H) syn, 4.92 (d, 1H, 7.5 Hz) anti, 4.27 (s, 1H)
anti, 4.01 (s, 1H) syn, 2.04 (s, 3H); 13C NMR (300 MHz, CDCl3): δ
203.4, 153.3, 145.5, 123.2, 123.1, 71.4, 60.0, 31.1; GC-MS m/z
228 (M+); Elemental analysis: Anal. Calcd for C11H13ClO3: C,
57.78; H, 5.73; Cl, 15.50; O, 20.99; Found C, 57.80; H, 5.74; Cl,
15.52; O, 20.96. Enantiomeric purity was determined by chiral
HPLC using Whelk-O1 (25 cm  4.6 mm), 20:80:0.5 IPA/hex-
ane/HOAc, flow rate 1.0 mL/min,  = 254 nm; tR(major) = 27.4
min, tR(minor) = 28.2 min, ee = 86%.
extracted with ethyl acetate. The collected organic layer was
washed with saturated brine solution and the product was
purified using column chromatography using silica gel (80–120
mesh).
Ethyl 2-cyano-3-(4-nitrophenyl)acrylate (9a). Light yellow
solid (261 mg, 79%), M.P. 168–170 °C [25]; 1H NMR (300 MHz,
CDCl3): δ 8.27 (s, 1H), 7.12–7.28 (m, 2H), 7.69–7.79 (m, 2H),
3.98 (q, 2H), 1.38 (t, 3H); 13C NMR (300 MHz, CDCl3): δ 165.03,
151.00, 146.65, 129.71, 122.58, 119.74, 117.18, 101.69, 59.21,
18.56; GC-MS m/z 246 (M+); Elemental analysis: Anal. Calcd for
C12H10N2O4: C, 58.54; H, 4.09; N, 11.38; O, 25.99; Found C,
58.53; H, 4.10; N, 11.36; O, 25.97.
Ethyl 2-cyano-3-(3-nitrophenyl)acrylate (9b). Yellow solid
1
(240 mg, 78%), M.P. 133–135 °C [26]; H NMR (300 MHz,
CDCl3): δ 8.19 (s, 1H), 8.21–8.26 (m, 1H), 7.91–7.98 (m, 1H),
7.81–7.89 (m, 2H), 4.12 (q, 2H), 1.25 (t, 3H); 13C NMR (300
MHz, CDCl3): δ 162.6, 152.30, 147.33, 132.91, 128.25, 126.81,
126.11, 122.61, 117.18, 105.16, 61.42, 14.87; GC-MS m/z 246
(M+); Elemental analysis: Anal. Calcd for C12H10N2O4: C, 58.54;
H, 4.09; N, 11.38; O, 25.99; Found C, 58.51; H, 4.11; N, 11.35; O,
26.02.
Ethyl 2-cyano-3-(4-fluorophenyl)acrylate (9c) (CAS No.
18861-57-9). Yellow crystalline (135 mg, 79%), M.P. 96–98 °C;
1H NMR (300 MHz, CDCl3): δ 8.42 (s, 1H), 7.01–7.19 (m, 2H),
7.82–8.10 (m, 2H), 4.26 (q, 2H), 1.60 (t, 3H); 13C NMR (300
MHz, CDCl3): δ 163.51, 162.24, 153.33, 126.03, 119.68, 117.27,
98.64, 55.87, 22.31; GC-MS m/z 219 (M+); Elemental analysis:
Anal. Calcd for C12H10FNO2: C, 65.75; H, 4.60; F, 8.67; N, 6.39; O,
14.60; Found C, 65.71; H, 4.63; F, 8.68; N, 6.40; O, 14.61.
Ethyl 2-cyano-3-(4-cyanophenyl)acrylate (9d). Colorless
solid (244 mg, 80%), M.P. 133–135 °C; 1H NMR (300 MHz,
CDCl3): δ 8.34 (s, 1H), 7.67–7.73 (m, 2H), 7.42–8.61 (m, 2H),
4.23 (q, 2H), 1.34 (t, 3H); 13C NMR (300 MHz, CDCl3): δ 161.54,
157.43, 138.61, 130.91, 129.17, 117.34, 117.02, 109.76, 99.97,
63.12, 15.43; GC-MS m/z 226 (M+); Elemental analysis: Anal.
Calcd for C13H10N2O2: C, 69.02; H, 4.46; N, 12.38; O, 14.14;
Found C, 68.99; H, 4.49; N, 12.36; O, 14.12.
Ethyl 3-(4-chlorophenyl)-2-cyanoacrylate (9e). Brownish
1
solid (240 mg, 76%), M.P. 92–94 °C [27]; H NMR (300 MHz,
CDCl3): δ 8.19 (s, 1H), 7.82–7.88 (m, 2H), 7.12–8.23 (m, 2H),
4.18 (q, 2H), 1.28 (t, 3H); 13C NMR (300 MHz, CDCl3): δ 162.71,
152.13, 135.37, 134.89, 131.29, 130.27, 118.35, 101.49, 62.94,
14.99; GC-MS m/z 235 (M+); Elemental analysis: Anal. Calcd for
2.4. General procedure for the Knoevenagel condensation
reaction (9a–9j)
C12H10ClNO2: C, 61.16; H, 4.28; Cl, 15.04; N, 5.94; O, 13.58;
Found C, 61.14; H, 4.31; Cl, 15.02; N, 5.96; O, 13.61.
To a solution of ethylcyanoacetate 8 (1.5 eq.) dissolved in
ethanol, a few drops of triethylamine (3–4 drops) was added
and the reaction mixture was stirred for 15–20 min. To this
stirred solution, an aromatic aldehyde 5(a–f) (1.0 eq.) and a
catalytic amount of the organocatalyst (S)-1-acetyl-N-tosylpyr-
rolidine-2-carboxamide 3 in ethanol was added. The reaction
mixture was stirred at 50 °C for an appropriate time (Table 4).
The progress of reaction was monitored by thin layer chroma-
tography. After completion of the reaction, the mixture was
cooled and the solvent was evaporated under vacuum. The
crude product was partitioned between ethyl acetate and wa-
ter. The organic layer was collected and the aqueous phase was
Ethyl 3-(2-chlorophenyl)-2-cyanoacrylate (9f). Reddish sol-
id (231 mg, 73%), M.P. 54–55 °C [27]; 1H NMR (300 MHz,
CDCl3): δ 8.11 (s, 1H), 7.54–7.49 (m, 1H), 7.31–8.44 (m, 2H),
4.23 (q, 2H), 1.32 (t, 3H); 13C NMR (300 MHz, CDCl3): δ 162.71,
150.84, 134.76, 130.41, 129.65, 129.01, 128.77, 116.97, 104.42,
63.24, 15.43; GC-MS m/z 235 (M+); Elemental analysis: Anal.
Calcd for C12H10ClNO2: C, 61.16; H, 4.28; Cl, 15.04; N, 5.94; O,
13.58; Found C, 61.13; H, 4.29; Cl, 15.03; N, 5.93; O, 13.60.
Ethyl 2-cyano-3-phenylacrylate (9g). White solid (210 mg,
72%), M.P. 51–53 °C [28]; 1H NMR (300 MHz, CDCl3): δ 8.24 (s,
1H), 7.33–7.39 (m, 1H), 7.33–8.10 (m, 4H), 4.20 (q, 2H), 1.27 (t,
3H); 13C NMR (300 MHz, CDCl3): δ 160.21, 154.11, 133.54,

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P. B. Thorat et al. / Chinese Journal of Catalysis 36 (2015) 1093–1100
132.87, 129.75, 129.22, 128.77, 117.16, 101.59, 60.89, 14.87;
GC-MS m/z 201 (M+); Elemental analysis: Anal. Calcd for
termined by chiral HPLC using Whelk-O1 (25 cm  4.6 mm),
20:80:0.5 IPA/hexane/HOAc, flow rate 1.0 mL/min,  = 254
nm; tR(major) = 7.7 min, tR(minor) = 15.2 min, ee = 81%.
Ethyl 2-cyano-3-(3-nitrophenyl)-3-hydroxypropanoate (10b).
Yellow viscous oil (261 mg, 85%); 1H NMR (300 MHz, CDCl3): δ
7.27–7.35 (m, 2H), 7.21–7.26 (m, 1H), 7.05–7.17 (m, 1H), 5.19
(bs, 1H, OH), 4.39 (d, 1H), 4.37 (q, 2H), 3.91 (d, 1H), 1.37 (t, 3H);
13C NMR (300 MHz, CDCl3): δ 164.33, 150.02, 143.32, 131.78,
130.65, 125.63, 123.81, 113.01, 72.64, 59.44, 41.21, 18.92;
GC-MS m/z 264 (M+); HRMS: Calculated 264.0746; Found
264.0747; Elemental analysis: Anal. Calcd for C12H12N2O5: C,
54.55; H, 4.58; N, 10.60; O, 30.28; Found C, 54.55; H, 4.58; N,
10.60; O, 30.28. Enantiomeric purity was determined by chiral
HPLC using Whelk-O1 (25 cm  4.6 mm), 20:80:0.5 IPA/hex-
ane/HOAc, flow rate 1.0 mL/min,  = 254 nm; tR(major) = 9.0
min, tR(minor) = 15.7 min, ee = 84%.
Ethyl 2-cyano-3-hydroxy-3-(4-flurophenyl) propanoate (10c).
Colorless oil (238 mg, 87%); 1H NMR (300 MHz, CDCl3): δ
7.94–8.29 (m, 2H), 7.18–7.29 (m, 2H), 5.28 (bs, 1H, OH), 4.90
(d, 1H), 4.30 (q, 2H), 3.31 (d, 1H), 1.29 (t, 3H); 13C NMR (300
MHz, CDCl3): δ 166.19, 165.51, 130.11, 127.03, 126.02, 110.13,
71.58, 66.70, 46.42, 14.59; GC-MS m/z 237 (M+); HRMS: Calcu-
lated 237.0801; Found 237.0802; Elemental analysis: Anal.
Calcd for C12H12FNO3: C, 60.76; H, 5.10; F, 8.01; N, 5.90; O,
20.23; Found C, 60.74; H, 5.13; F, 7.99; N, 5.93; O, 20.26. Enan-
tiomeric purity was determined by chiral HPLC using
Whelk-O1 (25 cm  4.6 mm), 20:80:0.5 IPA/hexane/HOAc, flow
rate 1.0 mL/min,  = 254 nm; tR(major) = 13.3 min, tR(minor) =
15.3 min, ee = 82%.
C12H11NO2: C, 71.63; H, 5.51; N, 6.96; O, 15.90; Found C, 71.63;
H, 5.51; N, 6.96; O, 15.90.
Ethyl 2-cyano-3-p-tolylacrylate (9h). White solid (203 mg,
74%), M.P. 90–92 °C [29]; 1H NMR (300 MHz, CDCl3): δ 8.17 (s,
1H), 7.76–8.88 (m, 2H), 7.28–7.39 (m, 2H), 4.01 (q, 2H), 2.40 (s,
3H), 1.31 (t, 3H); 13C NMR (300 MHz, CDCl3): δ 161.91, 151.77,
142.81, 122.72, 122.68, 119.27, 99.99, 60.08, 23.19, 16.29;
GC-MS m/z 215 (M+); Elemental analysis: Anal. Calcd for
C13H13NO2: C, 72.54; H, 6.09; N, 6.51; O, 14.87; Found C, 72.56;
H, 6.06; N, 6.53; O, 14.85.
Ethyl 2-cyano-3-(4-hydroxyphenyl)acrylate (9i). Reddish
solid (203 mg, 69%), M.P. 172–174 °C [30]; 1H NMR (300 MHz,
CDCl3): δ 9.28 (bs, 1H, OH), 8.68 (s, 1H), 8.21–8.40 (m, 2H),
7.28–7.71 (m, 2H), 4.08 (q, 2H), 1.26 (t, 3H); 13C NMR (300
MHz, CDCl3): δ 163.47, 159.83, 150.01, 138.30, 127.61, 121.89,
117.26, 108.05, 61.87, 23.24; GC-MS m/z 217 (M+); Elemental
analysis: Anal. Calcd for C12H11NO3: C, 66.35; H, 5.10; N, 6.45; O,
22.10; Found C, 66.33; H, 5.12; N, 6.43; O, 22.11.
Ethyl
2-cyano-3-(3,4-dimethoxyphenyl)acrylate
(9j).
Brownish solid (234 mg, 67%), M.P. 56–58 °C [31]; 1H NMR
(300 MHz, CDCl3): δ 8.23 (s, 1H), 7.23–7.10 (m, 2H), 7.01–7.06
(m, 1H), 4.16 (q, 2H), 3.90 (s, 6H), 1.31 (t, 3H); 13C NMR (300
MHz, CDCl3): δ 164.09, 151.85, 150.31, 149.78, 129.65, 123.76,
117.08, 116.98, 116.31, 102.37, 60.45, 58.93, 17.62; GC-MS m/z
261 (M+); Elemental analysis: Anal. Calcd for C14H15NO4: C,
64.36; H, 5.79; N, 5.36; O, 24.49; Found C, 64.34; H, 5.81; N,
5.39; O, 24.47.
Ethyl 2-cyano-3-(4-cyanophenyl)-3-hydroxypropanoate (10d).
Colorless oil (249 mg, 89%); 1H NMR (300 MHz, CDCl3): δ
7.32–7.57 (m, 4H), 5.32 (bs, 1H, OH), 4.87 (d, 1H), 4.35 (q, 2H),
3.31 (d, 1H), 1.31 (t, 3H); 13C NMR (300 MHz, CDCl3): δ 165.66,
147.39, 133.87, 127.03, 124.38, 120.57, 112.59, 71.56, 68.93,
42.67, 16.74; GC-MS m/z 244 (M+); HRMS: Calculated
244.0848; Found 244.0850; Elemental analysis: Anal. Calcd for
2.5. General procedure for the synthesis of hydroxy propanoate
derivatives (10a–10j)
To a solution of ethylcyanoacetate 8 (1.5 eq.) dissolved in
ethanol, a few drops of triethylamine (3–4 drops) was added
and the reaction mixture was stirred for 15–20 min. To this
stirred cold solution, an aromatic aldehyde 5(a–f) (1.0 equiva-
lent) and a catalytic amount of the organocatalyst (S)-1-acetyl-
N-tosylpyrrolidine-2-carboxamide 3 in ethanol was added. The
reaction mixture was cooled to –78 °C and stirred for an ap-
propriate time (Table 4). The progress of reaction was moni-
tored by thin layer chromatography. After completion of the
reaction, crushed ice was added to this cold solution and the
mixture was allowed to stand. The reaction mixture was ex-
tracted with ethyl acetate. The collected organic layer was
washed with saturated brine solution and the product was
purified using column chromatography using silica gel (80–120
mesh).
Ethyl 2-cyano-3-(4-nitrophenyl)-3-hydroxypropanoate (10a).
Yellow viscous oil (274 mg, 89%); 1H NMR (300 MHz, CDCl3): δ
7.48–60 (m, 2H), 7.19–7.30 (m, 2H), 5.17 (bs, 1H, OH), 4.44 (d,
1H), 4.31 (q, 2H), 3.87 (d, 1H), 1.32 (t, 3H); 13C NMR (300 MHz,
CDCl3): δ 163.85, 149.97, 148.69, 130.78, 125.63, 117.11, 74.83,
58.23, 39.00, 16.91; GC-MS m/z 264 (M+); HRMS: Calculated
264.0746; Found 264.0744; Elemental analysis: Anal. Calcd for
C13H12N2O3: C, 63.93; H, 4.95; N, 11.47; O, 19.65; Found C,
63.91; H, 4.98; N, 11.44; O, 19.63. Enantiomeric purity was de-
termined by chiral HPLC using Whelk-O1 (25 cm  4.6 mm),
20:80:0.5 IPA/hexane/HOAc, flow rate 1.0 mL/min,  = 254
nm; tR(major) = 19.1 min, tR(minor) = 19.9 min, ee = 79%.
Ethyl 3-(4-chlorophenyl)-2-cyano-3-hydroxypropanoate (10e).
1
Brown semisolid (247 mg, 84%); H NMR (300 MHz, CDCl3): δ
7.16–7.24 (m, 2H), 7.02–7.11 (m, 2H), 5.35 (bs, 1H, OH), 4.89
(d, 1H), 4.27 (q, 2H), 3.29 (d, 1H), 1.31 (t, 3H); 13C NMR (300
MHz, CDCl3): δ 164.22, 145.51, 137.23, 126.02, 124.32, 117.71,
69.55, 59.49, 39.41, 16.94; GC-MS m/z 253 (M+); HRMS: Calcu-
lated 253.0506; Found 253.0508; Elemental analysis: Anal.
Calcd for C12H12ClNO3: C, 56.81; H, 4.77; Cl, 13.98; N, 5.52; O,
18.92; Found C, 56.83; H, 4.78; Cl, 13.95; N, 5.55; O, 18.93. En-
antiomeric purity was determined by chiral HPLC using
Whelk-O1 (25 cm  4.6 mm), 20:80:0.5 IPA/hexane/HOAc, flow
rate 1.0 mL/min,  = 254 nm; tR(major) = 11.6 min, tR(minor) =
16.4 min, ee = 83%.
Ethyl 3-(2-chlorophenyl)-2-cyano-3-hydroxypropanoate (10f).
Reddish gum (238 mg, 81%); 1H NMR (300 MHz, CDCl3): δ
7.51–7.58 (m, 1H), 7.22–7.46 (m, 3H), 5.29 (bs, 1H, OH), 4.89
C12H12N2O5: C, 54.55; H, 4.58; N, 10.60; O, 30.28; Found C,
54.55; H, 4.58; N, 10.60; O, 30.28. Enantiomeric purity was de-

P. B. Thorat et al. / Chinese Journal of Catalysis 36 (2015) 1093–1100
1097
(d, 1H), 4.31 (q, 2H), 3.35 (d, 1H), 1.29 (t, 3H); 13C NMR (300
MHz, CDCl3): δ 164.62, 144.45, 133.28, 127.34, 127.27, 122.63,
118.84, 63.67, 60.34, 40.27, 15.92; GC-MS m/z 237 (M+);
HRMS: Calculated 253.0506; Found 253.0507; Elemental anal-
ysis: Anal. Calcd for C12H12ClNO3: C, 56.81; H, 4.77; Cl, 13.98; N,
5.52; O, 18.92; Found C, 56.79; H, 4.79; Cl, 13.96; N, 5.55; O,
18.93. Enantiomeric purity was determined by chiral HPLC
using Whelk-O1 (25 cm  4.6 mm), 20:80:0.5 IPA/hexane/
HOAc, flow rate 1.0 mL/min,  = 254 nm; tR(major) = 14.0 min,
tR(minor) = 20.3 min, ee = 77%.
Ethyl 2-cyano-3-hydroxy-3-phenylpropanoate (10g). Col-
orless oil (214 mg, 79%); 1H NMR (300 MHz, CDCl3): δ
7.04–7.48 (m, 4H), 5.33 (bs, 1H, OH), 4.94 (d, 1H), 4.33 (q, 2H),
3.30 (d, 1H), 1.31 (t, 3H); 13C NMR (300 MHz, CDCl3): δ 164.42,
141.32, 126.24, 125.25, 124.89, 117.83, 61.37, 60.07, 40.33,
15.43; GC-MS m/z 237 (M+); HRMS: Calculated 219.0895;
Found 219.0893; Elemental analysis: Anal. Calcd for C12H13NO3:
C, 65.74; H, 5.98; N, 6.39; O, 21.89; Found C, 65.71; H, 6.00; N,
6.41; O, 21.87. Enantiomeric purity was determined by chiral
HPLC using Whelk-O1 (25 cm  4.6 mm), 20:80:0.5 IPA/hex-
ane/HOAc, flow rate 1.0 mL/min,  = 254 nm; tR(major) = 10.1
min, tR(minor) = 11.0 min, ee = 78%.
determined by chiral HPLC using Whelk-O1 (25 cm  4.6 mm),
20:80:0.5 IPA/hexane/HOAc, flow rate 1.0 mL/min,  = 254
nm; tR(major) = 11.0 min, tR(minor) = 11.4 min, ee = 76%.
3. Results and discussion
In a continuation of our work on organocatalysis [32–36],
we explored these chiral organocatalysts in the asymmetric
aldol reaction. The aldol reaction of chloroacetone (6) and
p-nitrobenzaldehyde (5a) to afford 7a was performed in etha-
nol using 10 mol% of the synthesized organocatalysts 1–4
bearing different sulfonamide groups in the presence of tri-
ethylamine (Scheme 1).
Initially, when just N-acylated prolinamide 1 was used as
the catalyst in the aldol reaction, after stirring for 48 h, we ob-
tained only 29% yield. The diastereoselectivity and enantiose-
lectivity were not determined for the reaction (Table 1, entry
1). The methanesulfonamide catalyst 2 afforded some im-
proved yield (40%), but the diastereoselectivity and enantio-
meric excess were very poor. The best result with respect to
yield, diastereoselectivity, and enantioselectivity was with cat-
alyst 3 and triethylamine. The reaction with organocatalyst 3
gave 7a in good yield with good diastereoselectivity and im-
proved enantioselectivity 69% ee for anti-7a (Table 1, entry 3).
Catalyst 4 catalyzed the aldol reaction affording 59% yield and
decreased diastereoselectivity and enantiomeric excess (Table
1, entries 2–4). Although organocatalysts 3 and 4 only showed
moderate stereoselectivity, the reaction time was short, esp.
with organocatalyst 3, which completed the reaction within 20
h. Interestingly, the reaction gave enhanced stereoselectivity on
increasing the catalyst loading (Table 1, entries 7–8). When the
loading of organocatalyst 3 was increased to 12 mol%, the an-
ti-aldol product was obtained with good enantioselectivity
(74% ee). The breakthrough was achieved when 15 mol% of
catalyst 3 was employed with triethylamine as the co-catalyst.
Ethyl 2-cyano-3-hydroxy-3-p-tolylpropanoate (10h). White
amorphous (201 mg, 80%); 1H NMR (300 MHz, CDCl3): δ
7.34–8.45 (m, 2H), 7.14–7.26 (m, 2H), 5.30 (bs, 1H, OH), 4.95
(d, 1H), 4.31 (q, 2H), 3.83 (d, 1H), 2.68 (s, 3H), 1.25 (t, 3H); 13
C
NMR (300 MHz, CDCl3): δ 162.74, 147.75, 147.26, 122.09,
120.16, 117.61, 64.32, 58.78, 40.69, 21.73, 13.58; GC-MS m/z
233 (M+); HRMS: Calculated 235.0845; Found 235.0844; Ele-
mental analysis: Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48; N,
6.00; O, 20.58; Found C, 66.97; H, 6.45; N, 5.97; O, 20.59. Enan-
tiomeric purity was determined by chiral HPLC using
Whelk-O1 (25 cm  4.6 mm), 20:80:0.5 IPA/hexane/HOAc, flow
rate 1.0 mL/min,  = 254 nm; tR(major) = 14.6 min, tR(minor) =
17.5 min, ee = 75%.
Ethyl 2-cyano-3-hydroxy-3-(4-hydroxyphenyl) propanoate
(10i). Reddish viscous oil (207 mg, 77%); H NMR (300 MHz,
O
OH
1
O
O
Organocatalyst
Et3N, ethanol
CDCl3): δ 7.94–8.29 (m, 2H), 7.18–7.29 (m, 2H), 5.29 (bs, 1H,
OH), 4.96 (d, 1H), 4.28 (q, 2H), 3.73 (d, 1H), 1.26 (t, 3H); 13C
NMR (300 MHz, CDCl3): δ 165.03, 72.34, 157.62, 140.78,
122.09, 116.28, 115.55, 60.12, 57.08, 36.93, 12.96; GC-MS m/z
235 (M+); HRMS: Calculated 279.1107; Found 279.1106; Ele-
mental analysis: Anal. Calcd for C12H13NO4: C, 61.27; H, 5.57; N,
5.95; O, 27.21; Found C, 61.28; H, 5.59; N, 5.92; O, 27.24. Enan-
tiomeric purity was determined by chiral HPLC using
Whelk-O1 (25 cm  4.6 mm), 20:80:0.5 IPA/hexane/HOAc, flow
rate 1.0 mL/min,  = 254 nm; tR(major) = 12.3 min, tR(minor) =
19.2 min, ee = 76%.
Ethyl 2-cyano-3-hydroxy-3-(3,4-dimethoxyphenyl) pro-
panoate (10j). Brownish oil (233 mg, 73%); 1H NMR (300 MHz,
CDCl3): δ 7.57–8.69 (m, 2H), 7.24–7.33 (m, 2H), 5.20 (bs, 1H,
OH), 4.77 (d, 1H), 4.31 (q, 2H), 3.89 (s, 6H), 3.43 (d, 1H), 1.32 (t,
3H); 13C NMR (300 MHz, CDCl3): δ 163.09, 157.51, 157.13,
130.91, 118.83, 109.20, 106.00, 105.01, 78.25, 73.14, 62.00,
49.23, 20.50; GC-MS m/z 279 (M+); Elemental analysis: Anal.
Calcd for C14H17NO5: C, 60.21; H, 6.14; N, 5.02; O, 28.64; Found
C, 60.19; H, 6.17; N, 5.04; O, 28.66. Enantiomeric purity was
+
H
Cl
Cl
NO2
O2N
7a
5a
6
Scheme 1. Aldol reaction of chloroacetone with p-nitrobenzaldehyde.
Table 1
Optimization of the aldol reaction between chloroacetone and p-nitro
benzaldehyde.
Catalyst
(mol%)
Time
(h)
Yield a
(%)
anti ee c
(%)
Entry Catalyst
anti/syn b
1
2
3
4
5
6
7
8
1
2
3
4
3
3
3
4
10
10
10
10
12
15
20
15
48
48
20
24
18
15
26
19
29
40
68
59
75
90
53
61
Ndd
2:1
7:1
5:1
7:1
8:1
3:1
4:1
Ndd
36
69
57
74
79
45
66
a Isolated yield.
b Determined by 1H NMR.
c Determined by chiral-phase HPLC analysis.
d Not determined.

1098
P. B. Thorat et al. / Chinese Journal of Catalysis 36 (2015) 1093–1100
Table 2
Table 3
Aldol reaction of chloroacetone with various aldehydes.
Knoevenagel reaction between ethylcyanoacetate and p-nitrobenzal-
dehyde at different temperatures in the presence of organocatalyst 3b
(reaction time 20 h).
Yield a (%)
Entry
Temperature (°C)
9a
69
78
89
84
54
23
18
10a
—
—
—
—
26
40
73
Yield a
(%)
90
88
92
85
77
73
anti eec
(%)
92
92
90
88
84
86
1
2
3
4
5
6
7
RT
40
50
60
0
Time
(h)
15
15
16
18
20
24
Entry
Ar
Product
anti/syn b
1
2
3
4
5
6
p-NO2–C6H4
p-F–C6H4
p-CN–C6H4
p-Cl–C6H4
o-Br–C6H4
C6H5
7a
7b
7c
7d
7e
7f
8:1
7:1
8:1
7:1
6:1
6:1
–20
–78
a Isolated yield.
a Isolated yield.
b Determined by 1H NMR.
c Determined by chiral-phase HPLC analysis.
and analyzed for its structure. Our estimate was that the by-
product obtained could be 2-cyano-3-hydroxy-3-(4-nitro-
phenyl) propanoate formed during the reaction (Scheme 3).
This was confirmed by the spectral data: proton NMR gave a
broad singlet at 6.19 ppm attributed to the presence of a hy-
droxyl group which was not found in the proton NMR of ethyl-
2-cyano-3-(4-nitrophenyl) acrylate. Further confirmation was
provided by 13C NMR which showed a signal at 74.83 ppm for
the carbon atom bearing the hydroxyl group. In the
Knoevenagel product, the signal for the same carbon atom ap-
peared at 151 ppm. The stability of product 10a decreased
with increase in temperature.
The yield of product 10a was observed to increase with de-
crease in temperature. In the Knoevenagel reaction at a low
temperature, 2-cyano-3-hydroxy-3-(4-nitrophenyl) propanoate
is kinetically stable whereas at a higher temperature ethyl-
2-cyano-3-(4-nitrophenyl) acrylate is thermodynamically sta-
ble. After stirring for 20 h, the reaction yielded 54%
Knoevenagel adduct and 26% of product 10a at 0 °C. At the
lower temperature of –20 °C, only 23% of the Knoevenagel
product 9a was observed with an increased yield of compound
10a. When the temperature was decreased to –78 °C, the per-
centage of kinetic stable product 10a was 73%. However, at
elevated temperatures, compound 2-cyano-3-hydroxy-3-(4-
nitrophenyl) propanoate was not observed. At these tempera-
tures, only the Knoevenagel product was observed, which is
thermodynamically more stable.
Up to 90% of the desired product 7a was obtained with a high-
er selectivity (anti/syn was 8:1). The anti-aldol product was
obtained with the excellent enantioselectivity of 92%.
Further increase in the loading of catalyst 3 in the presence
of triethylamine gave no more improvement, and the result
showed significant deviation from the previous trend of opti-
mization. The aldol reaction under the optimized condition
using organocatalyst 4 in ethanol was also examined. This cat-
alyst showed lower diastereoselectivity and enantioselctivity
with decreased yield of the product 7a (Table 1, entries 5–7),
even with an extended reaction time.
The scope of this class of aldol reactions using organocata-
lyst 3 and co-catalyst triethylamine in ethanol was examined
with a series of arylaldehydes 5 (Table 2) and chloroacetones
6. Aromatic aldehydes with an electron-withdrawing substitu-
ent were excellent substrates. The reaction proceeded smooth-
ly to afford the desired products 7a–7f. In all cases, the reac-
tions afforded the anti-aldol products in high yield with excel-
lent enantioselectivity.
The scope of the catalyst system of chiral compound 3 and
triethylamine was also assessed for the Knoevenagel condensa-
tion reaction between p-nitrobenzaldehyde 5a and ethylcy-
anoacetate 8 using ethanol as solvent (Scheme 2).
The base-mediated reaction at room temperature afforded
the Knoevenagel adduct 9a in 69% yield. A good increase in the
product yield was observed with a slight raise in the tempera-
ture to 40 °C. At the still higher temperature condition of 50 °C,
the best yield for the Knoevenagel product was achieved. No
significant change in yield was observed by a further increase
in the temperature from 50 °C to 60 °C. The influence of tem-
perature on the Knoevenagel reaction is shown in Table 3.
Surprisingly, while experimenting on the same reaction at
cold conditions, a byproduct was observed in very low percent
yield. The byproduct was isolated by column chromatography
To check the necessity of the catalyst, the reaction was car-
ried out in the absence of the catalyst. The reaction did not
progress at a low temperature even after 48 h of stirring.
However, at an increased temperature, the reaction showed
some progress to give exclusively the Knoevenagel product. We
also performed the reaction in the absence of the base tri-
ethylamine. The catalyst was able to promote the reaction to
give a trace amount of product 9a only at high temperature.
When the reaction was carried out with the replacing of ethyl-
Scheme 3. Knoevenagel reaction between p-nitrobenzaldehyde 5a and
ethylcyanoacetate 8 using organocatalyst 3 and triethylamine at low
temperature.
Scheme 2. Knovenagel reaction between p-nitrobenzaldehyde 5a and
ethylcyanoacetate 8 using organocatalyst 3 and triethylamine.

P. B. Thorat et al. / Chinese Journal of Catalysis 36 (2015) 1093–1100
1099
cyanoacetate by malononitrile or diethyl malonate, the reaction
went to completion only at a high temperature to give only the
Knoevenagel product.
O
O
NH(Et)3
Y
N(Et)3
X = Cl, CN
Y
Y = Me, OEt
We extended this protocol to other aldehydes to ensure the
reproducibility of the results (Table 4). The reaction proceeded
smoothly to give both the products with the hydroxy propano-
ate derivatives as the major product at –78 °C. When reaction
was performed at room temperature, only the Knoevenagel
product was obtained. The reaction was effective with electron
withdrawing groups present on the aromatic ring while an
electron donating substituent gave a moderate performance.
X
X
O
O
O
O
O
O
N
N
N S
N
S
O
O
O
H
H O
Y
O
X
O
NH(Et)3
NH(Et)3
Y
X
1
II
Analysis by H NMR spectra of the ethyl 2-cyano-3-hydroxy-3-
I
Favored
(anti)
Disfavored
(syn)
(aryl) propanoate derivatives showed that only the anti prod-
uct was formed. We also determined the enantioselectivity to
give the anti isomer of all products. The enantioselectivities
were good to moderate.
Fig. 2. Suggested transition state for the organocatalysed asymmetric
aldol reaction.
Figure 2 shows a possible mechanism for the reaction,
which explains the results. Triethylamine converts the keto
form into the enol form by abstracting a hydrogen. The carbon-
yl group in p-nitrobenzaldehyde is activated by strong hydro-
gen bonding, which weakens the π bond interaction between
the carbon and oxygen of the carbonyl group and increases its
electrophilicity. The enol attacks the Re-face of the carbon of
the aldehyde, which leads to the formation of the favored tran-
sition state I shown in Fig. 2. The sulfur from the sulfonyl group
contributes by the formation of van der Waals interaction,
which plays a vital role in the transition state [32–36].
The hydroxy propanoate derivatives formed usually get de-
hydrated to give the Knoevenagel product. Due to the mild ba-
sicity, at low temperatures, the product does not get dehydrat-
ed, and hydroxy propanoate derivatives were obtained. How-
ever, at a higher temperature, the conditions were enough for
the dehydration of the product formed in the presence of the
base triethylamine.
4. Conclusions
We successfully used an organocatalyst in an asymmetric
aldol reaction. Our hypothesis on hydrogen bonding catalysis
using triethylamine and an organocatalyst having a pyrrolidine
ring as the backbone was verified. The organocatalyst (S)-1-
acetyl-N-tosylpyrrolidine-2-carboxamide 3 was an excellent
catalyst. Extending the scope of our organocatalyst 3, we also
studied the Knoevenagel reaction, which gave the usual
Knoevenagel product at elevated temperatures and hydroxy
propanoate derivatives at the low temperature of –78 °C. Our
results also demonstrated that hydrogen bonding and van der
Waals interactions are important in catalysis and can catalyze
the reaction by stabilizing the intermediate. This protocol of-
fers non-hazardous and eco-friendly reaction conditions with
good yield and enantioselectivity.
Acknowledgments
Table 4
We acknowledge Dr. P. L. More, Principal, Dnyanopasak
College, Parbhani, for providing necessary facilities and IICT
Hyderabad for providing spectral data.
Aldol reaction of ethylcyanoacetate with various aldehydes.
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Yield a (%)
anti ee c
(%)
Entry
Ar
Time (h)
9
10
73
72
79
75
69
67
68
61
63
59
1
2
3
4
5
6
7
8
9
10
p-NO2–C6H4 (5a)
m-NO2–C6H4 (5b)
p-F–C6H4 (5c)
p-CN–C6H4 (5d)
p-Cl–C6H4 (5e)
o-Cl–C6H4 (5f)
C6H5 (5g)
p-Me–C6H4 (5h)
p-OH–C6H4 (5i)
m,p-OCH3–C6H3 (5j)
20
21
19
22
26
25
30
30
31
31
89
85
87
88
84
81
79
80
77
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81
84
82
79
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78
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a Isolated yield at 50 °C.
b Isolated yield at –78 °C
c Determined by chiral-phase HPLC analysis for compounds 10a–10j.
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P. B. Thorat et al. / Chinese Journal of Catalysis 36 (2015) 1093–1100
Graphical Abstract
Chin. J. Catal., 2015, 36: 1093–1100 doi: 10.1016/S1872-2067(14)60317-X
Stereoselective synthesis of vic-halohydrins and an unusual
Knoevenagel product from an organocatalyzed aldol reaction:
A non-enamine mode
P. B. Thorat, S. V. Goswami, V. P. Sondankar, S. R. Bhusare *
Dnyanopasak College, India
Stereoselective synthesis of vic-halohydrins and an unusual
Knoevenagel product were obtained using a newly synthesized chiral
organocatalyst and triethylamine. The reaction gave the products in
excellent yield with high anti selectivity and enantioselectivity.
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