L-Proline-catalyzed Knoevenagel condensation: A facile, green synthesis of (E)-ethyl 2-cyano-3-(1H-indol-3-yl)acrylates and (E)-3-(1H-indol-3-yl) acrylonitriles

Article abstract of DOI:10.1080/00397911.2010.543382

L-Proline has been utilized as a novel and ecofriendly catalyst in ethanol medium for the Knoevenagel condensation of indole-3-carboxyaldehydes and their N-methyl derivatives 1(a-e) and 4(a-e) with the active methylene compound, ethyl cyanoacetate (2) to afford substituted (E)-ethyl 2-cyano-3-(1H-indol-3-yl) acrylates 3(a-e) and 5(a-e) respectively. These products were reacted with dimethyl sulfate in the presence of PEG-600 as an efficient and green solvent to afford the corresponding N-mthylated derivatives 5(a-e). These Knoevenagel products react with 5% NaOH, yielding (E)-3-(1H-indol-3-yl)acrylonitriles 6(a-e) and 7(a-e). Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.543382

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L-Proline-Catalyzed Knoevenagel
Condensation: A Facile, Green Synthesis
of (E)-Ethyl 2-Cyano-3-(1H-indol-3-
yl)acrylates and (E)-3-(1H-Indol-3-
yl)acrylonitriles
M. Venkatanarayana a & P. K. Dubey a
a Department of Chemistry, Jawaharlal Nehru Technological
University, Hyderabad College of Engineering, Kukatpally,
Hyderabad, India
Accepted author version posted online: 17 Nov 2011.Published
online: 27 Feb 2012.
To cite this article: M. Venkatanarayana & P. K. Dubey (2012): L-Proline-Catalyzed Knoevenagel
Condensation: A Facile, Green Synthesis of (E)-Ethyl 2-Cyano-3-(1H-indol-3-yl)acrylates and
(E)-3-(1H-Indol-3-yl)acrylonitriles, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 42:12, 1746-1759
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Synthetic Communications1, 42: 1746–1759, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.543382
L-PROLINE-CATALYZED KNOEVENAGEL
CONDENSATION: A FACILE, GREEN SYNTHESIS OF
(E)-ETHYL 2-CYANO-3-(1H-INDOL-3-YL)ACRYLATES
AND (E)-3-(1H-INDOL-3-YL)ACRYLONITRILES
M. Venkatanarayana and P. K. Dubey
Department of Chemistry, Jawaharlal Nehru Technological University,
Hyderabad College of Engineering, Kukatpally, Hyderabad, India
GRAPHICAL ABSTRACT
Abstract L-Proline has been utilized as a novel and ecofriendly catalyst in ethanol medium for
the Knoevenagel condensation of indole-3-carboxyaldehydes and their N-methyl derivatives
1(a–e) and 4(a–e) with the active methylene compound, ethyl cyanoacetate (2) to afford
substituted (E)-ethyl 2-cyano-3-(1H-indol-3-yl)acrylates 3(a–e) and 5(a–e) respectively.
These products were reacted with dimethyl sulfate in the presence of PEG-600 as an efficient
and green solvent to afford the corresponding N-mthylated derivatives 5(a–e). These
Knoevenagel products react with 5% NaOH, yielding (E)-3-(1H-indol-3-yl)acrylonitriles
6(a–e) and 7(a–e).
Keywords Alkylating agent; ethyl cyanoacetate; indole-3-aldehydes; Knoevenagel
reaction; L-proline; PEG-600
Received October 10, 2010.
Address correspondence to M. Venkatanarayana, Department of Chemistry, Jawaharlal Nehru
Technological University, Hyderabad College of Engineering, Kukatapally, Hyderabad, India. E-mail:
venkatphdm@gmail.com
1746

L-PROLINE-CATALYZED KNOEVENAGEL CONDENSATION
1747
INTRODUCTION
Knoevenagel condensation is an important carbon–carbon bond-forming
reaction in organic synthesis.[1] Ever since its discovery, the Knoevenagel reaction
has been widely used in organic synthesis to prepare coumarins and their derivatives,
which are known to be important intermediates in the synthesis of cosmetics, per-
fumes, and pharmaceuticals.[2] In recent times, there has been a growing interest in
Knoevenagel products because many of them have significant biological activity;
for example, tyrophostins, such as a-cyanothiocinnamide, are known to inhibit
autophosphorylation of the EGF receptor, in addition to possessing antiproliferative
effects on human keratinocytes.[3]
The Knoevenagel reaction is generally carried out in the presence of weak
bases such as ethylenediamine, piperidine or corresponding piperidinium salts, and
potassium fluroiodide.[4] In contrast, there are only a few acid catalysts that are
known to promote this reaction.[5] Recently, many efforts have been made to prepare
olefinic compounds via the Knoevenagel reaction under heterogeneous conditions
employing aluminum chloride, xonotlite=tert-butoxide, cation-exchanged zeolites,
alkali-containing MCM-41, SiO2, calcite or fluorite, and natural phosphate with
potassium fluoride (NP=KF) as heterogeneous catalysts.[6–10] More recently, ionic
liquids have also been employed to accomplish this reaction. In this report, we
describe our findings on L-proline-catalyzed condition of indole-3-carboxaldehydes
with the active methylene compound ethyl cyanoacetate and subsequent transforma-
tions of products to other derivatives.
RESULTS AND DISCUSSION
Treatment of each indole-3-carboxyldehydes 1(a–e) and their N-methyl
derivatives 4(a–e) independently with ethyl cyanoacetate (2) in the presence of
40 mol% of L-proline in ethanol at rt for 30 min resulted in the formation of (E)-ethyl
Scheme 1. L-proline-catalyzed Knoevenagel condensation.

1748
M. VENKATANARAYANA AND P. K. DUBEY
Table 1. L-proline-catalyzed synthesis of (E)-ethyl 2-cyano-3-(1H-indol-3-yl)acrylatesa,b
Substrate
Product
Yield (%)
Time (min)
Mp (ꢀC)
1a (R¼H, R1¼H)
3a (R¼H, R1¼H)
3b (R¼OMe, R1¼H)
3c (R¼H, R1¼OMe)
3d (R¼Br, R1¼H)
3e (R¼NO2, R1¼H)
5a (R¼H, R1¼H)
5b (R¼H, R¼OMe)
5c(R¼H, R1¼OMe)
5d (R¼Br, R1¼H)
5e (R¼NO2, R1¼H)
97a
95a
96a
92a
98a
95b
97b
96b
92b
98b
60
45
60
50
40
60
45
60
50
40
161–162
180
162
1b (R¼OMe, R1¼H)
1c (R¼H, R1¼OMe)
1d (R¼Br, R1¼H)
228
1e (R¼NO2, R1¼H)
241–243
144
138
3a or 4a (R¼H, R1¼H)
3b or 4b (R¼OMe, R1¼H)
3c or 4c (R¼H, R1¼OMe)
3d or 4d (R¼Br, R1¼H)
3e or 4e (R¼NO2, R1¼H)
146
160
240
aReaction conditions: ethyl cyanoacetate, indole-3-aldehydes, L-proline, and ethanol at rt.
bReaction conditions: PEG-600, dimethylsulfhate (DMS), and D (50–60 ꢀC).
2-cyano-3-(1H-indol-3-yl)acrylates 3(a–e) and their corresponding N-methyl deriva-
tives of 5(a–e) in around 98% yields (Scheme 1, Table 1) respectively.
In the absence of L-proline, the reaction does not proceed even after refluxing
the reactants in ethanol for 24 h. The use of L-proline as a catalyst helps to avoid
the use of environmentally unfavorable organic solvents (dimethylformamide,
C6H6, toluene, dimethylsulfoxide) as reaction media because the reaction proceeds
smoothly in ethanol only. Thus, L-proline serves as an ecofriendly and efficient
catalyst for this condensation in ethanol medium.
Treatment of 3(a–e) and 5(a–e) respectively with 5% aqueous NaOH under
reflux for 30 min resulted in the formation of (E)-3-(1H-indol-3-yl)acrylonitriles
6(a–e) and (E)-3-(1-methyl-1H-indol-3-yl)acrylonitriles 7(a–e) in 84–90% yields
(Table 2).
Each of the compounds 1(a–e), 3(a–e), and 6(a–e) could be smoothly trans-
formed into their corresponding N-methyl derivatives 4(a–e), 5(a–e), and 7(a–e)
respectively by heating with dimethylsulfate (DMS) in PEG-600 as a facile and ver-
satile reaction medium for 1 h at different temperatures in excellent yields. All the
reactions are summarized in Scheme 1.
Table 2. Synthesis of (E)-3-(1H-indol-3-yl)acrylonitriles using 5% aqueous NaOHa,b
Substrate
Product
Yield (%)
Time (min)
Mp (ꢀC)
3a (R¼H, R1¼H)
6a (R¼H, R1¼H)
6b (R¼OMe, R1¼H)
6c (R¼H, R1¼OMe)
6d (R¼Br, R1¼H)
6e (R¼NO2, R1¼H)
7a (R¼H, R1¼H)
7b (R¼H, R¼OMe)
7c (R¼H, R1¼OMe)
7d (R¼Br, R1¼H)
7e (R¼NO2, R1¼H)
90
87
84
90
95
82
79
83
86
88
30
26
30
29
30
60
55
45
60
60
144
152–154
280–282
146
3b (R¼OMe, R1¼H)
3c (R¼H, R1¼OMe)
3d (R¼Br, R1¼H)
3e (R¼NO2, R1¼H)
115
136
5a or 6a (R¼H, R1¼H)
5b or 6b (R¼OMe, R1¼H)
5c or 6c (R¼H, R1¼OMe)
5d or 6d (R¼Br, R1¼H)
5e or 6e (R¼NO2, R1¼H)
144
320
115–117
235
aReaction conditions: Knoevenagel products 3(a–e), 5% aquerous NaOH, and reflux.
bReaction conditions: PEG-600, dimethylsulfhate (DMS), and D (60 ꢀC).

L-PROLINE-CATALYZED KNOEVENAGEL CONDENSATION
1749
Scheme 2. Formation of 6 and 7 from 3 and 5 using aqueous NaOH.
It is obvious from these results that PEG-600 is a very effective solvent for
methylations of 1(a–e), 3(a–e), and 6(a–e), resulting in 4(a–e),[11] 5(a–e), and 7(a–e)
respectively. Mechanistic explanation of these results is that PEG-600 probably
dissolves the substrate [i.e., olefins 3(a–e) and 6(a–e)] and the reagent (i.e., alkylating
agent DMS), bringing them together and thereby providing an effective means for
chemical reaction to occur. Furthermore, use of PEG-600 eliminates the use of a
base in these reactions because PEG-600 is able to extract the hydrogen from the
–NH of the substrates (1 or 3) and retain it by chelation through several lone pairs
of electrons in its oxygen-containing chain. This role of PEG-600 is very similar to
that of the crown ethers or that of the proton sponge (i.e., 1, 8-dimethylamino-
naphthalene). Proton sponge (-NH or -OH) is a very strong base because of its
ability to extract hydrogen from an acidic substrate and then retain it by chelation
through lone pair of electrons on the two nitrogen atoms.
In the transformation of 3(a–e) to 6(a–e) and of 5(a–e) to 7(a–e) with hot
diluted aqueous NaOH, the reactions probably involve hydrolysis of the ester group
in the carboxylic acids 3(a–e) and 5(a–e) respectively, which being labile or unstable
intermediates (because one electron withdrawing group is attached to the same end
Scheme 3. Plausible mechanism for the formation of 3 in the presence of L-proline.

1750
M. VENKATANARAYANA AND P. K. DUBEY
of the double bond carbon) eventually lose carbon dioxide to yield 6(a–e) and 7(a–e)
respectively as shown in Scheme 2.
In this reaction, the product has been assigned E-configuration (first and
second priority groups, i.e., indolyl and -CN respectively, are trans to each other)
on the basis of the assumption that the groups with maximum stereochemical bulk
would be more stable in a trans configuration.
There are two possible mechanisms for the formation of 3 from 1 and 2 in the
presence of L-proline as catalyst as shown in Schemes 3 and 4 respectively. In the first
mechanism shown in Scheme 3, L-proline, in the form of its zwitter ion (Xb), extracts
the proton from ethyl cyanoacetate (2), forming the carbanion of ethyl cyanoacetate
(2l), which then attacks the protonated indole-3-carboxaldehyde (1l), forming the
corresponding intermediate (1ll) which loses water to form the end product 3.
In the second mechanism shown in Scheme 3, proline in its zwitterionic form Xb
reacts with 1, forming corresponding iminium intermediate 1ll. Compound 1ll extracts
Scheme 4. Plausible mechanism for the formation of 3 in the presence of L-proline.

1751

1752

L-PROLINE-CATALYZED KNOEVENAGEL CONDENSATION
1753
the proton from 2, forming the carbanion 2ll. Compound 2ll attacks 1ll, forming
intermediate 1lll, which eventually loses L-proline with displacement by water to form
1lll and the latter losing water to form 3.
In substance, it can be said that two mechanisms shown in Schemes 3 and 4
differ from one another in that Scheme 3 involves a simple proton-transfer process
catalyzed by the L-proline, whereas Scheme 4 involves an initial iminium ion inter-
mediate and its subsequent transformations leading to 3.
Table 3 clearly showed the comparison of catalytic activity with other various
catalysts described earlier.4–10 The main advantages of the method described here
that L-proline is a truly novel, ecofriendly, very low cost, high-yielding catalyst
without needing tedious workup and gives high purity of the products.
CONCLUSION
In summary, L-proline has been employed for the first time as a novel,
ecofriendly, and efficient catalyst for the preparation of olefinic compounds by a
Knoevenagel reaction in ethanol. This method is applicable to a wide range of
indole-3-carboxyldehydes 1(a–e) including N-substituted indole-3-carboxyldehydes
4(a–e). The attractive features of this procedure are the mild reaction conditions,
good conversions, operational simplicity, and inexpensive and readily available cata-
lyst, all of which make it a useful and attractive strategy for the preparation of olefins.
EXPERIMENTAL
Melting points were determined using a Buchi melting-point B-545 apparatus
and are uncorrected. Thin-layer chromatography (TLC) was done on glass plates
coated with silica gel–G, and spotting was done using iodine or an ultraviolet lamp.
Infrared (IR) spectra were recorded using Perkin-Elmer model-446 FTIR in KBr.
1H NMR spectra were recorded on Gemini-200 and AV-400 instruments operating
at 200 and 400 MHz respectively.
Preparation of (E)-Ethyl 2-Cyano-3-(1H-indol-3-yl)acrylates (3)
A mixture of 1 (5 mmol), 2 (6.5 mmol, 0.69 mL), and L-proline (40 mol%, 0.288 g)
in ethanol (10 mL) was stirred at rt for a specified period of time (Table 1). After com-
pletion (as shown by TLC) of the reaction, the mixture was poured into ice-cold water.
The separated solid was filtered, washed with water, and dried to obtain the crude
product 3. The latter was then recrystallized from ethyl acetate to afford pure 3.
(E)-Ethyl 2-cyano-3-(1H-indol-3-yl)acrylate (3a). Yellow solid; mp 161 ꢀC;
IR (KBr): 3322 (very broad -NH stretching), 2213 (medium, -CN stretching),
and 1698 (very strong-COOC2H5, highly conjugated ester carbonyl); 1H NMR
(DMSO-d6=TMS): d 1.30 (t, J ¼ 7.08 Hz, 3H), 4.28 (q, J ¼ 7.08 Hz, 2H), 7.24–7.25
(m, 2H), 7.31–7.5 (m, 1H), 7.96–7.98 (m, 1H), 8.56 (s, 1H, a-proton of the indole ring),
8.57 (s, 1H, vinylic proton), 12.57 (br, s, 1H, -NH proton); 13C NMR (DMSO-d6=
TMS): d 14.64, 61.90, 92.81, 110.45, 113.45, 118.52, 119.10, 122.65, 124.13, 127.40,

1754
M. VENKATANARAYANA AND P. K. DUBEY
133.77, 136.77, 147.14, 163.76; MS m=z ¼ 239 (Mꢁ1); Calcd. for C18H14N2O (240.26):
C, 69.99; H, 5.03; N, 11.66; found: C, 69.93; H, 5.09; N, 11.73.
(E)-Ethyl 2-cyano-3-(5-methoxy-1H-indol-3-yl)acrylate (3b). Yellow solid;
mp 180 ꢀC; IR (KBr): 3233 (very broad -NH stretching), 2211 (medium, -CN stretch-
ing), and 1686 (very strong-COOC2H5, highly conjugated ester carbonyl); 1H NMR
(DMSO-d6=TMS) d 1.29 (t, J ¼ 7.08 Hz, 3H), 3.82 (s, 3H, -OCH3), 4.27 (q,
J ¼ 7.08 Hz, 2H), 6.90 (s, 1H), 7.45–7.47 (m, 2H), 8.50 (s, 1H, a-proton of the indole
ring), 8.58 (s, 1H, vinylic proton), 12.46 (br, s, 1H, -NH proton); 13C NMR
(DMSO-d6=TMS): d 14.68, 56.00, 61.80, 91.84, 101.3, 110.63, 114.14, 114.23,
118.77, 128.42, 131.50, 133.32, 147.48, 156.25, 163.92; MS m=z ¼ 269 (Mꢁ1); Calcd.
for C15H14N2O3 (270.28): C, 66.66; H, 5.22; N, 10.36; O, 17.76; found: C, 66.68; H,
5.24; N, 10.35; O, 17.77.
(E)-Ethyl 2-cyano-3-(6-methoxy-1H-indol-3-yl)acrylate (3c). Yellow solid;
mp 162–163 ꢀC; IR (KBr): 3297 (very broad –NH stretching), 2215 (sharp -CN
stretching), and 1721 (very strong -COOC2H5, highly conjugated ester carbonyl);
1H NMR (DMSO-d6=TMS): d 1.31 (t, J ¼ 7.2 Hz, 3H), 3.81 (s, 3H, -OCH3), 4.28
(q, J ¼ 7.2 Hz, 2H), 6.91 (q, J ¼ 2 Hz, 1H), 7.06 (d, J ¼ 2 Hz, 1H), 7.90 (d, J ¼ 8.8 Hz,
1H), 8.64 (s, 1H, a-proton of the indole ring), 9.21 (s, 1H, vinylic proton) 12.68 (br, s,
1H, -NH proton); 13C NMR: d 14.65, 55.84, 61.85, 92.48, 96.39, 110.69, 112.48,
118.59, 120.07, 121.14, 132.80, 137.81, 147.37, 157.50, 163.84; MS m=z ¼ 269
(Mꢁ1), Calcd. for C15H14N2O3 (270.28): C, 72.71; H, 5.08; N, 14.13; O, 8.07; found:
C, 72.69; H, 5.09; N, 14.12; O, 8.09.
(E)-Ethyl 3-(5-bromo-1H-indol-3-yl)-2-cyanoacrylate (3d). Light yellow
solid; mp 228 ꢀC; IR (KBr): 3369 (very broad –NH stretching), 2217 (sharp, -CN
stretching), and 1687 (very strong -COOC2H5, highly conjugated ester carbonyl);
1H NMR (DMSO-d6=TMS): d 1.26 (t, J ¼ 7.1 Hz, 3H), 4.3 (q, J ¼ 7.1 Hz, 2H),
7.40–7.54 (m, 3H), 8.27 (s, 1H, a-proton of the indole ring), 8.59 (s, 1H, vinylic pro-
ton), 12.78 (br, s, 1H, -NH proton); 13C NMR (DMSO-d6=TMS): d 14.62, 40.63,
61.96, 93.88, 110.0, 115.4, 118.34, 121.95, 126.69, 129.20, 134.0, 135.52, 147.06,
163.51; MS m=z ¼ 317 (Mꢁ1). Calcd. for C14H11BrN2O2 (2319.15): C, 52.69; H,
3.47; Br, 25.04; N, 8.78; found: C, 52.68; H, 3.48; Br, 25.03; N, 8.79.
(E)-Ethyl 2-cyano-3-(5-nitro-1H-indol-3-yl)acrylate (3e). Yellow solid; mp
241–243 ꢀC; IR (KBr): 3249 (very broad –NH stretching), 2216 (sharp, -CN stretch-
ing), and 1690 (very strong -COOC2H5, highly conjugated ester carbonyl); 1H NMR
(DMSO-d6=TMS): d 1.28 (t, J ¼ 7.1 Hz, 3H), 4.4 (q, J ¼ 7.1 Hz, 2H), 7.73–8.16 (m,
3H), 8.71–8.73 (s, 1H, a-proton of the indole ring), 9.01–9.02 (s, 1H, vinylic proton),
12.98 (br, s, 1H, -NH proton); 13C NMR (DMSO-d6=TMS): d 14.61, 62.19, 95.94,
111.95, 114.12, 116.75, 117.98, 119.13, 126.87, 135.97, 139.90, 143.25, 146.85,
163.19; MS m=z ¼ 284 (Mꢁ1). Calcd for C14H11N3O4 (285.25): C, 58.95; H, 3.89;
N, 14.73; O, 22.44; found: C, 58.93; H, 3.90; N, 14.74; O, 22.41.
Preparation of (E)-Ethyl 2-Cyano-3-(1-methyl-1H-indol-3-yl)acrylates 5
A mixture of 3 (10 mM), dimethyl sulfate (DMS) (15 mM, 1.6 mL), and PEG-
600 (20 ml) was heated at 50–60 ꢀC for 1 h. At the end of this period, the mixture

L-PROLINE-CATALYZED KNOEVENAGEL CONDENSATION
1755
was poured into ice-cold water and then neutralized with 5% aqueous NaOH. The
separated solid was filtered, washed with water, and dried to obtain crude product.
The latter was then recrystallized from ethyl acetate to afford pure 5.
(E)-Ethyl 2-cyano-3-(1-methyl-1H-indol-3-yl)acrylate (5a). Light orange
solid; mp 144 ꢀC; IR (KBr): 2210 (sharp, -CN stretching) and 1710 (very strong-
COOC2H5, ester carbonyl); 1H NMR (DMSO-d6=TMS): d 1.29 (t, J ¼ 7.12 Hz,
3H), 4.0 (s, 3H, -N-CH3), 4.29 (q, J ¼ 7.12 Hz, 2H), 7.30–7.39 (m, 2H), 7.63–7.65
(m, 1H), 7.97–7.99 (m, 1H), 8.52 (s, 1H, a-proton of the indole ring), 8.55 (s, 1H,
vinylic proton); 13C NMR (DMSO-d6=TMS): d 14.64, 44.23, 62.90, 91.61, 110.25,
113.45, 118.51, 119.14, 123.01, 124.18, 127.41, 134.71, 136.12, 145.18, 163.54; MS
m=z ¼ 253 (Mꢁ1). Calcd. for C15H14N2O2 (254.28): C, 70.85; H, 5.55; N, 11.02; O,
12.58; found: C, 70.83; H, 5.56; N, 11.01; O, 12.60.
(E)-Ethyl 2-cyano-3-(5-methoxy-1-methyl-1H-indol-3-yl)acrylate (5b).
Yellow solid; mp 138 ꢀC; IR (KBr): 2211 (sharp, -CN stretching) and 1689 (very
1
strong-COOC2H5, highly conjugated ester carbonyl); H NMR (DMSO-d6=TMS)
d 1.28 (t, J ¼ 7.07 Hz, 3H), 3.81 (s, 3H, -OCH3), 4.11(s, 3H, -N-CH3), 4.28 (q,
7.07 Hz, 2H), 6.86–7.66 (m, 3H), 8.51 (s, 1H, a-proton of the indole ring), 8.59
(s, 1H, vinylic proton); MS m=z ¼ 283 (Mꢁ1). Calcd. for C16H16N2O3 (284.31): C,
67.59; H, 5.67; N, 9.85; O, 16.88; found: C, 67.58; H, 5.66; N, 9.86; O, 16.89.
(E)-Ethyl 2-cyano-3-(6-methoxy-1-methyl-1H-indol-3-yl)acrylate (5c).
Yellow solid; mp 146; IR (KBr): 2217 (sharp, -CN stretching) and 1719 (very strong
1
-COOC2H5, highly conjugated ester carbonyl); H NMR (DMSO-d6=TMS): d 1.27
(t, J ¼ 7.01 Hz, 3H), 3.83 (s, 3H, -OCH3), 4.12 (s, 3H, -N-CH3), 4.27 (q, J ¼ 7.01 Hz,
2H), 6.94–7.79 (m, 3H), 8.61 (s, 1H, a-proton of the indole ring), 8.99 (s, 1H, vinylic
proton); MS m=z ¼ 283 (Mꢁ1). Calcd. for C16H16N2O3 (284.31): C, 67.59; H, 5.67;
N, 9.85; O, 16.88; found: C, 67.58; H, 5.66; N, 9.86; O, 16.89.
(E)-Ethyl 3-(5-bromo-1-methyl-1H-indol-3-yl)-2-cyanoacrylate (5d). Pale
yellow solid; mp 160 ꢀC; IR (KBr): 2219 (sharp, -CN stretching) and 1697 (very
strong -COOC2H5, highly conjugated ester carbonyl); 1H NMR (DMSO-d6=
TMS): d 1.28 (t, J ¼ 7.06 Hz, 3H), 4.21–4.22 (s, 3H, -N-CH3) 4.30 (q, J ¼ 7.06 Hz,
2H), 7.42–7.78 (m, 3H), 8.67 (s, 1H, a-proton of the indole ring), 8.86 (s, 1H, vinylic
proton), MS m=z ¼ 332 (Mꢁ1). Calcd. for C14H11BrN2O2 (333.18): C, 54.07; H, 3.93;
Br, 23.98; N, 8.41; O, 9.60; found: C, 54.09; H 3.46; Br, 25.01; N, 8.81.
(E)-Ethyl 2-cyano-3-(5-nitro-1-methyl-1H-indol-3-yl)acrylate (5e). Yellow
solid; mp 240 ꢀC; IR (KBr): 2217 (sharp, -CN stretching) and 1689 (very strong
1
-COOC2H5, highly conjugated ester carbonyl); H NMR (DMSO-d6=TMS): d 1.30
(t, J ¼ 7.07 Hz, 3H), 4.01–4.03 (s, 3H, -N-CH3), 4.38 (q, J ¼ 7.07 Hz, 2H), 7.74–
8.12 (m, 3H), 8.73–8.74 (s, 1H, a-proton of the indole ring), 9.03–9.04 (s, 1H, vinylic
proton), MS m=z ¼ 284 (Mꢁ1). Calcd. for C15H13N3O4 (299.28): C, 60.20; H, 4.38;
N, 14.04; O, 21.38; found: C, 60.19; H, 4.40; N, 14.02; O, 21.39.

1756
M. VENKATANARAYANA AND P. K. DUBEY
Preparation of (E)-3-(1H-Indol-3-yl)acrylonitriles (6)
A mixture of 3 (10 mM) and 5% aqueous NaOH solution (20 mL) was refluxed
(at ꢂ100 ꢀC) for 30 min. At the end of this period, the mixture was cooled to room
temperature and poured into ice-cold water and neutralized with aqueous HCl. The
separated solid was filtered, washed with water, and dried to obtain crude 6. The
latter was then recrystallized from ethyl acetate to afford pure 6.
(E)-3-(-1H-Indol-3-yl)acrylonitrile (6a). Colorless solid; mp 144 ꢀC; IR (KBr):
1
3271 (very broad -NH stretching) 2256 (sharp, -CN stretching); H NMR (DMSO-
d6=TMS): d 5.13–5.15 (d, 1H, vinyl proton), 5.67 (d, 1H, vinyl proton), 7.20–7.25
(m, 2H), 7.50–7.56 (m, 1 H), 8.10–8.17 (m, 1H), 8.38–8.39 (s, 1H a-proton of indole
ring), 10.99 (br s, 1H, -NH, D2O exchangeable); MS m=z ¼ 169 (Mþ1). Calcd. for
C11H8N2 (168.19): C, 78.55; H, 4.79; N, 16.66; found: C, 78.57; H, 4.80; N, 16.66.
(E)-3-(5-Methoxy-1H-indol-3-yl)acrylonitrile (6b). Grey solid; mp 152–
154 ꢀC; IR (KBr): 3274 (very broad –NH stretching) and 2252 (sharp, -CN stretch-
ing); 1H NMR (DMSO-d6=TMS): d 3.76–3.79 (s, 3H -OCH3), 5.12–5.14 (d, 1H vinyl
proton), 5.63–5.65 (d, 1H vinyl proton), 6.74–7.64 (m, 3H aryl protons of the indole
ring), 8.30 (s, 1H, a-proton of the indole ring), 10.838 (br s, 1H, -NH, D2O exchange-
able); MS m=z ¼ 199 (Mþ1). Calcd. for C12H10N2O (198.22): C, 72.71; H, 5.08; N,
14.13; O, 8.07; found: C, 72.70; H, 5.09; N, 14.12; O, 8.08.
(E)-3-(6-Methoxy-1H-indol-3-yl)acrylonitrile (6c). Light grey solid; mp
280–282 ꢀC; IR (KBr): 3228 (very broad –NH stretchings) and 2257 (sharp, -CN
1
stretching); H NMR (DMSO-d6=TMS): d 3.79 (s, 3H –OCH3), 5.10–5.12 (d, 2H
vinyl protons), 6.86–8.25 (m, 4H three are aryl protons and one is a-proton of the
indole ring), 11.97 (br s, 1H, -NH, D2O); MS m=z ¼ 199 (Mþ1). Calcd. for
C12H10N2O (198.22): C, 72.71; H, 5.08; N, 14.13; O, 8.07; found: C, 72.70; H,
5.09; N, 14.12; O, 8.08.
(E)-3-(5-Bromo-1H-indol-3-yl)acrylonitrile (6d). Colorless solid; mp 146 ꢀC;
IR (KBr): 3263 (very broad –NH stretching) and 2251 (sharp, -CN stretching);
1H NMR (DMSO-d6=TMS) d 5.12–5.13 (d, 1H vinyl proton), 5.74–5.76 (d, 1H vinyl
proton), 7.17–7.86 (m, 4H three aryl protons and one is a-proton of the indole ring),
11.21 (br s, 1H, -NH, D2O); MS m=z ¼ 263 (Mþ1). Calcd. for C11H7BrN2 (245.98):
C, 53.47; H, 2.86; Br, 32.34; N, 11.34; found: C, 53.45; H, 2.87; Br, 32.36; N, 11.33.
(E)-3-(5-Nitro-1H-indol-3-yl)acrylonitrile (6e). Yellow solid; mp 115 ꢀC; IR
(KBr): 3468 (very broad –NH stretching) and 2249 (sharp, -CN stretching); 1H NMR
(DMSO-d6=TMS) d 5.16–5.26 (2H vinyl protons of the indole ring), 7.45–8.74 (m, 4H
three aryl protons and one is a-proton of the indole ring), d 11.61 (br s, 1H, -NH,
D2O); MS m=z ¼ 213 (Mþ1). Calcd. for C11H7N3O2 (213.19): C, 61.97; H, 3.31; N,
19.71; O, 15.01; found: C, 61.96; H, 3.34; N, 19.70.
Preparation of (E)-3-(1-Methyl-1H-indol-3-yl)acrylonitriles (7)
A mixture of 5 (10 mM) and 5% aqueous NaOH solution (20 mL) was refluxed
(at ꢂ100 ꢀC) for 30 min. At the end of this period, the mixture was cooled to room
temperature, poured into ice-cold water, and neutralized with aqueous HCl. The

L-PROLINE-CATALYZED KNOEVENAGEL CONDENSATION
1757
separated solid was filtered, washed with water, and dried to obtain crude 7. The
latter was then recrystallized from ethyl acetate to afford pure 7.
Alternative Preparation of (E)-3-(1-Methyl-1H-indol-3-yl)-
acrylonitriles (7)
A mixture of 6 (10 mM) and dimethyl sulfate (DMS) (10 mM, 1.6 mL) in PEG-
600 was heated at 50–60 ꢀC for 1 h. At the end of this period, the solution was poured
into ice-cold water and neutralized with 5% aqueous NaOH. The separated solid
was filtered, washed with water, and dried to obtain crude 7. The latter was then
recrystallized from ethyl acetate to afford pure 7.
(E)-3-(1-Methyl-1H-indol-3-yl)acrylonitrile (7a). Yellow solid; mp 136 ꢀC,
1
IR (KBr): 2234 (sharp, -CN stretching); H NMR (DMSO-d6=TMS) d 3.9 (s, 3H,
-N-CH3), 5.28–5.29 (d, 1H vinyl proton), 6.03 (d, 1H, vinyl proton), 7.59–8.74 (m,
4H three aryl protons and one is a-proton of the indole ring); MS m=z ¼ 183
(Mþ1). Calcd. for C12H10N2 (182): C, 79.10; H, 5.53; N, 15.37; found: C, 79.09;
H, 5.52; N, 15.40.
(E)-3-(5-Methoxy-1-methyl-1H-indol-3-yl)acrylonitrile
(7b). Colorless
1
solid; mp 144 ꢀC; IR (KBr): 2214 (sharp, -CN stretching); H NMR (DMSO-d6=
TMS) d 3.71 (s, 3H -OCH3), 4.01 (s, 3H, -NH3), 5.11–6.12 (d, 2H vinyl protons),
6.86–8.25 (m, 4H three are aryl protons þone is a-proton of the indole ring); MS
m=z ¼ 213 (Mþ1). Calcd. for C13H12N2O (212): C, 73.56; H, 5.70; N, 13.20; O,
7.54; found: C, 73.54; H, 5.69; N, 13.22; O, 7.54.
(E)-3-(6-Methoxy-1-methyl-1H-indol-3-yl)acrylonitrile (7c). Colorless solid;
=
1
mp 320 C; IR (KBr): 2224 (sharp, -CN stretching) and 1614 (-C O); H NMR
ꢀ
(DMSO-d6=TMS): d 3.85 (s, 3H -OCH3), 3.98 (s, 3H, -NH3), 5.20–5.22 (d, 2H vinyl
protons), 6.86–8.25 (m, 4H three are aryl protons and one is a-proton of the indole
ring), MS m=z ¼ 213 (Mþ1). Calcd. for C13H12N2O (212): C, 73.56; H, 5.70; N, 13.20;
O, 7.54; found: C, 73.54; H, 5.69; N, 13.22; O, 7.54.
(E)-3-(5-Bromo-1-methyl-1H-indol-3-yl)acrylonitrile (7d). Colorless solid;
1
mp 115–117 ꢀC; IR (KBr): 2224 (sharp, -CN stretching); H NMR (DMSO-d6=
TMS) d 4.1 (s, 3H, -NH3), 5.15–5.16 (d, 1H vinyl proton), 5.71–5.76 (d, 1H vinyl
proton), 7.32–8.24 (m, 4H three aryl protons þone is a-proton of the indole ring);
MS m=z ¼ 261 (Mþ1). Calcd. for C12H9BrN2 (261): C, 55.20; H, 3.47; Br, 30.60;
N, 10.73; found: C, 55.21; H, 3.45; Br, 30.59; N, 10.74.
(E)-3-(5-Nitro-1-methyl-1H-indol-3-yl)acrylonitrile (7e). Colorless solid;
1
mp 235 ꢀC; IR (KBr): 2229 (sharp, -CN stretching); H NMR (DMSO-d6=TMS) d
4.18 (s, 3H, -NH3), 5.18–5.29 (2H vinyl protons of the indole ring), 7.35–8.78 (m,
4H three aryl protons þone is a-proton of the indole ring); MS m=z ¼ 228 (Mþ1).
Calcd. for C12H9N3O2 (227): C, 63.43; H, 3.99; N, 18.49; O, 14.08; found: C,
63.44; H, 3.98; N, 18.46; O, 14.10.

1758
M. VENKATANARAYANA AND P. K. DUBEY
ACKNOWLEDGMENTS
The authors are highly indebted to the University Grants Commission,
Goverment of India, New Delhi, for providing financial support. They are also
thankful to the authorities of Jawaharlal Nehru Technological University,
Hyderabad, India, for providing laboratory facilities.
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