Simple and efficient Knoevenagel synthesis of (E)-2-((1H-indol-3-yl) methylene)-3-oxoindolylnitrile catalysed by PPh3

Article abstract of DOI:10.1007/s12039-011-0136-x

Triphenylphosphine (TPP) is found to be an efficient catalyst for the Knoevenagel condensation of indole-3-carboxyaldehydes 1(a-e) and their N-substituted derivatives 4(a-e) with the active methylene compound, i.e., 3-cyanoacetylindole (2), affording novel substituted olefins 3(a-e) and 5(a-e) respectively. The latter products reacted with DMS in the presence of PEG-600 to afford the corresponding N, N^l dimethylated derivatives 6(a-e). Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-011-0136-x

J. Chem. Sci. Vol. 123, No. 5, September 2011, pp. 609–614. ꢀc Indian Academy of Sciences.
Simple and efficient Knoevenagel synthesis of (E)-2-((1H-indol-3-yl)
methylene)-3-oxoindolylnitrile catalysed by PPh3
∗
M VENKATANARAYANA and P K DUBEY
Department of Chemistry, Jawaharlal Nehru Technological University, Hyderabad College of Engineering,
Kukatpally, Hyderabad 500 085, India
e-mail: venkatmuvvala@in.com
MS received 17 November 2010; revised 31 July 2011; accepted 1 August 2011
Abstract. Triphenylphosphine (TPP) is found to be an efficient catalyst for the Knoevenagel condensation of
indole-3-carboxyaldehydes 1(a–e) and their N-substituted derivatives 4(a–e) with the active methylene com-
pound, i.e., 3-cyanoacetylindole (2), affording novel substituted olefins 3(a–e) and 5(a–e) respectively. The
l
latter products reacted with DMS in the presence of PEG-600 to afford the corresponding N, N dimethylated
derivatives 6(a–e).
Keywords. Indole-3-aldehydes; 3-cyanoacetylindole; PPh3; Ethanol; PEG-600; DMS.
1
. Introduction
intramolecular imino Diels–Alder reactions for syn-
14
thesis of tetrahydrochromanoquinolines and Diels–
Alder synthesis of Pyranoquinoline, furoquninoline,
Knoevenagel condensation is an important carbon–
carbon bond-forming reaction in organic synthesis.
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 cosmet-
1
15
phenanthridine derivatives, and other different cat-
16−17
alytic applications.
2
ics, perfumes and pharmaceuticals. In recent times,
there has been a growing interest in Knoevenagel prod-
2. Experimental
ucts because many of them have significant biological Melting points were determined using a Buchi melting
activity.
point B-545 apparatus and are uncorrected. TLC check-
The Knoevenagel reaction is generally carried out in ing was done on glass plates coated with Silica Gel
the presence of weak bases such as ethylenediamine, –G and spotting was done using iodine or UV lamp.
piperidine or corresponding piperidinium salts, potas- IR spectra were recorded using Perkin Elmer model-
sium fluroiodide, etc.3–5 In contrast, there are only a 446 FTIR in KBr. H-NMR spectra were recorded on
few acid catalysts that are known to promote this reac- a Gemini-200 and AV-400 instruments operating at 200
1
6
tion. Recently many efforts have been made to prepare and 400 MHz respectively.
olefinic compounds via the Knoevenagel reaction under
heterogeneous conditions employing aluminum chlo-
ride, xonotlite/tert-butoxide, cation-exchanged zeolites,
alkali containing MCM-41, SiO , calcite or fluorite and
2
2.1 General procedure for the preparation of 3
7–10
NP/KF as heterogeneous catalysts.
More recently,
ionic liquids have also been employed to accomplish A mixture 1 (5 mmol), 2 (5 mmol, 0.91 g) and PPh 40%
3
11
this reaction.
(1.2 mmol, 412 mg) in ethanol (15 mL) was stirred at
Earlier, PPh3 has been used in different reac- RT for a specified period of time (table 1). After com-
tions like preparation of 3-acetylindoles and 3-bis- pletion of reaction (as shown by TLC checking), the
indolylmethane derivatives,1 Diels–Alder synthesis mixture was poured into ice-cold water. The separated
of Azabicyclo[2.2.2]octan-5-ones,13 mono- and bis- solid was filtered, washed with water and dried to obtain
2
the crude product 3. The latter were then recrystallized
from ethyl acetate to afford pure 3.
∗
For correspondence
609

610
M Venkatanarayana and P K Dubey
Table 1. Synthesis of Novel (E)-2-((1H-indol-3-yl)methylene)-3-oxoindolylnitrile products by using PPh3 as an efficient
a,b
catalyst.
◦
Sl. no.
Reactants
Product
Time (hrs.)
Yield (%)
M.P ( C)
1
1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
.
.
.
.
.
.
.
.
1a(R=H, R =H)
2
2
2
2
2
2
2
2
2
3a(R=H, R =H)
1.5
2
2
2
1.6
1
1
1
1
1
88
89
86
84
90
87
89
90
85
87
90
89
90
88
85
281–282
211–213
195–197
187
193–194
179–181
261–263
165
1
1
1b(R=OMe, R =H)
3b(R=OMe, R =H)
1
1
1c(R=H, R =OMe)
3c(R=H, R =OMe)
1
1
1d(R=Br, R =H)
3d(R=Br, R =H)
1
1
1e(R=NO2, R =H)
3e(R=NO2, R =H)
1
1
4a(R=H, R =H)
5a(R=H, R =H)
1
1
4b(R=OMe, R =H)
5b(R=OMe, R =H)
1
1
4c(R=H, R =OMe)
5c(R=H, R =OMe)
1
1
.
4d(R=Br, R =H)
5d(R=Br, R =H)
>285
1
1
0.
1.
2
3.
4.
5.
4e(R=NO2, R =H)
2
5e(R=NO2, R =H)
169–170
248–250
231–232
190
285
291
1
1
3a/5a (R=H, R =H)
DMS
DMS
DMS
DMS
DMS
6a(R=H, R =H)
1
1
1
1
1
1
3b/5b (R=OMe, R =H)
6b(R=OMe, R =H)
1
1
3c/5c (R=H, R =OMe)
6c(R=H, R =OMe)
1
1
3d/5d (R=Br, R =H)
6d(R=Br, R =H)
1
1
3e/5e (R=NO2, R =H)
6e(R=NO2, R =H)
1
a
Reaction conditions: indole-3-aldehyde, 3-cyanoacetylindole, PPh3, EtOH, and RT
Reaction conditions: Knoevenagel Products, PEG-600, DMS (dimethylsulphate) and ꢀ
b
−
1
2
.1a Characterization of 3a: Yellow solid; Yield: 1.36 (broad, –NH stretching), 2204 cm
(sharp, –CN
◦
−1
gms (88%); m.p. 281–282 C; IR(KBr): 3263 cm (due stretching) and 1637 (very strong, carbonyl –C=O);
−1
−1
1
to –NH), 2203 cm (due to –CN) and 1611 cm (due H-NMR (DMSO d /TMS): δ 3.45–3.46 (s, 3H,
6
1
to –CO); H-NMR spectrum (DMSO/d /TMS): δ 7.28– –OCH ), 7.29–7.86 (m, 7H, aryl protons of the indole
6
3
7
8
9
.98 (m, 8H, aryl protons of the two indole rings), δ rings), 8.21–8.42 (m, 2H, α-protons of the indole rings),
.04–8.55 (m, 2H, α-protons of the two indole rings), δ 9.54 (s, 1H, vinyl proton of the indole ring), 12.29–
.15 (vinylic proton of the indole ring), δ 12.13–12.49 12.31 (br, s, 2H, –NH protons of the indole rings); Its
13
(
br s, 2H, D O exchangeable, two –NH protons of the
C-NMR spectrum (DMSO/d /TMS): δ 55.3, 111.1,
2
6
13
indole ring); Its C-NMR spectrum (DMSO/d /TMS): 112.4, 113.1, 114.5, 118.4, 121.6, 122.8, 123.8, 124.0,
6
δ 110.7, 112.7, 113.1, 114.7, 118.9, 121.0, 121.9, 122.1, 125.1, 125.9, 126.5, 127.6, 130.6, 134.6, 135.3, 136.9,
1
1
22.3, 123.6, 123.8, 126.8, 127.7, 131.6, 134.2, 136.5, 150.3, 185.9; MS m/z = 342 (M+1).
36.7, 145.5, 181.1; MS m/z = 312 (M+1).
2
.1d Characterization of 3d: Yellow solid; Yield: 1.62
◦
−1
2
1
(
.1b Characterization of 3b: Yellow solid; Yield: gms (84%); m.p. 187 C; IR (KBr): 3218 cm (broad,
–NH stretching), 2206 cm (sharp, –CN stretching)
medium, –NH stretching), 2203 cm (sharp, –CN and 1611 (very strong, highly conjugated carbonyl
◦
−1
−1
.51 gms (89%); m.p. 211–213 C; IR(KBr): 3263 cm
−1
1
stretching) and 1639 (very strong, carbonyl –C=O); –C=O); H-NMR (DMSO d /TMS): δ 7.26–7.91
6
1
H-NMR (DMSO d /TMS): δ 3.23–3.26 (s, 3H, (m, 7H, aryl protons of the indole rings), 8.24–8.30
6
–
OCH ), 7.14–7.96 (m, 7H, aryl protons of the indole (m, 2H, α-protons of the indole rings), 9.87–9.89
3
rings), 8.04–8.29 (m, 2H, α-protons of the indole rings), (s, 1H, vinyl proton of the indole ring), 12.18–12.21
9
–
.23 (s, 1H, vinyl proton of the indole ring), 12.21 (br, s, 2H, −NH protons of the indole rings); Its
13
12.29 (br, s, 2H, –NH protons of the indole rings); C-NMR spectrum (DMSO/d /TMS): δ 110.7, 111.8,
6
13
Its C-NMR spectrum (DMSO/d /TMS): δ 54.9, 112.3, 113.4, 114.5, 117.6, 121.6, 123.2, 123.6, 124.2, 125.3,
6
113.1, 113.9, 115.3, 117.5, 121.6, 122.6, 122.8, 123.5, 125.8, 126.6, 128.3, 131.6, 133.5, 134.9, 136.9, 136.3,
123.7, 123.9, 126.8, 127.1, 130.6, 133.6, 135.5, 136.7, 185.2; MS m/z = 390 (M+1).
151.3, 186.1; MS m/z = 342 (M+1).
2
.1e Characterization of 3e: Yellow solid; Yield: 1.60
◦
−1
2
.1c Characterization of 3c: Red solid; Yield: 1.46 gms (90%); m.p. 193–194 C; IR (KBr): 3120 cm
◦
−1
−1
gms (86%); m.p. 195–197 C; IR (KBr): 3218 cm
(very broad, –NH stretching), 2208 cm (sharp, –CN

Simple and efficient Knoevenagel synthesis of (E)-2-((1H-indol-3-yl)methylene)-3-oxoindolylnitrile catalysed by PPh3 611
stretching) and 1615 (very strong, highly conjugated 2.2c Characterization of 5c: Yellow solid; Yield: 1.70
1
◦
−1
carbonyl –C=O); H-NMR (DMSO d /TMS): δ 7.12– gms (90%); m.p. 165 C; IR (KBr): 3229 cm (broad,
6
−1
8
8
1
1
.01 (m, 7H, aryl protons of the indole rings), 8.31– −NH stretching), 2209 cm (sharp, –CN stretching)
1
.36 (m, 2H,-α protons of the indole rings), 9.99– and 1631 (very strong, carbonyl –CO); H-NMR
0.01 (s, 1H, vinyl proton of the indole ring), 12.34– (DMSO d /TMS): δ 3.45–3.46 (s, 3H, –OCH ), 3.98
2.36 (br, s, 2H, –NH protons of the indole rings); Its (s, 3H, N-CH ), 7.31–7.91 (m, 7H, aryl protons of the
C-NMR spectrum (DMSO/d /TMS): δ 110.0, 110.1, indole rings), 8.16–8.52 (m, 2H, α-protons of the indole
6
3
3
13
6
1
1
1
11.0, 112.2, 114.5, 116.1, 117.5, 118.0, 119.3, 121.1, rings), 9.61 (s, 1H, vinyl proton of the indole ring),
23.3, 123.7, 125.6, 126.3, 127.0, 132.3, 133.1, 136.0, 12.31 (br, s, 1H, –NH proton of the indole ring); 13C-
86.3. MS m/z = 357 (M+1).
NMR spectrum (DMSO/d /TMS): δ 34.8, 55.1, 111.0,
6
112.8, 113.1, 114.0, 118.4, 121.0, 123.0, 123.8, 124.3,
25.3, 125.4, 126.0, 127.1, 131.6, 133.6, 135.9, 136.9,
1
2.2 General procedure for the preparation of 5
151.3, 186.9; MS m/z = 356 (M+1).
A mixture of 4 (10 mmol), 2 (10 mmol, 1.82 g) and PPh3
0% (1.2 mmol, 412 mg) in ethanol (15 mL) was stirred
4
2
.2d Characterization of 5d: Yellow solid; Yield: 2.01
◦
−1
at RT for a specified period of time (table 1). After com-
pletion of reaction (as shown by TLC checking), the
mixture was poured into ice-cold water. The separated
solid was filtered, washed with water and dried to obtain
the crude product. The latter were then recrystallized
from ethyl acetate to afford pure 5.
gms (85%); m.p. >285 C; IR (KBr): 3215 cm (broad,
–
and 1615 (very strong, highly conjugated carbonyl
−1
NH stretching), 2211 cm (sharp, –CN stretching)
1
–CO); H-NMR (DMSO d /TMS): δ 4.01 (s, 3H,
6
-
N-CH 7.21–7.98 (m, 7H, aryl protons of the indole
3
rings), 8.21–8.34 (m, 2H, α-protons of the indole rings),
.89 (s, 1H, vinyl proton of the indole ring), 12.19
9
13
(
br, s, 1H, –NH proton of the indole ring); Its C-NMR
2
.2a Characterization of 5a: Yellow solid; Yield: 1.38 spectrum (DMSO/d /TMS): δ 34.1, 110.9, 111.0, 113.1,
6
◦
−1
gms (87%); m.p. 172–181 C; IR (KBr): 3242 cm (due 114.5, 117.6, 121.5, 123.1, 123.5, 124.8, 125.0, 125.8,
to –NH), 2212 cm (due to –CN) and 1621 cm (due 126.5, 128.3, 130.6, 132.5, 134.9, 135.9, 136.3, 185.0.
−1
−1
1
to –CO); H-NMR spectrum (DMSO/d /TMS): δ 3.81 MS m/z = 403 (M+1).
6
(
s, 3H, -N-CH ), 7.21–8.1 (m, 8H, aryl protons of the
3
two indole rings), δ 8.21–8.61 (m, 2H, α-protons of
the two indole rings), δ 9.21 (vinylic proton of the
2
.2e Characterization of 5e: Yellow solid; Yield: 1.78
◦
−1
indole ring), δ 12.14 (br s, 1H, D O exchangeable,
2
3
gms (87%); m.p. 169–170 C; IR (KBr): 3199 cm
1
−1
−
NH proton of the indole ring); Its C-NMR spectrum
(very broad, –NH stretching), 2211 cm (sharp, –CN
(
DMSO/d /TMS): δ 34.5, 110.1, 112.1, 113.9, 115.1,
6
stretching) and 1621 (very strong, highly conjugated
carbonyl –CO); H-NMR (DMSO d /TMS): δ 3.99 (s,
1
118.5, 121.7, 121.6, 122.1, 122.3, 123.3, 123.1, 126.5,
127.7, 131.9, 134.4, 136.3, 136.7, 145.3, 183.7 MS m/z:
326 (M+1).
6
3
H, N-CH ), 7.19–8.16 (m, 7H, aryl protons of the
3
indole rings), 8.41–8.54 (m, 2H,-α protons of the indole
rings), 10.06 (s, 1H, vinyl proton of the indole ring),
1
13
2.41 (br, s, 1H, –NH proton of the indole ring); Its C-
2
1
.2b Characterization of 5b: Yellow solid; Yield: NMR spectrum (DMSO/d /TMS): δ 36.1, 110.3, 110.4,
6
◦
−1
.68 gms (89%); m.p: 261–263 C; IR(KBr): 3231 cm
111.0, 112.3, 114.4, 116.3, 117.9, 118.4, 119.2, 121.2,
−1
(medium, –NH stretching), 2208 cm (sharp, –CN 123.5, 123.9, 124.6, 126.3, 129.1, 132.3, 133, 135.2,
stretching) and 1624 (very strong, carbonyl –CO); 186.1. MS m/z = 372 (M+1).
1
H-NMR (DMSO d /TMS): δ 3.23–3.26 (s, 3H,
6
–
OCH ), 4.01 (s, 3H, N-H ), 7.11–7.89 (m, 7H,
3
3
aryl protons of the indole rings), 8.14–8.31 (m, 2H,
α-protons of the indole rings), 9.32 (s, 1H, vinyl pro-
2.3 General procedure for the preparation of 6 from 3
ton of the indole ring), 12.14 (br, s, 1H, –NH proton A mixture of 3 (5 mM), dimethyl sulphate (DMS)
of the indole ring); δ 34.9, 53.1, 112.1, 113.5, 113.7, (10 mM, 10.8 mL) and PEG-600 (20 ml) was heated at
◦
1
1
15.5, 116.5, 121.5, 122.3, 122.7, 123.8, 123.9, 124,2, ≈ 60 C for 1 h. At the end of this period, the mixture
26.8, 127.2, 130.1, 132.6, 135.4, 137.7, 151.5, 186.5 was poured into ice-cold water and neutralized with
MS m/z = 356 (M+1).
5% aq. NaOH. The separated solid was filtered, washed

612
M Venkatanarayana and P K Dubey
with water and dried to obtain crude product. The lat- 113.2, 114.0, 118.5, 121.1, 123.1, 123.8, 124.5, 125.5,
ter were then recrystallized from ethyl acetate to afford 125.8, 126.5, 127.8, 132.6, 133.7, 135.9, 136.6, 152.3,
pure 6.
184.9; MS m/z = 370 (M+1).
2
.3a Characterization of 6a: Yellow solid; Yield:
◦
−1
1.52 gms (90%); m.p. 248–250 C; IR(KBr): 2201 cm
2
.3d Characterization of 6d: Parrot green colour
−1
(medium, due to –CN stretching), 1621 cm
◦
solid; Yield: 1.83 gms (88%); m.p. 285 C; IR (KBr):
1
(strong, due to –CO stretching); H-NMR spectrum
−1
2212 cm (sharp, –CN stretching) and 1616 (very
(
DMSO/d /TMS): δ 3.94–4.02 (s, 6H, 2 N-CH ), 7.30–
1
6
3
strong, highly conjugated carbonyl –C=O); H-NMR
7
8
.99 (m, 8H, aryl protons of the two indole rings),
.22–8.24 (s, 2H, two α-protons of the two indole
(
DMSO d /TMS): δ 3.18–3.19 (s, 3H, -O-CH ), 3.86–
6 3
3
7
8
.88 (s, 3H, -N-CH ), 4.1–4.12 (s, 3H, -N-CH ), 7.29–
.99 (m, 7H, aryl protons of the indole rings), 8.31–
3
3
rings), 8.592–8.597 (s, 1H, vinylic proton of the indole
ring); δ 33.5, 34.8, 110.0, 111.2, 113.1, 114.1, 118.5,
.45 (m, 2H, α-protons of the indole rings), 9.12
121.7, 121.4, 122.8, 123.0, 123.3, 123.8, 126.5, 127.1,
13
(
s, 1H, vinyl proton of the indole ring); Its C-NMR
1
31.6, 134.2, 136.1, 136.5, 145.2, 182.1 MS m/z = 340
spectrum (DMSO/d /TMS): δ 33.9, 34.5, 111.9, 111.0,
6
(
M+1).
1
1
13.5, 114.3, 118.5, 120.5, 122.1, 123.5, 124.1, 125.2,
25.6, 126.5, 128.8, 130.3, 132.7, 134.9, 135.9, 136.5,
2
.3b Characterization of 6b: Yellow solid; Yield: 185.1 MS m/z = 418 (M+1).
◦
1.63 gms (89%); m.p. 231–232 C; IR (KBr): 2167
−1
cm (sharp, –CN stretching) and 1616 (very strong,
1
highly conjugated carbonyl –C=O); H-NMR (DMSO
2
.3e Characterization of 6e: Yellow solid; Yield: 1.63
d /TMS): δ 3.24–3.25 (s, 3H, -Oa-CH ), 3.98–3.99
6
3
◦
−1
gms (85%); m.p. 291 C; IR (KBr): 2222 cm (sharp,
CN stretching) and 1618 (very strong, highly con-
(
s, 3H, -N-CH ), 4.06–4.08 (s, 3H, -N-CH ),
3
3
–
7
8
.31–7.88 (m, 7H, aryl protons of the indole rings),
.24–8.39 (m, 2H, α-protons of the indole rings), 9.21
1
jugated carbonyl –C=O); H-NMR (DMSO d /TMS):
6
δ 3.18–3.20 (s, 3H, -O-CH ), 3.91–3.92 (s, 3H,
3
(
s, 1H, vinyl proton of the indole ring); δ 33.9, 34.6,
-
N-CH ), 4.12–4.13 (s, 3H, -N-CH ), 7.32–7.96 (m,
3
3
53.5, 112.0, 113.1, 113.5, 115.0, 116.2, 121.7, 122.3,
122.7, 123.9, 124.1, 124.4, 126.8, 127.0, 130.0, 132.0,
135.4, 137.5, 151.6, 185.5 MS m/z = 370 (M+1).
7
2
H, aryl protons of the indole rings), 8.36–8.43 (m,
H, α-protons of the indole rings), 9.98 (s, 1H, vinyl
13
proton of the indole ring); Its C-NMR spectrum
DMSO/d /TMS): δ 34.5, 34.9, 110.0, 110.6, 111.0,
(
6
2
.3c Characterization of 6c: Yellow solid; Yield: 1.65
1
1
12.3, 114.4, 116.3, 117.9, 118.4, 119.2, 121.0, 123.6,
23.8, 124.6, 126.5, 129.2, 132.3, 133.7, 135.2, 186.0.
◦
−1
gms (90%); m.p. 196 C; IR (KBr): 2197 cm (sharp,
CN stretching) and 1612 (very strong, highly con-
–
MS m/z = 386 (M+1).
1
jugated carbonyl –C=O); H-NMR (DMSO d /TMS):
6
δ 3.21–3.22 (s, 3H, -O-CH ), 3.96–3.99 (s, 3H,
3
-
N-CH ), 4.08–4.10 (s, 3H, -N-CH ), 7.31–7.98 (m,
3
3
7
2
H, aryl protons of the indole rings), 8.22–8.46 (m,
H, α-protons of the indole rings), 9.23 (s, 1H,
3
. Results and discussion
13
vinyl proton of the indole ring); C-NMR spectrum Treatment of indole-3-carboxyldehydes 1(a–e) and
(
DMSO/d /TMS): δ 34.0, 35.1, 53.5, 111.2, 112.5, 4(a–e) with 3-cyanoacetylindole (2) in the presence of
6
Table 2. Rate of reaction in different solvent mediums.
◦
Entry
Solvent
Time (Hrs) Temp ( C) Yield (%)
1
2
3
4
5
6
7
PPh3/ EtOH
PPh3/ CH3CN
PPh3/ DMF
Without catalyst / EtOH
PPh3/ DMSO
PPh3/ Benzene
PPh3/ CHCl3
1–2
6
5–8
24
4–6
15
20
RT
RT
RT
RT / ꢀ
RT
RT
85-90
20-30
44-50
NIL
30-40
10-15
NIL
RT

Simple and efficient Knoevenagel synthesis of (E)-2-((1H-indol-3-yl)methylene)-3-oxoindolylnitrile catalysed by PPh3 613
O
NC
O
H
CHO
N
H
R
R
N
H
3
EtOH / PPh / RT
CN
(
2)
R1
N
R1
N
H
(
1)
H
1-2 h
(3)
PEG-600 / DMS / 50-60OC / 1 h
PEG-600 / DMS
0
/
110-120 C
O
NC
O
H
O
H
N
H
CHO
R
N
R
CN
N
H
PEG-600 / DMS / 50-60O
1 h
CN
CH3
R
EtOH / PPh
3
/ RT / 1-2 h /
(2)
C
R1
N
R1
N
R1
N
CH3
CH
3
CH
3
(5)
(
4)
(6)
Scheme 1. TPP Catalysed Knoevenagel reaction.
PPh in ethanol at RT, for 1–1.5 h, resulted in the for-
In order to compare the rate of the reaction in the
3
mation of novel (E)-2-((1H-indol-3-yl)methylene)-3- presence of PPh in EtOH, we carried out the reaction
3
oxoindolylnitrile products 3(a–e) and their correspond- in different solvent media (table 2).
ing N-methyl derivatives of 5(a–e) in 85–90% yields
table 1) (scheme 1).
Treatment of 3(a–e) each with DMS independently,
18–20
(
in the presence of PEG-600
as a facile and versa-
◦
This method is very facile and convenient for the tile reaction medium, at ≈ 60 C for 1 h, without using
preparation of large amount of Knoevenagel adducts any base, gave N, N-disubstituted olefins 6(a–e) respec-
with high yields in less time. TPP acts as a mild Lewis tively in 85–90% yields (scheme 1). Alternatively, treat-
base to induce the reaction. In the absence of TPP, ment of 5(a–e) each with DMS, independently in the
the reaction does not proceed even after refluxing the presence of PEG-600, gave the corresponding 6(a–e)
reactants in ethanol for ≈ 24 h. The use of TPP as respectively. Each of the compounds 5(a–e) were
a catalyst helps to avoid the use of environmentally obtained from the respective 4(a–e) by condensation
unfavourable organic solvents (DMF, C H Toluene, with 2. The compounds 4(a–e) were obtained from
6
6,
DMSO, etc....,) as reaction medium. It is inexpensive, 1(a–e) by methylation with DMS in PEG-600 using
21
readily available and found to retain its activity even our earlier described green method. All the above
in the presence of water and other active functional reactions are summarized in scheme 1.
groups such as CHO, −CO, NO , and CN present
It is obvious from the above results that PEG-600 is a
in the substrates. In all cases, the reaction proceeded very effective solvent for methylations of 1(a–e), 3(a–e)
smoothly with 40 mol% of TPP to give products of good and 5(a–e) resulting in 4(a–e) and 6(a–e) respectively.
2
purity.
Mechanistic explanation of these results is that, proba-
In the above reaction, the product has been assigned bly, PEG-600 dissolves the substrate [i.e., olefins 3(a–e)
E-configuration (first and second priority groups i.e., and 5(a–e)] and the reagent (i.e., alkylating agent DMS)
indolyl and 3-cyanoacetylindol respectively are trans bringing them together thereby providing an effective
to each other) on the basis of the assumption that the means for chemical reaction to occur. Furthermore, use
groups with maximum stereochemical bulk would be of PEG-600 negates the use of base in these reactions
more stable in a trans configuration.
because PEG-600 is able to extract the hydrogen from
Table 3. The rate of reaction in different polyethylene glycol mediums.
Sl. no. Starting material Reagent used
used
Product
Reaction time
(ꢀ/ 60 C)/Yield (%)
◦
1
1
1.
2.
3.
3a (R=R =H)
PEG-600/DMS 6a (R=R =H)
1 h/90
8 h/66
12 h/59
1
1
3a (R=R =H)
PEG-400/DMS 6a (R=R =H)
1
1
3a (R=R =H)
PEG-200/DMS 6a (R=R =H)

614
M Venkatanarayana and P K Dubey
the –NH of the substrates (1 or 3 or 5) able to 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-dimethylaminonaphthalene). Proton
sponge (–NH or –OH) which is a very strong base due
to its ability to extract hydrogen from an acidic substrate
and then retain it in its claws by chelation through lone
pair of electrons on the two nitrogen atoms of proton
sponge.
3. (a) Lyall R, Zilberstien A, Gazit A, Gilon C,
Levitzki A and Schlessinger J 1989 J. Biol. Chem.
2
64 14503; (b) Shiraishi T, Owada M K, Tatsuki M,
Yamashita Y and Kaunaga T 1989 Cancer Res. 49,
374
2
4
5
6
. (a) Allen C F H and Spangler F W 1955 Org. Synth.
Coll. Vol. III 377; (b) Rand L, Swisher J V and Cronin
C J 1962 J. Org. Chem. 27 3505
. (a) Rao P S and Venkataratnam R V 1991 Tetrahedron
Lett. 32 5821; (b) Prajpati D, Lekhok K C, Sandhu J S
and Ghosh A C 1996 J. Chem. Soc., Pekin. Trans. 1 959
. (a) Texier-Boullet F and Foucaud A 1982 Tetrahedron
Lett. 23, 4927; (b) Cabello J A, Campelo J M, Garia A,
Luna D and Marinas J M 1984 J. Org. Chem. 49, 5195;
1
2
Reaction of 3a (i.e., R =R =H) with DMS in the
presence of PEG-600 gave N, N-disubstituted olefins
with high yields compare to in the presence of PEG-400
and PEG-200, the reason is due to its higher viscosity
(
c) Chalais S, Laszlo P and Mathy A 1985 Tetrahedron
Lett. 26, 4453; (d) Laszlo P 1986 Acc. Chem. Res. 19
21
. (a) Reddy T I and Varma R S 1997 Tetrahedron Lett.
8 1721; (b) Angeletti E, Canepa C, Martinetti G and
Venturello P 1989 J. Chem. Soc., Perkin. Trans. 1 105;
c) Rodriguez I, Iborra S, Corma A, Rey F and Jorda J L
999 Chem. Commun. 593
8. (a) Dela Cruz P, Diez-Barra E, Loupy A and Langa F
996 Tetrahedron Lett. 37 1113; (b) Kumar H M S,
1
22
of PEG-600 will help reacting partners to overcome
entropy barriers. The rate of the reaction in different
solvent mediums described in table 3.
7
3
(
1
4
. Conclusion
1
In summary, PPh has been employed as an effi-
Reddy B V S, Reddy E J and Yadav J S 1999 Tetrahe-
dron Lett. 40 2401
. (a) Kloetstra K R and Van Bekkum H 1995 J. Chem.
3
cient catalyst for the preparation of novel indolo
olefinic compounds by a Knoevenagel reaction in
ethanol. This method is applicable to a wide
range of indole-3-carboxyldehydes 1(a–e) including
9
Soc., Chem. Commun. 1005; (b) Wada S and Suzuki H
2003 Tetrahedron Lett. 44 399; (c) Sebti S, Smahi A and
Solhy A 2002 Tetrahedron Lett. 43 1813
N-substituted indole-3-carboxyldehydes 4(a–e). The 10. (a) Su C, Chen Z-C and Zheng Q G 2003 Synthesis.
5
55; (b) Harjani J R, Nara S J and Salunkhe M M 2002
attractive features of this procedure are the mild reac-
tion conditions, high conversions, operational simplic-
ity and inexpensive and ready availability of the cata-
lyst, all of which make it a useful and attractive strategy
for the preparation of olefins.
Tetrahedron Lett. 43 1127
1
1. Mahboobi S and Groh’s G 1994 Arc. Pharm.
(Weinheim). 327–349
1
2. Nagarajan R and Perumal P T 2002 Syn. Commun. 32(1)
105
1
1
3. Shanthi G and Perumal P T 2005 Syn. Commun. 35 1319
4. Anniyappan M, Muralidharan D and Perumal P T 2003
Tetrahedron Lett. 44 3653
Acknowledgements
The authors are thankful to the University Grants 15. Nagarajan R, Sundararajan C and Perumal P T 2001
Tetrahedron. 57 3419
6. Anniyappan M, Muralidharan D and Perumal P T 2002
Tetrahedron 58 10301
7. Behbehani H, Mohamed Ibrahim H and Maksheed S
Commission (UGC), Govt. of India, New Delhi, for
1
1
1
providing financial support and to the authorities of
Jawaharlal Nehru Technological University, Hyderabad,
for providing laboratory facilities.
2009 Heterocycls 78(12) 3081
8. Hai-feng L, Zu-liang H, Hui H, Guo-feng W, Liu-bin
W and Jin-sheng C 2008 Jiangxi Shifan Daxue Xuebao,
Ziran Kexueban 32(4) 478
References
1
9. Zu-liang U, Liu-bin W, Hui H, Jin-sheng C, Guo-feng
W and Hai-feng L 2008 Huaxue Shiji 30(9), 699–701,
704
1
. (a) Knoevenagel E 1898 Berichte 31 2585–2596;
b) Jones G 1967 Org. React. 15 204
(
2
. (a) Tietze L F and Beifuss U 1991 In Comprehensive 20. Hsu-Chin H and Hung-Shan H 2001 J. Chem. Technol.
Organic Synthesis (eds.: B M Trost, I Fleming, C H
and Biotechnol. 76(9) 959–965
Heathcock); Oxford: Pergamon Press, vol. 2, pp. 341; 21. Dubey P K and Venkatanarayana M 2010 Green Chem-
b) Bigi F, Chesini L, Magi R and Sartori G 1999 J. Org.
istry Letters and Reviews 4, 257
Chem. 64 1033; (c) Yu N, Armini J M, German M W 22. Zhang K, Yang J, Xuechun U, Zhang J and Wei X 2011
and Hung Z 2000 Tetrahedron Lett. 41 6993
J. Chem. and Eng. Data 56(7) 3083
(