Cyanoacetylation of indoles, pyrroles and aromatic amines with the combination cyanoacetic acid and acetic anhydride

Article abstract of DOI:10.1055/s-2004-831164

Cyanoacetic acid was activated with acetic anhydride and when heated this reagent reacted with a variety of both activated and deactivated pyrroles, indoles and aniline derivatives.

Full text of DOI:10.1055/s-2004-831164

2760
PRACTICAL SYNTHETIC PROCEDURES
Cyanoacetylation of Indoles, Pyrroles and Aromatic Amines with the Combi-
nation Cyanoacetic Acid and Acetic Anhydride
C
yanoacet
o
ylation
w
ith
h
Cyanoacetic
n
Acidand
A
c
etic
Anhydr
y
ide Slätt, Ivan Romero, Jan Bergman*
Unit for Organic Chemistry, Department of Biosciences, Karolinska Institute and Södertörn
University College, Novum Research Park, 141 57 Huddinge, Sweden
Fax +46(8)6089204; E-mail: jabe@cnt.ki.se
PSP
Received 1 March 2004; revised 19 April 2004
No32
Abstract: Cyanoacetic acid was activated with acetic anhydride and when heated this reagent reacted with a variety of both activated and
deactivated pyrroles, indoles and aniline derivatives.
Key words: acylations, electrophilic aromatic substitutions, heterocycles, indoles, pyrroles
Scheme 1
requires conversion of cyanoacetic acid to
CH3SO2OCOCH2CN.8 In our hands this relatively tedious
Introduction
Simple nitrogen containing heteroaromatic compounds procedure only gave moderate yields of 3-cyanoacetylin-
have received much attention in the literature over the dole. However short heating (5 min) at 60–70 °C of cy-
years. They are, among other things, pharmacophores of anoacetic acid together with indole in acetic anhydride
paramount importance,1 which have exciting biological (Table 1, entry 1) gave the desired product in an excellent
properties in their own right and also serve as important yield as a readily collectable precipitate. This procedure
synthetic building blocks in drug discovery.
could subsequently be extended to pyrroles, which readily
gave the expected cyanoacetylated derivatives. Only a
few cyanoacetylated pyrroles have been described in the
literature and they have invariably been prepared by dis-
placements of halide in haloacetylpyrroles with e.g. potas-
sium cyanide.11–13 This low-yield and time-consuming
approach has also been used in the indole series. Further-
more N-methyl-3-cyanoacetylindole (entry 4) has been
recently prepared by condensation of ethyl N-methylin-
dole-3-carboxylate with acetonitrile in the presence of
sodamide.14 This nitrile can likewise be conveniently pre-
pared by our procedure (entry 4). Dissolution of N-meth-
It is known that cyanoacetic acid can serve as a building
block in various reactions like cyclizations2 or syntheses
of coumarins3 and other heterocycles4. Activation of cy-
anoacetic acid by conversion to the mixed anhydride with
acetic anhydride has been used now and then5–8 but the
generality, simplicity and usefulness has not been appre-
ciated and the reagent has infrequently been used for N-
acetylations of e.g urea and C-acylations of enamines.9
Other activation procedures, such as conversion to cy-
anoacetyl chloride has also been used, albeit this reagent
is notorious for its tendency to selfpolymerization (partic-
ulary when heated).7,10
yl-3-cyanoacetylindole in hot (100 °C,
2
h)
polyphosphoric acid followed by addition of water gave
the corresponding amide,15 the NMR-data of which were
identical with those recently published.14
Scope and Limitations
Despite the fact that acetic anhydride is used as solvent no
The present study was initiated when a large amount of 3- acetylated products were ever isolated except for a few ac-
cyanoacetylindole was needed as starting material for var- tive anilines.16 Several acetic acid derivatives bearing
ious fused indoles (Scheme 1). Kreher and Wagner have electron-withdrawing groups can form ketenes17 and this
described the synthesis of this molecule, but the procedure could explain the high reactivity and selectivity. In most
cases it is preferable to use two equivalents of cyanoacetic
acid when the nucleophile is not very active, like 2-phe-
nylindole. However, indole, 2,2¢-biindolyl and pyrrole un-
derwent cyanoacetylation very easily. On the other hand,
SYNTHESIS 2004, No. 16, pp 2760–2765
Advanced online publication: 13.08.2004
DOI: 10.1055/s-2004-831164; Art ID: T02604SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
4

PRACTICAL SYNTHETIC PROCEDURES
Cyanoacetylation with Cyanoacetic Acid and Acetic Anhydride
2761
we have not been able to efficiently cyanoacetylate other derivatives of acetic acid, especially molecules bear-
thiophene, 4-nitroindole or 2,4-dinitroaniline (poor ing electron-withdrawing groups since methanesulfonyl-
yields, 10–15%). Most likely the procedure for cy- acetic acid was shown to react in the same fashion in
anoacetylation as developed will give considerable oppor- excellent yields (Table 1, entry 8).
tunities to use many other nucleophiles than those
presented here. There should also be a possibility to use
Table 1 Cyanoacetylation in Acetic Anhydride
Entry
1
Reactant
Product
Yield (%)
91
Lit. Yield (%)
84a
CN
O
N
H
N
H
2
3
4
91
90
90
–
MeO
CN
O
N
MeO
H
N
H
81a
CN
O
N
H
N
H
no yield given
CN
O
N
N
5
6
98a
0a
CN
CN
O
N
H
N
H
97a
–
O
N
N
7
8
90
92
–
–
CN
O
N
H
N
H
N
N
H
H
O
S
O
O
N
H
N
H
Synthesis 2004, No. 16, 2760–2765 © Thieme Stuttgart · New York

2762
J. Slätt et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 1 Cyanoacetylation in Acetic Anhydride (continued)
Entry
9
Reactant
Product
Yield (%)
68
Lit. Yield (%)
75a
O
CN
N
N
10
11
88
75
–
CN
N
H
N
H
O
O
no yield given
CN
N
H
N
H
12
13
14
87
92
91
no yield given
no yield given
–
CN
CN
N
N
O
N
H
N
H
O
N
H
N
CN
O
15
82
–
N
H
N
CN
O
16
17
51
92
–
–
CN
CN
O
CN
NH2
N
H
O
O
CN
CN
O
CN
NH2
N
H
18
99
95
O
N
O
N
O
CN
N
O
NH2
O
N
NH2
19
20
50
13
–
O
O
O
CN
EtO
EtO
NH2
NH2
63a
NH2
H
N
CN
F3C
NO2
O
NO2
F3C
a Two equivalents of cyanoacetic acid were used.
Synthesis 2004, No. 16, 2760–2765 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Procedures
Cyanoacetylation with Cyanoacetic Acid and Acetic Anhydride
2763
3-Cyanoacetyl-2,2¢-biindolyl (entry 7)
All starting materials and solvents (p.a. grade) are commercially
available and were used without any further purification. All tem-
peratures were measured in the reaction mixture unless stated oth-
erwise. NMR spectra were recorded in DMSO-d6 solutions, unless
stated otherwise, on a Bruker DPX 300 spectrometer, operating at
300 MHz for 1H and 75 MHz for 13C; d values are reported in ppm
and J values are in Hertz. IR spectra were recorded on a Perkin-
Elmer 1600 FTIR instrument using KBr pellets. Elemental analyses
were preformed by H. Kolbe Mikroanalytisches Laboratorium,
Mülheim an der Ruhr, Germany. Melting points were determined
using a Büchi melting point B-545 apparatus and are uncorrected.
Yield: 90%; mp 256 °C (Lit.18 mp 246–254 °C).
IR: 3305, 2944, 2264, 1639, 1614, 1547, 1469, 1446, 1392, 1338,
1236, 1182, 1160, 1088, 965, 925, 794, 762, 747, 727 cm–1.
1H NMR: d = 4.52 (s, 2 H), 7.09–7.14 (m, 1 H), 7.22–734 (m, 4 H),
7.52–7.55 (m, 1 H), 7.60–7.63 (m, 1 H), 7.68–7.70 (m, 1 H), 8.01–
8.03 (m, 1 H), 12.13 (br s, NH), 12.62 (br s, NH).
13C NMR: d = 32.6, (t), 104.7 (d), 111.5 (s), 112.1 (d), 112.2 (d),
116.1 (s), 120.1 (d), 120.7 (d), 121.2 (d), 122.5 (d), 123.2 (d), 123.7
(d), 126.3 (s), 127.6 (s), 128.1 (s), 136.0 (s), 136.5 (s), 137.7 (s),
184.8 (s).
3-Cyanoacetylindole (entry 1)
3-Methanesulfonylacetylindole (entry 8)
Indole (5.85g, 50 mmol) was added to a solution prepared by disso-
lution of cyanoacetic acid (5.0 g, 50 mmol) in Ac2O (50 mL) at 50
°C. The solution was heated at 85 °C for 5 min. During that period
3-cyanoacetylindole started to crystallize. After 5 more min, the
mixture was allowed to cool and the solid was collected, washed
with MeOH, and dried; yield: 8.38 g (91%); mp 241 °C (Lit.8 mp
240 °C).
Indole (1.17 g 10 mmol) was added to a solution prepared by disso-
lution of methanesulfonylacetic acid (1.38 g 10 mmol) in Ac2O (15
mL) at 85 °C. The solution was heated to 90 °C during 15 min,
whereupon the mixture was allowed to cool and the precipitate
formed was collected, washed with EtOH and dried.
Yield: 2.18 g (92%); mp 241 °C.
IR: 3214, 1615, 1516, 1435, 1380, 1286, 1237, 1178, 1126, 1093,
953, 903, 805, 742, 698, 648, 612, 516, 482 cm–1.
1H NMR: d = 3.18 (s, 3 H), 4.87 (s, 2 H), 7.25–7.27 (m, 2 H), 7.51–
7.52 (m, 1 H), 8.20–8.22 (m, 1 H), 8.58–8.58 (m, 1 H).
13C NMR: d = 42.6 (q), 62.4 (t), 113.0 (d), 117.4 (s), 121.8 (d), 123.0
(d), 124.0 (d), 125.9 (s), 137.4 (s), 137.7 (d), 183.7 (s).
IR: 3214, 3120, 2251, 1633, 1580, 1523, 1489, 1457, 1433, 1397,
1377, 1336, 1318, 1279, 1236, 1202, 1139, 1095, 1007, 980, 922,
900, 876, 784, 744 cm–1.
1H NMR: d = 4.50 (s, 2 H), 7.20–7.28 (m, 2 H), 7.50–7.55 (m, 1 H),
8.13–8.17 (m, 1 H), 8.38–8.39 (m, 1 H), 12.19 (br s, NH).
13C NMR: d = 29.4 (t), 112.4 (d), 114.4 (s), 116.4 (s), 121.0 (d),
122.3 (d), 123.3 (d), 125.1 (s), 135.4 (d), 136.6 (s), 182.8 (s).
Anal. Calcd for C11H11NO3 (237.3): C, 55.68; H, 4.67; N, 5.90.
Found: C, 55.76; H, 4.46; N, 5.87.
For entries 2–4 and 7 the procedure as given for entry 1 was used.
2-Cyanoacetylpyrrole (entry 13)
3-Cyanoacetyl-5-methoxyindole (entry 2)
Yield: 89%; mp 270 °C.
Pyrrole (10.7 g 0.16 mol) was added to a mixture of cyanoacetic
acid (13.7 g 0.16 mol) and Ac2O (80 mL) and heated at 75 °C for 35
min. The mixture was allowed to cool and poured on ice. The pre-
cipitate formed was collected and dried.
IR: 3223, 2258, 1631, 1589, 1522, 1484, 1466, 1434, 1298, 1287,
1263, 1235, 1209, 1158, 1091, 1023, 902, 849, 807, 745 cm–1.
1H NMR: d = 3.79 (s, 3 H), 4.46 (s, 2 H), 6.88 (dd, J = 2.7, 8.7, 1
H), 7.40 (d, J = 8.7 Hz, 1 H), 7.63 (d, J = 2.7 Hz, 1 H), 8.30 (d,
J = 3.2 Hz, 1 H), 12.08 (br s, HN).
13C NMR: d = 29.3 (t), 55.3 (d), 102.7 (d), 113.1 (d), 113.2 (d),
114.3 (d), 116.4 (s), 126.0 (s), 131.4 (s), 135.5 (d), 155.8 (s), 182.7
(s).
Yield: 15.0 g (70%); mp 78 °C (Lit.19 mp 79–81 °C).
IR: 3301, 2258, 1653, 1544, 1408, 1274, 1108, 1050, 906, 846, 758,
603, 534 cm–1.
1H NMR: d = 4.40 (s, 2 H), 6.23–6.24 (m, 1 H), 7.07–7.08 (m, 1 H),
7.19–7.20 (m, 1 H), 12.11 (br s, NH).
13C NMR: d = 28.8 (t), 111.0 (d), 116.7 (s), 119.2 (d), 127.8 (d),
130.0 (s), 178.2 (s).
Anal. Calcd for C12H10N2O2 (214.22): C, 67.28; H, 4.71; N, 13.08.
Found: C, 67.34; H, 4.79; N, 13.12
For entries 9–12 the procedure as given for entry 13 was used.
3-Cyanoacetyl-2-methylindole (entry 3)
Yield: 90%; mp 230 °C (Lit.8 mp 237 °C).
2-Cyanoacetyl-1,2,5-trimethylpyrrole (entry 9)
Yield: 68%; mp 110 °C (Lit.8 mp 108 °C).
IR: 3272, 2952, 2258, 1627, 1581, 1530, 1459, 1387, 1317, 1283,
1247, 1172, 1104, 1046, 964, 923, 888, 751, 713, 629, 583 cm–1.
1H NMR: d = 2.68 (s, 3 H), 4.51 (s, 2 H), 7.15–7.20 (m, 2 H), 7.37–
7.43 (m, 1 H), 7.94–8.00 (m, 1 H), 12.08 (br s, NH).
13C NMR: d = 14.9 (q), 32.5 (t), 111.0 (d), 111.4 (s), 116.2 (s), 120.4
(d), 121.8 (d), 122.2 (d), 126.4 (s), 134.7 (s), 145.8 (s), 183.3 (s).
2-Cyanoacetyl-3-ethyl-4,5-dimethylpyrrole (entry 10)
Yield: 88%: mp 215 °C.
IR: 3306, 2959, 2266, 1643, 1580, 1497, 1442, 1372, 1317, 1252,
1198, 1110, 1060, 972, 924, 822 cm–1.
1H NMR: d = 0.93–0.98 (m, 3 H), 2.16–2.19 (m, 6 H), 2.27–2.35 (m,
2 H), 4.22 (s, 2 H), 11.29 (br s NH).
13C NMR: d = 10.8 (q), 10.9 (q), 15.2 (q), 16.4 (t), 29.6 (t), 116.2
(s), 124.3 (s), 124.8 (s), 127.5 (s), 133.4 (s), 175.7 (s).
3-Cyanoacetyl-N-methylindole (entry 4)
Yield: 90%; mp 154 °C.
IR: 3100, 3043, 2256, 1639, 1603, 1577, 1448, 1421, 1402, 1375,
1336, 1299, 1235, 1197, 1147, 1129, 1085, 1048, 1009, 977, 890,
869, 796, 766, 750, 734 cm–1.
Anal. Calcd for C11H14N2O (190.24): C, 75.82; H, 8.10; N, 16.09.
Found: C, 75.55; H, 8.22; N, 15.95
1H NMR: d = 3.85 (s, 3 H), 4.47 (s, 2 H), 7.27–7.35 (m, 2 H), 7.53–
2-Cyanoacetyl-3,5-dimethylpyrrole (entry 11)
7.56 (m, 1 H), 8.15–8.18 (m, 1 H), 8.35 (s, 1 H).
Yield: 75%; mp 109 °C (Lit.16 mp 108 °C).
13C NMR: d = 29.5 (t), 33.4 (q), 110.9 (d), 113.3 (s), 116.3 (s), 121.1
(d), 122.7 (d), 123.4 (d), 125.6 (s), 137.3 (s), 138.7 (d), 182.3 (s).
3-Cyanoacetyl-N-methylpyrrole (entry 12)
Yield: 87%; mp 110 °C (Lit.20 mp 107–109 °C).
Synthesis 2004, No. 16, 2760–2765 © Thieme Stuttgart · New York

2764
J. Slätt et al.
PRACTICAL SYNTHETIC PROCEDURES
IR: 3141, 2259, 1639, 1530, 1467, 1438, 1410, 1396, 1384, 1294,
1250, 1212, 1105, 1074, 923, 907, 880, 762 cm–1.
13C NMR: d = 26.2 (t), 107.0 (s), 115.6 (s), 116.5 (s), 125.4 (d),
126.3 (d), 133.4 (d), 134.0 (d), 139.3 (d), 162.1 (s).
1H NMR: d = 3.85 (s, 3 H), 4.42 (s, 2 H), 6.16–6.17 (m, 1 H), 7.12–
7.13 (m, 1 H), 7.24–7.25 (m, 1 H).
Anal. Calcd for C10H7N3O (185.2): C, 64.86; H, 3.81; N, 22.69.
Found: C, 64.94; H, 3.77; N, 22.65.
13C NMR: d = 29.3 (t), 37.0 (q), 108.5 (d), 116.1 (s), 121.3 (d), 128.0
3-(6-Amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyri-
midinyl)-3-oxopropanenitrile (entry 18)
(s), 133.3 (d), 178.2 (s).
Yield: 99%; mp 260 °C (Lit.5 mp 250–251 °C).
N-Cyanoacetylcarbazole (entry 15)
Carbazole (2.0 g 12.0 mmol) was added to a mixture of cyanoacetic
acid (1.3 g 15.3 mmol) and Ac2O (15 mL) and then heated slowly
to 95 °C for 1.5 h. The reaction mixture was allowed to cool and left
overnight. The precipitate formed was collected by filtration and
dried; yield: 2.3 g (82%); mp 150 °C.
Ethyl (E)-3-Amino-2-(2-cyanoacetyl)but-2-enoate (entry 19)
Yield: 50%; mp 110 °C (Lit.9 mp 112–114 °C).
2-Cyano-N-[4-(trifluoromethyl)-2-nitrophenyl]acetamide (en-
try 20)
IR: 2956, 2263, 1691, 1596, 1490, 1477, 1444, 1406, 1395, 1334,
1304, 1272, 1238, 1195, 1105, 1155, 1125, 1102, 1038, 966, 943,
931, 870, 858 787, 775, 753, 720, 675 cm–1.
1H NMR: d = 5.00 (s, 2 H), 7.42–7.57 (m, 4 H), 8.14–8.25 (m, 4 H).
13C NMR: d = 30.8 (t), 115.1 (s), 116.4 (d), 120.3 (d), 124.2 (d),
125.9 (s), 127.7 (d), 164.0 (s).
4-Amino-3-nitrobenzotrifluoride (2.0 g 10 mmol) was added to a
solution prepared by dissolving cyanoacetic acid (1.7 g 20 mmol) in
Ac2O (12 mL). The reaction mixture was heated at 90 °C for 1 h and
then allowed to cool. The precipitate formed was collected by filtra-
tion after dilution with EtOH and dried; yield: 1.67 g (63%); mp 156
°C.
IR: 3317, 3128, 2955, 2261, 1715, 1637, 1593, 1525, 1467, 1402,
1355, 1324, 1275, 1233, 1173, 1130, 1086, 946, 898, 859, 765, 697,
620 cm–1.
Anal. Calcd for C15H10N2O (234.25): C, 76.91; H, 4.30; N, 11.96.
Found: C, 77.08; H, 4.35; N, 11.83.
For entry 14 the same procedure as for entry 15 was used.
1H NMR: d = 4.07 (s, 2 H), 7.92 (d, J = 8.7 Hz, 1 H), 8.10 (d, J = 8.7
Hz, 1 H), 8.32 (s, 1 H), 10.90 (br s, 1 H, NH).
3-Cyanoacetyl-5,6,7,8-tetrahydrocarbazole (entry 14)
Yield: 91%; mp 181 °C.
3
13C NMR: d = 26.5, 115.2, 122.5 (q, JC,F = 3.9 Hz), 122.9 (q,
2
1JC,F = 272.0 Hz), 125.5 (q, JC,F = 33.8 Hz), 126.1, 130.6 (q,
IR: 2946, 2860, 2259, 1699, 1618, 1453, 1374, 1331, 1282, 1215,
1181, 1097, 1020, 949, 779 cm–1.
1H NMR: d = 1.74–184 (m, 4 H), 2.49–2.61 (m, 2 H), 2.89–2.91 (m,
2 H), 4.70 (s, 2 H), 7.23& ndash;7.31 (m, 2 H), 7.41–7.44 (m, 1 H),
8.13–8.17 (m, 1 H).
13C NMR: d = 20.6 (t), 21.2 (t), 23.1 (t), 26.7 (t), 30.0 (t), 115.1 (s),
115.7 (d), 117.7 (d), 118.3 (s), 123.5 (d), 124.2 (d), 129.7 (s), 134.4
(s), 135.4 (s), 163.4 (s).
3JC,F = 3.9 Hz) 133.8, 141.7, 162.2.
Anal. Calcd for C10H6F3N3O3 (273.2): C, 43.97; H, 2.21; N, 15.38.
Found: C, 43.91; H, 1.87; N, 15.33.
For entries 5 and 6 the same procedure as given for entry 20 was
used.
3-Cyanoacetyl-2-phenylindole (entry 5)
Yield: 98%; mp 187 °C.
Anal. Calcd for C15H14N2O (238.28): C, 75.61; H, 5.92; N, 11.76.
Found: C, 75.54; H, 6.07; N, 11.68.
IR: 3254, 2259, 1627, 1585, 1450, 1434, 1386, 1374, 1319, 1242,
1187, 1122, 1102, 938, 918, 890, 751, 697, 644 cm–1.
1H NMR: d = 3.93 (s, 2 H), 7.23–7.31 (m, 2 H), 7.44–7.48 (m, 1 H),
7.56–7.60 (m, 3 H), 7.64–7.68 (m, 2 H), 8.14–8.17 (1 H), 12.39 (br
s, NH).
13C NMR: d = 31.8 (t), 111.9 (s), 112.0 (d), 115.9 (s), 121.3 (d),
122.4 (d), 123.4 (d), 126.7 (s), 128.7 (d), 129.9 (d), 130.0 (d), 131.7
(s), 135.5 (s), 146.1 (s), 183.6 (s).
4-Amino-3-cyano-N-cyanoacetylacetophenone (entry 17)
3-Cyano-4-amino-acetophenone (1.6 g, 10 mmol) was added to a
solution prepared by dissolving cyanoacetic acid (0.9 g, 11 mmol)
in Ac2O (10 mL) at 85 °C. The solution was heated at 90 °C for 5
min and allowed to cool. The precipitate formed was collected by
filtration and dried; yield: 2.09 g (92%); mp 211 °C.
IR: 3292, 2234, 1727, 1683, 1587, 1536, 1401, 1339, 1281, 1167,
1116, 922, 850, 607 cm–1.
Anal. Calcd for C17H12N2O (260.29): C, 78.44; H, 4.65; N, 10.76.
Found: C, 78.56; H, 4.71; N, 10.69.
1H NMR: d = 2.6 (s, 3 H), 4.09 (s, 2 H), 7.88 (d, J = 8.7 Hz, 1 H),
8.21 (dd, J = 2.3, 8.7 Hz, 1 H), 8.39 (d, J = 2.3 Hz, 1 H).
13C NMR: d = 27.2 (t), 27.2 (q), 106.3 (s), 116.0 (s), 116.5 (s), 124.8
(d), 133.9 (d), 134.2 (d), 134.6 (d), 143.6 (s), 163.0 (s), 196.2 (s).
3-Cyanoacetyl-N-methyl-2-phenylindole (entry 6)
Yield: 97%; mp 161 °C.
IR: 2251, 1637, 1577, 1527, 1464, 1437, 1402, 1377, 1252, 1129,
1081, 1049, 903, 852, 760, 704 cm–1.
1H NMR: d = 3.57 (s, 3 H), 3.60 (s, 2 H), 7.30–7.39 (m, 2 H), 7.56–
7.65 (m, 6 H), 8.26–8.29 (m, 1 H).
13C NMR: d = 31.0 (q), 31.5 (t), 111.0 (d), 112.6 (s), 121.4 (d), 123.0
(d), 123.3 (d), 123.6 (d), 125.9 (s), 129.1 (d), 130.2 (d), 130.3 (d),
130.4 (s), 136.5 (s), 147.4 (s), 183.0 (s).
Anal. Calcd for C12H9N3O2 (227.2): C, 63.43; H, 3.99; N, 18.49.
Found: C, 63.49; H, 3.94; N, 18.46.
For entries 16, 18, 19 the same procedure given for entry 17 was
used.
2-Cyano-N-(2-cyanophenyl)acetamide (entry 16)
Yield: 51%; mp 171 °C.
Anal. Calcd for C18H14N2O (274.31): C, 78.81; H, 5.14; N, 10.21.
Found: C, 78.82; H, 5.10; N, 10.14.
IR: 3263, 2972, 2922, 2262, 2229, 1672, 1607, 1581, 1539, 1447,
1388, 1349, 1296, 1253, 1191, 953, 767, 683 cm–1.
1H NMR: d = 4.01 (s, 2 H), 7.36–7.41 (m, 1 H), 7.61–7.64 (m, 1 H),
7.69–7.74 (m, 1 H), 7.82–7.85 (m, 1 H), 10.56 (br s, 1 H, NH).
3-Amidoacetyl-N-methylindole
N-Methyl-3-cyanoacetylindole (3.5 g 17.6 mmol) was added to
PPA (10 mL) and heated at 100 °C for 2 h, whereupon the mixture
was poured into ice. The precipitate formed was collected by filtra-
Synthesis 2004, No. 16, 2760–2765 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Cyanoacetylation with Cyanoacetic Acid and Acetic Anhydride
2765
tion and carefully washed with H2O and dried; yield 93%; mp 181
°C (Lit.14 mp 179.5–181.5 °C).
(5) Smirnova, N. M.; Cherdantseva, N. M.; Burova, O. A.;
Nesterov, V. M.; Safonova, T. S. Chem. Heterocycl. Compd.
1990, 811.
(6) Farbenfabriken Bayer, DE 175415, 1906; Chem. Abstr.
IR: 3553, 3326, 3167, 3102, 1672, 1614, 1576, 1529, 1490, 1464,
1444, 1427, 1376, 1338, 1293, 1261, 1234, 1192, 1143, 1127, 1087,
1050, 1008, 969, 954, 902, 882, 770, 748, 731 cm–1.
1H NMR: d = 3.66 (s, 2 H), 3.87 (s, 3 H), 7.03 (br s, 1 H, NH), 7.21–
7.32 (m, 2 H), 7.50 (br s, 1 H, NH), 7.53–7.56 (m, 1 H), 7.17–8.20
(m, 1 H), 8.35 (s, 1 H).
1907, 1, 6240.
(7) Schroeter, G.; Seidler, C.; Sulzbacher, M.; Kanitz, R. Ber.
Dtsch. Chem. Ges. 1932, 65, 432.
(8) Kreher, R.; Wagner, P. H. Chem. Ber. 1980, 113, 3675.
(9) Kappe, T.; Stelze, H. P.; Ziegler, E. Monatsh. Chem. 1983,
114, 953.
13C NMR: d = 33.5 (q), 47.8 (t), 111.0 (d), 115.6 (s), 121.7 (d), 122.6
(d), 123.4 (d), 126.1 (s), 137.6 (s), 138.9 (d), 169.6 (s), 189.0 (s).
(10) Schroeter, G.; Finck, E. Ber. Dtsch. Chem. Ges. 1938, 71,
671.
(11) Ingraffia, F. Gazz. Chim. Ital. 1934, 64, 778.
(12) Ingraffia, F. Gazz Chim. Ital. 1934, 64, 784.
(13) Fischer, H.; Schneller, K.; Zerweck, W. Ber. Dtsch. Chem.
Ges. 1922, 55, 2390.
(14) Gotor, V.; Liz, R.; Testera, A. M. Tetrahedron 2004, 60,
607.
Acknowledgment
We thank the National Network for Drug Development (NNDD) for
financial support.
(15) Takayama, K.; Iwata, M.; Hisamichi, H.; Okamoto, Y.;
Aoki, M.; Niwa, A. Chem. Pharm. Bull. 2002, 50, 1050.
(16) Slätt, J.; Bergman, J., unpublished results.
(17) Shelkov, R.; Nahmany, M.; Melman, A. J. Org. Chem. 2002,
67, 8975.
References
(1) Güner, I.; Osman, F. Pharmacophore Perception,
Development, and Use in Drug Design; International
University Line: La Jolla, California, 2000.
(18) Hayashi, H.; Ohmoto, S.; Somei, M. Heterocycles 1997, 45,
1647.
(19) Walker, G. N. Ciba-Geigy, European Patent 156091, 1984;
Chem. Abstr. 1987, 106, 156268.
(20) Walker, G. N. Ciba-Geigy, US Patent 4256759, 1981; Chem.
Abstr. 1981, 95, 7046.
(2) Batchelor, M. J.; Moffat, J.; David, F. C.; Davis, J. M.;
Hutchings, M. C. Celltech R & D Limited., PCT Int appl.
WO 2000078731, 2000; Chem. Abstr. 2000, 134, 71598.
(3) Schroeder, C.; Link, K. P. J. Am. Chem. Soc. 1953, 75, 1886.
(4) Baraldi, P. G.; Romagnoli, R.; Pavani, M. G.; Nuñez, M. C.;
Tabrizi, M. A.; Shryock, J. C.; Leung, E.; Moorman, A. R.;
Uluoglu, C.; Iannotta, V.; Merighi, S.; Borea, P. A. J. Med.
Chem. 2003, 46, 794.
Synthesis 2004, No. 16, 2760–2765 © Thieme Stuttgart · New York