Studies with azoles and benzoazoles: A novel simple approach for synthesis of 3-functionally substituted 3-acylindoles

Article abstract of DOI:10.1002/jhet.5570440119

(Chemical Equation Presented) 3-Substituted acylindoles 8 are obtained via refluxing carboxylic acids with indole in acetic anhydride solutions. The formed 3-substituted acylindole 8a is readily converted into 4-aminopyrazol-3- ylindoles 20, and into 22.

Full text of DOI:10.1002/jhet.5570440119

Jan-Feb 2007
109
Studies with Azoles and Benzoazoles: A Novel Simple Approach
for Synthesis of 3-Functionally Substituted 3-Acylindoles
Ramadan Maawad Abdel-Motaleba, Abdel-Moneim Abdel-Salam Makhloofa
Hamada Mohamed Ibrahima and Mohamed Hilmy Elnagdi*b
a Chemistry Department; Faculty of Science; Fayoum University; Fayoum; A. R. Egypt.
b Chemistry Department; Faculty of Science; Cairo University; Giza; A. R. Egypt
E-mail: Shelmy@ access.com.eg
Received April 25, 2006
O
O
CN
-
+
Ar N=N Cl
O
R
ROC
COCH3
N
NHAr
R = CH2CN
N
H
N
H
N
H
ClCH2X
O
ClCOCH2Cl
O
O
Nu
Cl
NH2
X
+
Nu
N
N
N
N
H
N
H
H
Ar
3-Substituted acylindoles 8 are obtained via refluxing carboxylic acids with indole in acetic anhydride
solutions. The formed 3-substituted acylindole 8a is readily converted into 4-aminopyrazol-3-ylindoles 20,
and into 22. Indole reacts with chloroacetyl chloride to yield: 3-chloroacetylindole 9 which could also be
utilized for synthesis of a number of 3-substituted indoles.
J. Heterocyclic Chem., 44, 109 (2007).
Me
3-Substituted indoles are important heterocycles both in
nature as well as pharmaceuticals [1,2]. For example
tryptophane 1 and indole-3-acetaldoxime 2 participate in
vital biological processes [3] while sumatriptan 3 is used
for migraine treatment [4]. Fortunately 3-substituted
indoles can be readily obtained by reacting indole with
electrophiles under mild conditions. Thus indole readily
couples at C-3 with aromatic diazonium salts [5], while
C-3 acylation is conducted with acid chlorides in pyridine
[6], N-acylation of indoles is generally conducted in the
presence of bases [7]. In conjunction to our interest [8] in
utilizing functionally susbstituted heteroaromatic ketones
as precursors to functionally substituted heteroaromatics,
COOH
NH2
Me
N
NOH
MeHNO2S
N
H
N
N
H
H
3
1
2
mixed anhydride 6. This, being more electrophillic than
acetic anhydride, reacts with indole to yield the
functionally substituted acyl derivatives 8a-e. It is of
value to report that compound 8d existed as indicated
1
from H nmr as an equilibrium mixture of both keto and
a
recent report [9] on synthesis of 3-indolyl-3-
enol form as expected for 1,3 diketone. On the other hand
mixing indole 7 with chloroacetyl chloride in dioxane
afforded the chloroacetylindole 9, hence, the utility of
Lewis acid catalyst to promote activity as recently
reported seemed to be of no value [11]. The chloroacetyl-
indole 9 could be readily converted into 8a on treatment
with potassium cyanide and into 10 on treatment with
ammonium thiocyanate. 3-Chloroacetylindole has
recently claimed to be formed from reaction with zinc salt
of indole with chloroacetyl chloride in presence of ZnCl2
[12]. However the product reported in literature is most
likely an N-acetyl indole 11 as it is different in every
respect from our product whose spectral data confirm that
it is 3-chloroacetylindole 9 (Scheme 1). Treatment of 9
with benzotriazole 12 in toluene/triethylamine afforded a
oxopropanenitrile 8a via refluxing indole with acetic
anhydride and cyanoacetic acid has attracted our attention
as it represents a new general synthetic route to
functionally substituted acylindoles that seemed
interesting as precursors to other 3-substituted indoles.
We were further stimulated to utilize 8a as precursors to
heteroaromatics by Slatt et al. report on the utility of 8a
for synthesis of substituted indoles and heteroaryl indoles
[10]. That would be of interest for biological activity
evaluation. It has been found that refluxing indole 7 with
organic acids 4a-e, which were preheated at 85°C for 10
minutes with acetic anhydride affords 8a-e in excellent
yields. We believe that initially the organic acid is
converted into the organic acid anhydride 5 or at least the

110
R. M. Abdel-Motaleb, A. A. Makhloof, H. M. Ibrahim and M. H. Elnagdi
Vol 44
1
product that was formulated as 14 rather 13 based on H
nmr which revealed non identity of all four benzotriazolyl
protons. Compound 13 is symmetrical and should have
shown only two signals for these protons (Scheme 1).
Compound 8a condensed with DMFDMA to yield:
enaminonitrile 21 which reacted with ethyl thioglycolate
and with ethyl glycinate in ethanol / potassium carbonate
solution to yield: 22. Trials to effect cyclisation of 22 into
Scheme 1
O
O
O
O
+
R
Ac2O
RCO2H
85oC
R
O
R
O
CH3
5
6
4a, R = CH2 CN
b, R = CH2 C6H4NO2-p
c, R = CH2 C6H5
d, R = CH2COOH
e, R = CH2CH2COOH
O
R 1
8a, R1 = CN
5 or 6
b, R1 = C6H4NO2-p
c, R1 = C6H5
d, R1 = indol-3-yl ketone
e, R1 = indol-3-ethanoyl
N
N
H
H
7
8 a-e
O
Cl
Cl
dioxane
O
Cl
KCN
8a
N
O
N
COCH2Cl
SCN
KSCN
H
11
9
N
N
N
H
N
H
12
10
N
N
N
N
CH2COR
N
N
CH2COR
14
13
13, 14, R = 3-indole
Compounds 8a,b,d coupled readily with aryldiazonium
chlorides to yield the arylhydrazones 15a-d in excellent
yields while compounds 8c,e failed to couple under
similar conditions. However when 8c was converted into
the enamine 16 via refluxing 8c with DMFDMA and the
product was then coupled with benzendiazonium chloride,
the phenylhydrazone 15e was formed. It is believed that,
as a result of nitrogen lone pair donation to enamine ꢀ-
carbon, the latter becomes sufficiently nucleophilic and
intermediate diazonium salt 17 is initially formed. This
then readily hydrolyses into the azo derivative 18 that
then undergo Japp-Klingmann cleavage [8] to yield 15e
(Scheme 2).
A novel route to 4-aminopyrazolecarboxylic acids with
indolyl substituent at C-3 which can be useful for
synthesis of pharmaceutically interesting condensed
pyrazoles could be developed. Thus reacting 15a,b with
chloroacetonitrile 19a, chloroacetone 19b and ethyl
chloroacetate 19c in triethylamine solution has afforded
20a-f in excellent yields. Intermediacy of 21 is most likely
(Scheme 3).
Scheme 2
O
R
-
+
Ar N=N Cl
N
NHAr
8
8a,b,d
N
H
DMFDMA
8c
15a-e
O
O
Ph
R
Ph
N
N
Cl-
Me
Me
N
N
+
N
Me
N
H
H
Me
16
17
15a, R = CN; Ar = C6H5
b, R = CN; Ar = C6H4 Cl-p
c, R = C6H4 NO2-p; Ar = C6H5
d, R = indol-3-yl ketone; Ar = C6H5
e, R = Ar = C6H5
O
Ph
N
Ph
N
+
H
15e
CHO
N
H
-
H2O
18

Jan-Feb 2007
Studies with Azoles and Benzoazoles
111
are reported in ꢀ units (ppm). Mass spectra were measured at 70
eV using shimadzu GCms-QP 1000 EX spectrometer.
Scheme 3
Microanalyses were performed on
Elemental Analyzer.
a LECO CHNS-932
O
CN
General procedures for preparation of compounds 8a-e.
Method a: For synthesis of 8a-e. A solution of the appropriate
carboxylic acids 4a-e (10 mmol) in acetic anhydride (10 mL,
100 mmol) was heated at 85°C for 10 min. then indole 7 (10
mmol) was added to the reaction mixture and heating was
continuing under reflux for further 30 min. The reaction mixture
was left to cool and poured onto cooled water. The solid product
so formed was collected by filtration, crystallized from the
appropriate solvent and identified as 8a-e.
Method b: Alternative method for synthesis of (8a). To a
warmed solution of 9 (1.00 g, 5 mmol) in benzene (10 mL) were
added 6 mmol of sodium cyanide solution in water (10 mL). The
reaction mixture was stirred at 50°C (bath temperature) for 1 hr
then the aqueous layer was separated and poured onto acidified
cooled water. The product so formed was collected by filtration,
dried and identified as 8a.
X
Cl
N
X
N
15a,b
19a, X= CN
b, X= COCH3
c, X= COOEt
N
Ar
H
21
20a, X = CN; Ar = C6H5
O
b, X = COCH3; Ar = C6H5
c, X = COOEt; Ar = C6H5
d, X = CN; Ar = C6H4 Cl-p
NH2
X
N
N
N
e, X = COCH3; Ar = C6H4 Cl-p
f, X = COOEt; Ar = C6H4 Cl-p
H
Ar
20
23 under variety of conditions failed. In protic medium 22
decomposed into 8a and in aprotic medium 22 was
recovered unrecated (Scheme 4).
3-(1H-Indol-3-yl)-3-oxopropanenitrile (8a). Crystallized
from acetic acid as creamy white crystals, yield: 1.75 g (95%),
mp 240 °C(Lit9.m.p 241 °C); ir (KBr): 3220.9 (NH), 2252 (CN),
Sxheme 4
O
O
CN
X
CN
Me
DMFDMA
XH
COOEt
Et3N
8a
N
COOEt
N
N
Me
H
H
22a, X= NH
b, X= S
21
O
NH2
COOEt
X
N
H
23
1638 cm-1 (CO). 1H nmr (DMSO-d6): ꢀ 4.48 (s, 2H, CH2), 7.23-
7.25 (m, 2H, indole H-5 and 6), 7.51 (d, 1H, J = 8.4 Hz, indole
H-4), 8.13 (d, 1H, J = 8.4 Hz, indole H-7), 8.36 (d, 1H, J = 2.4
Hz, indole H-2), and 12.15 ppm (br, 1H, NH); ms (EI): m/z (%)
144 (100), 184 (M+, 31.93), 185 (M++1, 4.6). Anal. Calcd. for
C11H8N2O (184.19): C, 71.73; H, 4.36; N, 15.21. Found: C,
71.48; H, 4.11; N, 15.02
CONCLUSION
In conclusion, organic acids in presence of acetic
anhydride can readily acylate indole regioselectively at
C-3. The formed acyl derivative is the one derived from
the most electrophilic center in the mixed acid anhydride,
this procedure is thus useful substitute for acylation by
acid chlorides in pyridine solution. Moreover chloroacetyl
chloride directly acylate indole at C-3 to give 3-Chloro-
acetylindole. The readily obtainable 3-functionally
substituted indoles have been shown to be excellent
precursors to biologically interesting azolylindoles that
are otherwise not readily obtainable.
1-(1H-Indol-3-yl)-2-(4-nitrophenyl)ethanone (8b) Crystallized
from ethanol as yellow crystals, yield: 2.1 g (75%), mp 212 °C;
ir (KBr): 3265 (NH), 1675 (CO), 1626 cm-1(C=C); 1H nmr
(DMSO-d6): ꢀ 4.37 (s, 2H, CH2), 7.16-7.25 (m, 2H, indole H-5
and 6), 7.52 (d, 1H, J = 7.5 Hz, indole H-4), 7.60 (d, 2H, J = 8.5
Hz, Ar-H), 8.15 (d, 2H, J = 8.5 Hz, Ar-H), 8.22 (d, 1H, J = 7.5
Hz, indole H-7), 8.56 (d, 1H, J = 2.4 Hz, indole H-2) and 12.09
ppm (br, 1H, NH); 13C nmr (DMSO-d6): ꢀ 45.32 (CH2), 112.26,
116.08, 121.41, 121.99, 123.06, 123.20, 125.60, 130.83, 134.85,
136.88, 144.61, 146.21 (Ar-C) and 191.21 (CO). ms (EI): m/z
(%) 144 (100), 280 (M+, 4.63), 281 (M++1, 0.91). Anal. Calcd.
for C16H12N2O3 (280.28): C, 68.56; H, 4.32; N, 9.99. Found: C,
68.46; H, 4.12; N, 9.73.
EXPERIMENTAL
General Remarks. All melting points are uncorrected. ir
spectra were recorded in KBr pellets with Satellite 2000
spectrophotometer. H nmr and 13C nmr spectra were recorded
on a Bruker AC-300 300 MHz spectrometer in DMSO-d6 and
CDCl3 as solvents and Tms as internal standard; chemical shifts
1
1-(1H-Indol-3-yl)-2-phenylethanone (8c) Crystallized from
ethanol as pale yellow crystals, yield: 1.7 g (72%), mp 197 °C; ir
(KBr): 3173 (NH), 1674 cm-1 (CO); ms (EI): m/z (%) 144

112
R. M. Abdel-Motaleb, A. A. Makhloof, H. M. Ibrahim and M. H. Elnagdi
Vol 44
(100), 235 (M+, 4.9), 236 (M++1, 1.32). Anal. Calcd. for
C16H13NO (235.28): C, 81.68; H, 5.57; N, 5.95. Found: C,
81.14; H, 5.60; N, 6.20.
and NH proton), 8.13 (d, 1H, J = 8.1 Hz, indole H-4) and 8.38
ppm (d, 1H, J = 8.1 Hz, indole H-7); ms (EI): m/z (%) 219
(100), 276 (M+, 57.5), 277 (M++1, 11.5). Anal. Calcd. for
C16H12N4O (276.29): C, 69.55; H, 4.38; N, 20.28. Found: C,
69.82; H, 4.50; N, 20.20.
General method for preparation of compounds 15a-d. To a
stirred solution of each of 4a,b,d (10 mmol) in dioxane (15 mL)
containing sodium acetate (10 g) was added the appropriate
diazonium salt (prepared from 10 mmol of the appropriate
aromatic amine and the appropriate quantities of sodium nitrite
and hydrochloric acid). The solid product separated on standing
was collected by filtration and crystallized from the appropriate
solvent.
1,3-Di-1H-indol-3-ylpropane-1,3-dione (8d) Crystallized
from dioxan as yellow crystals, yield, 2.5 g (83%), mp 152 °C; ir
(KBr): 3233 (NH), 1701 (CO), 1625 cm-1(C=C); 1H nmr
(DMSO-d6): ꢀ 4.76 and 5.04 (two s, CH2 keto form and CH enol
form), 6.73-8.60 (complex m, Ar-H of keto form and enol form),
10.87 (br, OH enolic) and 11.95-12.20 ppm (br, NH keto form
and enol form). Extra carbons for the presence of keto enol
tautomerism 13C nmr (DMSO-d6): ꢀ 44.98 (CH2), 108.62,
109.10, 109.36, 112.38, 116.04, 121.08, 121.27, 121.67, 123.40,
123.99, 124.88, 125.41, 126.12, 126.95, 127.23, 127.35, 128.88,
130.53, 135.11, 135.68, 136.15, 136.81, 162.34 and 165.75 (Ar -
C and CO carbons); ms (EI): m/z (%) 89(100), 302 (M+, 7.62),
303 (M++1, 2.18). Anal. Calcd. for C19H14N2O2 (302.33): C,
75.48; H, 4.67; N, 9.27. Found: C, 75.22; H, 4.31; N, 9.10.
1,4-Di-1H-indol-3ylbutane-1,4-dione (8e) crystallized from
dioxane as pale yellow crystals, yield: 1.75 g (55 %), m p 233
°C; ir (KBr) 3281 (NH), 1705 (CO), 1597 cm-1 (C=C); ms (EI):
m/z (%)144 (100), 316 (M+,26%). Anal. Calcd. for C20H16N2O2
(316.35): C, 75.93; H, 5.10; N, 8.86. Found: C, 75.40; H, 5.50;
N, 8.70.
3-(1H-Indol-3-yl)-3-oxo-2-(phenylhydrazono)propanenitrile
(15a) crystallized from dioxane as yellow crystals, yield: 2.2 g
(76 %), mp 251 °C; ir (KBr): 3440, 3234 (2 NH), 2214 (CN),
1
1698 cm-1 (CO); H nmr (DMSO-d6): ꢀ 7.11-7.26 (m, 3H, Ar-
H), 7.38-8.25 (m, 6H, Ar-H), 8.44 (d, 1H, J = 3.3 Hz, indole H-
2), 11.92 (br, 1H , indole NH) and 12.04 ppm (br, 1H, hydrazone
NH); ms (EI): m/z (%) 144 (100), 288 (M+, 43.9), 289 (M++1,
10.3). Anal. Calcd. for C17H12N4O (288.30): C, 70.82; H, 4.20;
N, 19.43. Found: C, 70.69; H, 4.01; N, 19.35
2-[(4-Chlorophenyl)hydrazono]-3-(1H-indol-3-yl)-3-oxo-
propanenitrile (15b) crystallized from DMF, yield: 2.5 g (78%,
mp 278-80 °C; ir (KBr): 3233, 3180 (2 NH), 2209 (CN), 1682
2-(1H-Indol-3-yl)-2-oxoethyl thiocyanate (10). To a warmed
solution of 9 (1.00 g, 5 mmol) in acetonitrile (10 mL) were
added ammonium thiocyanate (0.5 g, 6 mmol). The reaction
mixture was stirred at 50°C (bath temperature) for 1 hr then the
reaction mixture was poured onto ice cooled water. The product
so formed was collected by filtration. Crystallized from ethanol
as faint pink crystals, yield: 2.1 g (98 %), mp 126 °C; ir (KBr):
1
cm-1 (CO); H nmr (DMSO-d6): ꢀ 7.19-7.25 (m, 2H, Ar-H),
7.38-8.28 (m, 6H, Ar-H), 8.40 (d, 1H, J = 3 Hz, indole H-2)
11.94 (br, 1H, indole NH) and 12.05 ppm (br, 1H, hydrazone
NH); 13C nmr (DMSO-d6): ꢀ 115.62 (CN), 111.67, 112.31,
117.77, 121.45, 122.06, 123.10, 126.64, 128.14, 129.31, 135.36,
135.99, 141.36 (Ar-C) and 179.79 (CO); ms (EI): m/z (%) 144
(100), 322 (M+, 47.9), 323 (M++1, 11.9), 324 (M++2, 18.22), 325
(M++3, 4.14). Anal. Calcd. for C17H11ClN4O (322.84): C, 63.26;
H, 3.44; Cl, 10.98; N, 17.36. Found: C, 63.00; H, 3.21; Cl,
10.76; N, 17.25.
1-(1H-Indol-3yl)-2-(4-nitrophenyl)ethane-1,2-dione(2-phenyl-
hydrazone) (15c) crystallized from ethanol as orange crystals,
yield: 2.5 g (65%), mp 188-190 °C; ir (KBr): 3170, 3136 (2
NH), 1694 (CO), 1621 cm-1 (C=N); ms (EI): m/z (%)144 (100),
384 (M+, 3.9). Anal. Calcd. for C22H16N4O3 (384.39): C, 68.74;
H, 4.20; N, 14.58. Found: C, 68.41; H, 4.60; N, 14.19.
1,3-Di-1H-Indol-3-ylpropane-1,2,3-trione(2-phenylhydra-
zone) (15d) crystallized from ethanol as reddish brown crystals,
yield: 3.75 g (92 %), mp 104 °C; ir (KBr): 3173, 3150 (2 NH),
1703 (CO), 1600 cm-1 (C=N); ms (EI): m/z (%) 221 (100), 406
(M+, 1.0), 407 (M++1, 0.43). Anal. Calcd. for C25H18N4O2
(406.44): C, 73.88; H, 4.46; N, 13.78. Found: 73.60; H, 4.22; N,
13.69.
E-1-(1H-Indol-3-yl)-2-phenylethane-1,2-dione(2-phenyl-
hydrazone) (15e). To a solution of 16 (5 mmol) in ethanol (20
mL) containing sodium acetate (10 g) was added a solution of
phenyl diazonium Chloride (prepared from 5 mmol of aniline
and the appropriate amount of hydrochloric acid and sodium
nitrite). The solid obtained on standing was collected by
filtration and crystallized from ethanol as orange crystals; yield:
1.3 g (77 %), mp 106-08°C; ir (KBr): 3390, 3187 (2 NH),
1681cm-1 (CO); 1H nmr (DMSO-d6): ꢀ 7.23-7.36 (m, 9H, Ar-H),
7.86-8.28 (m, 5H, Ar-H), 8.65 (d, 1H, J = 3 Hz, indole H-2),
12.06 (br, 1H, indole NH) and 12.56 ppm (br,1H, hydrazone
NH); ms (EI): m/z (%) 144 (100), 339 (M+, 29.9), 340 (M++1,
7.5). Anal. Calcd. for C22H17N3O (339.39): C, 77.86; H, 5.05; N,
12.38. Found: C, 77.65; H, 4.90.05; N, 12.13.
1
3210 (NH), 2157 (SCN), 1696 cm-1 (CO); H nmr (DMSO-d6) :
ꢀ 4.48 (s, 2H, CH2), 7.20-7.28 (m, 2H, indole H-5 and 6), 7.50
(d, 1H, J = 8.7 Hz, indole H-4), 8.13 (d, 1H, J = 8.7 Hz, indole
H-7), 8.37 (d, 1H, J = 3 Hz, indole H-2), and 12.16 ppm (br, 1H,
NH); ms (EI): m/z (%): 117 (100), 216 (M+, 71.6%), 217 (M++1,
10.42), 218 (M++2, 4,56). Anal. Calcd. for C11H8N2OS (216.26):
C, 61.09; H, 3.73; N, 12.95; S, 14.83. Found: C, 61.00; H, 3.55;
N, 12.95; S, 14.76.
2-Chloro-1-(1H-indol-3-yl)ethanone (9). A mixture of 5 (1.2
g, 10 mmol) and chloroacetyl chloride (1.15 g, 10 mmol) in
dioxane (20 mL) was refluxed for 45 min. The mixture was
allowed to cool to r.t. then poured onto cooled water. The
obtained solid was collected by filtration and crystallized from
methanol as pale pink crystals, yield: 1.8 g (93 %), mp 105 °C;
1
ir (KBr): 3118 (NH), 1707 (CO), 1610 cm-1 (C=C); H nmr
(CDCL3): ꢀ 4.59 (s, 2H, CH2), 6.72 (d, 1H, J = 3.4 Hz, indole H-
2), 7.27-7.44 (m, 3H, indole H-5, 6 and NH proton), 7.60 (d, 1H,
J = 8.1 Hz, indole H-4), 8.44 ppm (d, 1H, J = 8.1 Hz, indole H-
7); ms (EI): m/z (%) 193 (M+, 100), 194 (M++1, 10.9), 195
(M++2, 26.1). Anal. Calcd. for C10H8ClNO (193.63): C, 62.03;
H, 4.16; Cl, 18.31; N, 7.23. Found: C, 62.20; H, 4.30; Cl, 18.18;
N, 7.15.
1-(1H-Indol-3-ylacetyl)-2H-1,2,3-benzotrizole (14).
A
mixture of 9 (1.93 g, 10 mmol), benzotriazole (1.2 g, 10 mmol)
and triethylamine (2 mL, 20 mmol) in toluene (15 mL) was
refluxed for 2 h. The solvent was removed under vacuum and
the remaining residue was triturated with 5% sodium hydroxide.
The solid product so formed was collected by filtration and
crystallized from ethanol as creamy white solid; yield: 2.1 g (76
%), mp 142 °C; ir (KBr): 3151 (NH), 1701 (CO), 1616 cm-1
1
(C=C); H nmr (CDCL3): ꢀ 6.04 (s, 2H, CH2), 6.79 (d, 1H, J =
3.4 Hz, indole H-2), 7.27-7.64 (m, 7H, 4 Ar-H, indole H-5, 6

Jan-Feb 2007
Studies with Azoles and Benzoazoles
113
3-(Dimethylamino)-1-(1H-indol-3-yl)-2-phenylprop-2-en-1-
one (16). A mixture of 8c (2.35 g, 10 mmol) and DMFDMA
(1.2 g, 10 mmol) in toluene (15 mL) was refluxed for 3 h. The
solid product obtained on standing was collected by filtration
and crystallized from toluene as yellow crystals; yield: 2.3 g (79
%), mp 200-202 °C; ir (KBr): 3134, (NH), 1604 cm-1 (CO). 1H
nmr (DMSO-d6): ꢀ 2.69 (s, 6H, 2 CH3), 6.84 (d, 1H, J = 3 Hz,
indole H-2), 7.05-7.36 (m, 8H, Ar-H), 7.46 (s, 1H, olefinicCH),
8.11 (d, 1H, J = 8.7 Hz, Ar-H) and 11.30 ppm (br, 1H, NH); ms
(EI): m/z (%) 144 (100), 290 (M+, 50.3), 291 (M++1, 11.97).
Anal. Calcd. for C19H18N2O (290.36): C, 78.59; H, 6.25; N, 9.65.
Found: C, 78.30; H, 6.40; N, 9.30.
General method for preparation of compounds 20a-f. To a
solution of each of 15a,b (1.45 g, 5 mmol) in a mixture of DMF
(2 mL) and triethylamine (10 mL) was added the appropriate
chloro derivative 19a-c (10 mmol). The reaction mixture was
refluxed for 40 min and left to cool to r.t. The obtained residual
product was triturated with ethanol to give a solid product that
was collected by filtration, washed with water and crystallized
from the appropriate solvent.
4-Amino-3-(1H-indol-3-ylcarbonyl)-1-phenyl-1H-pyrazole-
5-carbonitrile (20a) crystallized from ethanol as faint brown
crystals, yield: 1.5 g (91 %), m.p. 126-128 °C; ir (KBr): 3474,
3357, 3238 (NH2 and NH), 2216 (CN), 1630 (CO),1605 cm-1
(C=N); ms (EI): m/z (%) 144 (100), 327 (M+, 23.7), 328 (M++1,
6.81). Anal. Calcd. for C19H13N5O (327.34): C, 69.71; H, 4.00;
N, 21.39. Found: C, 69.56; H, 3.90; N, 21.18.
5-Acetyl-4-Amino-3-(1H-indol-3-ylcarbonyl)-1-phenyl-1H-
pyrazole (20b) crystallized from ethanol as orange crystals,
yield: 1.3 g (76%), mp 189°C; ir(KBr): 3416, 3338, 3234 (NH2
and NH), 1731, 1638 cm-1 (2 CO); ms (EI): m/z (%)144 (100),
344 (M+, 8.85), 345 (M++1, 2.2). Anal. Calcd. for C20H16N4O2
(344.37): C, 69.76 H, 4.68; N, 16.27, Found: C, 69.53 H, 4.59;
N, 15.96.
Ethyl 4-Amino-3-(1H-indol-3-ylcarbonyl)-1-phenyl-1H-
pyrazole-5-carboxylate (20c) crystallized from ethanol as
orange crystals yield: 1.4 g (74%), mp 192-194°C; ir(KBr):
3495, 3372, 3266 (NH2 and NH), 1719, 1636 cm-1 (2 CO). ms
(EI): m/z (%) 144 (100), 374 (M+, 25.4) 375 (M++1, 29.2). Anal.
Calcd. for C21H18N4O3 (374.39): C, 67.37 H, 4.85; N, 14.96.
Found: C, 67.82; H, 4.40; N, 14.53.
4-Amino-3-(1H-indol-3-ylcarbonyl)-1-(4-chlorophenyl)-
1H-pyrazole-5-carbonitrile (20d) crystallized from ethanol as
faint brown crystals; yield: 1.5 g (83 %), mp 252-254; ir (KBr):
3484, 3339, 3235 (NH2 and NH), 2218 (CN), 1702 cm-1 (CO);
1H nmr (DMSO-d6): ꢀ 6.55 (s, 2H, NH2), 7.20-7.25 (m, 2H,
indole H-5 and 6), 7.52 (d, 1H, J = 8.1 Hz, indole H-4), 7.65 (d,
2H, J = 9 Hz, Ar-H), 7.84 (d, 2H, J = 9 Hz, Ar-H), 8.36 (d, 1H,
J = 8.1 Hz, indole H-7), 8.79 (1H, J = 3 Hz, indole H-2) and
11.99 ppm (br, 1H, NH); 13C nmr (DMSO-d6): ꢀ 114.10 (CN),
98.09, 111.54, 112.34, 117.80, 121.62, 122.06, 123.05, 124.22,
126.53, 129.33, 129.70, 133.25, 135.97, 136.19, 137.22, 137.62,
145.09 (Ar-C) and 181.93 (CO); ms (EI): m/z (%) 144 (100),
361 (M+, 21.2), 362 (M++1, 7.24), 363 (M++2, 7.92), 364 (M++3,
1.7). Anal. Calcd. for C19H12ClN5O (361.34): C, 63.10; H, 3.32;
N, 19.36. Found: C, 63.19; H, 3.45; N, 19.29.
H-4), 8.40 (d, 1H, J = 8.1 Hz, indole H-7), 8.72 (d, 1H, J = 3 Hz,
indole H-2) and 12.00 ppm (br, 1H, NH); 13C nmr (DMSO-d6):
ꢀ 29.64 (CH3), 111.66, 112.31, 115.59, 117.81, 121.40, 122.07,
123.12, 126.60, 128.13, 129.23, 129.35, 135.42, 135.66, 135.99,
136.12, 141.39, 141.98 (Ar-C), 179.80 and 187.26(2CO); ms
(EI): m/z (%) 144 (100), 378 (M+, 6.33), 379 (M++1, 2.67), 380
(M++2, 2.3). Anal. Calcd. for C20H15ClN4O2 (378.5): C, 63.40; H,
3.96; N, 14.80. Found: C, 63.53 H, 3.90; N, 14.60.
Ethyl 4-Amino-3-(1H-indol-3-ylcarbonyl)-1-(4-chloro-
phenyl)-1H-pyrazole-5-carboxylate (20f) crystallized from
ethanol as orange crystals yield: 1.45 g (71 %), mp 259-260 °C;
ir (KBr): 3495, 3478, 3241 (NH2 and NH), 1716, 1668 cm-1 (2
1
CO); H nmr (DMSO-d6): ꢀ 1.21 (t, 3H, J = 7.2 Hz, CH3CH2),
4.23 (q, 2H, J = 7.2 Hz, CH3CH2), 5.34 (s, 2H, NH2), 7.22-7.32
(m, 2H, indole H-5 and 6), 7.40-7.58 (m, 5H, 4 Ar-H and indole
H-4), 8.26 (d, 1H, J = 8.4 Hz, indole H-7), 8.42 (d, 1H, J = 3 Hz,
indole H-2) and 12.10 ppm (br, 1H, NH); 13C nmr (DMSO-d6):
ꢀ 47.54 (CH2), 61.34 (CH3), 110.71, 111.63, 111.99, 115.19,
115.56, 117.83, 121.41, 122.05, 123.11, 126.62, 128.11, 129.35,
135.40, 135.99, 136.54, 139.07, 141.48 (Ar-C), 168.44 and
179.81(2CO); ms (EI): m/z (%) 144 (100), 408 (M+, 20.80), 409
(M++1, 8.75); Anal. Calcd. for C21H17ClN4O3 (408.39): C, 61.68
H, 4.16; N, 13.71. Found: C, 61.70, H, 4.10; N, 13.88.
3-(Dimethylamino-2-(1H-indol-3-ylcarbonyl)acrylonitrile
(21). A mixture of 8a (0.95 g, 5 mmol), DMFDMA (0.6 mL, 5
mmol) and few drops of DMF in toluene was refluxed for 3 h.
The solvent was evaporated under reduced pressure and the
remaining residue was crystallized from ethanol as yellow
crystals, yield: 0.9 g (75%), mp 186 °C; ir (KBr): 3299 (NH),
2193 (CN), 1630 (CO) cm-1; 1H nmr (DMSO-d6):ꢀ 3.20 (s, 3H,
CH3), 3.32 (s, 3H, CH3), 7.13-7.22 (m, 2H, indole H-5 and 6),
7.49 (d, 1H, J = 8.7 Hz, indole H-4), 7.99 (s, 1H, olefinic CH),
8.19 (d, 1H, J = 8.7 Hz, indole H-7), 8.32 (d, 1H, J = 2.5 Hz,
indole H-2) and 11.75 ppm (br, 1H, NH); 13C nmr (DMSO-d6): ꢀ
47.42 (CH3), 77.85 (CH3), 114.87 (CN), 111.97,121.22, 121.83,
121.88, 122.51, 122.57, 126.89, 131.25, 135.95, 158.69 (Ar-C
and olefinicC) and 181.87 (CO); ms (EI): m/z (%) 144 (100),
239 (M+, 31 %), 240 (M++1, 3.83%). Anal. Calcd. for C14H13N3O
(239.27): C, 70.86 H, 5.48; N, 17.56. Found: C, 70.70; H, 5.23;
N, 17.78.
General procedure for preparation of compounds 22a-b.
A solution of 21 (2.4 g, 10 mmol) in absolute ethanol (50 ml)
containing potassium carbonate (3 g), ethyl thioglycolate (1.2 g,
10 mmol), or ethyl glycinate hydrochloride (1.4 g, 10 mmol)
was refluxed for 5 h then concentrated upon evaporation to one
third its volume. The solid product so formed upon cooling was
collected by filtration.
[2-Cyano-3-(1H-indol-3-yl)-3-oxo-propenylamino]-acetic
acid ethyl ester (22a) crystallized from ethanol as yellow
crystals yield: 2.2 g (73%), mp146-148 °C; ir (KBr): 3301, 3149
1
(2NH), 2198 (CN),1730 (CO ester) and 1637 cm-1(CO); H nmr
(DMSO-d6): ꢀ 1.23 (t, 3H, J = 7.2 Hz, CH3CH2), 4.17 (q, 2H, J
= 7.2 Hz, CH3CH2), 4.27 (d, 2H, J = 6 Hz, CH2NH), 7.14-7.23
(m, 2H, indole H-5 and 6), 7.49 (d, 1H, J = 8 Hz, indole H-4),
7.81 (d, 1H, J = 13.5 Hz, olefinic CH), 8.26 (d, 1H, J = 8 Hz,
indole H-7), 8.44 (d, 1H, J = 3 Hz, indole H-2), 10.70-10.78 (m,
1H, NHCH2) and 11.85 ppm (br, 1H, indole NH); ms (EI): m/z
(%) 144 (100), 297 (M+, 28.3). Anal. Calcd. for C16H15N3O3
(297.31): C, 64.64; H, 5.09; N, 14.13. Found: C, 64.33; H, 4.95;
N, 14.00.
5-Acetyl-4-amino-3-(1H-indol-3-ylcarbonyl)-1-(4-chloro-
phenyl)-1H-pyrazole (20e) crystallized from ethanol as orange
crystals yield: 1.4 g (74 %), mp 242-244 °C; ir (KBr): 3421,
1
3315, 3240 (NH2 and NH), 1703, 1656 cm-1 (2 CO); H nmr
[2-Cyano-3-(1H-indol-3-yl)-3-oxo-propenylsulfanyl]-acetic
acid ethyl ester (22b) crystallized from ethanol as orange
(DMSO-d6): ꢀ 2.03 (s, 3H, CH3), 6.51 (s, 2H, NH2), 7.19-7.25
(m, 2H, indole H-5 and 6), 7.38-7.68 (m, 5H, 4 Ar-H and indole

114
R. M. Abdel-Motaleb, A. A. Makhloof, H. M. Ibrahim and M. H. Elnagdi
Vol 44
[3] J. Slatt, "Cyanoacetylation of Indoles, Pyrroles and Amines
and Synthetic uses of these Products" Karolinska Institutes, Department
of Biosciences at Novum, Center for Nutrition and Toxicology, Organic
Chemistry, Stockholm (2005)
[4] A. W. Oxford, Contemp. Org .Synth., 2, 35 (1995).
[5] B. S. Challis and H. S. Rzepa, J. Chem. Soc., Perkins Trans.
2, 1209 (1975).
[6] J. Bergman, J. E. Backvall and J. O. Lindstrom, Tetradedron,
29, 971 (1973).
[7] R. M. Acheson, "An Inroduction to the Chemistry of
Heterocyclic compounds, 3rd Ed” Wiley- Interscience, New York (1976).
[8] S. A. S. Ghozlan, I. A. Abdelhamid, H. M. Gober and M. H.
Elnagdi, J. Heterocyclic Chem., 42,1185 (2005).
crystals yield: 2 g (64%), mp 128-130 °C; ir (KBr): 3269 (NH),
2211 (CN), 1732 (CO ester) and 1638 (CO) cm-1; 1H nmr
(DMSO-d6): ꢀ 1.23 (t, 3H, J = 7.2 Hz, CH3CH2), 4.16 (q, 2H, J
= 7.2 Hz, CH3CH2), 4.22 (s, 2H, CH2S), 7.20-7.30 (m, 2H,
indole H-5 and 6), 7.53 (d, 1H, J = 8.7 Hz, indole H-4), 8.14 (d,
1H, J = 8.7 Hz, indole H-7), 8.32 (d, 1H, J = 3.3 Hz, indole H-
2), 8.83 (s, 1H, olefinic CH), and 12.21 ppm (br, 1H, NH); ms
(EI): m/z (%) 144 (100), 314 (M+, 39.06). Anal. Calcd. for
C16H14N2O3S (314.36): C, 61.13 H, 4.49; N, 8.91; S, 10.20.
Found: C, 61.01 H, 4.28; N, 8.94; S, 10.00.
[9] J. Slatt, I. Romero and J. Bergman, Synthesis, 2760 (2004).
[10] J. Slatt, T. Janosik, N. Wahlstrom and J. Bergman, J.
Heterocyclic Chem., 42, 141 (2005).
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