The synthesis of new heterocycles using 2-(4-Chloro-1,3-dihydro-3,3,7- trimethyl-2H-indol-2-ylidene) propanedial

Article abstract of DOI:10.1002/jhet.1626

4-Chloro-2,3,3,7-tetramethyl-3H-indole (an indolenine) was produced by the reaction of 5-chloro-2-methylphenylhydrazine hydrochloride with 3-methylbutan-2-one via Fischer reaction. Exposure of the indolenine to the Vilsmeier reagent at 50C produced a β-diformyl compound, 2-(4-chloro-1,3-dihydro-3,3,7-trimethyl-2H-indol-2-ylidene)propanedial. This dialdehyde was reacted with arylhydrazines, acetamidinium chloride, urea, thiourea, guanidinium chloride, and cyanoacetamide to give various 5-membered and 6-membered heterocyclic products, each carrying a 4-chloro-3,3,7-trimethyl- 3H-indol-2-yl unit as a substituent, in excellent yields.

Full text of DOI:10.1002/jhet.1626

854
The Synthesis of New Heterocycles Using 2-(4-Chloro-1,3-dihydro-3,3,
Vol 51
7-trimethyl-2H-indol-2-ylidene) Propanedial
a
a
b
c
*
Maryam Alyari, Mehdi M. Baradarani, Arash Afghan, and John A. Joule
aChemistry Department, Faculty of Science, Urmia University, Urmia 57154, Iran
bDepartment of Chemical Engineering, Urmia University of Technology, Urmia 57155-419, Iran
cThe School of Chemistry, The University of Manchester, Manchester M13 9PL, UK
*
E-mail: m.baradarani@urmia.ac.ir
Received September 5, 2011
DOI 10.1002/jhet.1626
Published online 3 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
4-Chloro-2,3,3,7-tetramethyl-3H-indole (an indolenine) was produced by the reaction of 5-chloro-2-methyl-
phenylhydrazine hydrochloride with 3-methylbutan-2-one via Fischer reaction. Exposure of the indolenine to
the Vilsmeier reagent at 50ꢀC produced a b-diformyl compound, 2-(4-chloro-1,3-dihydro-3,3,7-trimethyl-2H-
indol-2-ylidene)propanedial. This dialdehyde was reacted with arylhydrazines, acetamidinium chloride, urea,
thiourea, guanidinium chloride, and cyanoacetamide to give various 5-membered and 6-membered heterocyclic
products, each carrying a 4-chloro-3,3,7-trimethyl-3H-indol-2-yl unit as a substituent, in excellent yields.
J. Hetercycl Chem., 51, 854 (2014).
INTRODUCTION
reactions with hydrazides giving 4-(2,3,3-trimethyl-3H-
indol-2-yl)-substituted N-acyl- and N-thioacylpyrazoles [8].
We have now extended our studies of aminomethylene
malondialdehydes and demonstrated the synthesis of various
heterocycles by condensations with various reactants,
producing both 5-membered and 6-membered heterocycles.
In 1925 Fischer, Müller, and Vilsmeier [1] published a
paper describing the reaction between phosphoryl chloride
and N-methylacetanilide, giving a number of products,
including the quinolinium salt 1 and the salt 2 (Scheme 1).
The probable course of the reaction was given in a paper
by Vilsmeier and Haack [2] who made the important discov-
ery that the reagent obtained from N-methylformanilide and
phosphoryl chloride, represented as the salt 3, would react
with N,N-dimethylaniline, giving 4-(N,N-dimethylamino)
benzaldehyde 4 after a final hydrolytic step (Scheme 2). It
was later shown that the actual electrophilic species is the
N,N-dimethyl chloromethyleneiminium cation [3].
In 1959, Fritz [4] reported the N-formylation of a 3,3-disub-
stituted 3H-indole (indolenine) using the Vilsmeier reagent
from DMF and POCl3 giving an enamide, 6. Further reaction
of 6 with the Vilsmeier reagent and hydrolysis produced 8.
Formation of this product probably involves the intermediacy
of 7, from which the N-formyl group is hydrolytically
removed during work-up. The N-methyl enamine 9 was
directly C-formylated, producing 10 [4] (Scheme 3).
We have shown previously that the reaction of 2,3,3-tri-
methyl-3H-indoles with the Vilsmeier reagent, producing
aminomethylene malondialdehydes, for example, 11, is a
general process, by demonstrating the transformation using
variously substituted 2,3,3-trimethyl-3H-indoles [5–7]. Ad-
ditionally, we have described a simple and straightforward
preparation of 4-(2,3,3-trimethyl-3H-indol-2-yl)-substituted
pyrazoles by condensation of these aminomethylene malon-
dialdehydes with hydrazine and arylhydrazines [5,7]
(Scheme 4). Recently, other workers used the original ami-
nomethylene malondialdehyde 11 [5] in a similar way, in
RESULTS AND DISCUSSION
Diazotisation of 5-chloro-2-methylbenzenamine, then
reduction of the diazonium salt with tin(ΙΙ) chloride, pro-
duced the corresponding hydrazinium chloride 13. Reaction
of 5-chloro-2-methylphenylhydrazine hydrochloride 13
with isopropyl methyl ketone in a Fischer reaction produced
the 4-chloro-2,3,3,7-tetramethyl-3H-indole 14 in good yield.
The structure of the indolenine was evident from its molecu-
lar formula, a six-hydrogen singlet signal for the geminal
methyl groups at d 1.44 and a singlet signal for the imine
methyl group resonating at d 2.52.
The indolenine 14 was reacted with the Vilsmeier reagent
to produce a diformyl compound (2-(4-chloro-1,3-dihydro-
3,3,7-trimethyl-2H-indol-2-ylidene)propanedial, 15) in good
yield (Scheme 5). The structure of this compound rests on the
observation of two one-hydrogen singlets at d 9.79 and
9.81ppm corresponding to the two different aldehyde
protons and a one-hydrogen signal for the N-hydrogen
appearing at d 13.77.
1,3-Dialdehydes represent interesting building blocks for
the synthesis of various heterocyclic ring systems, which
often show high biological activities [9,10]. As in our previ-
ous work [5,7], the reaction of monosubstituted hydrazines
with aminomethylene malondialdehyde 15 resulted in the
© 2013 HeteroCorporation

May 2014
The Synthesis of New Heterocycles Using
855
2-(4-Chloro-1,3-dihydro-3,3,7-trimethyl-2H-indol-2-ylidene) Propanedial
Scheme 1
Me
Me
N
Me
Cl
N(Me)Ph
N(Me)Ph
POCl3
N
Cl
Me
+
O
Cl
1
2
Scheme 2
NMe2
NMe2
Me
N
H
H
POCl3
Ph(Me)N
Cl
OPOCl2
O
CHO
3
4
Scheme 3
Me
Me
Me
Me
DMF
POCl3
DMF
POCl3
H2O
CHO
CHO
N
N
CHO
N
H
N
CHO
5
6
7
8
Me
Me
Me
DMF
Me
POCl3
N
N
CHO
Me
Me
9
10
Scheme 4
Me
Me
Me
Me
Me
Me
DMF
POCl3
RNHNH2
EtOH, reflux
Me
CHO
N
N
N
R
N
N
CHO
H
11
12
efficient formation of pyrazoles 13a–f, with migration of the
double bond to reform the imine unit (Scheme 5).
In extension of this work, we also examined the reactions
of acetamidinium chloride, urea, thiourea, guanidinium
chloride, and 2-cyanoacetamide with aminomethylene
malondialdehyde 15.
Reaction of 1,3-dialdehyde 15 with acetamidinium chlo-
ride [11] produced a new heterocyclic compound 17
(Scheme 6). The evidence for the formation of the pyrimidine
ring and again the migration of the double bond back to give
an imine, rests on a signal at d 9.38 for the additional methyl
group and a two-hydrogen singlet for the aromatic pyrimidine
ring protons. There were three singlets, at d 1.73 ppm, d 2.62,
and d 2.87 ppm, for the geminal methyl groups, the benzene
methyl and the pyrimidine methyl, respectively.
Condensations of 1,3-dialdehyde 15 with urea and thio-
urea gave the corresponding six-membered heterocyclic
compounds 18a and 18b (Scheme 7). The structures of these
new compounds rest on the presence of N–H stretching
absorptions at 3140 cmÀ1 for 18a and 3145 cmÀ1 for 18b
and singlets at d 8.97 and d 9.43ppm for the pyridine ring
protons of 18a and 18b.
Journal of Heterocyclic Chemistry
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856
M. Alyari, M. M. Baradarani, A. Afghan, and J. A. Joule
Vol 51
Scheme 5
Cl
Cl
Me
Me
O
Me
Me
DMF, POCl3
75 C
Me
Me
AcOH, reflux
72%
+
87%
N
NHNH2.HCl
Me
Me
R
H
14
13
16a
Cl
Cl
Me
16b Ph
Me
RNHNH2
EtOH, reflux
Me
Me
CHO
CHO
16c 4-ClC6H4
16d 3-Cl-2-MeC6H3
16e 2,4-Me2C6H3
N
N
89-92%
N
N
R
H
Me
Me
16f 2,5-Cl2C6H3
15
16
The reaction of 1,3-dialdehyde 15 with guanidinium
chloride produced the product of further reaction of the
expected aminopyrimidine, namely a product in which
the first-formed aminopyrimidine had condensed with a
further mol equivalent of the dialdehyde. We speculate that
this product is one of the possible structural isomers in
which the amino group has reacted with one or other of
the aldehyde groups of 15 and hence have either the Z or
E structures 19a/19b shown in Scheme 8. Without further
evidence, it is not possible at this stage to distinguish these.
Finally, we studied the reaction of dialdehyde 15 with cya-
noacetamide and obtained 5-(4-chloro-3,3,7-trimethyl-3H-
indol-2-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile 20. The
pyridone was obtained pure in better than 80% yield with
no evidence of any other product being formed (Scheme 9).
Compound 20 was fully identified by 1H NMR spectroscopy
and by other techniques. IR absorptions at 3167 and 1663 cmÀ1
were evidence for the presence of N–H and C═O bonds,
respectively, further confirmed by an 1H NMR one-hydrogen
signal for the N-hydrogen appearing at d 13.06. The cyano
group was represented by an IR peak at 2231 cmÀ1. The pyri-
done ring protons resonated as singlets at d 8.44 and 8.81.
CONCLUSIONS
We have shown that 4-chloro-2,3,3,7-tetramethyl-3H-
indole can be produced by the reaction of 5-chloro-2-methyl-
phenylhydrazine hydrochloride with 3-methylbutan-2-one.
Exposure of this compound to the Vilsmeier reagent pro-
duced 2-(4-chloro-1,3-dihydro-3,3,7-trimethyl-2H-indol-2-
ylidene)propanedial. This dialdehyde was shown to react
with arylhydrazines, acetamidinium chloride, urea, thiourea,
guanidinium chloride, and cyanoacetamide to give various
5-membered and 6-membered heterocyclic products, each
carrying a 4-chloro-3,3,7-trimethyl-3H-indol-2-yl unit as a
substituent. We suggest that these intriguing and novel scaf-
folds could provide the basis for the development of libraries
for biological evaluation.
Scheme 6
Cl
Cl
Me
Me
Me
Me
ClH.HN
H2N
N
N
CHO
CHO
DMF, reflux
81%
+
Me
Me
N
N
H
Me
Me
15
17
Scheme 7
Cl
Cl
H
Me
Me
Me
Me
N
CHO
CHO
H2N
H2N
EtOH, piperidine
81%
X
+
X
N
N
N
H
Me
Me
R
O
S
15
18a
18b
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2014
The Synthesis of New Heterocycles Using
857
2-(4-Chloro-1,3-dihydro-3,3,7-trimethyl-2H-indol-2-ylidene) Propanedial
Scheme 8
Cl
CHO
Me
Me
Me
Me
N
N
N
N
HN
Cl
Cl
Me
19a
Me
Me
EtOH, piperidine
reflux
ClH.HN
H2N
CHO
CHO
Me
or
+
NH2
81%
N
Cl
CHO
NH
Me
Me
H
Me
N
N
N
Me
15
N
Me
Me
Cl
Me
19b
Scheme 9
Cl
Cl
Me
Me
EtOH, piperidine
Me
Me
H2N
NH
CHO
reflux
O
O
+
81%
N
N
CHO
CN
H
CN
Me
Me
15
20
of 2 h at below 25ꢀC. After addition was completed, a solution of
the trimethylindolenine 14 (2.6 g, 12.6 mmol) in DMF (10 mL) was
added dropwise. The cooling bath was removed and the reaction
mixture was stirred at 50ꢀC for 2 h. The resulting solution was
added to ice-cooled water, and the pH was adjusted to 8.0 by the
addition of aq. NaOH (35%) and the mixture was extracted with
EtOAc (3 Â 30 mL). The organic layer was washed with hot water
and dried over Na2SO4. The solvent was evaporated and the
resulting product was purified by crystallization from boiling aq.
ethanol, to give 15 (2.9 g, 87%); mp 150–151ꢀC; FT-IR (KBr)
EXPERIMENTAL
The chemicals used in this work were obtained from Fluka and
Merck and were used without purification. Melting points were
measured on an electrothermal IA9200 apparatus. H NMR and
1
13C NMR spectra were recorded on a Avance AQS 300 MHz spec-
trometer (Brucker, Karlsruhe, Germany) at 300 and 75 MHz, respec-
tively. Chemical shifts d are in parts per million (ppm) measured in
CDCl3 and DMSO-d6 as solvents and relative to TMS as the internal
standard. IR spectra were obtained on a Nexus 670 FT-IR instru-
ment (Thermonicolet, USA). High resolution mass spectra were
recorded on an Agilent Technology (HP, Santa Clara, CA) MS
Model: 5973 Network Mass, selective Detector Ion source: Electron
Impact (EI) 70 eV, ion source temperature: 230ꢀC Analyzer: quadru-
pole, and relative abundances of fragments are quoted in parentheses
after the m/z values. Elemental analyses were performed with Heraeus
(Germany) CHN-O rapid analyzer.
n
max/cmÀ1: 3055, 2980, 2925, 2873, 2761, 1626, 1604, 1520,
1
1469, 1236, 1161, 774; H NMR (CDCl3): d 1.92 (s, 6H), 2.40
(s, 3H), 7.06 (d, J= 8.1 Hz, 1H), 7.10 (d, J= 8.1 Hz, 1H), 9.79
(s, 1H), 9.81 (s, 1H), 13.77 (bs, 1H); 13C NMR (CDCl3): d 15.91,
19.69, 53.39, 109.11, 120.86, 126.79, 127.40, 130.86, 135,33, 140.00,
179.29, 187.52, 192.81; MS (EI) m/z 263 (M+), 236, 220(100),
35
192, 157; Found: M+ 263.0717, C14H ClNO2 requires M 263.0713.
14
4-Chloro-2,3,3,7-tetramethyl-3H-indole (14). A mixture of
arylhydrazine hydrochloride hydrazine 13 (5 g, 25 mmol) and
isopropyl methyl ketone (3.25 mL, 30 mmol) was heated at reflux
in acetic acid (30 mL) overnight and then cooled, diluted with H2O
(50 mL), and neutralized with solid Na2CO3, the aqueous solution
was extracted with EtOAc (3 Â 30 mL). The combined organic
layers were dried over Na2SO4 and solvent was evaporated to give 14
(4.4 g, 85%) as a viscous oil; FT-IR (KBr) nmax/cmÀ1: 3036, 2967,
2928, 2869, 1580, 1474, 1458, 1377, 923; 1H NMR (CDCl3):
d 1.44 (s, 6H), 2.28 (s, 3H), 2.52 (s, 3H), 6.99 (d, J=8.7Hz, 1H),
7.04 (d, J=8.7Hz, 1H); 13C NMR (CDCl3): d 15.24, 16.52, 19.86,
55.90, 125.68, 126.59, 128.15, 130.25, 140.73, 153.67, 187.84; MS
General procedure for synthesis of (16a–f). A mixture of 2-(4-
chloro-1,3-dihydro-3,3,7-trimethyl-2H-indol-2-ylidene)propanedial 15
(1.1 mmol) and hydrazine hydrate (80% w/w) or aryl hydrazine
hydrochloride (1.11 mmol) in absolute EtOH (5 mL) was heated with
stirring at reflux. After complete conversion (TLC), the reaction
mixture was cooled and concentrated; the resulting crystals were
collected by filtration and recrystallized from EtOH to give the
corresponding pyrazoles.
4-Chloro-3,3,7-trimethyl-2-(1H-pyrazol-4-yl)-3H-indole
(16a).
(Yield 90%); mp 259–260ꢀC; FT-IR (KBr) nmax/cmÀ1
;
3166, 2971, 2932, 1569, 1458, 951, 731; 1H NMR (CDCl3): d 1.69
(s, 6H), 2.60 (s, 3H), 7.06 (d, J= 8.1 Hz, 1H), 7.10 (d, J=8.1Hz,
1H), 8.37 (s, 2H), 9.50–10.50 (bs, 1H, NH); 13C NMR (CDCl3): d
16.66, 21.38, 55.48, 115.27, 126.06, 126.26, 128.50, 130.59,
134.74, 140.84, 153.02, 178.57; MS (EI): m/z 259 (M+), 115, 93
(EI) m/z 207 (M+), 206, 192(100),178, 166; Found: M+ 207.0814,
35
14
C12H ClN requires M 207.0815.
(100), 66; Found: M+ 259.0875, C14H ClN3 requires M 259.0876.
35
14
2-(4-Chloro-1,3-dihydro-3,3,7-trimethyl 2H-indol-2-ylidene)
propanedial (15). To DMF (10 mL) cooled in an ice bath was
added dropwise POCl3 (6 mL, 66 mmol) with stirring over a period
4-Chloro-3,3,7-trimethyl-2-(1-phenyl-1H-pyrazol-4-yl)-3H-
indole (16b).
(Yield 92%); mp 141–142ꢀC; FT-IR (KBr)
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M. Alyari, M. M. Baradarani, A. Afghan, and J. A. Joule
Vol 51
n
max/cmÀ1: 3055, 2971, 2932, 2873, 1557, 1500, 950, 753, 686; 1H
25.92, 56.02, 124.03, 126.15, 127.38, 130.21, 130.64, 141.72,
156.16, 168.98, 177.94; MS (EI): m/z 285 (M+), 270, 229, 192,
16
NMR (CDCl3): d 1.71 (s, 6H), 2.61 (s, 3H), 7.05 (d, J = 8.1 Hz, 1H),
7.11 (d, J= 8.1 Hz, 1H), 7.37 (t, J= 8.1 Hz, 1H), 7.52 (t, J=8.1Hz,
2H), 7.80 (d, J= 8.1Hz, 2H), 8.33 (s, 1H), 8.61 (s, 1H); 13C NMR
(CDCl3): d 16.58, 21.34, 55.51, 117.68, 119.54, 125.99, 126.21,
127.37, 127.50, 128.74, 129.61, 130.54, 139.50, 140.85, 141.04,
166, 115; Found: M+ 285.1030, C16H ClN3 requires M 285.1033.
35
General procedure for synthesis of (18a,b, 19, 20). Urea,
thiourea, or cyanoacetamide (0.626 mmol) was dissolved in hot
EtOH (8 mL, 95%) then dialdehyde 15 (0.57mmol) and piperidine
(0.11 g, 0.12 mL, and 1.25mmol) were added with stirring and the
mixture was heated at reflux for 24 h. The mixture was cooled,
filtered, and the precipitate washed with aqueous ethanol.
177.88; MS (EI): m/z 335 (M+), 115, 77 (100), 51; Found: M+
35
18
335.1186, C20H ClN3 requires M 335.1189.
4-Chloro-2-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)-3,3,7-trimethyl-
3H-indole (16c). (Yield 89%); mp 181–183ꢀC; FT-IR (KBr) nmax
/
5-(4-Chloro-3,3,7-trimethyl-3H-indol-2-yl)pyrimidin-2(1H)-
cmÀ1: 3065, 2971, 2930, 1577, 1499, 1457, 1228, 951, 831; 1H NMR
(CDCl3): d 1.91 (s, 6H), 2.91 (s, 3H), 7.23 (d, J= 8.1 Hz, 1H), 7.27 (d,
J=8.1Hz, 1H), 7.50 (d, J=8.7Hz, 2H), 7.91 (d, J= 8.7 Hz, 2H), 8.44
(s, 1H), 11.28 (s, 1H); 13C NMR (CDCl3): d 18.61, 22.46, 54.28,
111.07, 121.03, 126.88, 127.35, 129.21, 130.06, 132.62, 134.57,
one (18a). (Yield 79%); mp 300ꢀC (dec); FT-IR (KBr) nmax
/
cmÀ1: 3140, 3024, 2922, 2855, 1727, 1669, 1553, 1461, 1237; 1H
NMR (DMSO-d6): d 1.54 (s, 6H), 2.45 (s, 3H), 7.08 (d,
J = 8.1Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 8.97 (s, 2H), 12.51 (bs,
1H, NH); 13C NMR (DMSO-d6): d 16.49, 20.58, 55.38, 101.28,
136.08, 136.66, 137.14, 142.22, 179.43; MS (EI): m/z 369 (M+), 191,
109.44, 125.52, 126.51, 129.06, 131.15, 141.73, 153.28, 155.95,
14
35
178.09; Found: M+ 287.0824, C15H ClN3O requires M 287.0825.
35
154, 128, 111, 75; Found: M+ 369.0801, C20H Cl2N3 requires M
17
5-(4-Chloro-3,3,7-trimethyl-3H-indol-2-yl)pyrimidine-2(1H)-
369.0800.
thione (18b). (Yield 81%); mp 286–287ꢀC (dec); FT-IR (KBr)
n
4-Chloro-2-(1-(3-chloro-2-methylphenyl)-1H-pyrazol-4-yl)-
3,3,7-trimethyl-3H-indole (16d). (Yield 90%); mp 185–187ꢀC;
FT-IR (KBr) nmax/cmÀ1: 3060, 2971, 2927, 1561, 1496, 1453, 955,
max/cmÀ1: 3145, 2977, 2924, 2632, 2548, 1627, 1460, 1240, 982,
788; 1H NMR (DMSO-d6): d 1.58 (s, 6H), 2.48 (s, 3H), 7.13 (d,
1
J = 8.1 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 9.43 (s, 2H), 13.14 (bs,
840; H NMR (CDCl3): d 1.71 (s, 6H), 2.31 (s, 3H), 2.61 (s, 3H),
35
14
1H, NH); Anal. Calcd. for C15H ClN3S: C, 59.30; H, 4.64; N,
7.08 (d, J= 8.1 Hz, 1H), 7.10 (d, J= 8.1 Hz, 1H), 7.29–7.35
(m, 3H), 7.44 (s, 1H), 8.35 (s, 1H); 13C NMR (CDCl3): d 16.49,
17.80, 21.34, 55.51, 117.06, 126.09, 126.19, 126.49, 128.78,
129.02, 130.50, 131.07, 132.01, 132.12, 132.55, 139.94, 140.56,
13.83% Found: C, 59.16; H, 4.59; N, 13.77%.
3-((5-(4-Chloro-3,3,7-trimethyl-3H-indol-2-yl)pyrimidin-2-
yl)imino)-2-(4-chloro-1,3-dihydro-3,3,7-trimethyl-2H-indol-2-
ylidene)propanal (19a and 19b). To a solution of guanidine
hydrochloride (0.06 g, 0.63 mmol) in hot EtOH (8 mL, 95%),
dialdehyde 11 (0.33 g, 1.25 mmol) and piperidine (0.05 g,
0.63 mmol) were added with stirring, then the mixture was
heated at reflux for 24 h. The mixture was cooled and filtered
and the precipitate was washed with ethanol (95%) to give 19a
141.00,177.77; Found: M+ 383.0958, C21H Cl2N3 requires M
35
19
383.0956.
4-Chloro-2-(1-(2,4-dimethylphenyl)-1H-pyrazol-4-yl)-3,3,7-
trimethyl-3H-indole (16e). (Yield 91%); mp 188–190ꢀC; FT-
IR (KBr) nmax/cmÀ1: 3066, 2973, 2925, 1634, 1566, 1489, 1313,
1
1233, 733; H NMR (CDCl3): d 1.69 (s, 9H), 2.30 (s, 3H), 2.58
or 19b (0.51 g, 77%); mp 248–249ꢀC; FT-IR (KBr) nmax/cmÀ1
:
(s, 3H), 7.05 (d, J = 7.5Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H), 7.30 (d,
J = 7.8 Hz, 1H), 7.36 (d, J = 7.8 Hz,1H), 7.44 (s, 1H), 8.28 (s, 1H),
8.34 (s, 1H); 13C NMR (CDCl3): d 16.45, 17.80, 21.30, 55.56,
117.20, 125.89, 126.12, 126.18, 128.83, 129.00, 130.45, 131.02,
132.00, 132.15, 132.54, 139.98, 140.51, 141.15, 154.02, 177.76;
3160, 2975, 2929, 2869, 1678, 1618, 1569, 1461, 1294, 1183;
1H NMR (CDCl3): d 1.75 (s, 6H), 1.82 (s, 6H), 2.61 (s, 3H),
2.64 (s, 3H), 7.08–7.16 (m, 4H), 8.94 (s, 1H, H-C═N, due to
isomer 19a or 19b), 9.37 (s, 2H, pyrimidine ring protons), 9.63
(s, 1H, CHO), 14.40 (s, 1H, NH); 13C NMR (CDCl3): d 16.36,
16.62, 18.30, 20.64, 55.81, 57.25, 111.88, 122.66, 126.13,
126.22, 126.78, 127.23, 127.84, 130.04, 130.66, 140.80, 141.68,
151.34, 153.49, 153.49, 157.54, 158.27, 177.46, 182.70, 188.67;
Found: M+ 363.1502, C22H ClN3 requires M 363.1502.
35
22
4-Chloro-2-(1-(2,5-dichlorophenyl)-1H-pyrazol-4-yl)-3,3,7-
trimethyl-3H-indole (16f). (Yield 89%); mp 161–162ꢀC; FT-
IR (KBr) nmax/cmÀ1: 3065,2959, 2870, 2577, 2530, 1617, 1581,
1520, 1471, 1349, 1226, 1144; 1H NMR (CDCl3): d 1.69 (s, 6H),
2.59 (s, 3H), 7.05 (d, J = 8.1 Hz, 1H), 7.01 (d, J = 8.1 Hz), 7.37
(d, J = 8.7Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.73 (s, 1H), 8.39
(s, 1H), 8.55 (s, 1H); 13C NMR (CDCl3): d 16.54, 21.30, 55.52,
117.28, 126.20, 127.66, 128.42, 128.94, 129.56, 130.55, 131.69,
Found: M+ 531.1593, C29H Cl2N5O requires M 531.1593.
35
27
5-(4-Chloro-3,3,7-trimethyl-3H-indol-2-yl)-2-oxo-1,2-dihydropyridine-
3-carbonitrile (20). (Yield 81%); mp 300ꢀC (dec.); FT-IR (KBr)
n
max/cmÀ1: 3167, 3085, 2995, 2923, 2231, 1663, 1552, 1551,
1
1455, 1226; H NMR (DMSO-d6): d 1.56 (s, 6H), 2.46 (s, 3H),
7.10 (d, J = 7.8, 1H), 7.18 (d, J = 7.8, 1H), 8.44 (s, 1H), 8.81 (s,
1H), 13.06 (bs, 1H); 13C NMR (DMSO-d6): d 16.46, 20.56,
55.27, 104.90, 111.32, 116.16, 125.48, 126.71, 129.21, 131.15,
133.64, 138.18, 141.05, 141.33, 177.42; MS (EI): m/z 403 (M+)
35
271, 255, 220, 182, 162; Found: M+ 403.0409, C20H Cl3N3
16
requires M 403.0410.
4-Chloro-3,3,7-trimethyl-2-(2-methylpyrimidin-5-yl)-3H-indole
141.97, 142.69, 147.98, 152.94, 159.92, 178.03; Found: M+
35
14
311.0821, C17H ClN3O requires M 311.0825.
(17).
A mixture of 2-(4-chloro-1,3-dihydro-3,3,7-trimethyl-
2H-indol-2-ylidene)propanedial 15 (0.2 g, 0.76 mmol) and
acetamidine hydrochloride (0.078 g, 0.83 mmol) in DMF
(10 mL) was heated at reflux for 3 days. After complete
conversion (TLC), the reaction mixture was allowed to cool
overnight. Filtration furnished compound 17 (0.18 g, 83%).
Recrystallization from DMF gave pure product, mp 144–
146ꢀC; FT-IR (KBr) nmax/cmÀ1: 3055, 2979, 2926, 1582,
Acknowledgments. The authors are grateful to the University of
Urmia for financial support of this work.
REFERENCES AND NOTES
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1552, 1450, 1374, 991, 802; H NMR (CDCl3): d 1.73 (s, 6H),
2.62 (s, 3H), 2.87 (s, 3H), 7.13 (d, J = 8.1 Hz, 1H), 7.20 (d,
J = 8.1 Hz, 1H),9.38 (s, 2H); 13C NMR (CDCl3): 16.35, 20.46,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2014
The Synthesis of New Heterocycles Using
859
2-(4-Chloro-1,3-dihydro-3,3,7-trimethyl-2H-indol-2-ylidene) Propanedial
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