Vilsmeier-haack formylation of acetonitrile revisited: Synthesis of novel pyrazolo[1,5-a]pyrimidines and Triazolo[1,5-a]pyrimidine

Article abstract of DOI:10.1002/jhet.76

Vilsmeier-Haack formylation of acetonitrile using dimethylformamide and phosphorus oxychloride leading to a novel intermediate, N-((E)-3-(dimethylamino) -2-formylacryloyl)formamidine 2 and its utility in the synthesis of pyrimidine-fused heterocycles such

Full text of DOI:10.1002/jhet.76

March 2009
Vilsmeier–Haack Formylation of Acetonitrile Revisited:
Synthesis of Novel Pyrazolo[1,5-a]pyrimidines and
Triazolo[1,5-a]pyrimidine
327
Maruti G. Ghagare, Dilip R. Birari, Deepak P. Shelar,
Raghunath B. Toche, and Madhukar N. Jachak*
Department of Chemistry, Organic Chemistry Research Center, K.T.H.M. College, Nashik 422002,
Maharashtra, India
*E-mail: mn_jachak@hotmail.com
Received July 1, 2008
DOI 10.1002/jhet.76
Published online 13 April 2009 in Wiley InterScience (www.interscience.wiley.com).
Vilsmeier–Haack formylation of acetonitrile using dimethylformamide and phosphorus oxychloride
leading to a novel intermediate, N-((E)-3-(dimethylamino)-2-formylacryloyl)formamidine 2 and its
utility in the synthesis of pyrimidine-fused heterocycles such as pyrazolo[1,5-a]pyrimidines and
triazolo[1,5-a]pyrimidine is reported.
J. Heterocyclic Chem., 46, 327 (2009).
INTRODUCTION
of different annulated heterocycles [13,14]. Considering
the synthetic utility of Compound 1 [15–17] and our in-
terest in this area [18–20] prompted us to perform vari-
ous condensation reactions of 2 with 5(3)amino hetero-
cycles. We herein report the synthesis of an unexpected
compound, N-((E)-3-(dimethylamino)-2-formylacryloyl)
formamidine 2 and its utility in the synthesis of pyrimi-
dine-fused heterocycles such as pyrazolo[1,5-a]pyrimi-
dines and triazolo[1,5-a]pyrimidine.
The synthesis of pyrazolo[1,5-a]pyrimidines is a
promising avenue of research owing to various bioactiv-
ities displayed by this class of compounds. They have
been established as selective inhibitors of adenosine
cyclic mono phosphate (cAMP) phosphodiesterase
in vitro [1,2]. In addition to this some of these com-
pounds showed antischistosomal activity [3]. Another
class of compounds, [1,2,4]triazolo[1,5-a]pyrimidine
derivatives are promising inhibitors against trypanoso-
matid parasites [4], displaying inhibition percentages far
higher than those reached with traditional drugs used
against T. cruzi and L. donovani, such as ketoconazole
[5], pentavalent antimonials [6], nitroimidazole, and
itraconazole [7].
RESULTS AND DISCUSSION
The Vilsmeier–Haack formylation of acetonitrile was
carried out by Reichardt and Kermer by refluxing the
reaction mixture of acetonitrile, DMF, and phosphorus
oxychloride (1:0.6:0.6 mol) to furnish 3-dimethylamino-
2-formyl acrylonitrile 1 in 10–12% yield. The same
reaction carried out by us resulted in the formation of
two products 1 and 2. Encouraged by these results, we
optimized the reaction conditions using different molar
ratios of DMF and phosphorus oxychloride with respect
to acetonitrile (Table 1). The ratio of molar equivalents
played an important role in the formation of compounds
1 and 2. Thus, the best results were obtained when a
mixture of acetonitrile, DMF, and phosphorus oxychlor-
ide (1:3:3 mol) was heated to 50–55ꢀC for 72 h. The
reaction mixture was then poured into ice and neutral-
ized with sodium hydrogencarbonate. The resultant
Vilsmeier–Haack formylation has emerged as
a
powerful tool for the formylation of various organic
compounds. In 1970, Reichardt and Kermer [8] demon-
strated the synthesis of 3-dimethylamino-2-formyl acry-
lonitrile 1 via the Vilsmeier–Haack formylation of ace-
tonitrile. However, after intensive investigation of the
same reaction we have achieved two products, i.e., 3-
dimethylamino-2-formyl acrylonitrile 1 and an unusual
product N-((E)-3-(dimethylamino)-2-formylacryloyl)for-
mamidine 2 (Scheme 1). From literature, it was noted
that the related synthons have been used for the synthe-
sis of pyrimidines and condensed pyrimidines [9–12].
Previously, we have used compound 1 for the synthesis
C
V
2009 HeteroCorporation

328
M. G. Ghagare, D. R. Birari, D. P. Shelar, R. B. Toche, and M. N. Jachak
Vol 46
condensation of 2 with pyrimidine-2-carboxamidine 5
furnished 2-(pyrimidine-2-yl)pyrimidine-5-carboxamide
6 (Scheme 3) in 80% yield. Similarly, 1,2,4 triazolo[1,5-
a]pyrimidine-6-carboxamide 8 (Scheme 4) was synthe-
sized in 82% yield from the reaction of 5(3)-ami-
no[1,2,4]triazole 7 with 2. The structure of the com-
pounds 4, 6, and 8 were determined from spectroscopic
data. Several attempts to cyclize 2 with 2-amino hetero-
cycles 9a-e did not lead to the desired product (11a-e).
However, compound 2 on condensation with 2-aminopyr-
idines or 2-aminopyrimidine in ethanol at reflux tempera-
ture furnished open chain compounds 10a-e in 75–80%
yield (Scheme 5, Table 3). It was interesting to observe
that, the condensation of 2 with o-phenylenediamine 12
under similar reaction conditions furnished open chain
compound 13 with the N-formyl group remaining intact
(Scheme 6). Attempts to cyclize compound 12–14 were
unsuccessful.
Scheme 1. Vilsmeier–Haack formylation of acetonitrile leading to a
novel intermediate 2.
suspension was extracted with dichloromethane. The or-
ganic layer was dried and concentrated under vacuum to
give crude product, which was then recrystallized from
ethanol to afford a pale yellow solid, i.e., compound 2
in 25% yield. The aqueous layer was concentrated under
vacuum to a semisolid, which on recrystallization with
ethanol furnished compound 1 in 20% yield. Compound
1 gave satisfactory spectral and physical data and was
identical with that of reported earlier [8].
To conclude the Vilsmeier–Haack formylation of ace-
tonitrile with optimized reaction conditions leads to a
highly stable synthone N-((E)-3-(dimethylamino)-2-
formyl acryloyl)formamide 2 which can further be used
for the synthesis of various new heterocycles. Herein,
we have reported the synthesis of some pyrazolopyrimi-
dines and triazolopyrimidines. These heterocycles can
exhibit a number of bioactivities specifically inhibitory
action against cAMP phosphodiesterase. Biological
investigations are in progress in our laboratory and shall
be reported in a due course.
I
The structure of compound 2 was deduced from its H
and 13C NMR spectra. The mass spectrum of 2 dis-
played the molecular ion (Mþ) peak at 170 m/z, which
is consistent with the molecular weight of 2. The 1H
NMR spectrum of 2 showed singlet at d 8.03 represent-
ing olefinic proton, doublet at d 9.10 corresponding to
aldehyde proton neighboring to ANH of amide. The sin-
glet at d 9.31 represented another aldehyde proton. The
other signals appeared at d 3.20 (s, 3H, NCH3) and 3.40
(s, 3H, NCH3). The ANH proton appeared at d 11.43 as
abroad singlet.
We observed that Vilsmeier–Haack formylation of ace-
tonitrile with the optimized reaction conditions furnished
two compounds with different yields. The structure of
compound 2 was also supported by further nucleophilic
substitution reaction with 5(3)-amino heterocycles. Thus
condensation of compound 2 with 5(3)-amino pyrazoles
3a-c furnished pyrazolo[1,5-a]pyrimidines 4a-c in
(Scheme 2, Table 2) 75–80% yield. During condensation
of 2 with 3a-c it was observed that the N-formyl group in
2 undergoes hydrolysis to amido function in 4a-c. The
EXPERIMENTAL
Melting points were determined on a Buchi melting point
apparatus, Mod. B-545 and are uncorrected. The 1H (300
MHz) and 13C (75 MHz) NMR spectra were recorded on a
Varian XL-300 spectrometer. Chemical shifts are reported in
parts per million (ppm) relative to tetramethylsilane, and mul-
tiplicities are given as s (singlet), d (doublet), t (triplet), q
(quartet), or m (multiplate). The solvent for NMR spectra was
DMSO-d6 unless otherwise stated. Infrared spectra were taken
on Thermo Electron Corporation NICOLET 380 FTIR
Table 1
Vilsmeier–Haack formylation of acetonitrile,a comparison of the product yield with the molar proportion.
Entry
CH3CN (molar equiv.)
DMF (molar equiv.)
POCl3 (molar equiv.)
Compound 1 Yield (%)b
Compound 2 Yield (%)b
1
2
3
4
5
6
1 mol
1 mol
1 mol
1 mol
1 mol
1 mol
0.6 mol
1 mol
2 mol
1 mol
2 mol
3 mol
0.6 mol
1 mol
2 mol
2 mol
1 mol
3 mol
12.00%
11.50%
10.70%
04.00%
–
02.50%
04.70%
11.90%
05.20%
–
20.00%
25.00%
a Carried out at 50–55ꢀC for 72 h.
b Isolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2009
Vilsmeier–Haack Formylation of Acetonitrile Revisited: Synthesis of Novel
Pyrazolo[1,5-a]pyrimidines and Triazolo[1,5-a]pyrimidine
329
Scheme 2. Synthesis of compound 4a-c.
instrument in potassium bromide pellets unless otherwise
stated. Mass spectrum was recorded on Shimadzu GC-MS QP
2010A mass spectrometer with an ionization potential of 70
eV. Elemental analysis was performed on a Hosli CH-Ana-
lyzer and was within ꢁ0.4 of the theoretical percentage. All
reactions were monitored by thin layer chromatography, car-
ried out on 0.2-mm silica gel 60 F-254 (Merck) plates using
UV light (254 and 366 nm) for detection. Common reagent
grade chemicals are either commercially available and were
used without further purification or prepared by standard litera-
ture procedures.
3.7 mmol) in ethanol (2.5 mL) and catalytic amount of acetic
acid was refluxed until the starting material had been con-
sumed in the reaction (4–5 h, TLC monitoring). Reaction mass
was then cooled to room temperature. The precipitated solid
was collected by filtration and washed with cold ethanol to
obtain the crude product which was then recrystallized from
ethanol to give compound 4a as brown solid, 0.745 g (80%);
mp 318–320ꢀC. IR (KBr): 3371, 3179, 3033, 1651, 1614,
1
1452, 1396, 77 cmꢃ1. H NMR (300 MHz, DMSO): d 9.53 (d,
J ¼ 3.0 Hz, 1H, Ar-H), 8.91 (d, J ¼ 3.0 Hz, 1H, Ar-H), 8.18
(bs, 1H, NH), 8.03 (d, J ¼ 8.4 Hz, 2H, Ar-H), 7.74 (bs, 1H,
NH), 7.70 (d, J ¼ 8.70 Hz, 2H, Ar-H), 7.38 (s, 1H, Ar-H). 13C
NMR (75 MHz, DMSO): d 163.7, 157.9, 148.6, 146.7, 134.9,
132.6, 132.1, 128.9, 127.3, 126.6, 124.2, 121.9, 85.5. Anal.
Calcd. for C13H9BrN4O Calcd. C: 49.23; H: 2.86; N: 17.67.
Found. C: 49.25; H: 2.80; N: 17.50.
N-((E)-3-(Dimethylamino)-2-formylacryloyl) formamidine
(2). To a stirred solution of acetonitrile (41.05 g, 1000 mmol)
and DMF (219.30 g, 3000 mmol) at 0–5ꢀC was added drop-
wise over 1.5 h phosphorus oxychloride (459.99 g, 3000
mmol). The mixture was stirred at 50–55ꢀC for 72 h. It was
then quenched in ice, neutralized with sodium hydrogencar-
bonate. The resultant suspension was extracted with dichloro-
methane (9 ꢂ 500 mL). The combined organic extractions
were washed with saturated aqueous NaCl and dried. The sol-
vent was evaporated under reduced pressure, and the solid resi-
due was recrystallized from ethanol affording compound 2 as
a pale yellow solid, 42.5 g (25%) (Table 1, Entry 6); m.p 145–
147ꢀC, IR (KBr): 3049, 2920, 1700, 1653, 1578, 1273, 1176,
(4-Chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-6-carboxalic acid
amide (4b). Brown solid; Yield: 75%; mp 308–310ꢀC. IR (KBr):
3373, 3178, 3035, 1651, 1614, 1453, 1396, 1614, 1097 cmꢃ1. 1H
NMR (300 MHz, DMSO): d 9.52 (d, J ¼ 1.5 Hz, 1H, Ar-H), 8.90
(d, J ¼ 1.8 Hz, 1H, Ar-H), 8.18 (bs, 1H, NH), 8.08 (d, J ¼ 8.7
Hz, 2H, Ar-H), 7.73 (bs, 1H, NH), 7.57 (d, J ¼ 8.4 Hz, 2H, Ar-
H), 7.36 (s, 1H, Ar-H). 13C NMR (75 MHz, DMSO): d 163.1,
157.6, 148.4, 146.0, 135.4, 132.4, 131.6, 128.6, 126.7, 126.1,
124.7, 122.1, 84.5. Anal. Calcd. for C13H9ClN4O Calcd. C:
57.26; H: 3.33; N: 20.55. Found. C: 57.20; H: 3.25; N: 20.50.
3-Cyano-pyrazolo[1,5-a]pyrimidine-6-carboxalic acid amide
(4c). Yellow solid; Yield: 78%; mp 310–312ꢀC. IR (KBr):
1
840 cmꢃ1. H NMR (300 MHz, DMSO): d 11.43 (d, J ¼ 6.9
Hz,1H, NH), 9.31 (s, 1H, CHO), 9.10 (d, J ¼ 9.9 Hz,1H,
NHACHO), 8.03 (s, 1H, CH), 3.41 (s, 3H, NACH3), 3.21 (s,
3H, NACH3). 13C NMR (75 MHz, DMSO): d 186.8, 164.3,
163.5, 162.7, 101.7, 48.6, 43.3. Anal. Calcd. for C7H10N2O3
Calcd. C: 49.41; H: 5.92; N: 16.46. Found. C: 49.39; H: 5.90;
N: 16.47.
3395, 3328, 3058, 3121, 2235, 1674, 1624, 1421 cmꢃ1 1H
.
NMR (300 MHz, DMSO): d 9.74 (d, J ¼ 2.1 Hz, 1H, Ar-H),
9.20 (d, J ¼ 2.1 Hz, 1H, Ar-H), 8.94 (s, 1H, Ar-H), 8.33 (bs,
1H, NH), 7.93 (bs, 1H, NH). 13C NMR (75 MHz, DMSO): d
162.9, 152.8, 149.7, 149.0, 137.5, 117.9, 112.6, 81.5. Anal.
Calcd. for C8H5N5O Calcd. C: 51.34; H: 2.69; N: 37.42.
Found. C: 51.20; H: 2.55; N: 37.40.
General procedure for the synthesis of compound 4a-c,
6, 8, 10a-e and 13.
2-(4-Bromo-phenyl)-pyrazolo[1,5-a]pyrimidine-6-carboxalic
acid amide (4a). A mixture of 2 (0.5 g, 2.9 mmol), 3a (0.88 g,
2-(Pyrimidine-2-yl)pyrimidine-5-carboxamide (6). White solid;
Yield: 80%; mp 315–317ꢀC. IR (KBr): 3353, 3156, 3057,
Table 2
Synthesis of compounds 4a-ca.
Scheme 3. Synthesis of compound 6.
Entry
3, 4
R
Ar
Time (h)
Yield (%)a
1
2
3
a
b
c
H
H
p-Br-C6H4
p-Cl-C6H4
H
4
5
5
80
75
78
CN
a Yield refer to those of pure isolated products characterized by spec-
troscopic data.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

330
M. G. Ghagare, D. R. Birari, D. P. Shelar, R. B. Toche, and M. N. Jachak
Vol 46
Scheme 4. Synthesis of compound 8.
Scheme 5. Synthesis of compounds 10a-e.
1
1713, 1626, 1403, cmꢃ1. H NMR (300 MHz, DMSO): d 9.34
(s, 2H, Ar-H), 9.04 (d, J ¼ 4.8 Hz, 2H, Ar-H), 8.43 (bs, 1H,
NH), 7.91 (bs, 1H, NH), 7.69 (t, J ¼ 4.5Hz, 1H, Ar-H). 13C
NMR (75 MHz, DMSO): d 169.2, 165.4, 164.1, 158.5, 157.9,
156.3, 155.4, 127.2, 115.6. Anal. Calcd. for C9H7N5O Calcd.
C: 53.73; H: 3.51; N: 34.81. Found. C: 53.50; H: 3.62; N:
34.75.
[1,2,4]Triazolo[1,5-a]pyrimidine-6-carboxalic acid amide
(8). Yellow solid; Yield: 82%; mp 235–237ꢀC. IR (KBr):
C10H11N3O2 Calcd. C: 58.53; H: 5.40; N: 20.48. Found. C:
58.65; H: 5.50; N: 20.35.
3337, 3130, 3054, 1674, 1625, 1506, 1417 cmꢃ1 1H NMR
.
2-Formyl-3-(5-methyl-pyridine-2-ylamino)-acrylamide (10c). Yellow
solid; Yield: 78%; mp 194–196ꢀC. IR (KBr): 3371, 3190,
(300 MHz, DMSO): d 9.80 (d, J ¼ 2.4 Hz, 1H, Ar-H), 9.25
(d, J ¼ 2.1 Hz, 1H, Ar-H), 8.79 (s, 1H, Ar-H), 8.30 (bs, 1H,
NH), 7.90 (bs, 1H, NH). 13C NMR (75 MHz, DMSO): d
163.2, 157.1, 154.9, 154.6, 137.2, 117.7. Anal. Calcd. for
C6H5N5O Calcd. C: 44.17; H: 3.09; N: 42.93. Found. C:
44.20; H: 3.00; N: 42.80.
2-Formyl-3-(pyridine-2-ylamino)-acrylamide (10a). Pale yellow
solid; Yield: 75%; mp 187–189ꢀC. IR (KBr): 3371, 3057,
2873, 1666, 1628, 1594, 1408, 1152, 814, cmꢃ1 1H NMR
.
1
1644, 1601, 1491, 1394, 1209, 797 cmꢃ1. H NMR (300 MHz,
DMSO): d 12.31 (d, J ¼ 12.3 Hz, 1H, NH), 9.23 (s, 1H,
CHO), 8.71 (d, J ¼ 12.6 Hz 1H, CH), 8.32 (bs, 1H, NH), 8.21
(d, J ¼ 0.9 Hz, 1H, Ar-H), 7.69–7.66 (m, 1H, Ar-H), 7.54 (bs,
1H, NH), 7.35 (d, J ¼ 8.4 Hz, 1H Ar-H), 2.27 (s, 3H, CH3).
13C NMR (75 MHz, DMSO): d 190.3, 168.2, 156.6, 147.9,
147.9, 139.5, 129.6, 111.8, 106.3, 17.3. Anal. Calcd. for
C10H11N3O2 Calcd. C: 58.53; H: 5.40; N: 20.48. Found. C:
58.40; H: 5.45; N: 20.55.
(300 MHz, DMSO): d 12.30 (d, J ¼ 12.3 Hz, 1H, NH), 9.26
(s, 1H, CHO), 8.76 (d, J ¼ 12.3 Hz 1H, CH), 8.39–8.30 (m,
1H, Ar-H), 8.29 (bs, 1H, NH), 7.88–7.82 (m, 1H, Ar-H), 7.57
(bs, 1H, NH), 7.45–7.41 (m, 1H, Ar-H), 7.23–7.18 (m, 1H, Ar-
H). 13C NMR (75 MHz, DMSO): d 190.5, 168.1, 156.6, 149.9,
148.2, 139.1, 120.3, 112.3, 106.7. Anal. Calcd. for C9H9N3O2
Calcd. C: 56.54; H: 4.74; N: 21.98. Found. C: 56.44; H: 4.50;
N: 21.70.
2-Formyl-3-(6-methyl-pyridine-2-ylamino)-acrylamide (10d). Yellow
solid; Yield: 80%; mp 192–194ꢀC. IR (KBr): 3344, 3171,
.
2748, 1681, 1561, 1217, 809 cmꢃ1 1H NMR (300 MHz,
DMSO): d 12.26 (s, 1H, NH), 9.26 (s, 1H, CHO), 8.76 (bs,
1H, NH), 8.74 (d, J ¼ 12.3 Hz 1H, CH), 7.58 (t, J ¼ 7.8 Hz, 1H,
Ar-H), 6.94 (d, J ¼ 7.8 Hz, 1H, Ar-H), 6.73 (d, J ¼ 8.4 Hz 1H,
Ar-H), 5.55 (bs, 1H, NH), 2.52 (s, 3H, CH3). 13C NMR (75 MHz,
DMSO): d 189.9, 169.3, 158.2, 156.5, 148.9, 139.0, 120.1,
109.8, 106.4, 24.5. Anal. Calcd. for C10H11N3O2 Calcd. C:
58.53; H: 5.40; N: 20.48. Found. C: 58.45; H: 5.35; N: 20.45.
2-Formyl-3-(pyrimidine-2-ylamino)-acrylamide (10e). Off-
white solid; Yield: 76%; mp 206–208ꢀC. IR (KBr): 3360, 3177,
2-Formyl-3-(4-methyl-pyridine-2-ylamino)-acrylamide (10b). Yellow
solid; Yield: 78%; mp 205–207ꢀC. IR (KBr): 3342, 3166,
.
2756, 1676, 1611, 1587, 1556, 1413, 1151, 838 cmꢃ1 1H
NMR (300 MHz, DMSO): d 12.24 (d, J ¼ 12.3 Hz, 1H, NH),
9.24 (s, 1H, CHO), 8.73 (d, J ¼ 12.3 Hz 1H, CH), 8.30 (bs,
1H, NH), 8.23 (d, J ¼ 5.1 Hz, 1H, Ar-H), 7.55 (bs, 1H, NH),
7.25 (s, 1H, Ar-H), 7.05 (dd, J ¼ 0.9 and 4.2 Hz, 1H Ar-H),
2.33 (s, 3H, CH3). 13C NMR (75 MHz, DMSO): d 190.5,
168.1, 156.6, 147.7, 121.4, 112.4, 106.5, 20.5. Anal. Calcd. for
1
2764, 1677, 1654, 1576, 1560, 1205, 792 cmꢃ1. H NMR (300
MHz, DMSO): d 12.50 (d, J ¼ 12.3 Hz, 1H, NH), 9.34 (s, 1H,
CHO), 8.76–8.72 (m, 3H, CH, and Ar-H), 8.29 (bs, 1H, NH2),
7.74 (bs, 1H, NH2), 7.33 (t, J ¼ 4.8 Hz, 1H, Ar-H). 13C NMR (75
Table 3
Synthesis of compounds 10a-ea.
Entry
9, 10
R1
R2
R3
X
Yield (%)b
Mp (ꢀC)c
1
2
3
4
5
a
b
c
d
e
H
CH3
H
H
H
H
H
C
C
C
C
N
75
78
78
80
76
187–189
205–207
194–196
192–194
206–208
CH3
H
H
CH3
H
H
H
H
a All spectroscopic data are compatible with the proposed structures.
b Isolated yields.
c Melting points are uncorrected.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2009
Vilsmeier–Haack Formylation of Acetonitrile Revisited: Synthesis of Novel
Pyrazolo[1,5-a]pyrimidines and Triazolo[1,5-a]pyrimidine
331
Scheme 6. Synthesis of compound 13.
[5] Berman, J. D.; Chulay, J. D.; Hendricks, L. D.; Oster, C. N.
J Infect 1983, 31, 459.
MHz, DMSO): d 191.1, 167.9, 158.9, 156.7, 155.5, 117.6, 107.9.
Anal. Calcd. for C8H8N4O2 Calcd. C: 50.00; H: 4.20; N: 29.15.
Found. C: 50.21; H: 4.00; N: 29.35.
[6] Veiga, J. P.; Rosa, T. T.; Kimachi, T.; Wolf, E. R.; Sam-
paio, R. N.; Gagliardi, A. R. T.; Junqueira, L. F.; Costa, J. M. L.;
Marsden, P. D. Rev Inst Med Trop Sao Paulo 1985, 27, 665.
[7] Ram, V. J.; Haque, N.; Guru, P. Eur J Med Chem 1992, 27,
851.
(E)-3-(2-Aminophenylamino)-N, 2-diformylacrylamide (13). Yellow
solid; Yield: 75%; mp 179–181ꢀC. IR (KBr): 3366, 3200,
1
2855, 1700, 1631, 1489, 1471, 1195, 745 cmꢃ1. H NMR (300
MHz, DMSO): d 11.53 (d, J ¼ 13.5 Hz, 1H, NH), 11.35 (d, J
¼ 10.5 HZ, 1H, NH), 9.24 (s, 1H, CHO), 9.22 (d, J ¼ 7.2 Hz,
1H, CHO), 8.54 (d, J ¼ 13.8 Hz, 1H, CH), 7.35 (d, J ¼ 6.9
Hz, 1H, Ar-H), 7.06 (t, J ¼ 6.9 Hz, 1H, Ar-H), 6.87 (d, J ¼
6.6 Hz, 1H, Ar-H), 6.76 (t, J ¼ 8.1 Hz, 1H, ArH), 5.16 (s, 2H,
NH2). 13C NMR (75 MHz, DMSO): d 190.3, 166.5, 162.2,
161.8, 140.3, 127.5, 126.2, 119.6, 118.2. Anal. Calcd. for
C11H11N3O3 Calcd. C: 56.65; H: 4.75; N: 18.02. Found. C:
56.50; H: 4.80; N: 18.25.
[8] Reichardt, C.; Kermer, W. D. Synthesis 1970,
538.
[9] Breaux, E. J.; Zwikelmaier, K. E. J Heterocycl Chem 1981,
18, 183.
[10] Stanovnik, B.; Svete, J. Chem Rev 2004, 104,
2433.
[11] Pirc, S.; Bevk, D.; Golobic, A.; Stanovnik, B.; Svete, J.
Helv Chim Acta 2006, 89, 30.
[12] Bratusek, U.; Meden, A.; Svete, J.; Stanovnik, B. ARKI-
VOC, 2003, (V), 77.
[13] Jachak, M.; Kriessmamm, U.; Mittelbach, M.; Junek, H.
Monatsh Chem 1993, 124, 199.
Acknowledgments. This work was supported by UGC, New
Delhi, India. The authors thank Dr. V. B. Gaikwad for his
valuable cooperation.
[14] Jachak, M.; Mittelbach, M.; Junek, H. Heterocycles 1993,
36, 2281.
[15] Leimgruder, W.; Weigele, M. U.S. Patent 3,689,498, 1972;
Chem Abstr 1972, 77, 140130g.
REFERENCES AND NOTES
[16] Leimgruder, W.; Weigele, M. U.S. Pat 3,792,076, 1974;
Chem Abstr 1974, 80, 96011e.
[1] Novinson, T.; Hanson, R.; Dimmitt, M.; Simon, I.; Robin,
R.; Brien, D. J Med Chem 1974, 17, 645.
[17] Leimgruder, W.; Weigele, M. U.S. Pat 3,901,888, 1975;
Chem Abstr 1976, 84, 4996m.
[2] Novinson, T.; Miller, J.; Scholten, M.; Simon, I.; Robin, R.;
Brien, D.; Mayer. R. J Med Chem 1975, 18, 460.
[18] Jachak, M.; Avhale, A.; Tantak, C.; Toche, R.; Reidlinger,
C.; Stadlbauer, W. J Heterocycl Chem 2005, 42, 1311.
[19] Jachak, M.; Avhale, A.; Medhane, V.; Toche, R. J Hetero-
cycl Chem 2006, 43, 1169.
[3] Senga, K.; Novinson, T.; Wilson, H.; Robin, R. J Med
Chem 1981, 24, 610.
[4] Luque, F.; Fernandez-Ramos, C.; Entrala, E.; Rosales, M.
J.; Navarro, J. A.; Romaro, M. A.; Salas, J. M.; Sanchez-Moreno, M.
Comp Biochem Physiol C 2000, 126, 39.
[20] Jachak, M.; Avhale, A.; Toche, R.; Sabnis, R. J Heterocycl
Chem 2007, 44, 343.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet