Synthesis of some heterocyclic imides and azomethine derivatives under solvent free condition and their anti-inflammatory activity evaluation

Article abstract of DOI:10.1002/jhet.249

(Chemical Equation Presented) Condensation of various mono amines with various diacids gave heterocyclic imide derivatives and condensation of amines with various aldehydes gave azomethine derivatives in good yields under solvent free condition. Structure

Full text of DOI:10.1002/jhet.249

November 2009
Synthesis of Some Heterocyclic Imides and Azomethine
Derivatives Under Solvent Free Condition and Their
Anti-Inflammatory Activity Evaluation
1369
Sham M. Sondhi,a* Reshma Rani,a Amarendra Dhar Diwvedi,a
and Partha Royb
aDepartment of Chemistry, Indian Institute of Technology-Roorkee,
Roorkee Uttarakhand 247667, India
bDepartment of Biotechnology, Indian Institute of Technology-Roorkee,
Roorkee Uttarakhand 247667, India
*E-mail: sondifcy@iitr.ernet.in
Received May 26, 2009
DOI 10.1002/jhet.249
Published online 11 November 2009 in Wiley InterScience (www.interscience.wiley.com).
Condensation of various mono amines with various diacids gave heterocyclic imide derivatives and
condensation of amines with various aldehydes gave azomethine derivatives in good yields under sol-
vent free condition. Structures assigned to imide and azomethine derivatives are fully supported by
spectral data. All these compounds were screened for anti-inflammatory activity at a dose of 50 mg/kg
p.o. Compound 8a (6-((tetrahydrofuran-2-yl)methyl)-6H-pyrrolo[3,4]pyrazine-5,7-dione) exhibited anti-
inflammatory activity comparable to standard drug phenyl butazone which showed 37% activity at 50
mg/kg p.o.
J. Heterocyclic Chem., 46, 1369 (2009).
INTRODUCTION
a very short period of time. With this hypothesis and in
continuation of our work [15] in search of potent mole-
cules exhibiting the anti-inflammatory activity, we have
synthesized a number of heterocyclic imide and azome-
thine derivatives and screened them for anti-inflamma-
tory activity, which we wish to report in this article.
Increasing interest to synthesize small molecules as
the structural building block is driving the development
of new technologies under green chemistry research that
can produce highly pure compounds at very high rate in
very less time. Imides and azomethine derivatives are
well known compounds as the productive component in
various reactions [1]. Imides form structural part of vari-
ous important natural and synthetic molecules such as
fumaramidmycin [2], coniothyromycin [3], and SB-
253514 [4], thalidomide [5], granulatimide [6], and iso-
granulatimide [7]. Wide range of biological activities,
i.e., anti-inflammatory [8], anticancer [9], and insectici-
dal [10] are shown by imide derivatives. Azomethine
derivatives also possess anti-inflammatory [11], anti-
cancer [12], antibacterial [13], and antimicrobial [14]
activities.
RESULTS AND DISCUSSION
Chemistry. A number of heterocyclic imide deriva-
tives 7a–e, 8a–d, 9a, 10b and 11a (Scheme 1) have been
synthesized via the condensation of various amines (1a–
e; Scheme 1) with various diacids (2–6; Scheme 1) under
microwave irradiation conditions (power 600 Watt).
Microwave irradiation of a mixture of tetrahydrofurfuryl
amine (1a) and 4,5-imidazoledicarboxlic acid (1:1 molar
ratio) at 600W for 4 min gave product 7a. For compound
7a, IR absorption band at 1728 cmꢀ1 indicates the pres-
ence of ACOANACOA group. Spectral data of 7a
reported in experimental section fully support the struc-
ture assigned to it. Irradiation time and percentage yield
of 7b–e, 8a–d, 9a, 10b, and 11a synthesized by following
above method is reported in Table 1.
Microwave chemistry is relatively new technology
that has been reported to significantly improve produc-
tivity in generation of complex target molecules. Some
important features of microwave irradiation, i.e., solvent
free reactions, low waste, energy efficiency, high yield,
and short reaction time make this technique an impor-
tant tool for organic synthetic chemistry. Use of micro-
wave chemistry and solvent free reaction conditions
allow us to synthesize a large number of compounds in
A number of heterocyclic azomethine derivatives
15a–c and 16a–c have been synthesized via the con-
densation of 12, 1c and 1d amines with aromatic alde-
hydes 13 and 14 by following reaction Scheme 2.
C
V
2009 HeteroCorporation

1370
S. M. Sondhi, R. Rani, A. D. Diwvedi, and P. Roy
Vol 46
Scheme 1. Synthesis of heterocyclic imide derivatives.
Condensation of thiophen-2-ylmethanamine (12) with 2-
hydroxy-1-naphthaldehyde (13) by irradiating at 600W
for 1 min gave product 15a in 99% yield.
Spectral data of 15a reported in experimental section
of this article fully support the structure assigned to it.
By following above method other azomethine
derivatives, i.e., 15b–c and 16a–c have been synthesized.
Power level, Irradiation time and percentage yield of all
the azomethine derivatives synthesized is reported in
Table 2.
toluene [17b] or ethanol [17c] or chloroform [17d] for
long hours and still yields are not very good. Microwave
irradiation technique [18] is reported to be an efficient
way of energy transfer as compared to conventional
heating and thus reduces reaction time which leads to a
few side products and hence high yield of required prod-
ucts. In the synthesis of imide and azomethine, we used
microwave irradiation technique and got desired prod-
ucts in high yields but in a very short period of reaction
time.
Conventional methods for the synthesis of imide
derivatives involve refluxing of reactants in pyridine
[16a], or toluene [16b], or use of PCl3/CH3CN [16c]
etc. whereas synthesis of schiffs bases involve use of
P2O5/Al2O3 [17a] as a catalyst, refluxing of reactants in
Crystal structure of compound 15a. To get the
structure of compound 15a, single crystal of compound
15a was grown by slow evaporation of methanol solu-
tion. The quality of data for the crystal of 15a was not
very good but it was enough to predict the structure of
Table 1
Irradiation time, and percentage yield of compounds 7a–e, 8a–d, 9a, 10b, and 11a.
Compds
R
Time (min)
4
% Yield
95
Compds
R
Time (min)
2
% Yield
90
7a
8b
7b
7c
7d
7e
8a
4
4
2
4
3
93
89
92
96
92
8c
8d
3
86
85
98
96
95
3
9a
2
10b
11a
2
1.5
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009
Synthesis of Some Heterocyclic Imides and Azomethine Derivatives Under
Solvent Free Condition and Their Anti-Inflammatory Activity Evaluation
1371
Scheme 2. Synthesis of heterocyclic azomethine derivatives.
compound 15a (Fig. 1). The crystal data of 15a is sum-
marized in Table 3. The crystal structure give rise to
C¼¼N bond distance of 1.301 Aꢁ which is comparable to
reported value 1.282(3) Aꢁ [19].
very short time period using microwave irradiation tech-
nique. These imide and azomethine derivatives were
screened for anti-inflammatory activity and compound 8a
exhibited good anti-inflammatory activity. Microwave
technique is an important tool for synthetic organic
chemistry.
Biological activity. Anti-inflammatory [20] activity
evaluation of 7a–e, 8a–d, 9a, 10b, 11a, 15a–c and 16a–
c was carried out using carrageenan-induced paw
oedema model and results are summarized in Table 4.
Compound 8a exhibited 31% (50 mg/kg p.o.) where as
standard drug phenyl butazone exhibited 37% (50 mg/kg
p.o.) anti-inflammatory activity. Anti inflammatory ac-
tivity of 8a is comparable to phenyl butazone.
EXPERIMENTAL
General. Microwave oven model M197DL (Samsung) was
used for microwave irradiation. Compounds 7a, 8d, and 11a
were purified by crystallization from methanol/ ethyl acetate
(8:2) whereas all other compounds reported in this article were
purified by crystallization from methanol. Melting points (mp)
were determined on a JSGW apparatus and are uncorrected. IR
spectra were recorded using a Perkin Elmer 1600 FT spec-
CONCLUSION
A number of heterocyclic- imide and azomethine
derivatives have been synthesized in high yields in a
1
trometer H NMR spectra were recorded on a Bruker WH-500
spectrometer at a ca 5–15% (w/v) solution in DMSO-d6 (TMS
Table 2
Power (Watt), irradiation time, and percentage yield of 15a–c
and 16a–c.
Time
(min)
Compd.
R
Watt
% yield
99
15a
600W
1.5
15b
15c
16a
16b
16c
600W
600W
450W
450W
450W
2
2
2
3
2
98
95
98
94
90
Figure 1. Crystal structure of 15a. [Color figure can be viewed in the
online issue, which is available at www.interscience.wiley.com.]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1372
S. M. Sondhi, R. Rani, A. D. Diwvedi, and P. Roy
Vol 46
Table 3
Crystal data and X-ray experimental parameters for compound 15a.
m/z 177 (Mþ, 20%). Anal. Calcd. For C8H7N3O2 C, 54.23; H,
3.95; N, 23.72. Found C, 54.23; H, 3.93; N, 23.69.
5-(3-(1H-imidazol-1-yl)propyl)pyrrolo[3,4-d]imidazole-4,
6(1H,5H)-dione (7c). Mp 220–221ꢁC; IR (KBr) mmax: 3399
(NH), 1670 (ACOANACOA), 1601 and 1556 (Ar) cmꢀ1 1H
NMR d 1.94–1.99 (s, 2H, CH2), 2.75 (s, 2H, CH2), 4.07 (s,
2H, CH2), 6.95 (s, 1H, Ar), 7.27 (s, 1H, Ar), 7.72 (s, 1H, Ar),
7.77 (s, 1H, Ar), 7.99 (bs, 1H, NH, exch.) GC-MS m/z 245
(Mþ, 10%), Anal. Calcd. For C11H11N5O2 C, 53.87; H, 4.48;
N, 28.57. Found C, 53.85; H, 4.46; N, 28.53.
Formula
Colour
Crystal system
Space group
T(K)
C16H13NOS
White
P21/c
Monoclinic
273(2)
a( deg)
b(deg)
c(deg)
90.00
108.695(2)
90.00
1293.60(7)
2.506
1.198
0.1899
0.5181
4.216
3
V(Aꢁ
)
q
calcd(g cmꢀ3
)
a(Aꢁ)
9.8722(3)
9.8664(3)
14.0206(4)
26
l(mmꢀ1
R1a
)
b(Aꢁ)
c(Aꢁ)
wR2b
GOFc
5-(2-(Thiophen-2-yl)ethyl)pyrrolo[3,4-d]imidazole-4,6(1H,5H)-
Z
dione (7d). Mp 250–252ꢁC; IR (KBr) mmax
:
1698
(ACOANACOA), 1584, 1504, and 1431 (Ar) cmꢀ1 1H NMR d
3.07–3.16 (s, 4H, 2 ꢂ CH2), 6.97–6.99 (q, 2H, Ar), 7.41 (d, 1H,
Ar), 7.56 (s, 1H, Ar), 7.84 (s, 1H, NH exch.). GC-MS Does not
a R1 ¼ R|Fo| ꢀ |Fc|/RFo|.
b wR2 ¼ [R[w(F2o ꢀ Fc2)2]/R[w(F2o)2]]1/2
.
c GOF ¼ [R[w(Fo2 ꢀ Fc2)2]/M-N)]1/2 (M ¼ number of reflections, N ¼
show Mþ ion peak but gave fragments at m/z 151(C6H5N3O2
,
number of parameters refined).
9%), 150(C6H4N3Oꢃ2 , 7%), 137 (C5H3N3O2 , 12%),
110 (C6H6S , 98%), 97 (C5H5Sꢃ, 100%). Anal.
Calcd. For C11H9N3O2S C, 53.44; H, 3.64; N, 17.00; S,
as internal standard) FAB-MS was recorded on JEOL SX-120
(FAB) spectrometer. GC-MS was recorded on Perkin Elmer
Clarus 500 gas chromatograph where built in MS detector was
used. Elemental analysis was carried out on a Vario EL III ele-
mentor. Thin layer chromatography (TLC) was performed on
silica gel G for TLC (Merck) and spots were visualized by io-
dine vapour or by irradiation with ultraviolet light (254 nm).
The X-ray data collection and processing were performed on
Bruker Kappa Apex-II CCD diffractometer by using graphite
12.95. Found C, 53.40; H, 3.63; N, 17.00; S, 12.94.
5-Cyclohexylpyrrolo[3,4]imidazole-4,6-(1H,5H)-dione (7e). Mp
205–206ꢁC; IR (KBr) mmax: 1723 (ACOANACOA), 1589, and
1458 (Ar) cmꢀ1 1H NMR d 1.14–1.15 (m, 1H, aliphatic), 1.18–
1.27 (m, 4H, aliphatic), 1.55–1.58 (m, 1H, aliphatic), 1.69 (s,
2H, aliphatic), 1.87 (s, 2H, aliphatic), 2.94 (s, 1H, aliphatic),
7.87 (s, 1H, Ar). GC-MS Does not show Mþ ion peak but gave
fragmentation ions at m/z 191 (C10H13N3O , 12%), 83
˚
monochromated Mo-Ka radiation (k ¼ 0.71070 A) at 100 K.
(C6Hꢃ11, 12%). Anal. Calcd. For C11H13N3O2 C, 60.27;
H,5.93; N, 19.17. Found C, 60.25; H, 5.92; N, 19.15.
6-((Tetrahydrofuran-2-yl)methyl)-6H-pyrrolo[3,4]pyrazine-5,7-
Crystal structures were solved by direct methods. Structure so-
lution, refinement and data output were carried out with the
SHELXTL program [21,22]. All nonhydrogen atoms were
refined anisotropically. Hydrogen atoms were placed in geo-
metrically calculated positions and refined using a riding
model. Images were created with the DIAMOND program
[23].
dione (8a). Mp 128–129ꢁC; IR (KBr) mmax
:
1719
(ACOANACOA), 1585 and 1445 (Ar) cmꢀ1 1H NMR d
1.49–1.56 (m, 1H, aliphatic), 1.77–1.88 (m, 2H, aliphatic),
1.91–1.98 (m, 1H, aliphatic), 2.71–2.75 (q, 1H, aliphatic),
2.89–2.93 (dd, 1H, aliphatic), 3.64–3.68 (m, 1H, aliphatic),
3.74–3.79 (m, 1H, aliphatic), 3.95–4.00 (m, 1H, aliphatic),
8.73 (s, 2H, pyrazine). GC-MS m/z 233 (Mþ, 20%). Anal.
Calcd. For C11H11N3O3 C, 56.65; H, 4.72; N, 18.02. Found C,
56.64; H, 4.73; N, 18.00.
Reaction procedure for synthesis of 7a. 4,5-Imidazoledicar-
boxlic acid (0.200 g, 1.28 mmol) and tetrahydrofurfuryl amine
(0.20 mL, 1.98 mmol) were mixed together thoroughly in a pe-
tri dish to form a paste. This paste was subjected to microwave
irradiation for 4 min at a power level of 600 Watt. Completion
of reaction was checked by TLC. Crude reaction product was
washed with ether. The product so obtained was further puri-
fied by crystallization from ethylacetate:methanol (8:2). Yield
210mg (95%) m.p. 212ꢁC.
6-Cyclopropyl-6H-pyrrolo[3,4-b]pyrazine-5,7-dione (8b). Mp
195–196ꢁC; IR (KBr) mmax: 1718 (ACOANACOA), 1605 and
Similarly were prepared compounds 7a–e, 8a–d, 9a, 10b
and 11a.
Physical constant and spectral data of heterocyclic imidie
derivatives 7a–e, 8a–d, 9a, 10b, 11a.
Table 4
Anti-inflammatory activity evaluation of compounds 7a–e, 8a–d, 9a,
10b, 1 1a, 15a–c and 16a–c at 50 mg /kg p.o.
5-((Tetrahydrofuran-2-yl)methyl)pyrrolo[3,4-d]imidazole-
4,6(1H,5H)-dione (7a). Mp 212–214ꢁC; IR (KBr) mmax: 1728
(ACOANACOA), 1636, 1585, and 1462 (Ar) cmꢀ1 1H NMR d
1.20 (s, 1H, aliphatic), 1.66–1.69(d, 2H, aliphatic), 1.95–1.96 (d,
1H, aliphatic), 2.73–2.77 (t, 1H, aliphatic), 2.91–2.93 (d, 1H, ali-
phatic), 3.64–3.68 (q, 1H, aliphatic), 3.75–3.78 (t, 1H, CH2),
3.98 (s, 1H, CH2), 7.65 (s, 1H, imidazole), NH (not observed).
GC-MS m/z 221 (Mþ, 32%). Anal. Calcd. For C10H11N3O3 C,
54.29; H, 4.97; N, 19.00. Found C, 54.30; H, 4.93; N, 18.89.
5-Cyclopropylpyrrolo[3,4-d]imidazole-4,6(1H,5H)-dione (7b). Mp
235–236ꢁC; IR (KBr) mmax: 1709 (ACOANACOA), 1601,
1556, and 1489 (Ar) cmꢀ1 1H NMR d 0.66–0.71 (t, 4H,
ACH2ACH2A), one H of cyclopropyl ring merged with
DMSO-d6 signal, 7.63(s, 1H, Ar), NH (not observed). GC-MS
Anti-inflammatory
activity (%)
Anti-inflammatory
activity (%)
Compds
Compds
7a
7b
7c
7d
7e
8a
8b
8c
8d
25.4
1.4
9a
10b
11a
15a
15b
15c
16a
16b
16c
*PB
26.1
16.0
18.3
19.7
15.6
0.0
15.5
24.2
26.8
31.0
16.9
29.6
14.1
27.2
10.8
0.0
37
* PB denote for phenyl butzone.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009
Synthesis of Some Heterocyclic Imides and Azomethine Derivatives Under
Solvent Free Condition and Their Anti-Inflammatory Activity Evaluation
1373
1421 (Ar) cmꢀ1 1H NMR
d
0.48–0.71 (m, 4H,
(C¼¼N), 1544 and 1493 (Ar) cmꢀ1
.
1H NMR d 5.08 (s, 2H,
ACH2ACH2A), one H of cyclopropyl ring merged with
DMSO-d6 signal, 8.73 (s, 2H, pyrazine). GC-MS m/z 189
(Mþ, 13%). Anal. Calcd. For C9H7N3O2 C,57.14; H, 3.70; N,
22.22. Found C, 57.12; H, 3.71; N, 22.20.
6-(3-(1H-imidazole-1-yl)propyl)-6H-pyrrolo-[3,4-b]pyrazine-
5,7-dione (8c). Mp 189–191ꢁC; IR (KBr) mmax
CH2), 6.78–6.79 (d, 1H, Ar), 7.05–7.07 (q, 1H, Ar), 7.17–7.18
(q, 1H, Ar), 7.23–7.26 (m, 1H, Ar), 7.46–7.49 (m, 1H, Ar),
7.52–7.53 (q, 1H, Ar), 7.68–7.69 (q, 1H, Ar), 7.773–7.792 (d,
1H, Ar), 8.12–8.13 (d, 1H, Ar), 9.33–9.35 (d, 1H, Ar), 14.34
(s, 1H, OH exch.). GC-MS m/z 267 (Mþ, 58%), Anal. Calcd.
For C16H13NSO C, 71.91; H, 4.87; N, 5.24; S, 11.98. Found
C, 71.89; H, 4.86; N, 5.24; S, 11.96.
:
1698
(ACOANACOA), 1627, 1586, and 1564 (Ar) cmꢀ1 1H NMR
d 1.98 (bs, 2H, CH2), 2.64 (bs, 2H, CH2), 4.06 (bs, 2H, CH2),
6.92 (s, 1H, imidazole), 7.19 (s, 1H, imidazole), 7.66 (s, 1H,
imidazole), 8.71 (s, 2H, pyrazine). GC-MS m/z 257 (Mþ,
13%), Anal. Calcd. For C12H11N5O2 C, 54.30; H, 3.02; N,
12.67; S, 9.65. Found C, 54.37; H, 3.02; N, 12.65; S, 9.88.
6-(2-(Thiophene-2yl)ethyl)-6H-pyrrolo[3,4-b]pyrazine-5,7-dione
(8d). Mp 136–137ꢁC; IR (KBr) mmax: 1717 (ACOANACOA),
1635 and 1495 (Ar) cmꢀ1 1H NMR d 3.03–3.09 (m, 4H, 2 ꢂ
CH2), 6.95–6.98 (q, 2H, thiophene), 7.35–7.36 (m, 1H, thio-
phene), 8.71 (s, 2H, pyrazine). GC-MS m/z 259 (Mþ, 12%).
Anal. Calcd. For C12H9N3O2S C, 55.59; H, 3.47; N, 16.21; S,
12.35. Found C, 55.59; H, 3.47; N, 16.21; S, 12.35.
1-((3-(1H-imidazol-1-yl)propylimino)methyl)naphthalen-
2-ol (15b). Mp 95–96ꢁC; IR (KBr) mmax: 3428 (OH), 1631
(C¼¼N), 1542, 1523, and 1445 (Ar) cmꢀ1
.
1H NMR d 2.14–
2.19 (m, 2H, CH2), 3.60–3.64 (t, 2H, CH2), 4.06–4.09 (t, 2H,
CH2), 6.75–6.77 (d, 1H, Ar), 6.93 (s, 1H, Ar), 7.19–7.25 (m,
2H, Ar), 7.42–7.45 (m, 1H, Ar), 7.64–7.69 (m, 2H, Ar), 7.74–
7.76 (d, 1H, Ar), 8.07–8.09 (d, 1H, Ar), 9.10–9.12 (d, 1H, Ar),
14.21 (s, 1H, OH exch). GC-MS m/z 279 (Mþ, 20%). Anal.
Calcd. For C17H17N3O C, 73.11; H, 6.09; N, 15.05. Found C,
73.10; H, 6.02; N, 15.05.
1-((Thiophen-2-yl)ethylimino)methyl)naphthalen-2-ol (15c). Mp
115–116ꢁC; IR (KBr) mmax: 3442 (OH), 1638 (C¼¼N), 1598
2-((-Tetrahydrofuran-2-yl) methyl)-2H-pyrrolo[3,4-c]pyridine-
1,3dione (9a). Mp 107–108ꢁC; IR (KBr) mmax
and 1543 (Ar) cmꢀ1 1H NMR d 3.22–3.25 (t, 2H, CH2),
.
:
1715
3.90–3.92 (t, 2H, CH2), 6.71–6.73 (d, 1H, Ar), 6.97–6.99 (q,
2H, Ar), 7.17–7.21 (m, 1H, Ar), 7.36–7.38 (dd, 1H, Ar), 7.40–
7.43 (m, 1H, Ar), 7.62–7.64 (dd, 1H, Ar), 7.72–7.73 (d, 1H,
Ar), 8.00–8.02 (d, 1H, Ar), 9.05–9.07 (d, 1H, Ar), 14.0 (s, 1H,
OH exch.). GC-MS m/z 281 (Mþ, 49%), Anal. Calcd. For
C17H15NSO C, 72.59; H, 5.33; N, 4.98; S, 11.38. Found C,
72.59; H, 5.34; N, 4.95; S, 11.39.
(ACOANACOA), 1593, 1489, and1400 (Ar) cmꢀ1 1H NMR d
1.51–1.55 (q, 1H, aliphatic), 1.80–1.87 (m, 2H, aliphatic),
1.94–1.99 (m, 1H, aliphatic), 2.72–2.76 (m, 1H, aliphatic),
2.90–2.93 (m, 1H, aliphatic), 3.66–3.70 (m, 1H, aliphatic),
3.95–4.00 (m, 2H, CH2), 7.97–7.98 (d, 1H, py), 8.73–8.74 (d,
1H, py), 9.24 (s, 1H, py). GC-MS m/z 232 (Mþ, 21%). Anal.
Calcd. For C12H12N2O3 C, 62.06; H, 5.17; N, 12.06. Found C,
62.05; H, 5.17; N, 12.03.
N-(1H-Indol-3-yl)methylene)(thiophen-2-yl)methanamine
(16a). Semisolid; IR (KBr) mmax: 3395 (NH), 1637 (C¼¼N),
2-Cyclopropylisoquinoline-1,3-(2H,4H)-dione
(10b). Mp
1578, 1533, and 1453 (Ar) cmꢀ1 1H NMR d 4.89 (s, 2H,
.
40–41ꢁC; IR (KBr) mmax: 1715 (ACOANACOA), 1629 and
CH2), 7.00–7.03 (m, 2H, Ar), 7.12–7.15 (m, 1H, Ar), 7.19–
7.22 (m, 1H, Ar), 7.396–7.399 (dd, 1H, Ar), 7.41–7.47 (d, 1H,
Ar), 7.83 (s, 1H, Ar), 8.29–8.30 (t, 1H, Ar), 8.58 (s, 1H, Ar),
11.60 (s, 1H, NH exch.). GC-MS m/z 240 (Mþ, 100%). Anal.
Calcd. For C14H12N2S C, 70.00; H, 5.00; N, 11.66; S, 13.33.
Found C, 69.98; H, 5.00; N, 11.65; S, 13.30.
1
1590 (Ar) cmꢀ1. H NMR d 0.63–0.68 (m, 4H, CH2ACH2A),
one H of cyclopropyl ring merged with DMSO-d6 signal, 3.58
(s, 2H, CH2), 7.17–7.19 (d, 1H, Ar), 7.23–7.26 (t, 1H, Ar),
7.30–7.33 (m, 1H, Ar), 7.63–7.65 (d, 1H, Ar). GC-MS m/z
201 (Mþ, 35%). Anal. Calcd. For C12H11NO2 C, 71.64; H,
5.47; N, 6.96. Found C, 71.62; H, 5.44; N, 6.96.
N-((1H-indol-3-yl)methylene)-3-(1H-imidazol-1-yl)propan-1-
amine (16b). Semisolid; IR (KBr) mmax: 3434 (NH), 1635
3-(Tetrahydrofran-2-yl)methyl)-1H-benzo[d]azepine-2,4(3H,5H)-
dione (11a). Mp150–151ꢁC;
IR
(KBr)
mmax
:
1711
(C¼¼N), 1601, 1512, and 1499 (Ar) cmꢀ1
.
1H NMR d 2.04–
(ACOANACOA), 1634, 1582, and 1491 (Ar) cmꢀ1. H NMR
d 1.51–1.56 (m, 1H, aliphatic), 1.81–1.86(m, 2H, aliphatic),
1.93–1.96 (q, 1H, aliphatic), 2.68–2.73 (q, 1H, aliphatic),
2.84–2.87 (dd, 1H, aliphatic), 2.30 (s, 4H, 2 ꢂ CH2,) 3.76–
3.80 (m, 2H, aliphatic), 3.94–3.97 (q, 1H, aliphatic), 7.14–7.19
(m, 4H, Ar). GC-MS m/z 259 (Mþ, 2%), Anal. Calcd. For
C15H17NO3 C, 69.49; H, 6.56; N, 5.40. Found C, 69.47; H,
5.56; N, 5.38.
2.09 (m, 2H, CH2), 3.44–3.47 (t, 2H, CH2), 4.08–4.11 (t, 2H,
CH2), 6.911–6.912 (d, 1H, CH), 7.05–7.13 (m, 1H, Ar), 7.17–
7.19 (m, 1H, Ar), 7.23–7.24 (m, 1H, Ar), 7.42–7.43 (d, 1H,
Ar), 7.65 (s, 1H, Ar), 7.77–7.79 (d, 1H, Ar), 8.21–8.29 (t, 1H,
Ar), 8.44 (s, 1H, Ar), 11.54 (s, 1H, NH exch.). GC-MS m/z
252 (Mþ, 39%). Anal. Calcd. For C15H16N4 C, 71.43; H, 6.35;
N, 22.22. Found C, 71.42; H, 6.34; N, 22.22.
1
N-(1H-Indol-3-yl)methylene)(thiophen-2-yl)ethanamine
(16c). Mp 98–100ꢁC; IR (KBr) mmax: 3431(NH), 1627 (C¼¼N),
Reaction procedure for synthesis of 15a. 2-Hydroxy-1-
naphthaldehyde (0.200 g, 1.16 mmol) and thiophen-2-ylme-
thanamine (0.20 mL, 1.76 mmol) were mixed together thor-
oughly in a petri dish to form a paste. This paste was sub-
jected to microwave irradiation for 1.5 min at power level of
600 Watt.. Completion of reaction was checked by TLC.
Crude reaction product was washed with chilled ethyl acetate.
The product so obtained was further purified by crystallization
from Methanol. Yield 265mg (99%) m.p. 135ꢁC.
1
1543 and 1443 (Ar) cmꢀ1. H NMR d 3.15–3.18 (t, 2H, CH2),
3.75–3.77 (t, 2H, CH2), 6.92–6.95 (m, 2H, Ar), 7.10–7.13 (m,
1H, Ar), 7.17–7.20 (m, 1H, Ar), 7.29–7.30 (m, 1H, Ar),
7.426–7.432 (d, 1H, Ar), 7.74–7.77 (d, 1H, Ar), 8.27–8.28 (d,
1H, Ar), 8.42–8.44 (d, 1H, Ar), 11.52 (s, 1H, NHexch.). GC-
MS m/z 254 (Mþ, 12%). Anal. Calcd. For C15H14N2S C,
70.86; H, 5.51; N, 11.02; S, 12.59. Found C, 70.85; H, 5.52;
N, 11.00; S, 12.58.
Similarly compounds 15a–c, 16a,b and 16c were prepared.
Physical constants and spectral data is reported as below.
1-((Thiophen-2-ylmethylimino)methyl)naphthalen-2-ol
(15a). Mp 135–137ꢁC; IR (KBr) mmax: 3439 (OH), 1628
Preparation of single crystal for X-ray analysis. All the
crystallographic parameters are tabulated in Table 3 and
selected bond distance is reported in Text. Crystals of com-
pound 15a were obtained from slow evaporation of methanol
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1374
S. M. Sondhi, R. Rani, A. D. Diwvedi, and P. Roy
Vol 46
P.; Ready, S.; Sanchez-Pulles, J. M.; Sheridan, R.; Stefanska, A.;
Warr, S. J Antibiot 2000, 53, 664.
solution of compound 15a. Compound 15a crystallized in
monoclinic space group P21/c.
[5] Melchert, M.; List, A. Int J Biochem Cell Biol 2007, 39, 1489.
[6] Henon, H.; Messaoudi, S.; Hugon, B.; Anizon, F.; Pfeiffer,
B.; Prudhomme, M. Tetrahedron 2005, 61, 5599.
Anti-inflammatory activity [20]. Paw oedema inhibition
test was used on albino rats of Charles Foster by adopting the
method of Winter et al [20]. Groups of five animals of both
sexes (body weight 120–160 g), excluding pregnant females,
were given a dose of test compound. Thirty minute later, 0.20
mL of 1% freshly prepared carrageenan suspension in 0.9%
NaCl solution was injected subcutaneously into the planter ap-
oneurosis of the hind paw and the volume was measured by a
water plethysmometer apparatus and then measured again 1–3
h later. The mean increase of paw volume at each interval was
compared with that of control group (five rats treated with car-
rageenan but not with test compound) at the same intervals
and percent inhibition value calculated by the formula given
below.
[7] Hugon, B.; Pfeiffer, B.; Renard, P.; Prudhomme, M. Tetra-
hedron Lett 2003, 44, 3927.
[8] Collin, X.; Robert, J.-M.; Wielgosz, G.; Le Baut, G.;
Bobin-Dubigeon, C.; Grimaud, N.; Petit, J.-Y. Eur J Med Chem 2001,
36, 639.
[9] (a) Abdel-Aziz, A. A.-M. Eur J Med Chem 2007, 42, 614;
(b) Salvati, R. M.; Balog, A.; Wei, D. D.; Dacia, P.; Attar, R. M.;
Geng, J.; Rizzo, C. A.; Hunt, J. T.; Gottardis, M. M.; Weinmann, R.;
Martinez, R. Bioorg Med Chem Lett 2005, 15, 389.
[10] Kennedy, E. L.; Tchao, R.; Harvison, P. J. Toxicology
2003, 186, 79.
[11] Hamor, G. H.; Watson, L. D. J Pharm Sci 2006, 60, 925.
[12] Ren, S.; Wang, R.; Komatsu, K.; Bonaz-Krause, P.; Zyria-
nov, Y.; McKenna, C. E.; Csipke, C.; Tokes, Z. A.; Lien, E. J. J Med
Chem 2002, 45, 410.
% anti-inflammatory activity ¼ ½1 ꢀ Dt=Dcꢄ ꢂ 100
[13] Shi, L.; Ge, H. M.; Tan, S. H.; Li, H. Q.; Song, Y. C.; Zhu,
H. L.; Tan, R. X. Eur J Med Chem 2007, 42, 558.
Dt and Dc are paw volumes of oedema in tested and control
groups, respectively. Compounds 7a–e, 8a–d, 9a, 10b, 1 1a,
15a–c, and 16a–c were screened for anti-inflammatory activity
and results are summarized in Table 4.
[14] Sinha, D.; Tiwari, A. K.; Singh, S.; Shukla, G.; Mishra, P.;
Chandra, H. Mishra, A. K. Eur J Med Chem 2008, 43, 160.
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Sondhi, S. M.; Rani, R.; Partha, R.; Agrawal, S. K.; Saxena, A. K.
Bioorg Med Chem Lett 2009, 5, 51.
Acknowledgments. The authors are thankful to technical staff
and Prof. U. P. Singh of Chemistry Department, I. I. T. Roorkee,
for spectroscopic studies, elemental analysis and single crystal
analysis. Ms. Reshma Rani is thankful to CSIR, New Delhi, for
financial assistance.
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Bansal, R.; Palusczak, A.; Hartmann, R. W. IL Framaco, 2005, 60,
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