Utility of enaminonitriles in heterocyclic synthesis: Synthesis of some new azepine, azocine, and pyrroldione derivatives

Article abstract of DOI:10.1002/jhet.1829

Reactions of enaminonitrile derivative 3 with a variety of reagents lead to the syntheses of novel 1,2,4- triazepin 7, 1,4-thiazepinone 9, oxazocines 13, 14, oxadiazocines 15, 16, and pyrroldiones 17-22 with the aim to explore the use of this exceptionally reactive enaminonitrile 3 in heterocyclic synthesis. Newly synthesized compounds were characterized by elemental analyses and spectral data (IR, ¹H-NMR, ¹³C-NMR, and MS).

Full text of DOI:10.1002/jhet.1829

Month 2014
Utility of Enaminonitriles in Heterocyclic Synthesis: Synthesis of Some
New Azepine, Azocine, and Pyrroldione Derivatives
Ahmed A. Fadda and Khaled M. Elattar*
Chemistry Department, Faculty of Science, Mansoura University, El-Gomhoria Street, 35516 Mansoura, Egypt
*
E-mail: khaledelattar2@yahoo.com
Received April 21, 2012
DOI 10.1002/jhet.1829
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
Reactions of enaminonitrile derivative 3 with a variety of reagents lead to the syntheses of novel 1,2,4-
triazepin 7, 1,4-thiazepinone 9, oxazocines 13, 14, oxadiazocines 15, 16, and pyrroldiones 17–22 with the aim
to explore the use of this exceptionally reactive enaminonitrile 3 in heterocyclic synthesis. Newly synthesized
1
13
compounds were characterized by elemental analyses and spectral data (IR, H-NMR, C-NMR, and MS).
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
2-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-
-yl)-hydrazono] malononitrile (2) [17] was prepared by
4
Enaminonitriles are important intermediates for the
preparation of heterocyclic compounds possessing diverse
biological activities. They are of particular interest as very
promising reagents for cascade heterocyclization, which
will undoubtedly become one of the main approaches to
the targeted synthesis of heterocycles in the near future,
in the rapidly rising field of combinatorial chemistry [1–7].
Chemistry of cyclic enaminonitriles and enaminoesters
has been reviewed in 1992 by Wamhoff [8]. Although
the chemistry of enamines was recently reviewed in several
reports, little attention has been paid to the chemistry of
enaminonitriles [9–12]. Several of these enaminonitriles
have been investigated and found to exhibit a wide range
of bioactivities including antitumor [13], antimicrobial
diazo-coupling of 4-aminoantipyrine (1) with malononitrile
in ethanolic sodium acetate solution at 0–5 C. Compound 2
ꢀ
reacted with piperidine in refluxing ethanol to afford the
corresponding 1:1 acyclic enaminonitrile adduct 3, respec-
tively. The formation of enaminonitrile 3 was illustrated
through the initial addition of the secondary amines to
cyano function to form the imino form followed by [1,5]
H migration to form the enamine form (Scheme 1).
On the other hand, treatment of a vigorously stirred
solution of enaminonitrile 3 in DMF with carbon disulphide
and sodium hydroxide solution led to the formation of the
sodium salt of enaminonitrile 4, which was methylated with
dimethyl sulfate to obtain methyl mercaptan derivative 5.
Furthermore, refluxing of 5 with hydrazine hydrate in etha-
nol catalyzed by TEA led to the formation of 1,2,4-triazepin
derivative 7. The formation of 7 was preceded by the
addition of amino group in hydrazine hydrate to the cyano
function in enaminonitrile derivative 3 follow by cyclization
via the elimination of methyl mercaptan molecule
[14], antiviral [15], analgesic, and anti-inflammatory drugs
[16], and others, and their bioactivity diversities have been
reported in these contexts.
In this work, we report here the scope and applicability of
2
4
-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-
-yl)-hydrazono]malononitrile as a unique precursor for the
(Scheme 2). The structures 5 and 7 were established on the
synthesis of some previously unreported enaminonitriles in
which antipyrine ring is incorporated.
basis of elemental analyses and spectral data. The IR
spectrum of compound 5 showed characteristic absorption
ꢁ
1
band at 1178 cm due to (C═S) group, whereas the IR
ꢁ
1
spectrum of compound 7 showed the band at 2400 cm
RESULTS AND DISCUSSION
due to (SH) group and the absence of the bands
1
The synthetic strategies adopted to obtain the target
corresponding to cyano and (C═S) functions. The H-NMR
compounds are depicted in Schemes 1–7. The key precursor
spectrum of compound 5 revealed four singlet signals at d
©
2014 HeteroCorporation

A. A. Fadda and K. M. Elattar
Vol 000
Scheme 1. Synthesis of acyclic enaminonitrile derivative 3.
Scheme 2. Routes for the synthesis of 1,2,4-triazepin derivative 7.
in the presence of a catalytic amount of TEA (five drops)
afforded 1,2,4-triazepin 7 (Scheme 2). This reaction probably
involves the addition of the amino group of hydrazine
hydrate to cyano group in compound 3 followed by
cyclization of the adduct to give 7. The structure of metha-
nedithioic acid derivative 6 was established on the basis of
elemental analysis and spectral data. The IR spectrum
ꢁ
1
showed a band at 2350 cm due to the SH group. Also,
its mass spectrum showed the molecular ion peak at
+
m/z 357 (M -piperidyl, 4.7%) corresponding the molecular
formula (C H N OS ).
20
23
7
2
On the other hand, the reaction of enaminonitrile deriv-
ative 3 with thioglycolic acid in refluxing pyridine afforded
1
,4-thiazepinone 9. The formation of structure 9 via the
addition of the SH group in thioglycolic acid to cyano
group then cyclization by elimination of water molecule fol-
lowed by rearrangement of structure 8 took place (Scheme 3).
The structure of 9 was confirmed by elemental analysis and
spectral data. The IR spectrum showed absorption bands at
ꢁ
1
2
.44, 2.91, 3.10, and 7.97 ppm corresponding to (CH3),
3343, 3251 cm due to (NH ) group. Its mass spectrum
2
+
(SCH ), (N–CH ), and (NH) protons, respectively, and the
showed the molecular ion peak at m/z 439 (M , 16.7).
3
3
expected signals of piperidyl and aromatic protons. More-
over, the H-NMR spectrum of compound 7 revealed the
The reaction of compound 3 with isatin in refluxing
ethanol containing few drops of glacial acetic acid furn-
ished the corresponding Schiff base 11 instead of the
oxazepine derivative 10 (Scheme 4). The formation of
compound 11 is indicated by the disappearance of absorp-
1
absence of the signal at d 2.91 ppm of SCH protons and
3
revealed five singlet signals at d 1.63, 2.41, 3.08, 4.15,
and 7.1 ppm corresponding to (SH), (CH ), (N–CH ), (NH),
3
3
and (NH ) protons, respectively. The assigned structures 5and
tion band due to NH in its IR spectrum. The molecular
2
2
7
were further supported by the appearance of their respective
ion peak recorded in the mass spectrum was at m/z 480
+
+
molecular ion peaks in the mass spectra at m/z 455 (M ,
(M ꢁ CH , 10.2%), which is in agreement with the
3
+
29.6%) and 440 (M + 1, 9.4%), respectively.
molecular formula (C H N O ).
27 26 8 2
Moreover, acidification of 4 by dilute hydrochloric acid
yielded the corresponding methanedithioic acid derivative
, which upon heating with hydrazine hydrate in ethanol
On the other hand, cyclocondensation of enaminonitrile
derivative 3 with salicyaldehyde or 2-hydroxy-1-naphthal-
dehyde in refluxing ethanol in the presence of a catalytic
6
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Utility of Enaminonitriles in Heterocyclic Synthesis
Scheme 3. Synthesis of 1,4-thiazepinone 9.
Scheme 4. Reaction of enaminonitrile derivative 3 with isatin.
group in the aldehyde derivatives to cyano function. The
formation of both compounds is indicated by the presence
of (C═N) groups in the IR spectra at n 1527 and
ꢁ
1
1
541 cm , respectively, besides no bands of hydroxyl and
cyano groups were observed. The mass spectra gave an
additional evidence for both structures formation in which
+
the molecular ion peaks appeared at m/z 387 (M ꢁ piperidyl,
+
2
%) and 438 (M ꢁ piperidyl, 7.3%), respectively.
In a similar manner, enaminonitrile derivative 3 under-
went cycloaddition with 1-nitroso-2-naphthol or 2-nitroso-1-
naphthol in refluxing ethanol in the presence of a catalytic
amount of TEA to yield [1,4,5]oxadiazocine derivatives 14
and 15, respectively (Scheme 5). The structures of oxadiazo-
cine derivatives 14 and 15 were confirmed on the basis of
elemental analyses and spectral data. The mass spectra
+
amount of TEA afforded [1,5]oxazocine derivatives 12 and
3, respectively (Scheme 5). The reaction proceeded
initially via condensation of amino group of compound 3
showed the molecular ion peaks at m/z 520 (M , 3.7%) and
+
1
505 (M ꢁ CH , 38.5%), respectively.
3
In previous publications [18–21], it has been reported
with aldehyde group followed by the addition of hydroxyl
that fusion of acid anhydrides with amino group in the
Scheme 5. Synthesis of [1,5]oxazocine and [1,4,5]oxadiazocine derivatives 12–15.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. A. Fadda and K. M. Elattar
Vol 000
Scheme 6. Synthesis of pyrroldione derivatives 16–21.
Scheme 7. Mechanism of formation of pyrroldione derivatives 16–21.
presence of sodium acetate gave the corresponding pyrrol-
dione derivatives via ammonolysis followed by cyclization.
In the present work, fusion of the enaminonitrile 3 with
different anhydride derivatives, namely, phthalic anhydride,
maleic anhydride, 1,2,4,5-benzene tetracarboxylic anhy-
dride, 4-nitrophthalic anhydride, 1,2,4-benzene tricarboxylic
anhydride, or tetrabromophthalic anhydride in the presence
of freshly fused sodium acetate afforded the corresponding
pyrroldione derivatives 16–21, respectively (Scheme 6).
The structures of compounds 16–21 were elucidated on the
basis of elemental analysis and spectral data. The infrared
spectrum showed the absence of n (NH ) and the presence
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Utility of Enaminonitriles in Heterocyclic Synthesis
ꢁ
1
ꢀ
to the reaction mixture with stirring at 5–10 C; it was further
stirred for 3 h and poured into ice water; the solid obtained was
filtered, dried, and recrystallized from ethanol to afford 5. Yield
of bands at n = 1690–1680 cm corresponding to (amide
ꢁ
1
C═O) and bands at n = 2210–2190 cm corresponding to
n (C ꢂ N) functions. Also, the mass spectra of compounds
ꢀ
ꢁ1
(
2
88%). mp 152 C; orange powder, IR (KBr) cm : 3151 (NH),
173 (CN), 1641 (C═O), 1494 (N═N), 1178 (C═S), H-NMR
(400 MHz, DMSO-d ): d , 1.59–1.71 (m, 6H, 3CH , piperidine,
J = 7.2Hz), 2.44 (s, 3H, CH ), 2.91 (s, 3H, SCH ), 3.10 (s,
, piperidine, J = 7.2Hz),
7.15–7.50 (m, 5H, Ar–H), 7.97 (br, s, 1H, NH), C-NMR
100 MHz, DMSO-d ): dppm, 195.1 (C═S), 174.2 (C–NH), 160.4
C═O), 160.1 (C–CH ), 136.6, 130.5, 129.1, 123.0, (Ar–C),
03.7 (C–N═N), 113.0 (CN), 88.2 (C–CN), 51.6, 26.2, 24.1
5CH , piperidine), 39.8 (N–CH ), 25.7 (S–CH ), 15.1 (CH ).
MS: (m/z, %): 455 (M , 60.1) 239 ,(24.2) 288 ,(30.4) 384 ,(29.6),
88 (43.5), 175 (57.8), 144 (47.8), 84 (78.8), 70 (45.2). Anal.
Calcd for C H N OS (455.60): C, 55.36; H, 5.53; N, 21.52%.
1
(
2
6–21 showed the molecular ion peaks at m/z = 497
1
+
+
+
M + 2, 21.2%), 430 (M ꢁ CH , 35.7%), 536 [M ꢁ (H O,
3
2
6
ppm
2
+
+
CH ), 4.2%], 541 (M + 1, 17.9%), 497 (M ꢁ CO , 7.7%),
3
2
3
3
+
and 818 (M + 7, 5.7%), respectively, which are in agree-
ment with the molecular formula of the investigated com-
pounds 16–21. The general mechanistic consideration for
the formation of the corresponding pyrroldione derivatives
3H, N–CH
3
), 3.56–3.64 (m, 4H, 2CH
2
13
(
6
(
3
1
16–21 is shown in Scheme 7.
(
2
3
3
3
+
1
EXPERIMENTAL
All melting points are recorded on Gallenkamp electric melting
21
25
7
2
Found: C, 55.41; H, 5.58; N, 21.61%.
ꢁ
1
point apparatus. The IR spectra n cm (KBr) were on PerkinElmer
Synthesis of (Z)-2-cyano-2-((E)-(1,5-dimethyl-3-oxo-2-
phenyl-2,3-dihydro-1H-pyrazol-4-yl)diazenyl)-1-(piperidin-1-
1
3
infrared spectrophotometer model 157, Grating. The C-NMR and
H-NMR spectra were run on Varian spectrophotometer at 100
1
yl)vinylcarbamo-dithioic acid (6).
To a vigorously stirred
and 400MHz, respectively, using TMS as an internal reference
solution of enaminonitrile 3 (7.35 g, 0.02 mol) in DMF (10 mL)
at RT, carbon disulphide (1.57 mL, 0.026 mol) and aqueous
sodium hydroxide (1.2 mL, 20 mol solution) were added
simultaneously over 30 min. Stirring was continued for a
further 30 min. Dilute hydrochloric acid was added dropwise
and using DMSO-d as solvent. The mass spectra (EI) were run
6
at 70 eV with JEOL JMS600 equipment and/or a Varian MAT
3
11 A spectrometer. Elemental analyses (C, H, and N) were
carried out at the Microanalytical Center of Cairo University,
Giza, Egypt. The results were found to be in good agreement
with the calculated values.
ꢀ
to the reaction mixture with stirring at 5–10 C; it was
further stirred for 3 h and poured into ice water; the solid
obtained was filtered, dried, and recrystallized from ethanol
to afford methanedithioic acid derivative 6. Yield (68%); mp
2
-[(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-
ꢀ
yl)-hydrazono]malononitrile (2) [17]. Yield (93%), mp 140 C;
yellowish orange crystals; H-NMR (400 MHz, DMSO-d6):
1
ꢀ
ꢁ1
148–150 C; red powder; IR (KBr) cm : 3187 (NH), 2350
dppm, 2.26 (s, 3H, CH ), 3.25 (s, 3H, N–CH ), 7.35–7.56 (m, 5H,
(SH), 2198 (CN), 1643 (C═O), 1565 (C═N), 1415 (N═N),
3
3
+
13
Ph), 12.1 (br., s, 1H, NH); MS: (m/z, %): 281 (M +1, 4.3), 280
1224 (C═S); C-NMR (100 MHz, DMSO-d
(C═S), 174.3 (C–NH), 160.4 (C═O), 160.1 (C–CH
3
6
): dppm, 194.8
), 136.1,
131.2, 129.1, 125.0, (Ar–C), 104.3 (C–N═N), 114.2 (CN),
88.3 (C–CN), 51.6, 26.7, 24.0 (5CH , piperidine), 39.6
(N–CH ), 25.9 (S–CH ), 14.7 (CH ). MS: (m/z, %): 357
+
(
M , 13.4), 188 (5.2), 91 (8.1), 56 (100.0).
Synthesis of (Z)-3-amino-2-((E)-(1,5-dimethyl-3-oxo-2-phenyl-
2
,3-dihydro-1H-pyrazol-4-yl)diazenyl)-3-(piperidin-1-yl)
2
acrylonitrile (3). A mixture of 2 (1.4 g, 5 mmol) and
3
3
3
+
piperidine (0.49 mL, 5 mmol) in ethanol (15 mL) was refluxed
for 5 h. The reaction mixture was left to cool, and the
precipitated solid was filtered off, dried, and recrystallized from
EtOH/DMF (2:1) mixture to afford the corresponding acyclic
(M ꢁ piperidyl, 4.7%), 220 (6.3), 188 (25.6), 112 (8.1), 119
(12.8), 100 (18.6), 95 (16.3), 77 (30.2), 56 (100.0). Anal.
Calcd for C20H N OS (441.57): C, 54.40; H, 5.25; N,
23 7 2
22.20%. Found: C, 54.47; H, 5.31; N, 22.28%.
ꢀ
enaminonitrile derivative 3. Yield (91%), mp 209 C; dark
Synthesis of 4-((E)-((1E,3E,5E)-7-amino-3-mercapto-5-
(piperidin-1-yl)-2H-1,2,4-triazepin-6-yl)diazenyl)-1,5-dimethyl-
2-phenyl-1H-pyrazol-3(2H)-one (7). Method A: A mixture of 5
(2.28 g, 5 mmol) and hydrazine hydrate (0.24 mL, 5 mmol) in
ethanol (15 mL) in the presence of catalytic amount of TEA (five
drops) was refluxed for 8 h and until the evaluation of methyl
mercaptan odor. The reaction mixture was allowed to cool at RT.
The separated solid product was filtered, dried, and recrystallized
from ethanol to furnish 7.
ꢁ
1
green crystals; IR (KBr) cm : 3392, 3334 (NH
2
), 3189
(
(
NH), 2960 (C–H, stretching), 2171 (CN), 1639 (CO), 1448
1
6
N═N); H-NMR (400 MHz, DMSO-d ): dppm, 1.58–1.69 (m, 6H,
3
CH , piperidine, J= 7.2 Hz), 2.63 (s, 3H, CH ), 3.16 (s, 3H, N–
2
3
CH ), 3.52–3.62 (m, 4H, 2CH , piperidine, J = 7.2 Hz), 7.13 (br s,
3
2
13
2
d
1
2
3
H, NH
): dppm, 173.2 (C–NH
2
), 7.31–7.52 (m, 5H, Ph); C-NMR (100 MHz, DMSO-
), 160.4 (CO), 160.1 (C–CH ), 136.5,
6
2
3
29.1, 119.5 (Ar–C), 114.8 (CN), 113.0, 95.7 (C–CN), 46.8, 25.9,
5.7 (5CH , piperidine), 39.8 (N–CH ), 13.1 (CH ). MS: (m/z, %):
Method B: A mixture of methanedithioic acid derivative 6
(2.21 g, 5 mmol) and hydrazine hydrate (0.24 mL, 5 mmol) in
ethanol (15 mL) in the presence of catalytic amount of TEA (five
drops) was refluxed for 12 h. The reaction mixture was allowed to
cool to RT. The separated solid product was filtered, dried, and
recrystallized from ethanol to furnish 7. Yield (A, 79%; B,
2
3
3
+
+
67 (M +2, 2.3), 366 (M + 1, 14.5), 338 (12.2), 280 (11.0), 215
(11.0), 189 (77.9), 152 (100.0), 86 (12.8), 63 (26.7). Anal. Calcd
for C19 O (365.43): C, 62.45; H, 6.34; N, 26.83%. Found:
23 7
H N
C, 62.52; H, 6.38; N, 26.94%.
Synthesis of [2-cyano-2-(1,5-dimethyl-3-oxo-2-phenyl-
ꢀ
ꢁ1
2
,3-dihydro-1H-pyrazol-4-ylazo)-1-piperidin-1-yl-vinyl]-
68%). mp 220 C; yellowish green needles; IR (KBr) cm :
dithiocarbamic acid methyl ester (5). To a vigorously stirred
solution of enaminonitrile 3 (7.35 g, 0.02 mol) in DMF (10 mL)
at RT, carbon disulphide (1.57 mL, 0.026mol) and aqueous
sodium hydroxide (1.2mL, 20 mol solution) were added
simultaneously over 30min. Stirring was continued for a further
3341, 3211 (NH ), 3088 (NH), 2400 (SH), 1649 (C═O), 1518
2
1
(C═N), 1492 (N═N); H-NMR (400 MHz, DMSO-d ): dppm,
6
1.03–1.08 (m, 6H, 3CH , piperidine, J = 7.2 Hz), 1.63 (s, 1H,
2
SH), 2.41 (s, 3H, CH ), 3.08 (s, 3H, N–CH ), 3.44–3.56
3
3
(m, 4H, 2CH , piperidine, J = 7.2 Hz), 4.15 (s, 1H, NH), 7.1
2
13
3
0min. Dimethyl sulfate (1.9 mL, 0.02mol) was added dropwise
2
(s, 2H, NH ), 7.32–7.52 (m, 5H, Ar–H); C-NMR (100 MHz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. A. Fadda and K. M. Elattar
Vol 000
DMSO-d
6
): dppm, 164.7 (C═O), 164.6 (C–SH), 160.6 (C–CH
3
),
(C–N═N), 53.8, 27.2, 25.1 (5CH
, piperidyl), 35.8 (N–CH ), 25.9,
2 3
+
1
53.4 (N–C═C), 151.2 (C–NH ), 136.5, 129.1, 124.1, 123.0,
25.8, 25.7, 18.5, 13.2 (CH
3
). MS: (m/z, %): 387 (M ꢁ piperidyl,
2
+
(
(
4
Ar–C), 104.5 (C–N═N), 88.3 (N═N–C), 46.8, 25.9, 24.8
5CH , piperidine), 39.8 (N–CH ), 13.9 (CH ). MS: (m/z, %):
40 (M + 1, 109 ,(40.6) 118 ,(12.5) 201 ,(26.6) 203 ,(9.4
14.1), 91 (29.7), 84 (43.8), 70 (15.6), 56 (100.0). Anal. Calcd
for C H N OS (439.54): C, 54.65; H, 5.73; N, 28.68%. Found:
2%), 386 (M ꢁ 2, 4.0), 376 (6.0), 307 (17.4), 266 (12.1), 215
(13.4), 188 (15.4), 153 (12.1), 109 (11.4), 96 (14.8), 84 (23.5), 67
2
3
3
+
27 7 2
(22.8), 56 (100.0). Anal. Calcd for C26H N O (469.54): C, 66.51;
H, 5.80; N, 20.88%. Found: C, 66.58; H, 5.86; N, 20.93%.
(
4-((E)-((1Z,3E)-5-Imino-3-(piperidin-1-yl)-5H-naphtho[2,1-b]
20 25 9
[
1,5]oxazocin-4-yl)diazenyl)-1,5-dimethyl-2-phenyl-1H-pyrazol-3
C, 54.73; H, 5.69; N, 28.74%.
Synthesis of (4E,6E)-7-amino-6-((E)-(1,5-dimethyl-3-oxo-2-
phenyl-2,3-dihydro-1H-pyrazol-4-yl)diazenyl)-5-(piperidin-1-
ꢀ
(2H)-one (13). Yield (74%). mp: 258 C; dark red crystals; IR
ꢁ
3
1
(KBr) cm : 3316, 3251 (NH
), 1644 (CO), 1541 (C═N), 1423
(N═N); C-NMR (100MHz, DMSO-d ): dppm, 164.3 (C═NH),
164.0 (C═N), 163.5 (C═O), 160.7 (N–C–N), 160.3 (C–CH ),
2
1
yl)-1,4-thiazepin-3(2H)-one (9).
mmol) and thioglycolic acid (0.28 g, 4 mmol) in pyridine
15 mL) was refluxed on a water bath for 12h and allowed to
A solution of 3 (1.47 g,
6
4
(
3
153.6 (C–O), 133.7, 133.6, 132.4, 131.8, 129.4, 128.2, 127.6,
124.1, 123.7, 122.7, 118.0, 116.8 (Ar–C), 109.4 (C═C), 103.5
stand at RT for 1 day. The solution was then triturated with
aqueous ethanol (50 mL). The precipitated solid was filtered off
and recrystallized from ethanol to afford 9. Yield (74%); mp
(C–N═N), 83.1 (C–N═N), 53.6, 27.3, 25.2 (5CH
39.8 (N–CH ), 25.9, 25.8, 25.7, 13.8 (CH ). MS: (m/z, %): 438
, piperidyl),
2
3
3
ꢁ1
+
ꢀ
1
72 C; brown powder; IR (KBr) cm : 3282, 3261 (NH ), 1635
(M ꢁ piperidyl, 7.3%), 280 (25.5), 210 (16.4), 188 (12.7), 170
2
1
3
(
2C═O), 1492 (C═N), 1448 (N═N); C-NMR (100 MHz,
DMSO-d ): dppm, 197.3 (C═O), 165.1 (C–NH ), 160.4 (C═O),
60.1 (C═N), 159.8 (C–CH ), 136.8, 129.7, 123.3, 122.2 (Ar–C),
03.4 (C–N═N), 78.3 (C═C–NH ), 46.8, 26.2, 24.1 (5CH ,
(20.0), 119 (45.5), 96 (23.6), 77 (54.5), 56 (100.0). Anal. Calcd
29 7 2
for C30H N O (519.6): C, 69.35; H, 5.63; N, 18.87%. Found:
C, 69.42; H, 5.72; N, 18.95%.
6
2
1
1
3
General procedure for the synthesis of naphtho[(1,2-b) and
2
2
(2,1-b)][1,4,5]oxadiazocin-3-yl)diazenyl)-1,5-dimethyl-2-phenyl-
piperidine), 35.8 (N–CH ), 32.4 (CH ), 13.3 (CH ). MS: (m/z, %):
3
2
3
+
1H-pyrazol-3(2H)-one derivatives 14 and 15. An equimolar
4
39 (M , 16.7), 175 (20.0), 146 (20), 132 (20.0), 121 (40), 111
53.3), 100 (40), 86 (20.0), 76 (100). Anal. Calcd for
S (439.53): C, 57.38; H, 5.73; N, 22.31%. Found: C,
amounts of enaminonitrile derivative 3 (1.84 g, 5mmol) and
nitroso derivatives, namely, 1-nitroso-2-naphthol (0.87 g, 5 mmol)
or 2-nitroso-1-naphthol (0.87 g, 5 mmol) in ethanol (15 mL) in the
presence of catalytic amount of TEA (six drops) were refluxed for
12 and 13 h, respectively. The reaction mixture was left to cool at
RT. The precipitated solid was filtered off, washed with ethanol,
dried, and recrystallized from ethanol to yield oxadiazocine
derivatives 14 and 15, respectively.
(
21 25 7 2
C H N O
5
7.46; H, 5.80; N, 22.37%.
Synthesis of (E)-2-((E)-(1,5-dimethyl-3-oxo-2-phenyl-2,3-
dihydro-1H-pyrazol-4-yl) diazenyl)-3-((Z)-2-oxoindolin-3-
ylideneamino)-3-(piperidin-1-yl)acrylonitrile (11). A mixture
of 3 (1.84g, 5 mmol) and isatin (0.74g, 5 mmol) in ethanol
(15 mL) containing few drops of glacial acetic acid was refluxed
for 20h. The reaction mixture was poured into ice-cold water. The
formed solid product was filtered, dried, and crystallized from
4-((E)-((1Z,3E)-5-Imino-3-(piperidin-1-yl)-5H-naphtho[2,1-
b][1,4,5]oxadi-azocin-4-yl)diazenyl)-1,5-dimethyl-2-phenyl-1H-
ꢀ
ꢀ
ethanol to yield 11. Yield (83%). mp: 240 C; light brown powder;
pyrazol-3(2H)-one (14). Yield (71%). mp: 256 C; dark gray
ꢁ
1
ꢁ1
IR (KBr) cm : 1641, 1679 (2CO), 1538 (C═N), 1417 (N═N);
powder; IR (KBr) cm : 3109 (NH), 1652 (CO), 1423 (2N═N);
13
13
C-NMR (100MHz, DMSO-d
C═O), 160.1 (C–CH ), 153.7 (C═N), 141.2 (CO–NH), 143.2,
34.7, 131.3, 130.6, 124.8, 123.7, 121.6, 119.8, 117.8 (Ar–C),
6
): dppm, 173.3 (N–C–N), 160.6
C-NMR (100 MHz, DMSO-d
(C═O), 160.3 (C–CH ), 155.2 (C–O), 147.8 (N–C–N), 136.6,
3
6
): dppm, 164.7 (C═NH), 160.8
(
3
1
1
5
135.5, 130.3, 130.1, 129.6, 129.0, 128.6, 127.0, 124.5, 123.7,
122.3, 119.6 (Ar–C), 102.7 (C–N═N), 95.3 (C–N═N), 39.8
14.8 (CN), 108.2 (C–CN), 103.5 (C–N═N), 39.9 (N–CH3),
3.8, 26.8, 24.6 (5CH , piperidyl), 13.3 (CH ). MS: (m/z, %): 480
(N–CH ), 49.8, 26.2, 25.1 (5CH , piperidyl), 13.6 (CH ). MS:
2
3
3 2 3
+
+
(
M ꢁ CH
55 (30.6), 117 (61.2), 77 (100.0). Anal. Calcd for C27
494.55): C, 65.57; H, 5.30; N, 22.66%. Found: C, 65.64; H,
3
, 10.2), 319 (14.3), 280 (14.3), 248 (30.6), 213 (38.8),
(m/z, %): 520 (M , 3.7%), 466 (3.7), 364 (4.5), 329 (5.2), 280
1
H N O
26 8 2
(11.9), 214 (17.9), 188 (11.9), 151 (10.4), 119 (19.4), 84 (36.6),
56 (100.0). Anal. Calcd for C29H N O (520.59): C, 66.91; H,
28 8 2
(
5
.33; N, 22.72%.
5.42; N, 21.52%. Found: C, 66.86; H, 5.45; N, 21.56%.
General procedure for the synthesis of benzo[b][1,5]oxazocin
4-((E)-((3E,5Z)-2-Imino-4-(piperidin-1-yl)-2H-naphtho[1,2-b]
[1,4,5]oxadi-azocin-3-yl)di-azenyl)-1,5-dimethyl-2-phenyl-1H-
and naphtho[2,1-b][1,5]oxazocin derivatives 12 and 13. An
equimolar amounts of enaminonitrile derivative 3 (1.84 g, 5 mmol)
and aldehyde derivatives, namely, salicyaldehyde (0.53 mL,
mmol) or 2-hydroxy-1-naphthaldehyde (0.86 g, 5 mmol) in
ethanol (20 mL) in the presence of catalytic amount of TEA
four drops) were refluxed for 13 and 15h, respectively. The
reaction mixture was left to cool at RT. The precipitated solid was
filtered off, washed with ethanol, dried, and recrystallized from
ethanol to yield oxazocine derivatives 12 and 13, respectively.
ꢀ
pyrazol-3(2H)-one (15). Yield (64%). mp: 234 C; dark green
ꢁ
1
powder; IR (KBr) cm : 3116 (NH), 1648 (CO), 1418 (2 N═N);
13
5
6
C-NMR (100 MHz, DMSO-d ): dppm, 165.8 (C═NH), 160.4
(C═O), 160.1 (C–CH ), 153.7 (C–O), 147.8 (N–C–N), 134.6,
3
(
136.5, 131.9, 129.1, 127.0, 126.7, 123.6, 122.3, 121.0, 120.8
(Ar–C), 112.8 (C–N═N), 104.1, 95.3 (C–N═N), 35.8 (N–CH3),
51.8, 26.3, 25.2 (5CH , piperidyl), 13.2 (CH ). MS: (m/z, %):
2
3
+
505 (M ꢁ CH , 38.5%), 281 (7.3), 212 (46.2), 183 (53.8), 103
3
4
-((E)-((3E,5Z)-2-Imino-4-(piperidin-1-yl)-2H-benzo[b][1,5]
(46.2), 88 (83.5), 72 (38.5), 54 (100.0). Anal. Calcd for
oxazocin-3-yl)diazenyl)-1,5-di-methyl-2-phenyl-1H-pyrazol-3(2H)-
C H N O (520.59): C, 66.91; H, 5.42; N, 21.52%. Found: C,
66.96; H, 5.48; N, 21.59%.
29 28 8 2
ꢀ
one (12). Yield (69%). mp: 231 C; dark red crystals; IR (KBr)
ꢁ
1
cm : 3174, 3141 (NH
2
), 1648 (CO), 1527 (C═N), 1452 (N═N),
General procedure for the synthesis of pyrroldione derivatives
13
1
1
1
1
153 (C–O, stretching); C-NMR (100 MHz, DMSO-d
64.6 (C═NH), 164.2 (N–C–N), 163.8 (N═C), 160.5 (C═O),
60.1 (C–CH ), 158.3 (C–O), 136.7, 133.1, 133.7, 129.1, 122.3,
21.4, 119.8, 115.3 (Ar–C), 119.7 (C═C), 103.5 (C–N═N), 82.4
6
): dppm
,
16–21.
An equimolar amounts of enaminonitrile derivative 3
(1.84 g, 5 mmol) and different anhydride derivatives, namely,
phthalic anhydride (0.74 g, 5 mmol), maleic anhydride (0.49 g,
5 mmol), 1,2,4,5-benzene tetracarboxylic anhydride (1.18 g,
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Utility of Enaminonitriles in Heterocyclic Synthesis
ꢀ
ꢁ1
5
mmol), 4-nitrophthalic anhydride (0.97 g, 5 mmol), 1,2,4-benzene
290 C; brown powder; IR (KBr) cm : 1690 (C═O, amide),
13
tricarboxylic anhydride (0.96 g, 5 mmol), or tetrabromophthalic
anhydride (2.32 g, 5 mmol) in the presence of freshly fused sodium
acetate (5 mmol) were fused in sand bath for 2 h. The reaction
mixture was left to cool at RT. The precipitated solid was treated
with concd HCl then washed with water, filtered off, dried, and
recrystallized from ethanol to yield the corresponding pyrroldione
1651 (CO), 2190 (CN); C-NMR (100 MHz, DMSO-d ): dppm,
173.1, 169.8, 160.4 (4C═O), 160.1 (N–C–N), 159.7 (C–CH ),
3
138.6, 136.7, 136.5, 134.9, 132.1, 126.9, 124.0, 123.5, 123.8
(Ar–C), 114.7 (CN), 103.8 (C–N═N), 92.0 (C–CN), 50.4,
26.8, 25.3 (5CH , piperidyl), 39.8 (N–CH ), 26.1, 25.9, 25.8,
6
2
3
+
13.3 (CH ). MS: (m/z, %): 497 (M ꢁ CO , 7.7%), 329 (10.3),
3
2
derivatives 16–21, respectively.
119 (15.4), 104 (20.5), 84 (17.9), 77 (43.6), 64 (100.0), 56
(10.3). Anal. Calcd for C28 (539.54): C, 62.33; H,
0
(
E)-N -(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
25 7 5
H N O
pyrazol-4-yl)-2-(1,3-dioxoiso-indolin-2-yl)-2-(piperidin-1-yl)
4.67; N, 18.17%. Found: C, 62.39; H, 4.82; N, 18.22%.
(E)-N -(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-
4-yl)-2-(piperidin-1-yl)-2-(4,5,6,7-tetrabromo-1,3-dioxoisoindolin-
ꢀ
0
acetohydrazonoyl cyanide (16). Yield (71%). mp: 263 C; brown
ꢁ
1
powder; IR (KBr) cm : 1683 (C═O, amide), 1643 (CO), 2196
13
ꢀ
(
CN); C-NMR (100 MHz, DMSO-d
6
): dppm, 166.8 (2C═O),
2-yl)aceto-hydrazonoyl cyanide (21). Yield (66%). mp: 295 C;
ꢁ
1
1
1
1
60.4 (C═O), 161.2 (N–C–N), 160.1 (C–CH ), 135.8, 134.5,
32.4, 130.5, 124.1, 123.6, 122.9 (Ar–C), 114.6 (CN), 113.2,
3
brown powder; IR (KBr) cm : 2203 (CN), 1688 (C═O, amide),
13
1641 (CO); C-NMR (100MHz, DMSO-d ): dppm, 167.2,
6
03.0 (C–N═N), 91.7 (C–CN), 35.7 (N–CH ), 50.3, 25.9, 25.5
162.8 (3C═O), 160.5 (N–C–N), 160.1 (C–CH ), 139.3, 134.8,
3
3
+
(
5CH
2
, piperidyl), 13.0 (CH
3
). MS: (m/z, %): 497 (M + 2,
131.6, 125.6, 129.3, 124.2, 123.1 (Ar–C), 114.7 (CN), 102.7
2
9
6
1.2%), 388 (5.3), 333 (21.1), 229 (36.8), 186 (31.6), 147 (47.4),
3 (60.5), 56 (100.0). Anal. Calcd for C27 (495.53): C,
(C–N═N), 92.7 (C–CN), 36.7 (N–CH
3
), 50.2, 26.8, 25.3
+
H N O
25 7 3
(5CH , piperidyl), 13.3 (CH ). MS: (m/z, %): 818 (M + 7,
2
3
5.44; H, 5.09; N, 19.79%. Found: C, 65.37; H, 5.13; N, 19.86%.
5.7), 729 (11.4%), 627 (14.3), 524 (17.1), 462 (25.7), 420
(17.1), 338 (20.0), 267 (25.7), 160 (14.3), 118 (20.0), 94
0
(
E)-N -(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-
4
-yl)-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-2-(piperidin-1-yl)
4 7 3
(25.7), 84 (100.0), 56 (56.7). Anal. Calcd for C27H21Br N O
(811.12): C, 39.98; H, 2.61; N, 12.09%. Found: C, 39.92; H,
2.57; N, 12.01%.
ꢀ
acetohydrazonoyl cyanide (17).
brown powder; IR (KBr) cm : 1690 (C═O, amide), 1653 (CO),
Yield (76%). mp: 280 C;
ꢁ
1
13
2
192 (CN); C-NMR (100 MHz, DMSO-d ): dppm, 164.2, 161.3
6
(
3C═O), 161.0 (N–C–N), 160.6 (C–CH ), 136.5 (C═C), 134.6,
3
1
30.2, 125.1, 124.1 (Ar–C), 114.6 (CN), 103.2 (C–N═N), 92.3
REFERENCES AND NOTES
(
(
(
(
C–CN), 50.3, 25.9, 25.7 (5CH , piperidyl), 39.8 (N–CH ), 13.5
2
3
+
CH ). MS: (m/z, %): 430 (M ꢁ CH , 35.7%), 381 (35.7), 230
3
3
[
1] Madkour, H. M. F.; Afify, A. A. E.; Abdalha, A. A.;
Elsayed, G. A.; Salem, M.S. Phosphorus Sulfur Silicon Rel Elem
009, 184, 719.
[2] Shaaban, M. R.; Saleh, T. S.; Farag, A. M. Heterocycles 2009,
78, 151.
[3] Elkholy, A.; Al-Qalaf, F.; Elnagdi, M. H. Arkivoc 2008, xiv, 124.
4] Salaheldin, A. M.; Oliveira-Campos, A. M. F.; Rodrigues,
L. M. Arkivoc 2008, xiv, 180.
5] Madkour, H. M. F.; Afify, A. A. E.; Elsayed, G. A.; Salem,
M. S. Bulg Chem Comm 2008, 40, 147.
6] Azab, M. E. Phosphorus Sulfur Silicon Rel Elem 2008,
183, 1766.
[7] Dyachenko, V. D.; Dyachenko, A. D. Russ J Org Chem 2008,
44, 412.
50.0), 188 (100.0), 184 (71.4), 110 (64.3), 109 (50.0), 108
35.7), 96 (64.3), 93 (64.3), 84 (50.0), 83 (71.4), 77 (28.6). Anal.
2
Calcd for C23
Found: C, 61.87; H, 5.12; N, 21.85%.
E)-2-(2-Cyano-2-(2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-
dihydro-1H-pyrazol-4-yl)hydrazono)-1-(piperidin-1-yl)ethyl)-1,3-
dioxoisoindoline-5,6-dicarboxylic acid (18). Yield (69%). mp:
23 7 3
H N O (445.47): C, 62.01; H, 5.20; N, 22.01%.
(
[
ꢁ1
[
ꢀ
>
300 C; brown powder; IR (KBr) cm : 1687 (C═O, amide),
13
1
1
1
1
6
662 (CO), 2207 (CN). C-NMR (100 MHz, DMSO-d ): dppm,
[
68.4, 166.8, 161.4 (5C═O), 161.2 (NꢁCꢁN), 160.3 (CꢁCH ),
3
37.4, 134.4, 133.3, 136.8, 130.7, 128.1, 124.4, 123.3 (Ar-C),
14.8 (CN), 103.0 (CꢁN═N), 91.6 (CꢁCN), 50.3, 26.8, 25.4
[
8] Wamhoff, H.; Dzeni, J.; Hirota, K. Uracils: versatile starting
materials in heterocyclic synthesis. Adv Heterocyl Chem 1992,
5, 129.
9] Ferraz, H. M. C.; Goncalo, E. R. S. Quim Nova 2007,
30, 957.
(
2 3 3
5CH , piperidyl), 39.8 (N-CH ), 26.0, 25.9, 25.8, 13.6 (CH ).
+
MS: (m/z, %): 536 [M ꢁ (H
5.9), 280 (11.0), 216 (23.7), 171 (9.3), 102 (45.8), 56 (100.0).
Anal. Calcd for C H N O (583.55): C, 59.69; H, 4.32; N,
2 3
O, 2CH ), 4.2%], 402 (7.6), 333
5
(
[
2
9 25 7 7
1
6.80%. Found: C, 59.73; H, 4.41; N, 16.89%.
[
10] Elassar, A.; El-Kair, A. Tetrahedron 2003, 59, 8463.
[11] Nergi, G.; Kascheres, C.; Kascheres, A. J. J Heterocycl Chem
0
(
E)-N -(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-
4
-yl)-2-(5-nitro-1,3-dioxoiso-indolin-2-yl)-2-(piperidin-1-yl)
2004, 41, 461.
ꢀ
acetohydrazonoyl cyanide (19). Yield (81%). mp: 270 C;
brown powder; IR (KBr) cm : 1680 (C═O, amide), 1648
[12] Riyadh, S. M.; Abd-Elhamid, I. A.; Al-Matar, H. M.; Hilmy,
N. M.; Elnagdi, M. H. Heterocycles 2008, 75, 1849.
[13] Nishio, M.; Matsuda, M.; Ohyanagi, F.; Sato, Y.; Okumura, S.;
Tabata, D.; Morikawa, A.; Nakagawa, K.; Horai, T. Lung Cancer 2005,
ꢁ
1
13
(CO), 2210 (CN); C-NMR (100 MHz, DMSO-d
6
): dppm, 167.6,
1
1
1
61.7 (3C═O), 160.6 (N–C–N), 160.2 (C–CH ), 152.3, 138.3,
33.7, 132.5, 130.6, 129.3, 128.2, 124.5, 123.0, 122.3 (Ar-C),
14.7 (CN), 103.0 (C–N═N), 92.7 (C–CN), 50.3, 26.8, 24.3
3
49, 245.
[14] Bondock, S.; Rabie, R.; Etman, H. A.; Fadda, A. A. Eur J Med
Chem 2008, 43, 2122.
(
(
2
(
5CH
m/z, %): 541 (M + 1, 17.9%), 540 (M ꢁ 2, 21.4%), 240 (14.3),
27 (35.7), 199 (25.0), 188 (32.1), 173 (25.0), 142 (17.9), 119
35.7), 84 (100.0), 56 (96.4). Anal Calcd for C H N O (540.53):
2
, piperidyl), 39.8 (N–CH
3
), 25.9, 25.7, 25.6, 13.2 (CH
3
). MS:
[15] Mahmoud, M.; Abdel-Kader, R.; Hassanein, M.; Saleh, S.;
Botros, S. Eur J Pharmacol 2007, 569, 222.
+
+
[
16] Rostom, S. A. F.; El-Ashmawy, I. M.; Abd El Razik,
H. A.; Badr, M. H.; Ashour, H. M. A. Bioorg Med Chem 2009,
7, 882.
17] Kry ꢀs tof, V.; Canka ꢀr , P.; Fry ꢀs ová, I.; Slouka, J.; Kontopidis, G.;
27 24 8 5
1
C, 59.99; H, 4.48; N, 20.73%. Found: C, 59.86; H, 4.53; N, 20.82%.
E)-2-(2-Cyano-2-(2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-
dihydro-1H-pyrazol-4-yl)hydrazono)-1-(piperidin-1-yl)ethyl)-1,3-
dioxoisoindoline-5-carboxylic acid (20). Yield (76%). mp:
[
(
D ꢀz ubák, P.; Hajdúch, M.; Srovnal, J.; de Azevedo, W. F., Jr.; Orság, M.;
Paprská ꢀr ová, M.; Rolík, J.; Látr, A.; Fischer, P. M.; Strnad, M. J Med
Chem 2006, 49, 6500.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. A. Fadda and K. M. Elattar
Vol 000
[
18] Fadda, A. A.; Refat, H. M.; Zaki, M. E. A.; Abdel Razik, H. H.
Synth Commun 1999, 29, 3773.
19] Fadda, A. A.; Refat, H. M.; Zaki, M. E. A.; Monir, E. Synth
Commun 2001, 31, 3537.
[20] Fadda, A. A.; Refat, H. M.; Zaki, M. E. A.; Monier, E. Heterocycl
Commun 2006, 12, 47.
[21] Kharitonov, Yu. V.; Shults, E. E.; Shakirov, M. M.; Tolstikov,
G. A. Russ J Org Chem 2007, 43, 839.
[
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet