A novel synthesis of 2-arylhydrazono-6-amino-4-arylbenzene-1,3-dicarbonitriles and their conversion into phthalazines

Article abstract of DOI:10.1016/j.tetlet.2009.08.037

Compounds 1a-d react with benzylidenemalononitrile 2 to yield dihydroaminopyridazines 3a-d and, in contrast, compounds 1e,f react with 2 under the same conditions to yield aminobenzenedicarbonitriles 8e,f compound 8e underwent intramolecular cyclization t

Full text of DOI:10.1016/j.tetlet.2009.08.037

Tetrahedron Letters 50 (2009) 6411–6413
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel synthesis of 2-arylhydrazono-6-amino-4-arylbenzene-
1,3-dicarbonitriles and their conversion into phthalazines
*
Saleh M. Al-Mousawi , Moustafa Sherief Moustafa, Mohamed Hilmy Elnagdi
Department of Chemistry, Faculty of Science, University of Kuwait, PO Box 12613, Safat 13060, Kuwait
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 October 2008
Revised 10 May 2009
Accepted 14 August 2009
Available online 20 August 2009
Compounds 1a–d react with benzylidenemalononitrile 2 to yield dihydroaminopyridazines 3a–d and, in
contrast, compounds 1e,f react with 2 under the same conditions to yield aminobenzenedicarbonitriles
8e,f compound 8e underwent intramolecular cyclization to phthalazine 9e. Compound 10e reacted with
2a to yield 11e.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
In conclusion, as a result of the strong electron-withdrawing
nature of the nitro substituent, the hydrazone N lone pair reacts
Recently, we reported that 2-oxo-2-arylhydrazonals 1a,b re-
acted with ,b-unsaturated nitriles 2 to yield 1,4-dihydro-6-amin-
preferably at the aryl moiety rendering the hydrazone CH inactive
toward electrophiles and a new mode of reaction is thus followed
leading to novel benzenedicarbonitrile derivatives. We are now
exploring the effect of substituents on the aryl moiety on the nat-
ure of the products.
a
opyridazines 3a,b.1–3 We were interested to see if reactions of this
type could be extended to provide a new general route to deriva-
tives of 3. Our work has revealed that, while a variety of substi-
tuted 2-oxoarylhydrazonals 1c,d reacted similar to 1a,b yielding
3c,d; p- and o-nitro-substituted derivatives 1e,f reacted differently
yielding the title compounds which could be readily cyclised into
phthalazines 9.
2. General procedure for the synthesis of compounds 3c,d
A mixture of 1c,d (0.01 mol) and benzylidenemalononitrile
(1.54 g, 0.01 mol) in EtOH (10 mL) as a solvent was treated with
5 drops of piperidine and then refluxed for 2–4 h (monitored by
TLC using a mixture of petroleum ether (bp 60–80):EtOAc 2:1).
The reaction mixture was evaporated under reduced pressure.
Compounds 1a–d reacted with 2 to yield the dihydropyrida-
zines 3a–d in good yields. Although the reaction may also yield
4, structure 3 was established based on HMBC experiments which
revealed that dihydropyridazine H-4 and the C@O function showed
cross peaks (Scheme 1).
In contrast, compounds 1e,f reacted with 2a which exists in
equilibrium with malononitrile and benzaldehyde in ethanolic
solutions, to yield products that were identified as aminobenzen-
edicarbonitriles 8e,f. These were assumed to form via initial con-
densation of malononitrile with the acetyl moiety of 1e,f to yield
intermediates 5e,f that reacted further with 2 to yield products
8e,f via intermediates 6e,f and 7e,f (Scheme 2). Compound 8e was
cyclized into the phthalazine 9e in 80% yield on reflux in DMF in
the presence of ZnCl2 (Scheme 3).
To avoid potential participation of the carbonyl group, com-
pound 1e was reduced with sodium borohydride to give 10e. This
was reacted with p-methoxybenzylidenemalononitrile 2a to give
11e which is formed via condensation of phenyl hydrazine pro-
duced by hydrolysis of 10a with aldehyde produced from hydroly-
sis of 2a.
O
Ph
CN
R
4
N
O
N
NH2
R
N
NH
CN
CN
Ph
R1
3a-d
+
O
NH2
R1
CN
Ph
R
2
1
N
a, R = H, R1 = H
b, R = Me, R1 = H
N
c, R = H, R1 = m-NO2
d, R = H, R1 = p-Cl
e, R = H, R1 = o-NO2
f, R = H, R1 = p-NO2
4
R1
* Corresponding author. Tel.: +965 24987081; fax: +965 24816482.
E-mail address: salehalmousawi@hotmail.com (S.M. Al-Mousawi).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.037

6412
S. M. Al-Mousawi et al. / Tetrahedron Letters 50 (2009) 6411–6413
CN
NC
CN
N
NC
CN
NC
H3C
2
Ph
1e,f
2a
+
N
NH
NH
R1
6e,f
R1
5e,f
NH
NH2
NH2 NH
NC
NC
Ph
CN
NC
Ph
CN
N
NC
Ph
Ar
ZnCl
2
N
N
DMF
N
NH
9e
NH
Ar = 2-NO2C6H4
R1
R1
8e,f
7e,f
Scheme 2.
OH
CH3
350 (M+, 40), 307 (100), 273 (100), 244 (20), 231 (20), 204 (15),
153 (30), 127 (25), 128 (10), 111 (50), 75 (20).
NO2
2a
Ar
N
NaBH4
N
N
NH
1e
3. General procedure for the synthesis of compounds 8e,f
H
NO2
A mixture of 1e,f (0.01 mol) and benzylidenemalononitrile
(3.08 g, 0.02 mol) in EtOH (10 mL) was treated with 5 drops of
piperidine and then refluxed for 2–4 h (monitored by TLC using a
mixture of petroleum ether (bp 60–80):EtOAc 2:1). The reaction
mixture was evaporated under reduced pressure. The solid prod-
uct, so formed, was recrystallized from EtOH to give yellow
crystals.
11e
10e
Ar = p-CH3OC6H4
Scheme 3.
The solid product, so formed, was recrystallized from EtOH to give
yellow crystals.
3.1. 2-(2-Nitrophenyl)hydrazine-6-amino-4-arylbenzene-1,3-
dicarbonitrile 8e
2.1. 6-Acetyl-3-amino-2-(3-nitrophenyl)-5-phenyl-2,5-
dihydropyr-idazine-4-carbonitrile 3c
Yield 75%; mp 297–298 °C. Anal. Calcd for C21H14N6O2 (382.38):
C, 65.96; H, 3.69; N, 21.98. Found: C, 65.79; H, 3.67; N, 21.77; IR
(KBr, cmÀ1): 3462, 3369 (NH2), 3273 (NH), 2225 (CN), 2211 (CN);
1H NMR (400 MHz, DMSO-d6): d, ppm = 6.84 (br, 2H, NH2) D2O
exchangeable, 7.02–8.13 (m, 10H, Ar–H, CH), 8.72 (s, 1H, CH),
11.65 (br, 1H, NH) D2O exchangeable; 13C NMR (125 MHz, CDCl3):
d, ppm = 154.20, 149.78, 141.87, 140.16, 139.62, 137.62, 136.30,
132.20, 129.49, 128.82 (2C), 128.51 (2C), 125.70, 119.86, 116.74,
116.12, 115.48, 115.37, 94.66, 92.19. MS: m/z (%) 382 (M+, 40),
336 (100), 320 (20), 308 (10), 256 (10), 247 (15), 219 (10), 191
(30), 164 (15), 129 (25), 83 (15), 73 (40).
Yield 85%; mp 203–205 °C. Anal. Calcd for C19H15N5O3 (361.36):
C, 63.15; H, 4.18; N, 19.18. Found: C, 63.21; H, 4.24; N, 19.00; IR
(KBr, cmÀ1): 3400, 3328 (NH2), 2181 (CN), 1685 (CO); 1H NMR
(400 MHz, DMSO-d6): d, ppm = 2.36 (s, 3H, CH3), 4.77 (s, 1H, CH),
6.37 (br, 2H, NH2) D2O exchangeable, 7.2–7.37 (m, 5H, Ar–H), 7.8–
8.31 (m, 4H, Ar–H); 13C NMR (125 MHz, CDCl3): d, ppm = 196.50
(CO), 150.93, 149.12, 145.76, 142.48, 141.96, 132.82, 131.75,
129.89 (2C), 128.22, 127.76 (2C), 123.09, 121.18, 121.13, 58.58,
37.17, 25.63. MS: m/z (%) 361 (M+, 55), 318 (100), 272 (35), 245
(20), 195 (15), 155 (15), 128 (10).
2.2. 6-Acetyl-3-amino-2-(4-chlorophenyl)-5-phenyl-2,5-
dihydro-pyridazine-4-carbonitrile 3d
3.2. 2-(4-Nitrophenyl)hydrazine-6-amino-4-arylbenzene-1,3-
dicarbonitrile 8f
Yield 80%; mp 206–208 °C. Anal. Calcd for C19H15N4OCl
(350.81): C, 65.05; H, 4.31; N, 15.97. Found: C, 65.20; H, 4.33; N,
16.10; IR (KBr, cmÀ1): 3422, 3339 (NH2), 2211 (CN), 1665 (CO);
1H NMR (400 MHz, DMSO-d6): d, ppm = 2.33 (s, 3H, CH3), 4.75 (s,
1H, CH), 6.22 (br, 2H, NH2) D2O exchangeable, 7.17–7.70 (m, 9H,
Ar–H); 13C NMR (125 MHz, CDCl3): d, ppm = 196.19 (CO), 150.73,
144.68, 142.34, 139.53, 132.55, 129.90 (2C), 129.45 (2C), 128.08
(2C), 127.89, 127.35 (2C), 120.94, 57.33, 36.52, 25.14. MS: m/z (%)
Yield 65%; mp 299–300 °C. Anal. Calcd for C21H14N6O2 (382.38):
C, 65.96; H, 3.69; N, 21.98. Found: C, 65.80; H, 3.82; N, 21.83; IR
(KBr, cmÀ1): 3456, 3355 (NH2), 3230 (NH), 2221 (CN), 2204 (CN);
1H NMR (400 MHz, DMSO-d6): d, ppm = 6.66 (br, 2H, NH2) D2O
exchangeable, 7.23–7.98 (m, 8H, Ar–H, CH), 8.22 (d, 2H, Ar–H),
8.85 (s, 1H, CH), 11.77 (br, 1H, NH) D2O exchangeable; 13C NMR
(125 MHz, CDCl3): d, ppm = 161.81, 154.44, 150.50, 146.52,
145.95, 139.83, 137.76, 132.94, 130.60, 128.92 (2C), 127.31 (2C),

S. M. Al-Mousawi et al. / Tetrahedron Letters 50 (2009) 6411–6413
6413
127.06 (2C), 124.05 (2C), 116.75, 108.51, 105.49, 94.53. MS: m/z (%)
382 (M+, 60), 336 (100), 320 (55), 256 (35), 247 (65), 191 (30), 164
(15), 129 (25), 83 (15), 73 (50).
5H, Ar–H, CH); 13C NMR (125 MHz, CDCl3): d, ppm = 145.30,
141.66, 131.07, 136.18, 125.88, 118.37, 115.75, 67.13, 21.24. MS:
m/z (%) 209 (M+, 100), 191 (30), 166 (20), 148 (25), 138 (100),
119 (25), 106 (40), 91 (60), 77 (95), 69 (80), 65 (70).
3.3. Synthesis of 5-amino-4-imino-3-(2-nitrophenyl)-7-phenyl-
3,4-dihydrophthalazine-6-carbonitrile 9e
3.5. Synthesis of 1-(4-methoxybenzylidene)-2-(2-
nitrophenyl)hydrazine 11e
A mixture of 8e (3.82 g, 0.01 mol) and zinc chloride (0.5 g) in
DMF (10 mL) was refluxed for 4–6 h (monitored by TLC using a
mixture of petroleum ether (bp 60–80):EtOAc 2:1). The reaction
mixture was evaporated under reduced pressure. The solid prod-
uct, so formed, was recrystallized from EtOH to give a dark yellow
product, yield 80%; mp 240–242 °C. Anal. Calcd for C21H14N6O2
(382.38): C, 65.96; H, 3.69; N, 21.98. Found: C, 66.19; H, 3.80; N,
22.06; IR (KBr, cmÀ1): 3468, 3371 (NH2), 3328 (NH), 2202 (CN);
1H NMR (400 MHz, DMSO-d6): d, ppm = 6.89 (br, 2H, NH2) D2O
exchangeable, 7.13 (s, 1H, CH), 7.34–8.29 (m, 10H, Ar–H, CH),
10.51 (br, 1H, NH) D2O exchangeable; MS: m/z (%) 382 (M+, 35),
346 (50), 337 (100), 320 (10), 308 (10), 280 (10), 247 (25), 219
(10), 192 (30), 164 (25), 154 (25), 102 (15), 92 (10), 65 (20).
A mixture of 10e (2.09 g, 0.01 mol) and 4-methoxybenzylidene
malononitrile (1.84 g, 0.01 mol) in EtOH (10 mL) was treated with
5 drops of piperidine, and then refluxed for 2–4 h (monitored by
TLC using a 2:1 mixture of petroleum ether:EtOAc). The reaction
mixture was evaporated under reduced pressure. The solid prod-
uct, so formed, was recrystallized from EtOH to give a red product;
yield 80%; mp 210–212 °C. Anal. Calcd for C14H13N3O3 (271.28): C,
61.99; H, 4.83; N, 15.49. Found: C, 62.12; H, 4.61; N, 15.68; IR (KBr,
cmÀ1): 3295 (NH); 1H NMR (400 MHz, DMSO-d6): d, ppm = 3.81 (s,
3H, CH3), 6.87–8.12 (m, 8H, Ar–H), 8.44 (s, 1H, CH), 11.13 (br, 1H,
NH) D2O exchangeable; 13C NMR (125 MHz, CDCl3): d,
ppm = 160.54, 145.22, 141.51, 136.36, 130.34, 128.40 (2C),
127.07, 125.03, 117.83, 115.91, 114.35 (2C), 55.27. MS: m/z (%)
271 (M+, 100), 209 (20), 181 (20), 152 (25), 137 (50), 107 (15),
91 (20), 77 (50).
3.4. Synthesis of 1-(2-(2-nitrophenyl)hydrazono)propan-2-ol
10e
Acknowledgments
A solution of 1e (2.07 g, 0.01 mol) in isopropanol (5 mL) was
cooled to 0 °C. Sodium borohydride (0.756 g, 0.02 mol) was added
and the reaction mixture was stirred (monitored by TLC using ethyl
acetate:petroleum ether 1:2, until completion). The reaction was
carefully quenched with ice-H2O and 1 M HCl solution, and then
the reaction mixture was extracted with CH2Cl2, filtered, and con-
centrated. The crude product was recrystallized from petroleum
ether (60–80) to give a red product; yield 85%; mp 102–104 °C.
Anal. Calcd for C9H11N3O3 (209.20): C, 51.67; H, 5.30; N, 20.09.
Found: C, 51.48; H, 5.33; N, 19.88; IR (KBr, cmÀ1): 3391 (OH),
3306 (NH); 1H NMR (400 MHz, DMSO-d6): d, ppm = 1.46 (d, 3H,
J = 8, CH3), 2.67 (d, 1H, J = 8, OH), 4.60 (m, 1H, CH), 6.89–8.20 (m,
The authors are grateful to Kuwait University Research Admin-
istration for the financial support of project SC10/06 and for SAF
facilities project GS01/02 and GS03/01.
References and notes
1. Al-Mousawi, S. M.; Moustafa, M. S.; Elnagdi, M. H. Heterocycles 2008, 75, 2201.
2. Ghozlan, S. A.; Abdelhamid, I. A.; Hassaneen, H. M.; Elnagdi, M. H. J. Heterocycl.
Chem. 2007, 44, 105.
3. Aziz, S. I.; Anwar, H. F.; El-Apasery, M. A.; Elnagdi, M. H. J. Heterocycl. Chem. 2007,
44, 877.