A novel method for the synthesis of polysubstituted diaminobenzonitrile derivatives using controlled microwave heating

Article abstract of DOI:10.1016/j.tetlet.2010.09.114

A novel, simple and efficient method for the synthesis of polysubstituted diaminobenzonitriles has been developed that involves reaction of 1,1,3-tricyano-2-aminopropionitrile with nitroolefins under controlled microwave irradiation conditions.

Full text of DOI:10.1016/j.tetlet.2010.09.114

Tetrahedron Letters 51 (2010) 6319–6321
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Tetrahedron Letters
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A novel method for the synthesis of polysubstituted diaminobenzonitrile
derivatives using controlled microwave heating
Kamal Usef Sadek a, , Raafat M. Shaker a, Mohamed Abd Elrady a, Mohamed Hilmy Elnagdi b
⇑
a Chemistry Department, Faculty of Science, Minia University, 61519 Minia, Egypt
b Chemistry Department, Faculty of Science, University of Kuwait, 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 9 June 2010
Revised 9 September 2010
Accepted 24 September 2010
Available online 15 October 2010
A novel, simple and efficient method for the synthesis of polysubstituted diaminobenzonitriles has been
developed that involves reaction of 1,1,3-tricyano-2-aminopropionitrile with nitroolefins under con-
trolled microwave irradiation conditions.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
One-pot synthesis
Diaminobenzonitrile
Controlled microwave irradiation
Polysubstituted benzenes are of considerable interest in fields
related to the organic and medicinal chemistry of natural prod-
ucts.1 Based on the fact that these substances possess common
structural features found in bioactive molecules, several polyfunc-
tionalized benzenes have been employed as precursors for the syn-
thesis of bioactive heterocycles.2 Extensive effort has been devoted
to the investigations of acceptor-donor-acceptor systems that can
serve as potential mimics for photosynthesis.3 Polysubstituted
benzenes are generally synthesized by using aromatic substitution
reactions, which introduce substituents at various arene centres.4
This approach suffers from drawbacks of atom economy5 and envi-
ronmental impact. Alternatively, polysubstituted benzenes can be
accessed starting with acyclic precursors by processes that have re-
ceived growing interest owing to their concise nature and high
regioselectivities.6
It is well documented that introduction of amino, cyano or ester
groups onto the benzene ring is difficult.7 For example, diam-
inobenzonitriles, which are useful in the synthesis of N-(2-cyano-
3-aminophenyl)oxamate or N-(2-cyano-3-aminophenyl)tetrazole-
5-carboxamide anti-allergy agents, are typically prepared using
aromatic nucleophilic substitution reactions of 2,6-difluorobenzo-
nitrile with amines. It is worth mentioning that in these processes
harsh conditions (e.g., elevated temperature, and frequently pres-
sure) are required for the displacement of the second fluorine. In
addition, displacement of the first fluorine requires the use of a
large excess of amine.8 Recently, the results of an interesting study
dealing with the synthesis of polysubstituted benzenes containing
amino and cyano groups were described by Xue et al.9 Specifically,
these workers developed a one-pot, two-step procedure for the
synthesis of polysubstituted benzenes that employed triethyl-
amine-catalyzed vinylogous Michael addition reactions of vinyl
malononitriles and nitroolefins followed by aromatization of the
acyclic product promoted by heating in the presence of sodium
ethoxide. Also, Su et al.10 reported a convenient synthesis of poly-
functionalized benzenes that relied on Cu(OTf)2/Et3N-catalyzed
cyclocondensation of vinyl malononitriles and ethyl vinylcyanoac-
etate with nitroolefins in refluxing acetonitrile. Wang et al.11 de-
scribed a similar reaction promoted by triethylbenzylammonium
chloride (TEBAC) that utilized arylidenemalononitriles instead of
nitroolefins and which occurred in aqueous media in the presence
of K2CO3 at 50 °C. Although, these methods have specific merits,
they sometimes require extended reaction times, expensive and
environmentally harmful catalysts and/or lengthy procedures that
consume excess reagents.
Extensive effort has been given to the adoption of green tech-
nologies in synthetic organic chemistry. One such technology
involves microwave heating since it has advantageous features
that include operational simplicity, enhanced reaction rates, and
high yields and purities of products.12 In continuation13 of our
studies on performing reactions using microwave heating we have
developed an efficient one-pot method for the synthesis of poly-
substituted diaminobenzonitrile derivatives from simple starting
materials under controlled microwave heating conditions. The re-
sults are described below.
With the initial aim of optimizing the experimental conditions,
we explored the reaction of 1,1,3-tricyano-2-aminopropionitrile
(1) and (E)-(2-nitrovinyl)benzene (2a) in the presence of three
⇑
Corresponding author.
E-mail address: kusadek@yahoo.com (K.U. Sadek).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.114

6320
K. U. Sadek et al. / Tetrahedron Letters 51 (2010) 6319–6321
NH2
NC
2N
NO2
Ar
H
CN
NO2
MW / 100 °C
NC
CN
CN
3
+
1,4-dioxane/piperidine
Ar
H2N
NH2
NC
NO2
Ar
2
1
NC
N
4
Scheme 1.
drops of piperidine as the catalyst (Scheme 1). The reaction pro-
moted by microwave irradiation at 80 °C over 15 min did not occur
when water was used as the solvent, while in ethanol the process
led to a low yield of the target benzene derivative 3a. 1,4-Dioxane
was found to be the best solvent for this reaction. Other catalysts
such as triethylamine and sodium ethoxide were screened but they
resulted in low yielding reactions. To determine the role of the cat-
alyst, the reaction of 1,1,3-tricyano-2-aminopropionitrile (1) and
2a was carried out in the absence of catalyst under the same
reaction conditions. In this case, 3a was not formed even after pro-
longed microwave irradiation. This result indicates the require-
ment for the secondary amine catalyst in this transformation.
Finally, irrespective of the aryl substituent, reactions utilizing a
variety of nitroolefins took place in reasonable yields (Table 1).
The structures of compounds 3 could be established on the
basis of analytical and spectral data. Mass spectra of 3c showed
M+ peak at 309.2 (100%). 1H NMR revealed a broad singlet at
d = 5.04 ppm due to the four D2O exchangeable hydrogens of the
two amino functions. In addition it showed two doublets at
d = 7.07 and 7.39 ppm (J = 5.2 Hz) for aromatic protons and a sin-
glet at d = 3.82 ppm for OCH3 group. This excludes the possible for-
mation of the acyclic adducts 6 and 7 either by the addition of
active methylene or amino function in 1 to the activated double
bond in 2c or the pyridine derivative 4 produced from cyclization
of 7 and aromatization. 13C NMR measurements further confirm
this conclusion as no signals for sp3 carbons were found.
Table 1
Microwave-promoted synthesis of diaminobenzonitiles14
Entry
Ar
Product
Yield (%)
1
2
3
4
5
6
C6H5
3a
3b
3c
3d
3e
3f
73
70
72
70
72
70
C6H4Cl-p
C6H4–OMe-p
C6H4–NO2-m
2-Furyl
3,4-Cl2C6H3
NO2
NC
CO2Et
An attempt to extend the scope of this process to condensations
of ethyl cyanoacetate dimer 5 and nitroolefins 2 was unsuccessful.
Starting materials were recovered even after prolonged microwave
irradiation (Scheme 2). This could be a consequence of the compar-
atively weaker electron-withdrawing ability of CO2Et compared to
CN.
MW / 100 °C
+
No reaction
CO2Et
Ar
H2N
2
5
Scheme 2.
NH2
NC
CN
NC
CN NO2
NC
NO2
Ar
O2N
NC
CN
CN
piperidine
H2N
H2N
Ar
H2N
Ar
H2N
CN
CN
CN
[O]
1
2
6
air
NH2
NC
NO2
Ar
H2N
NH2
NO2
CN
3
NH2
NC
CN NO2
NC
NC
NC
NO2
Ar
[O]
air
NC
N
Ar
N
H
7
Ar
N
H
CN
4
Scheme 3.

K. U. Sadek et al. / Tetrahedron Letters 51 (2010) 6319–6321
6321
1359; (d) Smith, M. B.; March, J. In Advanced Organic Chemistry, 5th ed.; Wiley-
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9. Xue, D.; Li, J.; Zhang, Z.-T.; Deng, J.-G. J. Org. Chem. 2007, 72, 5443.
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Microwave-Enhanced Chemistry; Kinsington, H. M., Haswell, S. J., Eds.; American
Chemical Society: Washington, DC, 1997; p 455.
A plausible mechanism for the formation of 3, displayed in
Scheme 3, involves Michael addition of the carbanion produced
from 1 to the activated double bond of the nitroolefin yielding Mi-
chael adduct intermediate 6 followed by cyclization and aromati-
zation via aerial oxidation. Addition of the enamine nitrogen in 1
to the activated double bond in 2 would result in the formation
of acyclic adduct 7 which upon cyclization and aerial oxidation
would produce pyridine derivative 4
In conclusion, the method described above represents a simple
and convenient protocol for the microwave irradiation promoted
synthesis of polysubstituted diaminobenzonitrile derivatives from
simple starting materials.
13. (a) Barsy, M. A.; Abdel Ltif, F. M.; Aref, A. M.; Sadek, K. U. Green Chem. 2002, 4,
196; (b) Mekheimer, R. A.; Sadek, K. U. J. Heterocycl. Chem. 2009, 295; (c)
Mekheimer, R. A.; Abdel-Hameed, A.; Sadek, K. U. Green Chem. 2008, 10, 592;
Sadek, K. U.; Al-Qalay, F.; Abdelkhalik, M. M.; Elnagdi, M. H. J. Heterocycl. Chem.
2010, 47, 284.
14. General procedure for the synthesis of polysubstituted diaminobenzonitrile
derivatives 3. A solution of 1,1,3-tricyano-2-aminopropionitrile 1 (1 mmol)
and nitroolefin 2 (1 mmol) in 1,4-dioxane (15 mL) and piperidine (three drops)
was heated under reflux in a Milestone Microwave Labstation at 100 °C for
15 min. The solvent was evaporated under reduced pressure and the residue
was triturated with ice cold water and neutralized with HCl. The solid product
was collected by filtration and crystallized from EtOH. Spectral data for
selected products.
Acknowledgment
K.U.S. is grateful to the AvH foundation for donating a Milestone
Microwave Labstation which was of great help in finishing this
work.
References and notes
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3,5-Diamino-6-nitrobiphenyl-2,4-dicarbonitrile (3a). Greenish yellow powder,
mp 305–306 °C, yield: 73%. 1H NMR (400 MHz, DMSO-d6): d: 7.31–7.29 (m, 4H,
integrated for 2H on D2O exchange); 7.39 (br s, 2H, D2O exchangeable); 7.47–
7.45 (m, 3H, Ar-H); 13C NMR (100 MHz, DMSO-d6): d: 86.0, 86.4, 115.6, 117.2,
125.3, 127.6, 127.7, 129.4, 136.2, 150.8, 159.7. IR (KBr)
3215, 2923, 2215, 1638 cmꢀ1. MS (EI): m/z (%) = 279.1 (100). Anal. Calcd for
14H9N5O2: C, 60.21; H, 3.25; N, 25.08. Found: C, 60.11; H, 3.37; N, 25.13.
mmax: 3437, 3350, 3320,
C
3,5-Diamino-40-methoxy-6-nitrobiphenyl-2,4-dicarbonitrile
(3c).
Greenish
yellow powder, mp 266–267 °C, yield: 72%. 1H NMR (400 MHz, DMSO-d6): d:
3.82 (s, 3H), 5.07 (br s, 4H, D2O exchangeable); 7.07 (d, J = 5.2 Hz, 2H), 7.39 (d,
J = 5.2 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): d: 55.6, 86.0, 86.4, 114.7, 115.9,
3. Kurreck, H.; Huber, M. Angew. Chem., Int. Ed. Engl. 1995, 34, 849.
4. (a) Olah, G.. In Friedel–Crafts and Related Reactions; Wiley Interscience: New
York, 1963; Vols. I–IV, (b) Pearson, D. E.; Buehler, C. A. Syntheses 1972, 533; (c)
Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemarire, M. Chem. Rev. 2002, 102,
117.3, 125.2, 128.9, 130.2, 141.1, 150.7, 159.5, 159.9. IR (KBr)
3322, 2924, 2215, 1633 cmꢀ1. MS (EI): m/z (%) = 309.2 (100). Anal. Calcd for
15H11N5O3: C, 58.25; H, 3.58; N, 22.64. Found: C, 58.19; H, 3.63; N, 22.60.
mmax: 3435, 3340,
C