Auto-redox reaction: Tin(II) chloride-mediated one-step reductive cyclization leading to the synthesis of novel biheterocyclic 5,6-dihydro-quinazolino[4,3-b]quinazolin-8-ones with three-point diversity

Article abstract of DOI:10.1021/jo0518912

A tin (II) chloride-mediated short, efficient, and practical regioselective synthesis of biheterocyclic 5,6-dihydro-quinazolino[4,3-b]quinazolin-8-ones with three-point diversity is reported. A one-step reductive transformation of 2-(2-nitro-phenyl)-3H-quinazolin-4-one in various alcohols furnished the desired tetracyclic product in good yields with high purity.

Full text of DOI:10.1021/jo0518912

Among the nitrogen-containing heterocycles, substituted
quinazolinones and quinazolines represent the medicinally and
pharmaceutically important class of compounds5 because of their
diverse range of biological activities such as anticancer, diuretic,
anti-inflammatory, anticonvulsant, and antihypertensive agents.6
The quinazolin-4(3H)-ones ring system has traditionally been
generated by the reaction of anthranilamides with aldehydes,7
ketones, or acid chlorides under acidic or basic conditions,8 by
the condensation of imidates with anthranilic acid,9 and by aza-
Wittig reactions of R-azido-substituted aromatic imides.10 The
synthesis of quinazoline derivatives has mainly been achieved
by introducing the chlorine atom at the 4 position in the
Auto-Redox Reaction: Tin(II) Chloride-Mediated
One-Step Reductive Cyclization Leading to the
Synthesis of Novel Biheterocyclic
5,6-Dihydro-quinazolino[4,3-b]quinazolin-8-ones
with Three-Point Diversity†
Abhijeet Deb Roy, Arunachalam Subramanian, and
Raja Roy*
DiVision of SAIF, Central Drug Research Institute,
Lucknow 226 001, India
rajaroy_cdri@yahoo.com
11
quinazolinone skeleton either by using POCl3 or by using
ReceiVed September 8, 2005
thionyl chloride,12 followed by its substitution by various
primary and secondary amines or by palladium-catalyzed
intramolecular reductive N-heterocyclization.13
Although some of the methods provide useful strategies for
the synthesis of these bicyclic compounds, they suffer major
drawbacks, such as involving a multistep synthesis, producing
low yields, and requiring expensive catalysts, and are, thus, less
desirable commercially. Moreover, few methods exist in the
literature for the one-step synthesis of quinazolin-4(3H)-ones,
but they are not general in scope and require harsh conditions,
such as a very high temperature14 and hazardous metal
catalysts.15 While there are two reports16 available in the
literature dealing with the synthesis of biheterocyclic quinazoli-
noquinazolinone molecules, they involve multiple steps with
A tin(II) chloride-mediated short, efficient, and practical
regioselective synthesis of biheterocyclic 5,6-dihydro-quin-
azolino[4,3-b]quinazolin-8-ones with three-point diversity is
reported. A one-step reductive transformation of 2-(2-nitro-
phenyl)-3H-quinazolin-4-one in various alcohols furnished
the desired tetracyclic product in good yields with high
purity.
(4) (a) Acharya, A. N.; Ostresh, J. M.; Houghten, R. A. J. Comb. Chem.
2002, 4, 214. (b) Kamal, A.; Ramana, K. V.; Rao, M. V. J. Org. Chem.
2001, 66, 997. (c) Branowska, D.; Rykowski, A.; Wysocki, W. Tetrahedron
Lett. 2005, 46, 6223. (d) Goswami, S.; Adak, A. K.; Mukherjee, R.; Jana,
S.; Dey, S.; Gallagher, J. F. Tetrahedron 2005, 61, 4289. (e) Landreau, C.;
Deniaud, D.; Meslin, J. C. J. Org. Chem. 2003, 68, 4912.
(5) (a) Bonola, G.; Da Re, P.; Magistretti, M. J.; Massarani, E.; Setnikar,
I. J. Med. Chem. 1968, 11, 1136. (b) Okumura, K.; Oine, T.; Yamada, Y.;
Hayashi, G.; Nakama, M. J. Med. Chem. 1968, 11, 348.
(6) (a) Chan, J. H.; Hong, J. S.; Kuyper, L. F.; Jones, M. L.; Baccanari,
D. P.; Tansik, R. L.; Boytos, C. M.; Rudolph, S. K.; Brown, A. D. J.
Heterocycl. Chem. 1997, 34, 145. (b) Gackenheimer, S. L.; Schaus, J. M.;
Gehlert, D. R. J. Pharmacol. Exp. Ther. 1996, 732, 113. (c) Dempcy, R.
O.; Skibo, E. B. Biochemistry 1991, 30, 8480. (d) Nordisk-Droge. 18113;
Patent, N. A., Ed.; Nordisk Drogeand Kemi-Kalieforretning AIS: Luch-
thaven Schiphol, The Netherlands, 1965.
(7) For a review, see the following: Connoly, D. J.; Cusack, D.;
O’Sullivan, T. P.; Guiry, P. J. Tetrahedron 2005, 61, 10153.
(8) (a) Yale, H. L. J. Heterocycl. Chem. 1977, 14, 1357. (b) Feldman, J.
R.; Wagner, E. C. J. Org. Chem. 1942, 7, 31. (c) Mhaske, S. B.; Argade,
N. P. J. Org. Chem. 2004, 69, 4563.
(9) (a) Ried, W.; Sinharray, A. Chem. Ber. 1963, 96, 3306. (b) Hennequin,
L. F.; Boyle, F. T.; Wardleworth, J. M.; Marsham, P. R.; Kimbell, R.;
Juckman, A. L. J. Med. Chem. 1996, 39, 9. (c) Connolly, D. J.; Guiry, P.
J. Synlett 2001, 11, 1707.
Over the past decade, the synthesis of heterocycles has
become the cornerstone of synthetic organic chemistry as a result
of a wide variety of applications of these heterocycles in
medicinal and pharmaceutical chemistry.1 The exploration of
heterocycles as privileged structures in drug discovery is, beyond
doubt, one of the major areas in medicinal chemistry.2 These
privileged structures represent a class of molecules that act as
ligands for various biological receptors with a high degree of
binding affinity. Exploitation of these molecules should allow
the medicinal chemist to rapidly discover new biologically active
compounds across a broad range of therapeutic areas in a shorter
time scale.3 In recent years, the emphasis of heterocyclic
chemistry has relied on the synthesis of biheterocyclic structures
that include conjugated tri- or tetracyclic molecules consisting
of more than one privileged class of compounds.4
† CDRI Communication No. 6877.
(1) (a) ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996. (b) Undheim, K.;
Benneche, T. In AdVances in Heterocyclic Chemistry; Gilchrist, T. L.,
Gribble, G. W., Eds.; Pergamon: Oxford, 1999; Vol. 11, p 21. (c) Joule, J.
A.; Mills, K. Heterocyclic Chemistry; Blackwell Science: Oxford, 2000.
(d) Katritzky, A. R.; Pozharskii, A. F. Handbook of Heterocyclic Chemistry;
Pergamon: Oxford, 2003.
(2) For reviews, see the following: (a) Nicolaou, K. C.; Vourloinis, D.;
Winssinger, N.; Baran, P. S. Angew. Chem., Int. Ed. 2000, 39, 44. (b) Arya,
P.; Chou, D. T. H.; Back, M. G. Angew. Chem., Int. Ed. 2001, 40, 339.
(3) (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson,
P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.;
Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235.
(b) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.;
Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000, 122, 9939.
(10) (a) Takeuchi, H.; Haguvara, S.; Eguchi, S. Tetrahedron 1989, 45,
6375. (b) Takeuchi, H.; Haguvara, S.; Eguchi, S. J. Org. Chem. 1991, 56,
1535.
(11) Alexandre, F.-R.; Berecibar, A.; Wrigglesworth, R.; Besson, T.
Tetrahedron 2003, 59, 1413.
(12) (a) Rewcastle, G. W.; Palmer, B. D.; Bridges, A. J. J. Med. Chem.
1996, 39, 918. (b) Tobe, M.; Isobe, Y.; Tomizawa, H.; Nagasaki, T.;
Takahashi, H.; Fukazawa, T.; Hayashi, H. Bioorg. Med. Chem. 2003, 11,
383.
(13) Akazome, M.; Yamamoto, J.; Kondo, T.; Watanabe, Y. J. Orga-
nomet. Chem. 1995, 494, 229.
(14) (a) Gotthelf, P.; Bogert, M. T. J. Am. Chem. Soc. 1901, 23, 611.
(b) Endicott, M. M.; Wick, E.; Mercury, M. L.; Sherrill, M. J. Am. Chem.
Soc. 1946, 68, 1299.
(15) Shi, D.; Rong, L.; Wang, J.; Zhuang, Q.; Wang, X.; Hu, H.
Tetrahedron Lett. 2003, 44, 3199.
10.1021/jo0518912 CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/24/2005
382
J. Org. Chem. 2006, 71, 382-385

SCHEME 1. Novel Strategy for the Synthesis of
low yields, strongly acidic conditions, the usage of commercially
nonviable reagents, and poor regioselectivity that lead to the
formation of both linearly and angularly fused compounds.
However, these methods could achieve only 6-aryl-substituted
molecules, and there has been no report regarding the synthesis
of 6-alkyl-substituted quinazolino[4,3-b]quinazolin-8-one de-
rivatives.
5,6-Dihydro-quinazolino[4,3-b]quinazolin-8-onea
As per our ongoing efforts to synthesize privileged-class
biheterocyclic molecules,17 we herein report a convenient and
rapid one-step regioselective methodology for synthesizing
biheterocyclic trisubstituted 5,6-dihydro-quinazolino[4,3-b]-
quinazolin-8-one derivatives from 2-(2-nitrophenyl)-3H-quinazo-
lin-4-one in the presence of tin(II) chloride using a variety of
alcohols.
The initial aim of our work was to synthesize 2-(2-aminophe-
nyl)-3H-quinazolin-4-one derivatives. To accomplish this, it was
first essential to synthesize 2-(2-nitrophenyl)-3H-quinazolin-4-
one derivatives, followed by the reduction of the nitro group
using tin(II) chloride, using ethanol as a solvent. Interestingly,
the product obtained after the reduction was not the desired
2-amino derivative but rather an unusual dihydro-quinazolino
quinazolin-8-one derivative with a high yield and purity.
The strategy for the synthesis of 5,6-dihydro-quinazolino-
[4,3-b]quinazolin-8-one with three-point diversity has been
depicted in Scheme 1. The synthetic methodology commenced
with the synthesis of anthranilamide 2 by the oxidation of
2-amino benzonitrile, followed by its amidation using 2-nitro
benzoyl chloride and triethylamine to give the uncyclized amide
intermediate 3. Subsequently, the 2-(2-nitrophenyl)-3H-quinazo-
lin-4-one 4 was prepared by the oxidative ring closure of 3 under
basic conditions, using potassium hydroxide and ethanol, in
excellent yield and purity. Further, to obtain the amine
functionality, attempts were made using the conventional
procedure for the reduction of the nitro group using SnCl2 and
ethanol as a solvent, which furnished the final product in 90%
yield and in high purity. The completion of the reaction was
monitored by TLC at regular intervals, and the disappearance
of the starting material was observed within 2 h. The unexpect-
edly high Rf value of the major product 5a and a mass difference
of 4 amu rather than the expected 30 amu led us to envisage
the structure of the final product through one- and two-
dimensional NMR spectroscopy.
a Reagents and conditions: (a) 5 equiv of KOH, EtOH, reflux, 2 h, 80%;
(b) 2 equiv of TEA, CHCl3, rt, 2 h, 80-85%; (c) 10% aqueous KOH, EtOH,
reflux, 10 min, 95%; (d) R3CH2OH, 5 equiv of SnCl2‚2H2O, 80 °C, 1-2
h, 65-92% of 5a-i.
1
The H NMR spectrum of the final product 5a showed a
doublet accounting for three protons at 1.49 ppm, a multiplet
accounting for one proton at 6.42 ppm, a broad signal at 4.61
ppm accounting for an exchangeable proton, and eight aromatic
protons. Similarly, the 13C spectrum showed a methyl at 20.0
ppm and a methine carbon at 59.5 ppm, apart from the eight
aromatic methines and six quaternary carbons, which further
reinforced the formation of an unexpected product. In the
heteronuclear single-quantum coherence (HSQC) spectrum, the
multiplet at 6.4 ppm showed a correlation with the methine
carbon at 56.0 ppm, which, in the heteronuclear multiple-bond
correlation (HMBC) spectrum, provided a long-range two-bond
correlation with the methyl carbon, followed by a three-bond
correlation with three quaternary carbons, namely, the amide
carbonyl at 160.1 ppm, the 2-position quaternary carbon at 146.7
FIGURE 1. Selected HMBC and NOE correlations observed for 5a.
ppm, and the NH-substituted aromatic quaternary carbon at
143.7 ppm. The long-range heteronuclear proton carbon cor-
relations established the structure of the final product as a novel
6-methyl-5,6-dihydro-quinazolino[4,3-b]quinazolin-8-one 5a
formed after the insertion of the ethyl group between the primary
aromatic amine and the secondary amide. The selected HMBC
correlations observed for 5a have been depicted in Figure 1.
Further, the relative stereochemistry of the dihydro product was
established by one-dimensional NOE, which indicated that the
NH and the 6-position methine proton are cis in nature. Once
(16) (a) Ratnam, C. V.; Hanumanthu, P. Indian J. Chem., Sect. B 1979,
17, 349. (b) Rao, C. V. C.; Reddy, K. K.; Rao, N. V. S. Indian J. Chem.,
Sect. B 1980, 19, 655.
(17) Roy, A. D.; Sharma, S.; Grover, R. K.; Kundu, B.; Roy, R. Org.
Lett. 2004, 6, 4763.
J. Org. Chem, Vol. 71, No. 1, 2006 383

TABLE 1. Summary of the Conditions Used To Synthesize
Tetracyclic Compounds 5a-j
SCHEME 2
T
time
compd R1
R2
R3
-CH3
alcohol used
ethanol
(°C) (h) yield
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
H
H
H
H
H
H
4-CH3
4-CH3
H
H
80
90
90
90
90
80
80
80
90
2
2
2
1
1
2
2
2
1
2
85
72
64
92
80
78
68
82
73
76
H
H
H
H
-CH2CH3
n-propanol
-CH2CH2CH3 n-butanol
-C6H5
benzyl alcohol
phenethyl alcohol
ethanol
propanol
ethanol
-CH2C6H5
3-Cl -CH3
3-Cl -CH2CH3
the structure of the final product was established, the scope,
limitations, and mechanism of the reaction were explored using
a variety of alcohols, from low-boiling methanol to high-boiling
phenethyl alcohol.
H
H
H
-CH3
-C6H5
H
benzyl alcohol
5j
N,N′-dimethyl amino 80
ethanol or
propargyl alcohol
While the procedure worked nicely for many alcohols, such
as n-propanol and n-butanol forming the n-propyl and n-butyl
derivatives, respectively, the use of methanol and 2-propanol
led to the synthesis of the undesired 2-(2-aminophenyl)-3H-
quinazolin-4-one 6 (Scheme 2).
Throughout the whole reaction time, no marked changes were
observed in the proton NMR spectra. TLC of the final mixture
revealed the formation of the undesired amine 6, reinstating the
importance of the actual temperature being maintained during
the reaction. Armed with these observations, we conclude that
the optimal reaction conditions for the one-step synthesis of
the novel 6-methyl-5,6-dihydro-quinazolino[4,3-b]quinazolin-
8-one 5 could be achieved by using 5 equiv of tin(II) chloride
and by maintaining the temperature at 80 °C, bypassing the
formation of the amine 6.
Once the reaction conditions for the synthesis of the trisub-
stituted 5,6-dihydro-quinazolino[4,3-b]quinazolin-8-one 5 were
optimized, a series of 10 compounds with three-point diversity
were synthesized using five different alcohols as solvents. In
addition to this, another interesting observation was identified
while using two different alcohols for creating diversity, namely,
dimethyl amino ethanol and propargyl alcohol. The product
obtained in both cases was identified to be 5,6-dihydro-
quinazolino[4,3-b]quinazolin-8-one 5j instead of the expected
dimethyl aminoethyl and propyne derivatives (Scheme 3). The
product thus obtained was due to the elimination of the
trimethylamine group in the former and ethyne in the latter.
During the preparation of the manuscript, a thorough search
of any synthetic precedence for this type of synthetic transfor-
mation revealed only one very recent report stating the conver-
sion of o-nitrobenzamides to bicyclic dihydroquinazolinones.19
This method, however, suffers from major drawbacks, such as
the usage of an alcoholic HCl solution, a longer reaction time
of 2 days, and the inability to achieve cyclization using high-
boiling benzyl alcohol. It is noteworthy that, by using our present
protocol, high-boiling phenethyl alcohol as well as benzyl
alcohol furnished the expected products 5d, 5e, and 5h in
excellent yields and in a lesser reaction time of 1 h, whereas
no product could be isolated following the reported method.19
A summary of the diversities used and the conditions for all
the synthesized compounds are presented in Table 1.
On the basis of the above observations, the authors propose
the mechanism for the formation of 5 as the result of a redox
reaction. It has been documented in the literature that the
alcohols are prone to get oxidized to their corresponding
aldehydes in the presence of tin(II) chloride and a base under
an oxygen atmosphere.18 It was, therefore, envisioned that there
might be a possibility of a reduction of the nitro group using
tin(II) chloride along with the oxidation of the alcohols to the
corresponding aldehydes, which in turn resulted in the formation
of a Schiff base and ultimately led to the cyclization with the
resulting diamine. The inability to form the dihydro product
with methanol and 2-propanol could be explained on the basis
of the formation of their corresponding oxidized products, which
is formaldehyde in the case of the former and acetone in the
case of the latter. It was thus anticipated that, under these
reaction conditions, the formation of the Schiff base would not
be feasible with both of the above-mentioned oxidized products.
Having thus obtained a plausible explanation for the indif-
ferent behavior of methanol and 2-propanol, we turned our
attention toward the mechanism of the formation of the cyclized
product via a Schiff base intermediate. Interestingly, it was found
that the mechanism for the formation of the amine and the
subsequent conversion to the Schiff base was concerted. To
establish this, a set of reactions was carried out under different
temperatures and by varying the reaction times. It was observed
that below 80 °C the reaction proceeded to form the stable
undesired amine 6 instead of the dihydroquinazoline 5, irrespec-
tive of increasing the temperature afterward up to 100 °C or
maintaining a longer reaction time of 6-8 h. This was further
reconfirmed with the help of in situ NMR studies by mimicking
the reaction conditions within the NMR tube so as to elucidate
the reaction mechanism. The intermediate nitro 4, 5 equiv of
tin(II) chloride, and 10 equiv of ethanol were combined in
ethanol-d6, and the reaction was carried out at 70 °C. 1H NMR
spectra were recorded at regular intervals of 1.5 min for 3 h.
In summary, the present methodology provides an entry for
the convenient one-step synthesis of biheterocyclic 5,6-dihydro-
SCHEME 3
384 J. Org. Chem., Vol. 71, No. 1, 2006

removed in vacuo, and the aqueous layer was extracted with ethyl
acetate (50 mL × 3). The organic layer was washed with a saturated
solution of NaHCO3 and brine and dried over Na2SO4. The
concentration of the organic layer in vacuo was followed by silica
gel column chromatographic purification of the residue using
hexanes-ethyl acetate as an eluant that gave pure 4a as a light
brown solid. 4a: 1.8 g (95%); mp 210-212 °C; 1H NMR (DMSO-
d6, 300 MHz) δ 7.57 (t, J ) 7.5 Hz, 1H, ArH), 7.65 (d, J ) 8.4,
1H, ArH), 7.80-7.94 (m, 4H, ArH), 8.19 (t, J ) 8.1 Hz, 1H, ArH);
13C NMR (DMSO-d6, 75 MHz) δ 121.2, 124.6, 125.9, 127.1, 127.3,
129.2, 131.5, 131.6, 134.0, 134.7, 147.5, 148.5, 151.7, 161.6; MS
(FAB, m/z) 268 (M+ + 1). Anal. Calcd for C14H9N3O3: C, 62.92;
H, 3.39; N, 15.72. Found: C, 62.78; H, 3.56; N, 15.97.
quinazolino[4,3-b]quinazolin-8-one derivatives with three-point
diversity from the 2-(2-nitrophenyl)-3H-quinazolin-4-ones using
a variety of alcohols, furnishing products with a high degree of
yield and purity. All the compounds have been characterized
using various one- and two-dimensional NMR spectroscopic
techniques. The strategy can be useful for the synthesis of similar
kinds of medicinally important conjugated heterocyles as well
as in the generation of large libraries in fewer steps and in a
shorter time scale, which is in contrast to the methods reported
earlier.16
Experimental Section
6-Methyl-5,6-dihydro-quinazolino[4,3-b]quinazolin-8-one (5a).
A solution of 4a (200 mg, 0.75 mmol) and SnCl2‚2H2O (850 mg,
3.75 mmol) was dissolved in ethanol and refluxed at 80 °C for 2
h. The reaction mixture was concentrated in vacuo and diluted in
ethyl acetate (10 mL). The organic layer was washed with saturated
NaHCO3 and a brine solution and dried over Na2SO4. The organic
layer was evaporated under reduced pressure, and the residue was
purified by column chromatography (5% EtOAc in hexane) to
provide 5a as a light yellow solid. 5a: 170 mg (85% yield); mp
132-133 °C; 1H NMR (CDCl3, 300 MHz) δ 1.49 (d, J ) 5.4 Hz,
3H, -CH3), 4.61 (br s, 1H, -NH), 6.42 (m, 1H, -CH), 6.77 (d, J
) 7.8 Hz, 1H, ArH), 6.98 (t, J ) 7.2 Hz, 1H, ArH), 7.32-7.44
[m(o), 2H, ArH], 7.73 (br s, 2H, ArH), 8.28 [d(o), J ) 7.5 Hz, 1H,
ArH], 8.36 [d(o), J ) 7.5 Hz, 1H, ArH]; 13C NMR (CDCl3, 75
MHz) δ 20.0, 59.5, 116.4, 116.8, 120.2, 120.6, 125.9, 126.7, 127.4,
127.6, 133.3, 134.3, 143.7, 146.7, 148.2, 160.1; MS (FAB, m/z)
264 (M+ + 1). Anal. Calcd for C16H13N3O: C, 72.99; H, 4.98; N,
15.96. Found: C, 73.16; H, 5.14; N, 16.09.
6-Phenyl-5,6-dihydro-quinazolino[4,3-b]quinazolin-8-one (5d).
A solution of 4a (200 mg, 0.75 mmol) and SnCl2‚2H2O (850 mg,
3.75 mmol) was dissolved in benzyl alcohol and heated at 90 °C
for 1 h. The reaction mixture was concentrated in vacuo and diluted
in ethyl acetate (10 mL). The organic layer was washed with
saturated NaHCO3 and a brine solution, and the resulting benzyl
alcohol was evaporated by vacuum distillation. The solid was dried
in vacuo, and the residue was purified by column chromatography
(5% EtOAc in hexane) to provide 5d as a reddish-brown solid. 5d:
224 mg (92% yield); mp 188-189 °C; 1H NMR (CDCl3, 300 MHz)
δ 5.14 (br s, 1H, -NH), 6.77 (d, J ) 9 Hz, 1H, ArH), 6.94 (t, J )
7.8 Hz, 1H, ArH), 7.18-7.44 (m, 8H, ArH), 7.75 (br s, 2H, ArH),
8.31 (t, J ) 8.4 Hz, 2H, ArH); 13C NMR (CDCl3, 75 MHz) δ 63.6,
116.3, 117.7, 120.5, 126.0, 126.1, 127.1, 127.5, 127.6, 128.5, 128.6,
133.4, 134.5, 139.2, 143.6, 147.1, 148.2, 160.7; MS (FAB, m/z)
326 (M+ + 1). Anal. Calcd for C21H15N3O: C, 74.20; H, 5.88; N,
14.42. Found: C, 74.41; H, 5.90; N, 14.31.
General Considerations. See Supporting Information.
General Procedure for the Synthesis of 2-Amino Benzamide
(2a). 2-Amino benzonitrile (1a, 1.04 g, 8.50 mmol) and potassium
hydroxide (2.40 g, 42.5 mmol) were dissolved in hot ethanol (25
mL), and the reaction mixture was refluxed for 2 h. The resulting
yellowish-brown solution was allowed to cool to room temperature,
and the ethanol was removed in vacuo. The resulting brown solid
was washed with water, a saturated solution of NaHCO3, and brine
and extracted with ethyl acetate (50 mL × 3). The organic layer
was evaporated in vacuo, and the analytically pure product was
obtained by recrystallization from ethanol as a white solid. 2a: 0.96
1
g (80% yield); mp 112-114 °C; H NMR (DMSO-d6, 300 MHz)
δ 6.45 (t, J ) 7.8 Hz, 1H, ArH), 6.55 (br s, 2H, ArNH), 6.65 (d,
J ) 8.4 Hz, 1H, ArH), 7.05 [br s(o), 1H, -CONH], 7.11 [t(o), J )
8.1 Hz, 1H, ArH], 7.51 (d, J ) 8.1 Hz, 1H, ArH), 7.90 (br s, 1H,
-CONH); 13C NMR (DMSO-d6, 75 MHz) δ 113.7, 114.4, 116.4,
117.2, 128.8, 131.9, 150.2, 171.3. MS (FAB, m/z) 137 (M+ + 1).
Anal. Calcd for C7H8N2O: C, 61.75; H, 5.92; N, 20.58. Found:
C, 61.63; H, 5.94; N, 20.66.
N-[2-(Aminocarbonyl)phenyl]-2-nitrobenzamide (3a). 2-Ni-
trobenzoic acid (1.02 g, 6.1 mmol) and thionyl chloride (8 mL)
were combined, and the reaction mixture was refluxed for 2 h at
80 °C. The solution was allowed to cool at room temperature,
followed by the evaporation of the thionyl chloride in vacuo. The
resulting wine-red solution was added dropwise to a solution of
anthranilamide (2a; 1.04 g, 8.5 mmol) and triethylamine (3.1 mL,
17 mmol) in chloroform (25 mL) and stirred at room temperature
for 2 h. The precipitated solid was filtered and washed with ethanol
to obtain compound 3a. The analytically pure sample was obtained
by recrystallization from methanol as a white colored solid. 3a:
1
2.2 g (86% yield); mp 195-197 °C; H NMR (DMSO-d6, 300
MHz) δ 7.22 (t, J ) 8.4 Hz, 1H, ArH), 7.57 (t, J ) 8.1 Hz, 1H,
ArH), 7.75-7.90 (m, 5H, ArH and -CONH), 8.10 (d, J ) 8.7 Hz,
1H, ArH), 8.34 (br s, 1H, -CONH), 8.46 (br d, J ) 8.4 Hz, 1H,
ArH), 12.49 (s, 1H, ArNH); 13C NMR (DMSO-d6, 75 MHz) δ
120.1, 120.4, 123.4, 124.6, 128.3, 128.7, 131.6, 132.0, 132.4, 134.0,
139.1, 147.1, 163.3, 170.6. MS (FAB, m/z) 286. Anal. Calcd for
C14H11N3O4: C, 58.95; H, 3.89; N, 14.73. Found: C, 59.12; H,
3.98; N, 14.58.
Acknowledgment. A.D.R. is thankful to CSIR, New Delhi,
for providing a fellowship. The authors are highly grateful to
Dr. A. K. Misra for his valuable suggestions during the course
of the work.
2-(2-Nitrophenyl)-3H-quinazolin-4-one (4a). A mixture of
benzamide (3a; 2.2 g, 7.0 mmol) in 10% aqueous KOH (50 mL)
and EtOH (25 mL) was heated to reflux for 10 min. Ethanol was
1
Supporting Information Available: H, 13C, DEPT90, DEPT135,
COSY, and HSQC NMR spectra of 5a-j, HMBC spectra of 5a,
5e, 5f, 5i, and 5j, and 1H NMR spectra of 2a, 3a, 4a, and 4b. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(18) Berentsveig, V. V.; Barinova, T. V.; Rudenko, A. P. React. Kinet.
Catal. Lett. 1979, 10, 333.
(19) Yoo, C. L.; Fettinger, J. C.; Kurth, M. J. J. Org. Chem. 2005, 70,
6941.
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