Stannous chloride in alcohol: A one-pot conversion of 2-Nitro-N- arylbenzamides to 2,3-Dihydro-1H-quinazoline-4-ones

Article abstract of DOI:10.1021/jo050450f

A novel one-step synthesis of 2,3-dihydro-1H-quinazolin-4-ones from 2-nitrobenzamides is reported. These reactions are mediated by stannous chloride in 0.02 M methanolic or ethanolic HCl solution and proceed in good yields.

Full text of DOI:10.1021/jo050450f

is limited by the nature of this reaction. A one-pot
synthesis of DHQ by reductive cyclization of o-nitrobenz-
amides with aldehydes or ketones using TiCl4/Zn in
anhydrous THF has also been reported.12 However, none
of the DHQ compounds prepared by this method con-
tained 3-aryl substituents with electron-withdrawing
groups at the ortho position. Herein, we describe a new
one-pot synthesis of DHQ derivatives accommodating
3-aryl substituents with ortho electron-withdrawing groups
by treating the corresponding o-nitrobenzamides with
stannous chloride in alcoholic 0.02 M HCl.
Stannous Chloride in Alcohol: A One-Pot
Conversion of 2-Nitro-N-arylbenzamides to
2,3-Dihydro-1H-quinazoline-4-ones
Choong Leol Yoo, James C. Fettinger, and
Mark J. Kurth*
Department of Chemistry, University of California,
One Shields Avenue, Davis, California 95616-5295
mjkurth@ucdavis.edu
Received March 8, 2005
The genesis of this work was another project for which
we needed a general procedure for the preparation of
anthranilamides 3, and our starting point was to evaluate
the reaction of anilines (2) with isatoic anhydride (1).
While this procedure worked nicely for many anilines,
hindered and/or electron-deficient anilines such as 2-tri-
fluoromethylaniline (2a) and 2,6-dichloroaniline (2b)
delivered, at best, only a trace amount of the desired
anthranilamide 3 (Scheme 1).
Clearly, these anilines have insufficient nucleophilicity;
a literature report suggests that even o-chloroaniline (2c)
is too deactivated (an 8% yield of 3c was obtained).6 To
countermand this lack of reactivity, we decided to inves-
tigate the use of o-nitrobenzoyl chloride (4) in place of
isatoic anhydride in hopes that its increased electrophi-
licity would induce nucleophilic attack by poor nucleo-
philes such as 2a-c. Indeed, o-nitrobenzamides 5 were
obtained in good yields by the reaction of these anilines
2 in refluxing chloroform solution. Having thus solved
this reactivity problem and with o-nitrobenzamides 5 in
hand, we turned our attention to nitro group reduction
employing excess stannous chloride in methanol. Sur-
prisingly, the major product of this reduction was not the
anticipated anthranilamide 3, but rather the heterocyclic
DHQ product 6 (Scheme 2).
While we find no synthetic precedents for this interest-
ing transformation, others have reported mechanistic
studies in which it is claimed that autoxidation of
stannous chloride subsequently induces oxidation of other
molecular species including benzyl and allyl alcohols
using atmospheric oxygen.13-15 The authors of these
papers explained their observations through a peroxide
theory of autoxidation in which oxidations of these types
are due to the formation of metastable peroxides.13 In a
similar study, alcohols, including methanol and ethanol,
were oxidized in the presence of stannous chloride and
base in aqueous solution.16
A novel one-step synthesis of 2,3-dihydro-1H-quinazolin-4-
ones from 2-nitrobenzamides is reported. These reactions are
mediated by stannous chloride in 0.02 M methanolic or
ethanolic HCl solution and proceed in good yields.
Like other members of the quinazolinone family, 2,3-
dihydro-1H-quinazolin-4-one (DHQ)1 derivatives are es-
tablished biologically and pharmaceutically important
compounds.2-4 The DHQ ring system can generally be
prepared by the reaction of anthranilamides with alde-
hydes or ketones under either acidic or basic conditions,5-8
and the typical preparation of anthranilamides, in turn,
proceeds by the reaction of anilines with isatoic anhy-
dride. However, this is not an effective protocol if the
anilines are substituted with an electron-withdrawing
group9 or present either two ortho substituents or one
bulky ortho substituent. In these cases, the aniline does
not react with isatoic anhydride even at elevated tem-
peratures.10
A recent report details the preparation of DHQ com-
pounds by the reductive desulfurization of 2-thioxo-3H-
quinazolin-4-ones with nickel boride in dry methanol,11
but its usefulness is offset by the fact that the 2-thioxo-
3H-quinazolin-4-one preparation is a multistep process
as well as the fact that derivatization of the C2 position
* To whom correspondence should be addressed. Phone: (530) 752-
8192.
(1) DHQ is for 2,3-dihydro-1H-quinazolin-4-one(s) throughout the
paper.
Our results, coupled with these previous studies,
suggest that stannous chloride-mediated conversion of
5 to 6 in methanol proceeds via the generation of
formaldehyde by methanol oxidation with subsequent
(2) Bonola, G.; Da Re, P.; Magistretti, M. J.; Massarani, E.; Setnikar,
I. J. Med. Chem. 1968, 11, 1136-1139.
(3) Levin, J. I.; Chan, P. S.; Bailey, T.; Katocs, A. S., Jr.; Venkatesan,
A. M. Bioorg. Med. Chem. Lett. 1994, 4, 1141-1146.
(4) Okumura, K.; Oine, T.; Yamada, Y.; Hayashi, G.; Nakama, M.
J. Med. Chem. 1968, 11, 348-352.
(5) Ozaki, K.; Yamada, Y.; Oine, T.; Ishizuka, T.; Iwasawa, Y. J.
Med. Chem. 1985, 28, 568-576.
(12) Shi, D.; Rong, L.; Wang, J.; Zhuang, Q.; Wang, X.; Hu, H.
Tetrahedron Lett. 2003, 44, 3199-3201.
(6) Yale, H. L. J. Heterocycl. Chem. 1977, 14, 1357-1359.
(7) Kilroe Smith, T. A.; Stephen, H. Tetrahedron 1957, 1, 38-44.
(8) Feldman, J. R.; Wagner, E. C. J. Org. Chem. 1942, 7, 31-47.
(9) Tani, J.; Yamada, Y.; Oine, T.; Ochiai, T.; Ishida, R.; Inoue, I. J.
Med. Chem. 1979, 22, 95-99.
(13) Haring, R. C.; Walton, J. H. J. Phys. Chem. 1933, 37, 133-
145.
(14) Haring, R. C.; Walton, J. H. J. Phys. Chem. 1933, 37, 375-
380.
(15) Haring, R. C.; Walton, J. H. J. Phys. Chem. 1934, 38, 153-
160.
(10) Coyne, W. E.; Cusic, J. W. J. Med. Chem. 1968, 11, 1208-1213.
(11) Khurana, J. M.; Kukreja, G. J. Heterocycl. Chem. 2003, 40,
677-679.
(16) Berentsveig, V. V.; Barinova, T. V.; Rudenko, A. P. React. Kinet.
Catal. Lett. 1979, 10, 333-336.
10.1021/jo050450f CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/19/2005
J. Org. Chem. 2005, 70, 6941-6943
6941

SCHEME 1
SCHEME 4
TABLE 1. Synthesis of 6 (10 equiv of SnCl2, 0.02 M HCl,
RCH2OH)
SCHEME 2. Synthesis of 6a
entry
product
R
Ar
yield (%)a
1
2
3
4
5
6
6a
6b
6d
6e
6f
H
2,6-(Cl)2C6H3
2-CF3C6H4
C6H5
2,6-(Cl)2C6H3
2-CF3C6H4
C6H5
59
63
62
73
64
50
H
H
CH3
CH3
CH3
6g
a 2-Amino-N-arylbenzamide 3 was isolated in ∼20-30% yield
in each case.
a Reagents and conditions: (a) CHCl3, reflux, 3 h, 80-85%; (b)
10 equiv of SnCl2, MeOH, reflux, 2 days, 29-40% of 6a-c.
SCHEME 3
FIGURE 1. ORTEP diagram of 6b.
anthranilamide condensation (Scheme 3). While the
major products of these nitro reduction reactions were
DHQ, the yields of 6 were between 29% and 47% and
the anthranilamides (3) were observed but in only trace
amounts.
Literature reports indicated that the autoxidation rate
of stannous chloride increases linearly with increasing
concentrations of hydrochloric acid in alcohol15 as well
as with increasing temperature - presumably due to the
greater solubility of oxygen at elevated temperature.13
Armed with these observations, we set out to optimize
the conditions for 3 f 6 by varying the concentration of
HCl in the alcohol solution while setting the temperature
at reflux. Initially 0.5 M HCl solutions of methanol and
ethanol were employed together with 5-30 equiv of
stannous chloride. However, reaction yields of 6 dropped
to below 10%. After various trials in which the concen-
tration of HCl was decreased, we concluded optimal
conditions are 0.02 M HCl solutions together with stan-
nous chloride (10 equiv) at reflux (Scheme 4). As il-
lustrated in Table 1, these conditions produced yields
ranging from 50% to 73%.
FIGURE 2. ORTEP diagram of 6f.
difficult due to the high boiling point of benzyl alcohol.
Finally, the structures of 6a,b,d-g were confirmed by
IR, 1H NMR, and 13C NMR. The structures of 6b and 6f
were further confirmed by X-ray analysis (Figures 1 and
2).
In summary, we have discovered a novel one-pot
conversion of o-nitrobenzamides to DHQs by the action
of stannous chloride in methanolic or ethanolic 0.02 M
HCl solution under atmospheric oxygen. On the basis
of related mechanistic work, this reaction appears to
proceed by autoxidation of stannous chloride, which
produces peroxides, the species that ultimately oxidizes
the alcohol.
Attempts to employ benzyl alcohol as solvent/reactant,
both with and without HCl, produced complicated reac-
tion mixtures. In addition, the reaction workup was
6942 J. Org. Chem., Vol. 70, No. 17, 2005

130.7, 129.5, 128.8, 128.5 (q, 38 Hz), 127.6 (q, 4.6 Hz), 123.6 (q,
270 Hz), 120.5, 118.1, 116.3, 62.8.
Experimental Section
N-(2,6-Dichlorophenyl)-2-nitrobenzamide (5a). 2-Ni-
trobenzoyl chloride 4 (1 g, 5.4 mmol) in CHCl3 was treated with
2,6-dichloroaniline 2a (3.5 g, 21.6 mmol) under a nitrogen
atmosphere at reflux for 3 h. Upon cooling, the reaction mixture
was diluted with CHCl3 and washed consecutively with aq 1 M
HCl and saturated aq NaHCO3. The organic layer was dried over
anhydrous sodium sulfate and concentrated under reduced
pressure. Crystallization of the residue in CHCl3 gave 5a (1.4
g, 84%) as white needles: mp 223-224 °C; IR (neat) 3226, 1665,
3-Phenyl-2,3-dihydro-1H-quinazolin-4-one (6d). Follow-
ing the procedure described for 6a, 5d gave 6d: white solid in
62% yield; mp 173-174 °C; IR (neat) 3292, 1645, 1612 cm-1; 1H
NMR (CDCl3, 400 MHz) δ 8.02 (d, J ) 8 Hz, 1H), 7.45-7.20 (m,
6H), 6.93 (dd, J ) 8 Hz, 1H), 6.75 (d, J ) 8 Hz, 1H), 4.95 (s,
2H), 4.6-3.6 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ 163.5,
147.8, 141.2, 133.8, 129.6, 129.3, 126.7, 125.3, 120.3, 118.4, 115.6,
62.3.
3-(2,6-Dichlorophenyl)-2-methyl-2,3-dihydro-1H-quinazo-
lin-4-one (6e). Following the procedure described for 6a, 5a gave
6e: white solid in 73% yield; mp 184-186 °C; IR (neat) 3315,
1
1616, 1520, 1352 cm-1; H NMR (CDCl3, 400 MHz) δ 8.13 (d, J
) 8 Hz, 1H), 7.81 (d, J ) 8 Hz, 1H), 7.51 (dd, J ) 8 Hz, 1H),
7.66 (dd, J ) 8 Hz, 1H), 7.43 (d, J ) 8 Hz, 2H), 7.36 (br s, 1H),
7.25 (d, J ) 8 Hz, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 164.7,
147.8, 134.6, 134.4, 132.7, 132.1, 130.3, 129.9, 129.3, 125.0.
2-Nitro-N-(2-trifluoromethylphenyl)benzamide (5b). Fol-
lowing the procedure described for 5a, 4 and 2b gave 5b: white
needles in 85% yield; mp 179-180 °C; IR (neat) 3219, 1650, 1610,
1639, 1606 cm-1 1H NMR (CDCl3, 400 MHz) δ 7.97 (d, J ) 8
;
Hz, 1H), 7.46-7.36 (m, 2H), 7.32 (dd, J ) 8 Hz, 1H), 7.24 (dd, J
) 8 Hz, 1H), 6.89 (dd, J ) 8 Hz, 1H), 6.72 (d, J ) 8 Hz, 1H),
5.39 (q, J ) 6 Hz, 1H), 4.8-4.6 (br s, 1H), 1.28 (d, J ) 6 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ 163.0, 147.6, 136.8, 135.8,
135.4, 134.0, 129.9, 129.5, 129.0, 128.8, 119.9, 116.8, 115.7, 66.8,
19.7.
1522, 1351 cm-1 1H NMR (CDCl3, 400 MHz) δ 8.28 (d, J ) 8
;
Hz, 1H), 8.17 (d, J ) 8 Hz, 1H), 7.76 (dd, J ) 8 Hz, 8 Hz, 1H),
7.72-7.62 (m, 5H), 7.34 (dd, J ) 7.2 Hz, 1H); 13C NMR (DMSO-
d6, 100 MHz) δ 166.3, 147.1, 135.4, 134.9, 133.9, 133, 131.7,
130.8, 129.6, 128.1, 127.1 (q, J ) 4.5 Hz), 126.3 (q, 30 Hz), 125.0,
124.2 (q, 272 Hz).
2-Methyl-3-(2-trifluoromethylphenyl)-2,3-dihydro-1H-
quinazolin-4-one (6f). Following the procedure described for
6a, 5b gave 6f: white solid in 64% yield; mp 195-196 °C; IR
(neat) 3318, 1634, 1611 cm-1 1H NMR (CDCl3, 400 MHz) δ
;
7.99-7.93 (m, 1H), 7.79-7.75 (m, 1H), 7.63 (dd, J ) 8 Hz, 1H),
7.54-7.44 (m, 1H), 7.41 (d, J ) 8 Hz, 1H), 7.37-7.30 (m, 1H),
6.94-6.86 (m, 1H), 6.74-6.70 (m, 1H), 5.35 (q, J ) 6 Hz, 0.3 ×
1H), 5.09 (q, J ) 6 Hz, 0.7 × 1H), 4.6-4.4 (br s, 1H), 1.41 (d, J
) 6 Hz, 0.7 × 3H), 1.23 (d, J ) 6 Hz, 0.3 × 3H); 13C NMR (CDCl3,
100 MHz) δ 163.4, 147.4, 146.2, 137.9, 135.2, 134.0, 133.3, 133.1,
131.2, 130.6, 129.7, 129.3, 128.8, 128.6, 127.8, 127.7, 127.6, 124.9,
122.2, 120.1, 119.9, 117.2, 116.9, 116.0, 115.5, 68.2, 67.7, 20.6,
19.8.
2-Nitro-N-phenylbenzamide (5d). Following the procedure
described for 5a, 4 and 2d gave 5d: yellow solid in 80% yield;
mp 152-153 °C; IR (neat) 3249, 1656, 1600, 1527, 1342 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 8.08 (d, J ) 8 Hz, 1H), 7.72-7.54
(m, 6H), 7.35 (dd, J ) 7.2 Hz, 2H), 7.17 (dd, J ) 7.2 Hz, 1H);
13C NMR (CDCl3, 100 MHz) δ 164.6, 146.5, 137.5, 134.1, 133.1,
131.0, 129.4, 128.8, 125.4, 124.9, 120.7.
3-(2,6-Dichlorophenyl)-2,3-dihydro-1H-quinazolin-4-
one (6a). SnCl2‚2H2O (1.1 g, 5 mmol) and 5a (155 mg, 0.5 mmol)
were dissolved in 0.02 M methanolic HCl solution and refluxed
for 2 d under atmospheric oxygen. The reaction mixture was
concentrated under reduced pressure, diluted with ethyl acetate,
and washed with aq NaHCO3 and water. The organic layer was
dried over anhydrous sodium sulfate, concentrated, and the
residue was purified by column chromatography (30% EtOAc
in n-hexane) to give 6a (86 mg, 59%) as a white solid: mp 155-
2-Methyl-3-phenyl-2,3-dihydro-1H-quinazolin-4-one (6g).
Following the procedure described for 6a, 5d gave 6g: white
solid in 50% yield; mp 167-169 °C; IR (neat) 3295, 1632, 1611
cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.97 (d, J ) 8 Hz, 1H), 7.41
(dd, J ) 8 Hz, 2H), 7.34-7.28 (m, 4H), 6.87 (dd, J ) 7 Hz, 1H),
6.67 (d, J ) 8 Hz, 1H), 5.20 (q, J ) 6 Hz, 1H), 4.7-4.5 (br s,
1H), 1.39 (d, J ) 6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 163.1,
146.2, 140.4, 133.9, 129.5, 129.3, 128.0, 127.5, 119.6, 116.8, 115.3,
68.7, 21.1.
157 °C; IR (neat) 3351, 1644, 1609 cm-1; H NMR (CDCl3, 400
1
MHz) δ 8.01 (d, J ) 8 Hz, 1H), 7.39 (d, J ) 8 Hz, 2H), 7.34 (dd,
J ) 8 Hz, 1H), 7.21 (dd, J ) 8 Hz, 1H), 6.93 (dd, J ) 8 Hz, 1H),
6.77 (d, J ) 8 Hz, 1H), 4.83 (s, 1H), 4.53 (br s, 1H); 13C NMR
(CDCl3, 100 MHz) δ 162.5, 148.1, 136.4, 135.3, 134.0, 129.9,
129.5, 128.0, 120.4, 117.8, 116.3, 61.0.
Acknowledgment. We thank the National Science
Foundation (CHE-0313888) and the National Institutes
of Health (1RO1 EY15924) for support of this work. The
400 and 300 MHz NMR spectrometers used in this
study were funded in part by a grant from NSF (CHE-
9808183).
Supporting Information Available: 1H NMR and 13C
NMR spectra of compounds 5a,b,d and 6a,b,d-g; crystal-
lographic data for compounds 6b and 6f. This material is
available free of charge via the Internet at http://pubs.acs.org.
3-(2-Trifluoromethylphenyl)-2,3-dihydro-1H-quinazolin-
4-one (6b). Following the procedure described for 6a, 5b gave
6b: white solid in 63% yield; mp 169-171 °C; IR (neat) 3341,
1672, 1611 cm-1 1H NMR (CDCl3, 400 MHz) δ 7.99 (d, J ) 8
;
Hz, 1H), 7.76 (d, J ) 8 Hz, 1H), 7.63 (dd, J ) 8 Hz, 1H), 7.48
(dd, J ) 8 Hz, 1H), 7.40 (d, J ) 8 Hz, 1H), 7.35 (dd, J ) 8 Hz,
1H), 6.93 (dd, J ) 8 Hz, 1H), 6.76 (d, J ) 8 Hz, 1H), 4.89 (d, J
) 10 Hz, 1H), 4.69 (d, J ) 10 Hz, 1H), 4.64-4.36 (br s, 1H); 13
C
NMR (CDCl3, 100 MHz) δ 164.4, 147.9, 139.1, 133.9, 133.6, 131.2,
JO050450F
J. Org. Chem, Vol. 70, No. 17, 2005 6943