New conditions for synthesis of (plusmn;)-2-monosubstituted and (plusmn;)-2,2-disubstituted 2,3-dihydro-4(1H)-quinazolinones from 2-nitro- and 2-aminobenzamide

Article abstract of DOI:10.1002/jhet.672

An efficient synthesis of (plusmn;)-2-monosubstituted and (plusmn;)-2,2-disubstituted 2,3-dihydro-4(1H)-quinazolinones has been developed using a dissolving metal reduction-condensative cyclization strategy. Treatment of 2-nitrobenzamide and an aldehyde or ketone with iron powder in refluxing acetic acid affords high yields of the title compounds. More complex ring systems are available by incorporating additional reactive functionality γ to the carbonyl of the aldehyde or ketone substrate. The scope and limitations of the process along with optimized procedural details are presented. The same target molecules are also accessible by reaction of 2-aminobenzamide with aldehydes and ketones in refluxing acetic acid.

Full text of DOI:10.1002/jhet.672

September 2011
New Conditions for Synthesis of (6)-2-Monosubstituted and
(6)-2,2-Disubstituted 2,3-Dihydro-4(1H)-quinazolinones
from 2-Nitro- and 2-Aminobenzamide
991
Richard A. Bunce* and Baskar Nammalwar
Department of Chemistry, Oklahoma State University Stillwater, Oklahoma 74078-3071
*E-mail: rab@okstate.edu
Received June 8, 2010
DOI 10.1002/jhet.672
Published online 21 April 2011 in Wiley Online Library (wileyonlinelibrary.com).
An efficient synthesis of (6)-2-monosubstituted and (6)-2,2-disubstituted 2,3-dihydro-4(1H)-quinazo-
linones has been developed using a dissolving metal reduction-condensative cyclization strategy. Treat-
ment of 2-nitrobenzamide and an aldehyde or ketone with iron powder in refluxing acetic acid affords
high yields of the title compounds. More complex ring systems are available by incorporating additional
reactive functionality c to the carbonyl of the aldehyde or ketone substrate. The scope and limitations
of the process along with optimized procedural details are presented. The same target molecules are
also accessible by reaction of 2-aminobenzamide with aldehydes and ketones in refluxing acetic acid.
J. Heterocyclic Chem., 48, 991 (2011).
INTRODUCTION
densation of 4 with aldehydes or ketones in the presence
of catalysts such as gallium(III) triflate [17], scandi-
um(III) triflate [18] or by heating in solvents such as tri-
fluoroethanol [19]. Most of these reagents and catalysts
are expensive and require dry box conditions; addition-
ally, the reaction workup procedures are often tedious.
An alternative approach has been reported using isatoic
anhydride with amines and carbonyl compounds in the
presence of montmorillonite K-10 [20], p-toluenesulfonic
acid [21], Amberlyst-15 under microwave conditions
[22], and aluminum tris(dihydrogenphosphate) [23], but
the yields were slightly lower (ca 5% on average) than
those in this work, and each procedure was evaluated
using only aryl aldehydes. To expand on this foundation,
we report modified conditions, which use inexpensive,
readily available reagents to afford dihydroquinazolinones
from a wide variety of aldehydes and ketones. The only
general procedure that yields comparable results involves
the cyclization of 4 with aldehydes and ketones promoted
by catalytic ammonium chloride in ethanol [24].
Dihydroquinazolinones are an important class of het-
erocycles that have expressed a broad spectrum of bio-
logical activities [1]. This ring system is found as the
core structure in compounds investigated as anticancer
[2], anti-inflammatory [3], anticonvulsant [4], antibacte-
rial [5], antifungal [6], anti-osteoporosis [7], and diuretic
[8] drug candidates. Additionally, several dihydroquina-
zolinone derivatives have been found to be potent plant
growth regulators and herbicidal agents [9].
We have previously utilized tandem reactions initiated
by dissolving metal reduction of nitroarenes to prepare
indole-3-carboxylic esters [10] and benzo-fused oxepi-
nones, diazepinones, [11] and carbazoles [12] as well as
various linear-fused ring systems [13]. In this project, we
have used a tandem reduction-condensative cyclization
strategy involving 2-nitrobenzamide (1) and aldehydes
2a–h or ketones 2i–o for the formation of 2-monosubsti-
tuted and 2,2-disubstituted 2,3-dihydro-4(1H)-quinazoli-
nones 3. This method has been further extended to
include sequences involving additional reactions follow-
ing the initial heterocyclic ring closure. Additionally, we
have found that heating 2-aminobenzamide (4) with alde-
hydes and ketones in glacial acetic acid also provides the
target heterocycles cleanly and in high yield.
RESULTS AND DISCUSSION
The results of our tandem synthesis of dihydroquina-
zolinones from reductive cyclization of 1 with aldehydes
and ketones are summarized in Figure 1. The current
reaction is performed by reacting a 1:1 mole ratio of
2-nitrobenzamide (1) and the carbonyl compound 2 with
five equivalents of iron powder in acetic acid at 115ꢀC for
30 min. After quenching with water, extractive workup
Earlier methods to prepare dihydroquinazolinones
have reacted 1 with aldehydes and ketones in the pres-
ence of titanium(IV) chloride and zinc [14], samarium
iodide [15] and samarium in the presence of iodine [16].
The target compounds have also been prepared by con-
C
V
2011 HeteroCorporation

992
R. A. Bunce and B. Nammalwar
Vol 48
Scheme 1. Mechanism for dihydroquinazolinone formation.
pared in comparable yields by reacting 2-aminobenza-
mide (4) with an aldehyde or ketone (1:1) in acetic acid
at 115ꢀC for 30 min or 23ꢀC for 4 h (see Fig. 2).
The reaction sequence from 1 begins with dissolving
metal reduction of the nitro function to give 4. The
resulting amino group then reacts with the aldehyde or
ketone in 2 to form an iminium intermediate 5, which is
attacked by the amide nitrogen to close the heterocyclic
portion of the structure. Reactions starting with 4 do not
require added iron and proceed rapidly at 115ꢀC or
more slowly at 23ꢀC (see Scheme 1). Thus, the iron is
only important for the reduction process and is not
required for the ring closure.
Further studies sought to extend the tandem reaction
sequence to generate more complex structures such as
6–9 by using aldehydes and ketones bearing a second re-
active group c to the carbonyl function (see Scheme 2).
Cyclization of 1 with these substrates would yield dihy-
droquinazolinones with functionality d to the aniline
nitrogen such that a subsequent reaction would close a
five-membered ring. For example, the reaction of 1 with
5-chloro-2-pentanone (10) under dissolving metal condi-
tions furnished tetrahydropyrrolo[1,2-a]quinazolinone 6
in 73% yield [25]. This reaction involved reduction of
the nitro function and ring closure to generate the dihy-
droquinazolinone bearing a chloride leaving group d to
the aniline nitrogen. Subsequent SN2 displacement of
Figure 1. Cyclization of aldehydes and ketones with 1.
and recrystallization from ethanol, dihydroquinazoli-
nones 3 are isolated in pure form. Only rarely is chro-
matographic purification required (e.g., 3g and 3h).
Alternatively, the target heterocycles can also be pre-
Scheme 2. Preparation of more complex systems from 1 [a].
Figure 2. Cyclization of aldehydes and ketones with 4.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011 New Conditions for Synthesis of (6)-2-Monosubstituted and (6)-2,2-Disubstituted
2,3-Dihydro-4(1H)-quinazolinones from 2-Nitro- and 2-Aminobenzamide
993
chloride by the more reactive aniline nitrogen [26] then
delivered the final tricyclic product. The extremely mild
nature of the reduction conditions was evidenced by the
fact that no hydrogenolysis of the aliphatic chloride was
observed [27]. A second extended sequence resulted
when 1 was reacted with c-ketoesters such as methyl
levulinate (11) or methyl 3-benzoylpropionate (12).
These reactions proceeded to give reduction, condensa-
tive ring closure and cyclization by addition-elimination
of the aniline nitrogen with the d ester groups to give
tetrahydropyrrolo[1,2-a]quinazolin-1,5-diones 7a and 7b
in 74% and 77% yields, respectively [28]. It should be
noted that five-membered rings were the only ones that
could be successfully formed in the final step of these
extended tandem reactions. Oxoesters with greater sepa-
ration between the carbonyl moieties (e.g., 2g and 2h)
failed to undergo the final cyclization, even after reflux-
ing for an additional 24 h. In a related transformation, 1
was reduced in the presence of methyl 2-formylbenzoate
(13) [29] to produce 6,6a-dihydroisoindolo[2,1-a]quinazo-
lin-5,11-dione (8) in 72% yield. Finally, 1 was also
reacted with diphosgene (14) to afford 2,4(1H,3H)-quina-
zolinedione (9) in 86% yield.
One extended reaction was investigated using 4 as the
starting material (see Scheme 3). Treatment of 4 with
11 in acetic acid at 23ꢀC for 24 h gave (6)-methyl 3-
(1,2,3,4-tetrahydro-2-methyl-4-oxoquinazolin-2-yl)propa-
noate (15) in 70% yield. Further heating of 15 in acetic
acid at 115ꢀC for 8 h then effected quantitative ring clo-
sure to 7a. This two-step synthesis could be simplified
to a one-step process by running the reaction at 115ꢀC.
In the reaction of 1 with 11 under dissolving metal con-
ditions at 115ꢀC, intermediate 15 could not be isolated.
tional functionality c to the carbonyl of the aldehyde or
ketone (d to the aniline nitrogen in the initially formed dihy-
droquinazolinone) so that subsequent reactions can occur.
EXPERIMENTAL
All reactions were run under dry nitrogen in oven-dried
glassware. Reactions were monitored by thin layer chromatog-
raphy on silica gel GF plates (Analtech No 21521). Commer-
cial reagents and solvents were used as received. Preparative
separations were performed using flash column chromatogra-
phy [30] on silica gel (Grade 62, 60–200 mesh) mixed with
UV-active phosphor (Sorbent Technologies No UV-5); band
elution was monitored using a hand-held UV lamp. Melting
points were uncorrected. FT-IR spectra were run as thin films
1
on sodium chloride disks. Unless otherwise indicated, H- and
13C-NMR spectra were measured in dimethyl sulfoxide-d6 at
300 MHz and 75 MHz, respectively, and were referenced to
internal tetramethylsilane; coupling constants (J) are reported
in Hz. Low-resolution mass spectra (electron impact/direct
probe) were run at 70 eV or 30 eV as indicated.
Representative procedure from 2-nitrobenzamide: (6)-
2,3-Dihydro-2-phenyl-4(1H)-quinazolinone (3a). A 100-mL
three-necked round-bottomed flask, equipped with a reflux
condenser, a magnetic stirrer, and a nitrogen inlet, was charged
with 9 mL of glacial acetic acid, 498 mg (3.00 mmoles) of
2-nitrobenzamide (1), and 318 mg (3.00 mmoles) of benzalde-
hyde (2a). The flask was placed in an oil bath preheated to
105ꢀC to dissolve the reactants. The heat was briefly removed,
840 mg (15.0 mmoles, 5 equiv.) of iron powder (>100 mesh)
was added, and the reaction was refluxed for 30 min. [Caution!
The addition was sufficiently exothermic to boil the mixture
and some frothing occurred as the iron was added. The reac-
tion flask should be at least 10 times the volume of the reac-
tants at this scale.] The reaction mixture was cooled, poured
into saturated aqueous sodium chloride, and extracted with
ether (1 ꢁ 50 mL) and ethyl acetate (1 ꢁ 50 mL). The com-
bined organic layers were washed with saturated aqueous so-
dium bicarbonate (two times) and saturated aqueous sodium
chloride (one time), then dried (magnesium sulfate) and con-
centrated under vacuum to give a light tan solid. Recrystalliza-
tion of the crude product from ethanol theꢀn gave 610 mg
(90%) of 3a as a white solid, mp 220–221 ꢂC1 (ref. 24; mp
CONCLUSIONS
We have developed efficient one-pot syntheses of
(6)-2-monosubstituted and (6)-2,2-disubstituted 2,3-
dihydro-4(1H)-quinazolinones from 2-nitro- and 2-amino-
benzamide. The procedures utilize inexpensive reagents,
mild conditions, and simple laboratory procedures. The
method furnishes high yields of the title compounds from a
wide range of aldehydes and ketones without the need for
extensive purification. This method can be extended to the
synthesis of more complex structures by positioning addi-
218–220ꢀC). IR: 3302, 3185, 1652, 1611 cm
;
1H-NMR: d
8.29 (br s, 1H), 7.61 (d, 1H, J ¼ 7.8), 7.49 (d, 2H, J ¼ 7.0),
7.42–7.32 (complex, 3H), 7.24 (td, 1H, J ¼ 7.6, 1.6), 7.11
(br s, 1H), 6.75 (d, 1H, J ¼ 8.0), 6.67 (t, 1H, J ¼ 7.6), 5.75
(s, 1H); 13C-NMR: d 163.6, 147.9, 141.6, 133.3, 128.4,
128.3, 127.3, 126.8, 117.1, 114.9, 114.4, 66.5; ms (30 eV): m/z
224 (Mþ).
(6)-2,3-Dihydro-2-(4-methoxyphenyl)-4(1H)-quinazoli-
none (3b). This was prepared from 498 mg (3.00 mmoles) of
1, 408 mg (3.00 mmoles) of 4-methoxybenzaldehyde (2b), and
840 mg (15.0 mmoles) of iron powder in 9 mL of acetic acid
using the procedure outlined for the preparation of 3a. Product
3b (686 mg, 90%) was isolated as a white solid, mp 192–
193ꢀC (ref. 24; mp 193–195ꢀC). IR: 3300, 3188, 1655, 1609
Scheme 3. Preparation of a complex system from 4 [a].
1
cmꢂ1; H-NMR: d 8.17 (br s, 1H), 7.61 (d, 1H, J ¼ 6.6), 7.41
(d, 2H, J ¼ 8.6), 7.23 (td, 1H, J ¼ 7.6, 1.4), 6.99 (br s, 1H), 6.94
(d, 2H, J ¼ 8.6), 6.72 (d, 1H, J ¼ 8.2), 6.67 (t, 1H, J ¼ 7.7),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

994
R. A. Bunce and B. Nammalwar
Vol 48
5.70 (s, 1H), 3.74 (s, 3H); 13C-NMR: d 163.4, 159.4, 148.0,
133.4, 133.2, 128.2, 127.3, 117.0, 115.0, 114.4, 113.6, 66.3,
55.1; ms (30 eV): m/z 254 (Mþ).
(6)-Ethyl 4-(1,2,3,4-tetrahydro-4-oxoquinazolin-2-yl)bu-
tanoate (3g). This compound was prepared from 332 mg (2.00
mmoles) of 1, 288 mg (2.00 mmoles) of ethyl 5-oxopenta-
noate (2g) [31], and 560 mg (10.0 mmoles) of iron powder in
7 mL of acetic acid using the procedure outlined for the prep-
aration of 3a. Product 3g (408 mg, 78%) was isolated as a
white solid following flash chromatography on a 30 cm ꢁ
2 cm silica gel column eluted with 50% ether in hexanes con-
taining 1% methanol, mp 106–108ꢀC. IR: 3302, 3204, 1731,
(6)-2,3-Dihydro-2-[4-(trifluoromethyl)phenyl]-4(1H)-quina-
zolinone (3c). This compound was prepared from 498 mg
(3.00 mmoles) of 1, 522 mg (3.00 mmoles) of 2-(trifluorome-
thyl)benzaldehyde (2c), and 840 mg (15.0 mmoles) of iron
powder in 9 mL of acetic acid using the procedure outlined
for the preparation of 3a. Product 3c (779 mg, 89%) was iso-
lated as a white solid, mp 194–196ꢀC. IR: 3285, 3187, 1648,
1661, 1614 cmꢂ1
;
1H-NMR (CDCl3): d 7.87 (d, 1 H, J ¼
1618 cmꢂ1
;
1H-NMR: d 8.46 (d, 1H, J ¼ 1.3), 7.78 (d, 2H,
7.7), 7.30 (t, 1H, J ¼ 7.7), 7.04 (br s, 1H), 6.84 (t, 1H, J ¼
7.7), 6.69 (d, 1 H, J ¼ 8.2), 4.91 (s, 1 H), 4.49 (br s, 1H),
4.14 (q, 2 H, J ¼ 7.1), 2.39 (m, 2H), 1.82 (m, 4H), 1.26
(t, 3H, J ¼ 7.1); 13C-NMR (CDCl3): d 173.2, 165.5, 147.3,
133.8, 128.4, 119.2, 115.8, 114.8, 64.9, 60.6, 34.7, 33.5,
19.1; ms (30 eV): m/z 262 (Mþ). Anal. Calcd. for
C14H18N2O3: C, 64.12; H, 6.87; N, 10.69. Found: C, 64.23;
H, 6.91; N, 10.63. Extended heating of this reaction for 24 h
failed to induce further cyclization.
J ¼ 8.2), 7.72 (d, 2H, J ¼ 8.2), 7.63 (dd, 1H, J ¼ 7.7, 1.1),
7.26 (overlapping td, 1H, J ¼ 7.1, 1.1 and br s, 1H), 6.77 (d, 1
H, J ¼ 7.7), 6.69 (t, 1H, J ¼ 7.7), 5.88 (d, 1H, J ¼ 1.3);
13C-NMR: d 163.4, 147.5, 146.4, 133.5, 129.0, 128.9 (q, J ¼
31.7), 127.7 (2C), 127.4, 125.3 (q, J ¼ 3.7), 124.2 (q, J ¼
271.6), 117.4, 114.9, 114.5, 65.7; ms (30 eV): m/z 292 (Mþ).
Anal. Calcd. for C15H11F3N2O: C, 61.64; H, 3.79; N, 9.59.
Found: C, 61.58; H, 3.81; N, 9.56.
(6)-Ethyl 5-(1,2,3,4-tetrahydro-4-oxoquinazolin-2-yl)pen-
tanoate (3h). This compound was prepared from 332 mg
(2.00 mmoles) of 1, 316 mg (2.00 mmoles) of ethyl 6-oxohex-
anoate (2h) [32], and 560 mg (10.0 mmoles) of iron powder in
7 mL of acetic acid using the procedure outlined for the prepa-
ration of 3a. Product 3h (402 mg, 73%) was isolated as a
white solid following flash chromatography on a 30 cm ꢁ
2 cm silica gel column eluted with 50% ether in hexanes con-
taining 1% methanol, mp 110–113ꢀC. IR: 3307, 3203, 1736,
(6)-2-(2-Chlorophenyl)-2,3-dihydro-4(1H)-quinazolinone
(3d). This compound was prepared from 498 mg (3.00
mmoles) of 1, 421 mg (3.00 mmoles) of 2-chlorobenzaldehyde
(2d), and 840 mg (15.0 mmoles) of iron powder in 9 mL of
acetic acid using the procedure outlined for the preparation of
3a. Product 3d (721 mg, 93%) was isolated as an off-white
solid, mp 205–206ꢀC. IR: 3286, 3192, 1645, 1614 cmꢂ1 1H-
;
NMR: d 8.20 (s, 1 H), 7.65 (d, 1 H, J ¼ 6.6), 7.50 (m, 1H),
7.40 (m, 2H), 7.26 (t, 2H, J ¼ 7.1), 7.00 (s, 1H), 6.74 (m,
2H); 13C-NMR: d 163.6, 147.6, 137.8, 133.4, 131.8, 130.2,
129.5, 128.7, 127.4, 127.3, 117.4, 114.6, 114.5, 63.6; ms (30
eV): m/z 258, 260 (Mþ:Mþþ2, 3:1). Anal. Calcd. for
C14H11ClN2O: C, 64.99; H, 4.29; N, 10.83. Found: C, 65.03;
H, 4.28; N, 10.79.
1
1643, 1614 cmꢂ1; H-NMR (CDCl3): d 7.88 (d, 1H, J ¼ 7.7),
7.31 (t, 1H, J ¼ 7.7), 6.86 (t, 1H, J ¼ 7.7), 6.69 (d, 1H, J ¼
8.2), 6.24 (br s, 2H), 4.91 (t, 1H, J ¼ 5.8), 4.14 (q, 2H, J ¼
7.1), 2.35 (t, 2H, J ¼ 7.1), 1.80 (q, 2H, J ¼ 7.1), 1.69 (quintet,
2H, J ¼ 7.1), 1.51 (m, 2H), 1.26 (t, 3H, J ¼ 7.1); 13C-NMR
(CDCl3): d 173.4, 165.4, 147.4, 133.7, 128.4, 119.2, 115.8,
114.7, 65.0, 60.4, 35.0, 33.8, 24.3, 23.4, 14.2; ms (30 eV): m/z
276 (Mþ). Anal. Calcd. for C15H20N2O3: C, 65.22; H, 7.24;
N, 10.14. Found: C, 65.31; H, 7.27; N, 10.08. Extended heating
of this reaction for 24 h failed to induce further cyclization.
(6)-2-Butyl-2,3-dihydro-4(1H)-quinazolinone (3e). This
compound was prepared from 332 mg (2.00 mmoles) of 1, 172
mg (2.00 mmoles) of pentanal (2e), and 560 mg (10.0 mmoles)
of iron powder in 7 mL of acetic acid using the procedure out-
lined for the preparation of 3a. Product 3e (383 mg, 94%) was
isolated as a white solid, mp 143–144ꢀC (ref 15; mp 144–
2,3-Dihydro-2,2-dimethyl-4(1H)-quinazolinone (3i). This
compound was prepared from 332 mg (2.00 mmoles) of 1, 116
mg (2.00 mmoles) of acetone (2i), and 560 mg (10.0 mmoles) of
iron powder in 7 mL of acetic acid using the procedure outlined
for the preparation of 3a. Product 3i (334 mg, 95%) was isolated
as a white solid, mp 182–183ꢀC (ref. 33; mp 183–184ꢀC). IR:
146ꢀC). IR: 3293, 1651, 1614 cmꢂ1 1H-NMR: d 7.90 (br s,
;
1H), 7.58 (d, 1H, J ¼ 7.7), 7.23 (t, 1H, J ¼ 7.7), 6.73 (d, 1H,
J ¼ 7.7), 6.65 (t, 1H, J ¼ 7.7), 6.58 (br s, 1H), 4.69 (s, 1H),
1.62 (m, 2H), 1.40 (m, 2H), 1.30 (m, 2H), 0.88 (t, 3H, J ¼
6.8); 13C-NMR: d 163.9, 148.5, 133.0, 127.3, 116.8, 115.0,
114.3, 64.4, 34.7, 25.4, 22.1, 13.9; ms (70 eV): m/z 147 (Mþ-
C4H9).
1
3260, 3172, 1640, 1614 cmꢂ1; H-NMR: d 7.94 (br s, 1H), 7.57
(d, 1H, J ¼ 8.2), 7.20 (t, 1H, J ¼ 7.7), 6.63 (br s, 1H), 6.62 (d,
1H, J ¼ 8.2), 6.61 (t, 1H, J ¼ 7.7), 1.36 (s, 6H); 13C-NMR: d
163.1, 147.1, 133.2, 127.2, 116.4, 114.2, 113.8, 66.8, 29.0; ms
(70 eV): m/z 161 (Mþ-CH3).
(6)-2,3-Dihydro-2-[(1E)-2-phenylethenyl]-4(1H)-quina-
zolinone (3f). This compound was prepared from 332 mg
(2.00 mmoles) of 1, 264 mg (2.00 mmoles) of trans-cinnamal-
dehyde (2f), and 560 mg (10.0 mmoles) of iron powder in 7
mL of acetic acid using the procedure outlined for the prepara-
tion of 3a. Product 3f (445 mg, 89%) was isolated as a yellow
solid, mp 170–173ꢀC (ref. 7; mp 168–172ꢀC). IR: 3276, 1651,
(6)-2,3-Dihydro-2-methyl-2-propyl-4(1H)-quinazolinone
(3j). This compound was prepared from 332 mg (2.00
mmoles) of 1, 172 mg (2.00 mmoles) of 2-pentanone (2j), and
560 mg (10.0 mmoles) of iron powder in 7 mL of acetic acid
using the procedure outlined for the preparation of 3a. Product
3j (367 mg, 90%) was isolated as a white solid, mp 192–
1
1611 cmꢂ1; H-NMR: d 8.16 (br s, 1H), 7.63 (d, 1H, J ¼ 7.7),
1
7.46 (d, 2H, J ¼ 8.2), 7.35 (t, 2H, J ¼ 7.7), 7.26 (m, 2H),
6.90 (s, 1H), 6.76 (d, 1H, J ¼ 8.2), 6.68 (d, 1H, J ¼ 15.9),
6.67 (d, 1H, J ¼ 7.7), 6.38 (dd, 1H, J ¼ 15.9, 6.6), 5.31 (d,
1H, J ¼ 6.6); 13C-NMR: d 163.3, 147.8, 135.7, 133.2, 131.6,
128.7, 128.3, 128.1, 127.4, 126.6, 117.1, 114.8, 114.5, 65.8;
ms (30 eV): m/z 250 (Mþ).
195ꢀC. IR: 3272, 3184, 1645, 1613 cmꢂ1; H-NMR: d 7.90 (br
s, 1H), 7.56 (d, 1H, J ¼ 7.7), 7.20 (td, 1H, J ¼ 8.2, 1.6), 6.64
(d, 1H, J ¼ 8.2), 6.59 (br s, 1H), 6.59 (t, 1H, J ¼ 7.7), 1.60
(m, 2H), 1.35 (m, 2H), 1.34 (s, 3H), 0.84 (t, 3H, J ¼ 7.1);
13C-NMR: d 163.1, 147.2, 133.1, 127.1, 116.0, 113.9, 113.5,
69.0, 43.7, 27.9, 16.7, 14.1; ms (70 eV): m/z 161 (Mþ-C3H7).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011 New Conditions for Synthesis of (6)-2-Monosubstituted and (6)-2,2-Disubstituted
2,3-Dihydro-4(1H)-quinazolinones from 2-Nitro- and 2-Aminobenzamide
995
Anal. Calcd. for C12H16N2O: C, 70.59; H, 7.84; N, 13.73.
Found: C, 70.64; H, 7.86; N, 13.70.
1H-NMR: d 7.94 (br s, 1H), 7.57 (d, 1H, J ¼ 7.7), 7.22 (td,
1H, J ¼ 8.2, 1.1), 6,82 (d, 1H, J ¼ 8.2), 6.62 (t, 1H, J ¼ 7.1),
6.62 (br s, 1H), 1.74 (m, 2H), 1.61 (m, 2H), 1.58 (m, 4H),
1.42 (m, 1H), 1.25 (m, 1H); 13C-NMR: d 163.2, 146.8, 133.1,
127.1, 116.5, 114.6, 114.4, 67.8, 37.2, 24.7, 20.9; ms (30 eV):
m/z 216 (Mþ).
(6)-2,3-Dihydro-2-methyl-2-phenyl-4(1H)-quinazolinone
(3k). This compound was prepared from 332 mg (2.00 mmoles)
of 1, 240 mg (2.00 mmoles) of acetophenone (2k), and 560 mg
(10.0 mmoles) of iron powder in 7 mL of acetic acid using the
procedure outlined for the preparation of 3a. Product 3k (409
mg, 86%) was isolated as a white solid, mp 222–224ꢀC. IR:
(6)-3a-Methyl-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin-
5(1H)-one (6). This compound was prepared from 415 mg
(2.50 mmoles) of 1, 301 mg (2.50 mmoles) of 5-chloro-2-pen-
tanone (10), and 698 mg (12.5 mmoles) of iron powder in 8
mL of acetic acid using the procedure outlined for the prepara-
tion of 3a with the reflux period extended to 8 h. Product 6
(368 mg, 73%) was isolated directly from the reaction as a
white solid, mp 163–165ꢀC (ref. 25; mp 165–167ꢀC). IR:
1
3297, 3182, 1651, 1611 cmꢂ1; H-NMR: d 8.76 (br s, 1H), 7.63
(br s, 1H), 7.48 (m, 3H), 7.28 (d, 2H, J ¼ 7.4), 7.19 (m, 2H),
6.77 (d, 1H, J ¼ 8.0), 6.57 (t, 1H, J ¼ 7.1), 1.64 (s, 3H);
13C-NMR: d 163.8, 147.7, 147.2, 133.3, 127.9, 127.2, 127.0,
125.1, 116.8, 115.0, 114.3, 70.1, 30.7; ms (70 eV): m/z 223 (Mþ-
CH3). Anal. Calcd. for C15H14N2O: C, 75.63; H, 5.88; N, 11.76.
Found: C, 75.61; H, 5.89; N, 11.73.
3190, 1660, 1609 cmꢂ1 1H-NMR (CDCl3): d 7.92 (dd, 1H,
;
J ¼ 7.7, 1.1), 7.36 (td, 1H, J ¼ 7.7, 1.6), 7.04 (br s, 1H), 6.78
(t, 1H, J ¼ 7.1), 6.59 (d, 1H, J ¼ 8.2), 3.50 (m, 2H), 2.17 (m,
2H), 2.04 (m, 1H), 1.39 (s, 3H); 13C-NMR (CDCl3): d 164.9,
145.3, 134.0, 128.6, 117.3, 114.9, 113.8, 74.9, 47.1, 39.6, 25.6,
21.8; ms (30 eV): m/z 202 (Mþ). Anal. Calcd. for C11H14N2O:
C, 71.29; H, 6.93; N, 13.86. Found: 71.33; H, 6.94; N, 13.83.
(6)-2-Benzyl-2,3-dihydro-2-methyl-4(1H)-quinazolinone
(3l). This compound was prepared from 332 mg (2.00
mmoles) of 1, 268 mg (2.00 mmoles) of phenylacetone (2l),
and 560 mg (10.0 mmoles) of iron powder in 7 mL of acetic
acid using the procedure outlined for the preparation of 3a.
Product 3l (458 mg, 91%) was isolated as a white solid, mp
1
162–165ꢀC. IR: 3292, 1655, 1615 cmꢂ1; H-NMR: d 7.96 (br
(6)-2,3,3a,4-Tetrahydro-3a-methylpyrrolo[1,2-a]quinaz-
oline-1,5-dione (7a). This compound was prepared from
415 mg (2.50 mmoles) of 1, 325 mg (2.50 mmoles) of methyl
levulinate (11), and 698 mg (12.5 mmoles) of iron powder in 8
mL of acetic acid using the procedure outlined for the prepara-
tion of 3a with the reflux period extended to 8 h. Product 7a
(400 mg, 74%) was isolated as a pale yellow solid following
purification by flash chromatography on a 30 cm ꢁ 2 cm silica
gel column eluted with 50% ether in hexanes containing 2%
methanol, mp 175–177ꢀC (ref. 28; mp 179–180ꢀC). IR: 3321,
s, 1H), 7.50 (d, 1H, J ¼ 7.7), 7.22 (m, 3H), 7.15 (d, 2H, J ¼
7.1), 6.71 (br s, 1H), 6.65 (d, 1H, J ¼ 8.2), 6.57 (t, 1H, J ¼
7.7), 2.93 (d, 1H, J ¼ 13.2), 2.83 (d, 1H, J ¼ 13.2), 1.37 (s,
3H); 13C-NMR: d 163.0, 146.8, 136.5, 133.2, 130.7, 127.7,
127.0, 126.2, 116.1, 114.0, 113.6, 69.3, 46.5, 27.5; ms (70
eV): m/z 161 (Mþ-C7H7). Anal. Calcd. for C16H16N2O: C,
76.19; H, 6.35; H, 11.11. Found: C, 76.24; H, 6.36; N, 11.05.
2,3-Dihydro-2,2-diphenyl-4(1H)-quinazolinone (3m). This
compound was prepared from 332 mg (2.00 mmoles) of 1, 364
mg (2.00 mmoles) of benzophenone (2m), and 560 mg (10.0
mmoles) of iron powder in 7 mL of acetic acid using the pro-
cedure outlined for the preparation of 3a. Product 3m (360
mg, 60%) was isolated as a white solid, mp 203–205ꢀC. IR:
1712, 1669, 1604 cmꢂ1 1H-NMR: d 8.25 (br s, 1H), 8.16 (d,
;
1H, J ¼ 8.2), 8.06 (dd, 1H, J ¼ 7.8, 1.4), 7.59 (td, 1H, J ¼ 7.8,
1,4), 7.29 (t, 1H, J ¼ 8.2), 2.71 (m, 2H), 2.40 (m, 2H), 1.58 (s,
3H); 13C-NMR: d 171.7, 163.5, 135.8, 133.8, 128.2, 125.0,
120.7, 119.5, 74.5, 32.9, 30.0, 26.9; ms (30 eV): m/z 216 (Mþ).
3378, 3281, 1650, 1614 cmꢂ1
;
1H-NMR: d 7.80 (d, 1H, J ¼
7.7), 7.38 (m, 4H), 7.30 (m, 7H), 6.77 (t, 1H, J ¼ 7.7), 6.70
(d, 1H, J ¼ 8.2), 6.60 (br s, 1H), 5.25 (br s, 1H); 13C-NMR:
d 164.1, 145.5, 143.6, 134.1, 128.6, 128.4 (2C), 127.2, 119.2,
115.4, 114.8, 75.9; ms (30 eV) 300 (Mþ). Anal. Calcd. for
C20H16N2O: C, 80.00; H, 5.33; N, 9.33. Found: C, 79.88; H,
5.37; N, 9.26.
(6)-2,3,3a,4-Tetrahydro-3a-phenylpyrrolo[1,2-a]quinaz-
oline-1,5-dione (7b). This compound was prepared from 415
mg (2.50 mmoles) of 1, 480 mg (2.50 mmoles) of methyl 3-
benzoylpropionate (12), and 698 mg (12.5 mmoles) of iron
powder in 8 mL of acetic acid using the procedure outlined for
the preparation of 3a with the reflux period extended to 8 h.
Product 7b (536 mg, 77%) was isolated as a pale yellow solid
following flash chromatography on a 30 cm ꢁ 2 cm silica gel
column eluted with 50% ether in hexanes containing 2% metha-
nol, mp 290ꢀC (decomposition) (ref. 28; mp >290ꢀC). IR:
Spiro[cyclopentane-1,20(10H)-quinazolin]-40(30H)-one (3n).
This compound was prepared from 332 mg (2.00 mmoles) of
1, 168 mg (2.00 mmoles) of cyclopentanone (2n), and 560 mg
(10.0 mmoles) of iron powder in 7 mL of acetic acid using the
procedure outlined for the preparation of 3a. Product 3n (3ꢀ74
mg, 93%) was isolated as an off-white solid, mp 258–259ꢂC1
1
3203, 1716, 1668, 1604 cmꢂ1; H-NMR: d 9.82 (br s, 1H), 8.09
(d, 1H, J ¼ 8.2), 7.77 (dd, 1H, J ¼ 7.7, 1.1), 7.60 (td, 1H, J ¼
7.7, 1.6), 7.34 (m, 4H), 7.26 (m, 2H), 2.68 (m, 3H), 2.26 (m,
1H); 13C-NMR: d 173.0, 161.9, 144.0, 136.3, 133.3, 128.7,
128.0, 127.6, 124.9, 124.8, 120.8, 120.7, 77.2, 34.7, 29.3; ms
(30 eV): m/z 278 (Mþ).
(ref. 24; mp 257–260ꢀC). IR: 3289, 3162, 1638, 1613 cm
;
1H-NMR: d 8.10 (br s, 1H), 7.59 (d, 1H, J ¼ 7.7), 7.22 (t, 1H,
J ¼ 7.7), 6.75 (br s, 1H), 6.70 (d, 1H, J ¼ 8.2), 6.63 (t, 1H,
J ¼ 7.7), 1.80 (s, 4H), 1.67 (s, 4H); 13C-NMR: d 163.4, 147.5,
133.0, 127.2, 116.5, 114.6, 114.3, 77.1, 39.3, 22.0; ms (30
eV): m/z 202 (Mþ).
(6)-6,6a-Dihydroisoindolo[2,1-a]quinazoline-5,11-dione
(8). This compound was prepared from 415 mg (2.50 mmoles)
of 1, 415 mg (2.50 mmoles) of methyl 2-formylbenzoate (13)
[29], and 698 mg (12.5 mmoles) of iron powder in 8 mL of ace-
tic acid using the procedure outlined for the preparation of 3a
with the reflux period extended to 8 h. Product 8 (415 mg, 72%)
was isolated following flash chromatography on a 30 cm ꢁ
2 cm silica gel column eluted with 50% ether in hexanes con-
taining 5% methanol, mp 255–258ꢀC. IR: 3154, 1715, 1681,
Spiro[cyclohexane-1,20(10H)-quinazolin]-40(30H)-one (3o).
This compound was prepared from 332 mg (2.00 mmoles) of
1, 196 mg (2.00 mmoles) of cyclohexanone (2o), and 560 mg
(10.0 mmoles) of iron powder in 7 mL of acetic acid using the
procedure outlined for the preparation of 3a. Product 3o (396
mg, 92%) was isolated as an off-white solid, mp 216–218ꢀC
(ref. 24; mp 217–219ꢀC). IR: 3287, 1651, 1613 cmꢂ1
;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

996
R. A. Bunce and B. Nammalwar
Vol 48
1605 cmꢂ1 1H-NMR: d 9.43 (br s, 1H), 8.30–7.55 (complex,
;
2,3-Dihydro-2,2-diphenyl-4(1H)-quinazolinone (3m). This
compound (309 mg, 56%) was prepared from 250 mg (1.84
mmoles) of 4 and 335 mg (1.84 mmoles) of 2m in 7 mL of ace-
tic acid. The mp and spectral data matched those reported above.
Spiro[cyclohexane-1,20(10H)-quinazolin]-40(30H)-one
(3o). This compound (357 mg, 90%) was prepared from 250
mg (1.84 mmoles) of 4 and 180 mg (1.84 mmoles) of 2o in 7
mL of acetic acid. The mp and spectral data matched those
reported above.
7H), 7.36 (br s, 1H), 6.25 (br s, 1H); 13C-NMR: d 164.1, 163.6,
140.7, 137.1, 133.5, 133.2, 131.1, 130.1, 128.1, 124.7, 124.1,
123.8, 119.9, 119.5, 67.0; ms (30 eV): m/z 250 (Mþ). Anal.
Calcd. for C15H10N2O2: C, 72.00; H, 4.00; N, 11.20. Found: C,
72.03; H, 3.99; N, 11.15.
2,4(1H,3H)-Quinazolinedione (9). This compound was pre-
pared from 415 mg (2.50 mmoles) of 1, 495 mg (2.50
mmoles) of diphosgene (14), and 698 mg (12.5 mmoles) of
iron powder in 8 mL of acetic acid using the procedure out-
lined for the preparation of 3a with the reflux period extended
to 8 h. Product 9 (348 mg, 86%) was isolated directly from
the reaction mixture as a gray solid, mp 343–345ꢀC (ref. 34;
mp > 300ꢀC). The spectral data matched those reported previ-
ously [34].
(6)-Methyl 3-(1,2,3,4-Tetrahydro-2-methyl-4-oxoquinazo-
lin-2-yl)propanoate (15). This compound was prepared by stir-
ring 150 mg (1.10 mmoles) of 4 and 143 mg (1.10 mmoles) of 11
in 5 mL of acetic acid at 23ꢀC for 24 h. Workup as above and
recrystallization from methanol gave 192 mg (70%) of 15 aꢂs 1a
white solid, mp 141–142ꢀC. IR: 3287, 1722, 1655, 1615 cm
;
Representative procedure from 2-aminobenzamide: (6)-
2,3-Dihydro-2-phenyl-4(1H)-quinazolinone (3a). A 100-mL
three-necked round-bottomed flask, equipped with a reflux
condenser, a magnetic stirrer and a nitrogen inlet, was charged
with 7 mL of acetic acid, 250 mg (1.84 mmoles) of 2-amino-
benzamide (4), and 195 mg (1.84 mmoles) of benzaldehyde
(2a). The resulting solution was stirred at 23ꢀC for 4 h or,
alternatively, at 115ꢀC for 30 min. The reaction mixture was
cooled (if necessary), poured into saturated aqueous sodium
chloride, and extracted with ether (1 ꢁ 50 mL) and ethyl ace-
tate (1 ꢁ 50 mL). The combined organic layers were washed
with saturated aqueous sodium bicarbonate (two times) and sat-
urated aqueous sodium chloride (one time), then dried (magne-
sium sulfate) and concentrated under vacuum and recrystallized
from ethanol to give 370 mg (90%) of 3a as a white solid. The
mp and spectral data matched those reported above.
1H-NMR: d 7.85 (dd, 1H, J ¼ 7.7, 1.6), 7.28 (ddd, 1 H, J ¼ 8.2,
7.7, 1.6), 6.80 (t, 1H, J ¼ 7.7), 6.62 (br s, 1H), 6.59 (d, 1H, J ¼
8.2), 4.22, (br s, 1H), 3.65 (s, 3H), 2.64 (dt, 1H, J ¼ 17.0, 7.1),
2.52 (dt, 1H, J ¼ 17.0, 7.1), 2.15 (dt, 1H, J ¼ 14.0, 7.1), 2.06 (dt,
1H, J ¼ 14.0, 7.1), 1.55, 2, 3H); 13C-NMR d 174.2, 164.5, 145.8,
134.0, 128.3, 118.6, 114.5, 114.0, 69.8, 51.9, 36.4, 29.0, 28.7; ms
(30 eV): m/z 248 (Mþ). Anal. Calcd. for C13H16N2O3: C, 62.90;
H, 6.45; N, 11.29. Found: C, 62.96; H, 6.46; N, 11.21. Treatment
of equimolar amounts of 4 and 11 in 5 mL of acetic acid at 115ꢀC
for 8 gave 7a in 75% yield. Additionally, heating 15 in acetic acid
at 115ꢀC for 8 h resulted in 98% conversion to 7a. The mp and
spectral data for 7a matched those reported above.
Acknowledgments. B. N. thanks Oklahoma State University for
a research assistantship and the Department of Chemistry for an
O. C. Dermer Scholarship. Funding for the 300 MHz NMR spec-
trometer of the Oklahoma Statewide Shared NMR Facility was
provided by NSF (BIR-9512269), the Oklahoma State Regents
for Higher Education, the W. M. Keck Foundation, and Conoco,
Inc. Finally, the authors wish to thank the OSU College of Arts
and Sciences for funds to upgrade our departmental FT-IR and
GC-MS instruments.
(6)-2,3-Dihydro-2-(4-methoxyphenyl)-4(1H)-quinazolinone
(3b). This compound (420 mg, 90%) was prepared from
250 mg (1.84 mmoles) of 4 and 250 mg (1.84 mmoles) of 2b
in 7 mL of acetic acid. The mp and spectral data matched
those reported above.
(6)-2-(2-Chlorophenyl)-2,3-dihydro-4(1H)-quinazolinone
(3d). This compound (437 mg, 92%) was prepared from
250 mg (1.84 mmoles) of 4 and 258 mg (1.84 mmoles) of 2d
in 7 mL of acetic acid. The mp and spectral data matched
those reported above.
REFERENCES AND NOTES
(6)-Ethyl 4-(1,2,3,4-Tetrahydro-4-oxoquinazolin-2-yl)bu-
tanoate (3g). This compound (366 mg, 76%) was prepared
from 250 mg (1.84 mmoles) of 4 and 265 mg (1.84 mmoles)
of 2g in 7 mL of acetic acid. The mp and spectral data
matched those reported above.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011 New Conditions for Synthesis of (6)-2-Monosubstituted and (6)-2,2-Disubstituted
2,3-Dihydro-4(1H)-quinazolinones from 2-Nitro- and 2-Aminobenzamide
997
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet