Synthesis of 3,4-dihydroquinazolin-4-one: Selenium-catalyzed reductive N-heterocyclization of N-(2-nitrobenzoyl)amides with carbon monoxide

Article abstract of DOI:10.1016/S0040-4039(02)00035-7

A catalytic synthetic method of 3,4-dihydroquinazolin-4-ones has been developed. When N-(2-nitrobenzoyl)amides were treated with carbon monoxide in the presence of a catalytic amount of selenium, reductive N-heterocyclization of N-(2-nitrobenzoyl)amide efficiently proceeded to give the corresponding 3,4-dihydroquinazolin-4-ones in moderate to good yields.

Full text of DOI:10.1016/S0040-4039(02)00035-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1855–1858
Synthesis of 3,4-dihydroquinazolin-4-one: selenium-catalyzed
reductive N-heterocyclization of N-(2-nitrobenzoyl)amides with
carbon monoxide
Yutaka Nishiyama,* Masaharu Hirose, Wataru Kitagaito and Noboru Sonoda*
Department of Applied Chemistry, Faculty of Engineering, Kansai University, 3-3-35 Yamate chou, Suita, Osaka 564-8680,
Japan
Received 9 October 2001; accepted 21 December 2001
Abstract—A catalytic synthetic method of 3,4-dihydroquinazolin-4-ones has been developed. When N-(2-nitrobenzoyl)amides
were treated with carbon monoxide in the presence of a catalytic amount of selenium, reductive N-heterocyclization of
N-(2-nitrobenzoyl)amide efficiently proceeded to give the corresponding 3,4-dihydroquinazolin-4-ones in moderate to good yields.
© 2002 Elsevier Science Ltd. All rights reserved.
NO2
O
O
Ring-closing reactions continue to emerge as a useful
approach for the construction of various heterocyclic
compounds. The development of a synthetic method of
quinazolinones has recently received considerable atten-
tion, because these compounds show pharmacological
activity.1 There are many methods for the synthesis of
quinazolinones; however, the catalytic method is lim-
ited to the transition metal complex-catalyzed reductive
N-heterocyclization of N-(2-nitrobenzoyl)amides with
carbon monoxide3 and the palladium-catalyzed cou-
pling of o-iodoaniline, lactames and carbon monoxide.4
We have recently shown that selenium catalyzed the
reductive N-heterocyclization of 2-nitrostyrenes with
carbon monoxide giving the corresponding indoles in
moderate to good yields.5 In the course of our study on
the use of the SeꢀCO reaction system in organic synthe-
sis, it was found that selenium-catalyzed reductive N-
heterocyclization of N-(2-nitrobenzoyl)amides (1) with
carbon monoxide affords the corresponding 3,4-dihy-
droquinazolin-4-ones in moderate to good yields
(Scheme 1).6
cat.Se
+
CO
N
R"
R'
O
1
R'
N
N
R"
2
Scheme 1.
of a catalytic amount of selenium (5 mol%) in DMF
solution at 100°C for 10 h, the reductive N-heterocy-
clization of 1a efficiently proceeded to give 7,8,9,10-tet-
rahydro-6H-azepino[2,1-b]quinazolin-12-one (2a) in
92% yield (entry 2 in Table 1).7,9 In the presence of a
catalytic amount of selenium 1a was reacted with car-
bon monoxide under various reaction conditions, and
the results are shown in Table 1. When the reaction was
carried out at a lower temperature (80°C), the yield of
2a was slightly decreased (entry 1). DMF is the best
solvent for this reaction (entries 2–5). The use of 1,8-
When N-(2-nitrobenzoyl)-2-azacycloheptanone (1a) was
treated with carbon monoxide (5 atm) in the presence
diazabicyclohexa-[5,4,0]undec-5-ene
(DBU),
N-
methylpyrrolidine, pyridine and K2CO3 instead of
triethylamine as a base led to a decreased yield of 2a
(entries 2 and 6–9). Table 2 shows the results of the
synthesis of the 3,4-dihydroquinazolin-4-ones by the
* Corresponding authors. Tel.: +81-6-6368-1121; fax: +81-6-6339-
4026; e-mail: nishiya@ipcku.kansai-u.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00035-7

1856
Y. Nishiyama et al. / Tetrahedron Letters 43 (2002) 1855–1858
Table 1. Selenium-catalyzed reductive N-heterocyclization
of N-(2-nitrobenzoyl)-2-azacycloheptane (1a) with carbon
monoxidea
Although a detailed study of the reaction pathway
has not yet been completed, the present reaction can
be understood by assuming the following reaction
pathway. The first step involves the deoxygenation of
N-(2-nitrobenzoyl)amide (1) with SeCO, which was
generated in situ by the reaction of elemental sele-
nium with carbon monoxide in the presence of tri-
ethylamine,10
to
generate
the
corresponding
short-lived nitrene or nitrenoid species (3a or 3b).
Compound 3 abstracted the hydrogen atoms from tri-
ethylamine and/or the solvent to form the aniline
derivative (4).11,12 The intramolecular nucleophilic
addition of an amino group onto the carbonyl carbon
of 4 and subsequent dehydration afforded the corre-
sponding 3,4-dihydroquinazolin-4-one (2).13 At the
present time, however, other possibilities including the
direct intramolecular nucleophilic addition of nitrene
or nitrenoid intermediate 3 onto the carbonyl group
of 1 cannot be rigorously ruled out.14
O
N
O
O
N
O
N
R"
N
R"
R'
R'
3a
3b
O
O
N
R"
R'
NH2
selenium-catalyzed reductive N-heterocyclization of
N-(2-nitrobenzoyl)amides with carbon monoxide. N-
(2-Nitrobenzoyl)-2-azacyclohexanone, N-(2-nitroben-
zoyl)-2-azacycloheptanone and N-(2-nitrobenzoyl)-2-
azacyclooctanone were converted into the correspond-
ing 3,4-dihydroquinazolin-4-ones in 82–93% yields
(entries 1, 2 and 8). The reductive N-heterocycliza-
tion of N-(2-nitro-4-chlorobenzoyl)-, N-(2-nitro-5-
methoxy)-, and N-(2-nitro-5-methylbenzoyl)-2-azacy-
cloheptanone also proceeded smoothly to give the
corresponding 3,4-dihydroquinazolin-4-ones in good
yields (entries 3, 5 and 6). However, for a sterically
congested substrate such as N-(2-nitro-3-methylben-
zoyl)-2-azacycloheptanone, the yield of the 2-methyl-
7,8,9,10-tetrahydro-6H-azepino[2,1-b]-quinazolinone
was 19% (entry 4). The reaction proceeded smoothly
even when methyl-substituted N-(2-nitrobenzoyl)-2-
azacyclopentanones were used as a substrate, and the
corresponding dihydroquinozolinones were formed in
93 and 98% yields, respectively (entries 8 and 9). On
the other hand, for N-(2-nitrobenzoyl)-N-benzylac-
etamide having linear alkyl chains, the yield was
slightly decreased owing to the formation of various
by-products (entry 10).
4
In summary, we have found a catalytic synthetic
method of 3,4-dihydroquinazolin-4-one. Further stud-
ies regarding the widespread use of the selenium-cata-
N-heterocyclization
mechanism are now in progress.
lyzed
reductive
and
the
Acknowledgements
This research was supported in part by Grant-in Aid
for Scientific Research in Priority Area (No.
12650840) from the Ministry of Education, Science,
Culture and Sports, Government of Japan.

Y. Nishiyama et al. / Tetrahedron Letters 43 (2002) 1855–1858
Table 2. Synthesis of various 3,4-dihydroquinazolin-4-onea
1857
entry
product (%)b
entry
product (%)b
substrate
substrate
O
O
N
N
NO2
O
NO2
O
O
N
O
MeO
N
N
N
1
6d
N
OMe
NO2
(75)
O
(81)
NO2
O
O
O
N
O
O
N
2
3
N
7
N
N
(91)
(82)
NO2
O
O
O
N
O
O
N
N
NO2
O
N
CH3
8d
N
Cl
Cl
N
CH3
(91)
(93)
NO2
O
O
N
N
O
O
NO2
O
O
Me
CH3
N
O
4c
N
9d
N
N
H3C
Me
(19)
(98)
O
NO2
O
O
NO2
O
O
Me
N
N
5d
N
Ph
Me
10e
N
Me
Ph
N
N
Me
(82)
(35)
a Reaction conditions : substrate (0.5 mmol), Se (0.025 mmol), Et3N (5 mmol), DMF (5 mL) and CO (5 atm) at
100°C for 10 h. b GC yield. c At 100°C for 20 h. d At 100°C for 15 h. e At 80°C for 24 h.
References
and the coupling reaction o-aminobenzamide with suc-
cinic anhydride derivative8 have been developed.
7. Eguchi, S.; Suzuki, T.; Okawa, T.; Matsushita, Y.;
Yashima, E.; Okamoto, Y. J. Org. Chem. 1996, 61, 7316
and references cited therein.
1. It has already been reported that many of the quinazoli-
none alkaloids such as tryptanthrine,2a,b,c vasicinone,2d,e
anisotine,2f and rutaecarpine2g have biological activities.
2. (a) Honda, G.; Tabata, M. Planta Med. 1978, 36, 85; (b)
Honda, G.; Tabata, M.; Tsuda, M. Planta Med. 1979, 37,
172; (c) Bergman, J.; Lindstrom, J. O.; Tilstam, U. Tetra-
hedron 1985, 41, 2879; (d) Mehta, D. R.; Naravane, J. S.;
Desai, R. M. J. Org. Chem. 1963, 28, 445; (e) Johne, S.;
Groger, D.; Hesse, M. Helv. Chim. Acta 1971, 54, 826; (f)
Arndt, R. R.; Eggers, S.; Jordaan, A. Tetrahedron 1967,
23, 3521; (g) Asahina, Y.; Manske, R. H. F.; Robinson,
R. J. Chem. Soc. 1927, 1708.
8. Mhaske, S. B.; Argade, N. P. J. Org. Chem. 2001, 66,
9038.
9. A typical procedure is as follows: in a 50 mL stainless
steel autoclave were placed N-(2-nitrobenzoyl)amide (0.5
mmol), selenium (2 mg, 0.025 mmol), triethylamine (505
mg, 5 mmol) DMF (5 mL) and a magnetic stirring bar.
The apparatus was flushed several times with carbon
monoxide and charged at 5 atm. The mixture was heated
at 100°C along with magnetic stirring for 10ꢀ20 h. After
the reaction, the carbon monoxide was purged in a
well-ventilated hood, and the resulting mixture was
extracted with diisopropyl ether (25 mL×3). The organic
layer was dried over MgSO4 and evaporation of the
solvent gave the crude product, which was chro-
matographed on silica gel to give 3,4-dihydroquinazolin-
4-ones.
3. Akazome, M.; Kondo, T.; Watanabe, Y. J. Org. Chem.
1993, 58, 310.
4. Mori, M.; Kobayashi, H.; Kimura, M.; Ban, Y. Hetero-
cycles 1985, 23, 2803.
5. Nishiyama, Y.; Maema, R.; Ohno, K.; Hirose, M.;
Sonoda, N. Tetrahedron Lett. 1999, 5717.
6. Recently a synthetic method of 3,4-dihydroquinazolin-4-
ones based on the intramolecular Aza-Wittig reaction7

1858
Y. Nishiyama et al. / Tetrahedron Letters 43 (2002) 1855–1858
Scheme 2.
10. Kondo, K.; Yokoyama, S.; Miyoshi, N.; Murai, S.;
Sonoda, N. Angew. Chem., Int. Ed. Engl. 1979, 18, 691.
11. In the selenium-catalyzed reductive N-heterocyclization
of o-nitrostyrene with carbon monoxide in the presence
of a tertiary amine, o-aminostyrene was formed as a
by-product.5 Based on this result, the abstraction reaction
of the hydrogen atom from the tertiary amine and/or
solvent by short-lived nitrene or nitrenoid species was
suggested.
12. The generation of carbon dioxide was ascertained by
bubbling of the resulting gas into the aq. Ba(OH)2.
13. Selenium catalyzed reductive N-heterocyclization of o-
nitrostyrene with carbon monoxide was promoted by the
addition of a small amount of water (Scheme 2).
14. For the reaction of a transition metal complex-catalyzed
reductive N-heterocyclization of N-(2-nitrobenzoyl)-
amides by carbon monoxide, nitrene species is proposed
for this pathway: see Ref. 3.