Copper-catalyzed domino synthesis of quinazolinones via Ullmann-type coupling and aerobic oxidative C-H amidation

Article abstract of DOI:10.1021/ol1030266

An efficient copper-catalyzed approach to quinazolinone derivatives has been developed, and the protocol uses cheap and readily available substituted 2-halobenzamides and (aryl)methanamines as the starting materials as well as economical and environmentally friendly air as the oxidant. This can be the first example of constructing N-heterocycles via sequential Ullmann-type coupling under air and aerobic oxidative C-H amidation.

Full text of DOI:10.1021/ol1030266

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1274–1277
Copper-Catalyzed Domino Synthesis of
Quinazolinones via Ullmann-Type
Coupling and Aerobic Oxidative
C-H Amidation
Wei Xu,† Yibao Jin,‡ Hongxia Liu,‡ Yuyang Jiang,‡ and and Hua Fu*,†
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry
of Education), Department of Chemistry, Tsinghua University, Beijing 100084, P. R.
China, and Key Laboratory of Chemical Biology (Guangdong Province), Graduate
School of Shenzhen, Tsinghua University, Shenzhen 518057, P. R. China
fuhua@mail.tsinghua.edu.cn
Received December 14, 2010
ABSTRACT
An efficient copper-catalyzed approach to quinazolinone derivatives has been developed, and the protocol uses cheap and readily available
substituted 2-halobenzamides and (aryl)methanamines as the starting materials as well as economical and environmentally friendly air as the
oxidant. This can be the first example of constructing N-heterocycles via sequential Ullmann-type coupling under air and aerobic oxidative C-H
amidation.
Quinazolinone derivatives widely occur in natural
products,1 and they show a wide range of useful biological
and pharmacological activities.2 The quinazolinone deri-
vatives exhibit many central nervous system (CNS) effects,
such as analgesic, antiparkinsonian, CNS depressant, and
CNS stimulant activities; they also act as psychotropic,
hypnotic, cardiotonic, and antihistamine agents3 and pos-
sess cardiovascular activity (including antihypertensive,
antiarrhymic, vasodilatory, and lipid-lowering effects)
and antiinflammatory activity (including inhibition of
cyclooxygenase activity and leukocyte function).3,4 They
are also potent antibacterial, antifungal, antiviral, antimy-
cobacterial, and antimalarial agents and possess anthel-
mintic activity.5 Quinazolinone derivatives are used as
inhibitors of various enzymes, and these enzymes include
(4) de Laszlo, S. E.; Quagliato, C. S.; Greenlee, W. J.; Patchett, A. A.;
Chang, R. S. L.; Lotti, V. J.; Chen, T.-B.; Scheck, S. A.; Faust, K. A.;
Kivlighn, S. S.; Schorn, T. S.; Zingaro, G. J.; Siegl, P. K. S. J. Med.
Chem. 1993, 36, 3207.
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Baldwin, J. J.; Lynch, R. J.; Zhang, G.; Gould, R. J. Bioorg. Med. Chem.
Lett. 1998, 8, 483.
(6) Zhang, W.; Mayer, J. P.; Hall, S. E.; Weigel, J. A. J. Comb. Chem.
2001, 3, 255.
(7) Witt, A.; Bergman, J. Curr. Org. Chem. 2003, 7, 659 and refer-
ences cited therein.
(8) For selected examples, see: (a) Griess, P. Ber 1869, 2, 415. (b)
Griess, P. Ber 1878, 11, 1985. (c) von Niementowski, S. J. Prakt. Chem.
1895, 51, 564. (d) Liu, J.-F.; Ye, P.; Zhang, B.; Bi, G.; Sargent, K.; Yu, L.;
Yohannes, D.; Baldino, C. M. J. Org. Chem. 2005, 70, 6339. (e) Liu, J.-
F.; Kaselj, M.; Isome, Y.; Ye, P.; Sargent, K.; Sprague, K.; Cherrak, D.;
Wilson, C. J.; Si, Y.; Yohannes, D.; Ng, S.-C. J. Comb. Chem. 2006, 8, 7.
(f) Roy, A. D.; Subramanian, A.; Roy, R. J. Org. Chem. 2006, 71, 382. (g)
Yoo, C. L.; Fettinger, J. C.; Kurth, M. J. J. Org. Chem. 2005, 70, 6941.
(h) Kamal, A.; Reddy, K. S.; Prasad, B. R.; Babu, A. H.; Ramana, A. V.
Tetrahedron Lett. 2004, 45, 6517. (i) Larksarp, C.; Alper, H. J. Org.
Chem. 2000, 65, 2773.
† Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Biology (Ministry of Education), Department of Chemistry, Tsinghua
University.
‡ Key Laboratory of Chemical Biology (Guangdong Province), Graduate
School of Shenzhen, Tsinghua University.
(1) (a) Ma, Z.-Z.; Hano, Y.; Nomura, T.; Chen, Y.-J. Heterocycles
1997, 46, 541. (b) Yoshida, S.; Aoyagi, T.; Harada, S.; Matsuda, N.;
Ikeda, T.; Naganawa, H.; Hamada, M.; Takeuchi, T. J. Antibiot. 1991,
44, 111. (c) Deng, Y.; Xu, R.; Ye, Y. J. Chin. Pharm. Sci. 2000, 9, 116. (d)
Wattanapiromsakul, C.; Forster, P. I.; Waterman, P. G. Phytochemistry
2003, 64, 609.
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103, 893. (b) Mhaske, S. B.; Argade, N. P. Tetrahedron 2006, 62, 9787
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r
10.1021/ol1030266
Published on Web 02/23/2011
2011 American Chemical Society

monoamine oxidase, aldose reductase, tumor necrosis
factor R, and thymidylate synthase.5,6 Therefore, they are
interesting as structural scaffolds and have been assigned
as privileged structures in drug development.2a Many
methods for syntheses of quinazolinone derivatives2,7,8
have been developed; however, ortho-amino or ortho-nitro
benzoic acid derivatives are usually used as the starting
materials, and they are not readily available or are difficult
to prepare. Recently, copper-catalyzed Ullmann N-aryla-
tions have made great progress,9 and the N-arylation
strategy has been used to make N-heterocycles.10 We have
also developed some efficient methods for copper-cata-
lyzed cross couplings11 and synthesis of N-heterocycles.12
However, to the best of our knowledge, there is no example
of constructing N-heterocycles via sequential Ullmann-
type coupling under air together with aerobic oxidative
C-H amidation. Herein, we report a simple, practical, and
efficient copper-catalyzed strategy for synthesis of quina-
zolinone derivatives through cascade reactions of substi-
tuted 2-halobenzamides and (aryl)methanamines under air
without the addition of any ligand or additive.
Initially, 2-iodobenzamide and benzylamine were used
as the model substrates to optimize reaction conditions
including catalysts, bases, solvents, and reaction tempera-
tures under air (1 atm). As shown in Table 1, five copper
catalysts (0.1 equiv) were tested with 3 equiv of K2CO3
(relative to amount of 2-iodobenzamide) as the base and
DMSO as the solvent at 110 °C (entries 1-5), and CuBr
provided the highest yield (entry 2). Other bases, Cs2CO3,
Na2CO3, and K3PO4 (entries 6-8), were screened, and
Table 1. Copper-Catalyzed Cascade Coupling of 2-Iodobenza-
mide with Benzylamine To Form 2-Phenylquinazolin-4(3H)-
one under Air: Optimization of Conditionsa
entry
cat.
CuI
base
solvent
temp (°C) yield (%)b
1
2
K2CO3
K2CO3
K2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
110
110
110
110
110
110
110
110
110
110
61
75
CuBr
3
Cu2O
56
4
Cu(OAc)2 K2CO3
70
5
CuO
K2CO3
trace
42
6
CuBr
CuBr
CuBr
CuBr
CuBr
Cs2CO3
7
Na2CO3 DMSO
69
8
K3PO4
K2CO3
K2CO3
DMSO
DMF
48
9
12
10
ethylene
glycol
18
11
12
13
14
15
16
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
dioxane
toluene
DMSO
DMSO
DMSO
DMSO
110
110
70
0
0
0
90
42
70
11c
130
110
a Reaction conditions: 2-iodobenzamide (0.2 mmol), benzylamine
(0.4 mmol), catalyst (0.02 mmol), base (0.6 mmol), solvent (2 mL) under
air. b Isolated yield. c Under nitrogen atmosphere (extrusion of air).
K2CO3 showed the best activity (compare entries 2, 6-8).
The effect of solvents was also investigated, and DMSO
was the optimal solvent (compare entries 2 and 9-12). We
attempted different reaction temperatures (entries 13-15),
and 110 °C was the better choice. A major Ullmann-type
N-arylation product, 2-(benzylamino)benzamide (4), was
observed with a small amount of 2-phenylquinazolin-
4(3H)-one appearing when coupling of 2-iodobenzamide
with benzylamine was carried out under a nitrogen atmo-
sphere (extrusion of air) (entry 16).
The scope of copper-catalyzed domino reactions of
substituted 2-halobenzamides with (aryl)methanamines
was investigated under the optimized conditions [using 10
mol % of CuBr as the catalyst, 3 equiv of K2CO3 as the base
(relative to the amount of 2-halobenzamides), and DMSO
as the solvent]. As shown in Table 2, most of the substrates
examined provided good yields at 100-120 °C. For sub-
stituted 2-halobenzamides, the aryl iodides showed higher
reactivity than the corresponding bromides, and only aryl
chloride containing an electron-withdrawing group could
perform this domino reaction (entry 25). In general, no
significant difference of reactivity was observed for the
examined substituted 2-bromobenzamides and (aryl)me-
thanamines with varied electronic properties, including
electron-rich, electron-poor, and neutral substrates. The
copper-catalyzed domino synthesis of quinazolinones
could tolerate various functional groups including ether
(entries 14-16), a C-Cl bond (entries 17-20), nitro (ent-
ries 21-23, 25) in the substituted 2-halobenzamides, ether
(9) For recent reviews on copper-catalyzed cross couplings, see: (a)
Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428. (b) Ley, S. V.;
Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (c) Beletskaya,
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S. L. Angew. Chem., Int. Ed. 2006, 45, 7079. (b) Evindar, G.; Batey, R. A.
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Org. Lett., Vol. 13, No. 6, 2011
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Table 2. Copper-Catalyzed Domino Synthesis of Quinazolinone Derivatives via Ullmann-Type Coupling and Aerobic Oxidative C-H
Activationa
a Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), CuBr (0.02 mmol), K2CO3 (0.6 mmol), DMSO (2 mL) under air. b Isolated yield.
(entries 3, 11, and 18), a C-Cl bond (entries 4 and 22), a
naphthalene ring (entry 5), and heterocycles containing
nitrogen, oxygen, or sulfur (entries 6-8, 12, 13, 16, and
20) in the arylmethanamines.
1276
Org. Lett., Vol. 13, No. 6, 2011

Scheme 1. (A) Copper-Catalyzed Ullmann-Type Coupling of 1a
with 2a under N2; (B) Copper-Catalyzed Aerobic Oxidative
Domino Reaction of 4; (C) Copper-Catalyzed Aerobic Oxida-
tive Cascade Coupling of 5 with 6
Scheme 2. Possible Mechanism for Copper-Catalyzed Aerobic
Oxidative Domino Synthesis of Quinazolinones
Finally, further aerobic oxidation of III provides the
target product 3a.
In order to explore the reaction mechanism for synth-
esis of quinazoline derivatives, the following control
experiments were performed as shown in Scheme 1.
Copper-catalyzed coupling of 2-iodobenzamide (1a)
with benzylamine (2a) provided 2-(benzylamino)-
benzamide (4) in 70% yield under a nitrogen atmosphere
(extrusion of air), and only a small amount of quinazo-
line was observed (see Scheme 1A and entry 16 in
Table 1). 4 transformed into 2-phenylquinazolin-4(3H)-
one (3a) in 84% yield under our standard conditions (see
Scheme 1B). Copper-catalyzed cascade coupling of
2-aminobenzamide (5) with benzaldehyde (6) provided
3a in 81% yield (see Scheme 1C).
A possible mechanism for synthesis of quinazolinone
derivatives is proposed in Scheme 2 according to the
results above. Copper-catalyzed Ullmann-type coupling
of substituted 2-halobenzamide with (aryl)methanamine
first provides a N-arylation product (I). Interestingly, no
ligand or additive was required in the reaction system,
and the result showed an ortho-substituent effect12,13 of
the amide group in 1 during N-arylation. Copper-cata-
lyzed aerobic oxidation of I affords intermediate II
containing a CdN bond, and intramolecular nucleophi-
lic addition of the amide to the CdN bond in II gives III.
In summary, we have developed a simple and efficient
copper-catalyzed method for the synthesis of quinazolinone
derivatives. The protocol uses cheap and readily available
CuBr as the catalyst, substituted 2-halobenzamides and
(aryl)methanamines asthe starting materials, and econom-
ical and environmentally friendly air as the oxidant; the
domino reactions underwent sequential copper-catalyzed
Ullmann-type coupling, aerobic oxidation, and an intra-
molecular nucleophilic addition process without the addi-
tion of any ligand and additive, and the corresponding
quinazolinone derivatives were obtained in good yields.
This can be the first example of constructing N-hetero-
cycles via sequential Ullmann-type coupling and aerobic
oxidative C-H amidation under air. The method is of high
tolerance toward various functional groups in the sub-
strates, and it will attract much attention in academic and
industrial research.
Acknowledgment. The authors wish to thank the Na-
tional Natural Science Foundation of China (Grant No.
20972083) and the Ministry of Science and Technology of
China (2009ZX09501-004) for financial support.
Supporting Information Available. Synthetic proce-
1
dures, characterization data, and H, 13C NMR spectra
(13) (a) Nicolaou, K. C.; Boddy, C. N. C.; Natarajar, S.; Yue, T.-Y.;
€
of these synthesized compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
Li, H.; Brase, S.; Ramanjulu, J. M. J. Am. Chem. Soc. 1997, 119, 3421.
(b) Cai, Q.; Zou, B.; Ma, D. Angew. Chem., Int. Ed. 2006, 45, 1276.
Org. Lett., Vol. 13, No. 6, 2011
1277