Synthesis of 3-substituted and 2,3-disubstituted quinazolinones via Cu-catalyzed aryl amidation

Article abstract of DOI:10.1021/ol300084v

CuI/4-hydroxy-l-proline catalyzed coupling of N-substituted o-bromobenzamides with formamide takes place at 80 °C, affording 3-substituted quinazolinones directly. Under these conditions other amides that were tested only provided simple coupling products, which can be converted into 2,3-disubstituted quinazolinones via HMDS/ZnCl₂ mediated condensative cyclization.

Full text of DOI:10.1021/ol300084v

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1150–1153
Synthesis of 3-Substituted and
2,3-Disubstituted Quinazolinones via
Cu-Catalyzed Aryl Amidation
Lanting Xu,† Yongwen Jiang,‡ and Dawei Ma*,‡
Department of Chemistry, Fudan University, Shanghai 200433, China, and
State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, China
Madw@mail.sioc.ac.cn
Received January 13, 2012
ABSTRACT
CuI/4-hydroxy-L-proline catalyzed coupling of N-substituted o-bromobenzamides with formamide takes place at 80 °C, affording 3-substituted
quinazolinones directly. Under these conditions other amides that were tested only provided simple coupling products, which can be converted
into 2,3-disubstituted quinazolinones via HMDS/ZnCl2 mediated condensative cyclization.
Substituted quinazolinones are an important class of
fused heterocyclic compoundsdue totheir wide presence in
natural products.1 These include compound 1 (Figure 1)
from Aconitum plants,2 dictyoquinazol A 2from Dictyophora
indusata,3 (þ)-febrifugine 3 from Hydrangea chinensis,4 and
chaetominine 4 from Adenophora axilliflora.5 In addition,
many unnatural quinazolinones have shown significant bio-
logical activities which include anticancer,6 antibacterial,7
antiinflammatory,8 antihypertensive,9 antidiabetic,10 and
anticonvulsant11 properties. For example, KSP ATPase
inhibitor 5 displays antimitotic activity and now is in phase
II clinical trials as a potential anticancer chemotherapeutic
agent, while methaqualone 6 is a clinically used sedative-
hypnotic drug.12
† Fudan University.
‡ Chinese Academy of Sciences.
Although a number of methods have been developed for
the synthesis of quinazolinones,13 these routes mainly rely
(1) (a) Michael, J. P. Nat. Prod. Rep. 2004, 21, 650. (b) Mhaske, S. B.;
Argade, N. P. Tetrahedron 2006, 62, 9787.
(2) Lygin, A. V.; Meijere, A. Org. Lett. 2008, 11, 389.
(3) Lee, I. K.; Yun, B. S.; Han, G.; Cho, D. H.; Kim, Y. H.; Yoo, I. D.
J. Nat. Prod. 2002, 65, 1769.
(4) Khalil, A. T.; Chang, F. R.; Lee, Y. H.; Chen, C. Y.; Liaw, C. C.;
Ramesh, P.; Yuan, S. S. F.; Wu, Y. C. Arch. Pharmacal. Res. 2003,
26, 15.
(5) Jiao, R. H.; Xu, S.; Liu, J. Y.; Ge, H. M.; Ding, H.; Xu, C.; Zhu,
H. L.; Tan, R. X. Org. Lett. 2006, 8, 5709.
(6) (a) Jiang, J. B.; Hesson, D.; Dusak, B.; Dexter, D.; Kang, G.;
Hamel, E. J. Med. Chem. 1990, 33, 1721. (b) Cao, S. L.; Feng, Y. P.;
Jiang, Y. Y.; Liu, S. Y.; Ding, G. Y.; Li, R. T. Bioorg. Med. Chem. Lett.
2005, 15, 1915.
(7) (a) Pendergast, W.; Johnson, J. V.; Dickerson, S. H.; Dev, I. K.;
Duch, D. S.; Ferone, R.; Hall, W. R.; Humphreys, J.; Kelly, J. M.;
Wilson, D. C. J. Med. Chem. 1993, 36, 2279. (b) Kung, P. P.; Casper,
M. D.; Cook, K. L.; Wilson-Lingardo, L.; Risen, L. M.; Vickers, T. A.;
Ranken, R.; Blyn, L. B.; Wyatt, J. R.; Cook, P. D. J. Med. Chem. 1999,
42, 4705.
(8) 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. J. Med. Chem. 1993, 36, 3207.
(9) Chern, J. W.; Tao, P. L.; Wang, K. C.; Gutcait, A.; Liu, S. W.;
Yen, M. H.; Chien, S. L.; Rong, J. K. J. Med. Chem. 1998, 41, 3128.
(10) Malamas, M. S.; Millen, J. J. Med. Chem. 1991, 34, 1492.
(11) Wolfe, J. F.; Rathman, T. L.; Sleevi, M. C.; Campbell, J. A.;
Greenwood, T. D. J. Med. Chem. 1990, 33, 161.
(12) (a) Wood, K. W.; Bergnes, G. Annu. Rep. Med. Chem. 2004, 39,
173. (b) Bergnes, G.; Brejc, K.; Belmont, L. Curr. Top. Med. Chem. 2005,
5, 127.
(13) (a) Bergman, J.; Witt, A. Curr. Org. Chem. 2003, 7, 659. (b)
Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893.
(c) Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J. Tetrahedron
2005, 61, 10153. (d) Patil, A.; Patil, O.; Patil, B.; Surana, J. Mini-Rev. Med.
Chem. 2011, 11, 633.
r
10.1021/ol300084v
Published on Web 02/07/2012
2012 American Chemical Society

Scheme 1
As indicated in Table 1, we selected the reaction of
2-bromo-N-phenylbenzamide 7a with formamide 8a as a
model to explore the optimized conditions. It was found
that, under the catalysis of CuI and 4-hydroxy-L-proline,
7a was consumed completely after 24 h at 80 °C, delivering
11a in 84% yield (entry 1). Using K3PO4 as a base gave a
similar result (entry 2). However, the best yield was
observed with Cs2CO3 as the base (entry 3). Replacement
of 4-hydroxy-L-proline with L-proline, glycine, N,N-
dimethylglycine, or 1,10-phenanthroline gave slightly low
yields (entries 4ꢀ7). Changing solvent from DMF to
DMSO, dioxane, or toluene also decreased the reaction
yields (entries 8ꢀ10). Based on these results, we concluded
that, withCuI/4-hydroxy-L-prolineasthe catalyst, Cs2CO3
asthebase, andDMF asthe solvent, thiswastheoptimized
set of conditions for this transformation.
Figure 1. Structures of natural and synthesized biologically
important quinazolinones.
on using anthranilic acid14 or its derivatives15 as the
starting materials and generally suffer from low yields,
multistep reactions, or harsh reaction conditions. These
problems have stimulated several groups to apply metal-
catalyzed reactionstodevelop new methods for assembling
substituted quinazolinones.16ꢀ18 Recently, the Ding and
Fu groups independently discovered that copper-catalyzed
N-arylation ofo-bromobenzoicacidderivativeswith amid-
ines and subsequent intramolecular condensation could
afford 2-substituted and 2,3-disubstituted quinazolinones.17
During our studies on heterocycle synthesis via copper-
catalyzed reactions,19,20 we found that more conveniently
available amides could serve as suitable nucleophiles for
coupling reactions with N-substituted o-bromobenza-
mides, affording 3-substituted and 2,3-disubstituted quin-
azolinones after condensative cyclization as depicted in
Scheme 1. Herein, we wish to disclose our results.
Table 1. Coupling of 2-Bromo-N-phenylbenzamide with For-
mamide under Different Conditionsa
entry
ligandb
base
solvent
yield (%)c
(14) (a) Segarra, V.; Isabel Crespo, M.; Pujol, F.; Beleta, J.; Domenech,
T.; Miralpeix, M.; Palacios, J. M.; Castro, A.; Martinez, A. Bioorg. Med.
Chem. Lett. 1998, 8, 505. (b) Connolly, D. J.; Guiry, P. J. Synlett 2001, 1707.
(c) Hattori, K.; Kido, Y.; Yamamoto, H.; Ishida, J.; Kamijo, K.;
Murano, K.; Ohkubo, M.; Kinoshita, T.; Iwashita, A.; Mihara, K.
J. Med. Chem. 2004, 47, 4151. (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. J. Comb.
Chem. 2006, 8, 7. (f) Adib, M.; Ansari, S.; Mohammadi, A.; Bijanzadeh,
H. R. Tetrahedron Lett. 2010, 51, 30. (h) Kshirsagar, U. A.; Argade,
N. P. Org. Lett. 2010, 12, 3716.
(15) (a) Kotsuki, H.; Sakai, H.; Morimoto, H.; Suenaga, H. Synlett
1999, 1993. (b) Witt, A.; Bergman, J. Tetrahedron 2000, 56, 7245. (c)
Yoo, C. L.; Fettinger, J. C.; Kurth, M. J. J. Org. Chem. 2005, 70, 6941.
(d) Roy, A. D.; Subramanian, A.; Roy, R. J. Org. Chem. 2006, 71, 382.
(e) Zhou, J.; Fang, J. J. Org. Chem. 2011, 76, 7730.
1
2
A
A
A
B
C
D
E
A
A
A
K2CO3
K3PO4
DMF
84
83
95
72
75
68
40
51
67
40
DMF
DMF
3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
4
DMF
5
DMF
6
DMF
7
DMF
8
DMSO
dioxane
toluene
9
10
a Reaction conditions: 7a (0.25 mmol), 8a (0.5 mmol), CuI
(0.025 mmol), ligand (0.025 mmol), base (0.5 mmol), solvent (1 mL),
80 °C, 24 h. b A: 4-hydroxy-L-proline. B: L-proline. C: glycine. D: N,N-
dimethylglycine. E: 1,10-phenanthroline. c Isolated yield.
(16) (a) Zheng, Z.; Alper, H. Org. Lett. 2008, 10, 829. (b) Zeng, F.;
Alper, H. Org. Lett. 2010, 12, 3642. (c) Ma, B.; Wang, Y.; Peng, J.; Zhu,
Q. J. Org. Chem. 2011, 76, 6362.
(17) (a) Zhou, J.; Fu, L.; Lv, M.; Liu, J.; Pei, D.; Ding, K. Synthesis
2008, 15, 3974. (b) Liu, X.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem.
2009, 121, 354.
(18) (a) Xu, W.; Fu, H. J. Org. Chem. 2011, 76, 3846. (b) Xu, W.; Jin,
Y.; Liu, H.; Jiang, Y.; Fu, H. Org. Lett. 2011, 13, 1274.
With these conditions identified, we next investigated
a series of 2-bromobenzamides to examine the scope and
the limitations of this process. As shown in Table 2, our
Org. Lett., Vol. 14, No. 4, 2012
1151

process to generate the corresponding products in good to
excellent yields (entries 1ꢀ10). The results indicated that
electronic variations on the benzene rings have a minor
impact on the yields. But electronic effects in association
with steric hindrance seem to diminish the product yield
significantly. In the case of the 2,4-dimethylaniline-derived
substrate, the yield of product 11k wasup to90%(entry 10).
In contrast, when a substrate derived from methyl
2-aminobenzoate was used, the reaction became sluggish
even at 90 °C and only a 69% yield of 11l was obtained
(entry 11). The catalyticsystemcould alsotoleratea variety
of nonaromatic N-substituents, including cyclic and acy-
clic alkyl, benzyl groups and functionalized carbon
chains (entries 12ꢀ15). Pyridinyl and naphthyl groups as
N-substituents also afforded the corresponding products
11q and 11r in 78% and 90% yields, respectively (entries 16
and 17). Noteworthy is that product 11j could be easily
converted to dictyoquinazol A 2 according to a known
procedure,21 indicating that the utility of our method in
natural product synthesis is promising.
Table 2. Synthesis of 3-Substituted Quinazolinones from
2-Bromobenzamides and Formamidea
Table 3. Stepwise Synthesis of 2,3-Disubstituted Quinazolinones
from 2-Bromobenzamides and Amidesa
a Reaction conditions: 7 (0.25 mmol), 8a (0.5 mmol), CuI (0.025 mmol),
4-hydroxy-L-proline (0.025 mmol), Cs2CO3 (0.5 mmol), DMF (1 mL),
80 °C, 24 h. b Isolated yield. c The reaction was carried out at 90 °C.
a Reaction conditions: Step 1: 7 (0.25 mmol), 8 (0.5 mmol), CuI
(0.025 mmol), 4-hydroxy-L-proline (0.025 mmol), Cs2CO3 (0.5 mmol),
DMF (1 mL), 80 °C, 24 h. Step 2: HMDS (0.75 mmol), ZnCl2
(0.125 mmol), DMF (1 mL), rt. b Isolated yield. c The cyclization
reaction was carried out at 120 °C. d The cyclization reaction was
carried out at 140 °C.
catalytic system worked well for a wide range of aryl
bromides. Substrates derived from functionalized 2-brom-
obenzoic acids and substituted anilines with either
electron-donating or -withdrawing groups engaged in this
1152
Org. Lett., Vol. 14, No. 4, 2012

After success in the elaboration of 3-substituted quina-
zolinones, we moved our attention to investigate a variety
of aliphatic and aromatic amides as coupling partners. Our
first attempt to employ ethyl amide met with limited
success, with only the simple coupling product being
obtained under the current reaction conditions. Hence we
had to isolate thisproduct and thenconduct the cyclization
step with HMDS/ZnCl2 at room temperature.22 Using this
two-step procedure, a number of aliphatic amides were
surveyed and the corresponding quinazolinones were iso-
lated in yields ranging from 60% to 96% (Table 3, entries
1ꢀ5). Noteworthy is that, by using this method, metha-
qualone 6 was obtained directly in 90% yield. Interest-
ingly, when aromatic amides were used, the corresponding
coupling products could not be converted into quinazoli-
nones at room temperature via HMDS/ZnCl2 treatment.
After some experimentation, we were pleased to find that
this problem could be solved by increasing the reaction
temperatures to 120ꢀ140 °C (entries 6ꢀ9).
In conclusion, we have developed a facile and efficient
approach for assembling substituted quinazolinones,
which relies on a copper-catalyzed aryl amidation reaction
of N-substituted o-bromobenzamides with amides and
subsequent spontaneous or HMDS/ZnCl2 mediated con-
densative cyclization. The protocol could tolerate a variety
of functional groups, providing a wide range of 3-substi-
tuted and 2,3-disubstituted quinazolinones in good to
excellent yields. Its usage has been demonstrated by formal
synthesis of dictyoquinazol A 2 and facile preparation of
methaqualone 6. The relatively mild coupling conditions
used here are remarkable and may result from the ortho-
substitution effect displayed by N-alkyl and N-aryl ami-
nocarbonyl groups.23 Investigations on the detailed me-
chanism of this coupling reaction are actively being
pursued, and these results will be disclosed in due course.
(19) (a) Lu, B.; Ma, D. Org. Lett. 2006, 8, 6155. (b) Zou, B.; Yuan, Q.;
Ma, D. Angew. Chem., Int. Ed. 2007, 46, 2598. (c) Zou, B.; Yuan, Q.;
Ma, D. Org. Lett. 2007, 9, 4291. (d) Chen, Y.; Xie, X.; Ma, D. J. Org.
Chem. 2007, 72, 9329. (e) Chen, Y.; Wang, Y.; Sun, Z.; Ma, D. Org. Lett.
2008, 10, 625. (f) Yuan, Q.; Ma, D. J. Org. Chem. 2008, 73, 5159.
(g) Diao, X.; Wang, Y.; Jiang, Y.; Ma, D. J. Org. Chem. 2009, 74, 7974.
(h) Ma, D.; Xie, S.; Xue, P.; Zhang, X.; Dong, J.; Jiang, Y. Angew.
Chem., Int. Ed. 2009, 48, 4222. (i) Ma, D.; Geng., Q.; Zhang, H.; Jiang,
Y. Angew. Chem., Int. Ed. 2010, 49, 1291. (j) Ma, D.; Lu, X.; Shi, L.;
Zhang, H.; Jiang, Y.; Liu, X. Angew. Chem., Int. Ed. 2011, 50, 1118.
(20) For related studies from other groups, see: (a) Martin, R.;
Rodriguez, R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 7079.
(c) Coste, A.; Toumi, M.; Wright, K.; Razafimahaleo, V.; Conty, F.;
Marrot, J.; Evano, G. Org. Lett. 2008, 10, 3841. (d) Bao, W.; Liu, Y.; Lv,
X.; Qian, W. Org. Lett. 2008, 10, 3899. Park, I.; Suh, S.; Lim, B.; Cho, C.
Org. Lett. 2009, 11, 5454. (e) Kumar, M.; Park, A.; Park, N.; Lee, S. Org.
Lett. 2011, 13, 3542.
Acknowledgment. The authors are grateful to the Chinese
Academy of Sciences, National Natural Science Foundation
of China (Grants 20921091 and 20572119), and Ministry
of Science & Technology (Grant 2009CB940900) for their
financial support.
Supporting Information Available. Experimental pro-
1
cedures and copies of H and 13C NMR spectra for all
new products. This material is available free of charge via
the Internet at http://pubs.acs.org.
(21) Oh, C. H.; Song, C. H. Synth. Commun. 2007, 37, 3311.
(22) (a) Kshirsagar, U. A.; Mhaske, S. B.; Argade, N. P. Tetrahedron
Lett. 2007, 48, 3243. (b) Chan, J.; Burke, B. J.; Baucom, K.; Hansen, K.;
Bio, M. M.; DiVirgilio, E.; Faul, M.; Murry, J. J. Org. Chem. 2011, 76,
1767.
(23) Diao, X.; Xu, L.; Zhu, W.; Jiang, Y.; Wang, H.; Guo, Y.; Ma, D.
Org. Lett. 2011, 13, 6422.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
1153