Copper-catalyzed domino synthesis of benzimidazo[2,1-b]quin-azolin-12(6H)- ones using cyanamide as a building block

Article abstract of DOI:10.1002/adsc.201100580

A convenient copper-catalyzed domino method for the synthesis of benzimidazo[2,1-b]quinazolin-12(6H)-ones has been developed via reactions of readily available substituted 2-bromo-N-(2-halophenyl)benzamides with cyanamide, in which cyanamide acts as a useful building block. Copyright

Full text of DOI:10.1002/adsc.201100580

FULL PAPERS
DOI: 10.1002/adsc.201100580
Copper-Catalyzed Domino Synthesis of Benzimidazo[2,1-b]quin-
G
azolin-12(6H)-ones Using Cyanamide as a Building Block
Daoshan Yang,a Yuyuan Wang,a Haijun Yang,a Tao Liu,a and Hua Fua,*
a
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of
Chemistry, Tsinghua University, Beijing 100084, Peopleꢀs Republic of China
Fax : (+ 86)-10-6278-1695; e-mail: fuhua@mail.tsinghua.edu.cn
Received: July 22, 2011; Revised: October 26, 2011; Published online: February 9, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100580.
Abstract: A convenient copper-catalyzed domino phenyl)benzamides with cyanamide, in which cyana-
method for the synthesis of benzimidazoACTHUNRTGNEUNG[2,1-b]quina- mide acts as a useful building block.
zolin-12(6H)-ones has been developed via reactions
of readily available substituted 2-bromo-N-(2-halo- Keywords:
benzimidazoACTHUNGTERNNU[G 2,1-b]quinazolin-12(6H)-
ones; building blocks; copper; cyanamide; domino
method
Introduction
by o-phenylenediamine in refluxing acetic acid,[16] and
the microwave-mediated heterocyclization of o-aryl
Benzimidazoles and quinazolinones are two important isothiocyanate esters and o-phenylenediamines.[17]
subclasses of N-heterocycles that widely occur in bio- Transition metal-catalyzed transformations are useful
logically active molecules.[1] Benzimidazoles are often tools in synthetic organic chemistry.[18] Recently,
used as enzyme inhibitors,[2] drugs,[3] dyes,[4] and poly- copper-catalyzed C N bond formation has received
À
mers.[5] Quinazolinones act as anti-inflammatory,[6] an- significant attention and has provided a useful strat-
tifungal,[7] hypnotic,[8] sedative,[9] analgesic, anticon- egy for the synthesis of heterocyclic compounds,[19]
vulsant,[10] antibacterial,[11] anticancer agents and and various N-heterocycles have been constructed via
AMPA receptor antagonists.[12] The combined struc- the copper-catalyzed Ullmann couplings by us[20] and
ture of benzimidazole and quinazolinone frameworks, other research groups.[21] In 2009, Molina and co-
the benzimidazoACTHUNRTGNEUNG[2,1-b]quinazolin-12(6H)-one ring workers reported a practical method for the prepara-
system (Figure 1), has attracted much attention for its tion of benzimidazoquinazoline derivatives via the
[22]
application in antitumor agents[13] and potential im- copper-catalyzed intramolecular C N formation.
À
munosuppressors.[14] To the best of our knowledge, no However, the route involved a multistep process, the
natural product with the benzimidazoquinazolinone starting materials were not readily available, and the
skeleton has been found thus far. Some approaches to total yields were not high. To the best of our knowl-
benzimidazo
ACHTUNGTRENNUNG
have been developed, such as the thermal rearrange- benzimidazoAHCTUNTGRENNUNG
ment of 3-oxo-2-phenyl-2,3-dihydro-1H-indazolecar- pot copper-catalyzed domino process. Herein, we
bonitrile at 2708C,[15] the attack of isatoic anhydrides report a practical and efficient copper-catalyzed syn-
thesis of benzimidazoACTHUNGTRENNG[U 2,1-b]quinazolin-12(6H)-one
derivatives under mild conditions.
Results and Discussion
As shown in Table 1, 2-bromo-N-(2-bromophenyl)-
benzamide (1a) was used as the partner of cyanamide
to optimize reaction conditions including catalysts, li-
Figure 1. Structure of benzimidazoquinazolines containing
both benzimidazole and quinazolinone frameworks.
Adv. Synth. Catal. 2012, 354, 477 – 482
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
477

Daoshan Yang et al.
FULL PAPERS
Table 1. Copper-catalyzed domino synthesis of benzimidazo-
ACHTUNGTRENNUNG[2,1-b]quinazolin-12(6H)-one (2a) via reaction of 2-bromo-
afforded a 41% yield in the absence of ligand
(entry 13).
N-(2-bromophenyl)benzamide (1a) with cyanamide: optimi-
We investigated the scope of such copper-catalyzed
domino coupling reactions of substituted 2-bromo-N-
(2-bromophenyl)benzamides with cyanamide under
the standard condition (10 mol% CuI as the catalyst,
20 mol% l-proline as the ligand, 4 equivalents of
K2CO3 as the base, DMF as the solvent at 1208C
under a nitrogen atmosphere). As shown in Table 2,
most of the examined substrates provided good yields
(entries 1–14). For the substituted 2-bromo-N-(2-bro-
mophenyl)benzamides, the substrates containing nitro
groups gave moderate yields (entries 15–17). We at-
tempted use of a solvent mixture of DMF and
DMSO, and the yields were not high (entries 16).
One possible reason is that introduction of a nitro
group in the para-bromo position of the substrates
weakened the oxidative addition of copper catalyst.
zation of conditions.[a]
À
In addition, the substrates containing a C Cl bond
also showed moderate reactivity (entries 18–20). The
copper-catalyzed domino reactions could tolerate
some functional groups such as amide, ether (en-
Entry Cat.
Ligand Base
Solvent Yield [%][b]
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
CuI
A
A
A
A
A
B
C
D
E
F
Cs2CO3 DMSO 53
À
tries 5, 6 and 19), ester (entry 4), C Cl bonds (en-
tries 9–11), C Br bonds (entries 3, 8, 11–14, 17 and
18), and nitro groups (entries 15–17).
K3PO3
K2CO3
DMSO
DMSO
45
51
64
67
67
60
65
59
63
60
63
41[c]
À
Cs2CO3 DMF
We investigated the reaction mechanism for the
synthesis of benzimidazoACTHNURGTNE[UNG 2,1-b]quinazolin-12(6H)-
ones. As shown in Scheme 1, four control experiments
were performed under the standard conditions. Reac-
tions of 2-bromo-N-p-tolylbenzamide (3) with cyan-
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
9
10
11
12
13
AHCTUNGTREGaNNUN mide provided 2-amino-3-p-tolylquinazolin-4(3H)-
A
A
–
one (4) in 73% yield [(Scheme 1 (A)]. Treatment of
N-(2-bromophenyl)-4-methylbenzamide (5) in the
presence of cyanamide produced 2-p-tolylbenzo[d]ox-
azole (6) [Scheme 1 (B)]. In fact, cyanamide did not
participate in the coupling reaction. Coupling of N-p-
tolylbenzACTHUNTGRNEUNGamide (7) with cyanamide did not work
under the standard conditions [Scheme 1 (C)]. We at-
tempted coupling of (2-bromophenyl)acetamide (9)
with cyanACTHNUGRTNEUNGamide, but no cross-coupling product (10)
[a]
Reaction conditions: under a nitrogen atmosphere, 2-
bromo-N-(2-bromophenyl)benzamide (1a) (0.5 mmol),
cyanamide (1.0 mmol), catalyst (0.05 mmol), base
(2.0 mmol), solvent (2 mL), reaction temperature
(1208C), reaction time (24 h).
[b]
[c]
Isolated yield.
In the absence of ligand.
and intramolecular cyclization product (11) were
found [Scheme 1 (D)].
Therefore, a possible mechanism for the synthesis
gands, bases, and solvents at 1208C under a nitrogen of benzimidazoACTHNUTRGNE[UNG 2,1-b]quinazolin-12(6H)-ones is sug-
atmosphere. First, bases were investigated by using gested in Scheme 2 according to the above results.
0.1 equivalent of CuI as the catalyst, 0.2 equivalents First, intermolecular N-arylation of cyanamide with 1
of l-proline as the ligand, and DMSO as the solvent provides intermediate I under copper catalysis, then
(entries 1–3), and Cs2CO3 and K2CO3 gave better intramolecular addition of NH to CN in I leads to II,
yields. When DMF replaced DMSO as the solvent and tautomerization of II forms III. Finally, intramo-
(entries 4 and 5), and K2CO3 provided a higher yield lecular N-arylation of III gives the target product 2.
(entry 5). The effect of ligands was also investigated
(compare entries 5–10), and l-proline and piperidine-
2-carboxylic acid gave better results (entries 5 and 6). Conclusions
Here, l-proline was used as the ligand. Other copper
salts, CuBr and CuCl, were tested in DMF (entries 11 We have developed a practical and efficient, copper-
and 12), and CuI was found to be the most effective catalyzed method for the synthesis of benzimidazo-
catalyst (compare entries 5, 11 and 12). The reaction
ACHTUNGTREN[NUGN 2,1-b]quinazolin-12(6H)-ones. The protocol uses in-
478
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 477 – 482

Copper-Catalyzed Domino Synthesis of BenzimidazoCAHTUNGTRENNUNG
Table 2. Copper-catalyzed domino synthesis of benzimidazoACHTUNGTRENNUNG
Entry
1
1
2
Yield [%][b]
67
1a
1b
1c
2a
2b
2c
2
3
64
72
4
1d
2d
76
5
1e
1f
1g
1h
1i
2e
2f
2g
2h
2i
82
66
61
71
62
59
70
75
55
6
7
8
9
10
11
12
13
1j
2j
1k
1l
2k
2l
1m
2m
Adv. Synth. Catal. 2012, 354, 477 – 482
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
479

Daoshan Yang et al.
FULL PAPERS
Table 2. (Continued)
Entry
1
2
Yield [%][b]
54
14
15
16
17
18
19
1n
1o
1p
1q
2n
2o
2p
2q
39
45; 43;[d] 37[e]
52
1r
1s
1t
2c
2e
2a
47
61
20
33[c]
[a]
Reaction conditions: under a nitrogen atmosphere, 2-bromo-N-(2-bromophenyl)benzamide (1) (0.5 mmol), cyanamide
(1.0 mmol), CuI (0.05 mmol), l-proline (0.1 mmol), K2CO3 (2.0 mmol), DMF (2 mL), reaction temperature (1208C), reac-
tion time (24 h).
Isolated yield.
At 1308C for 48 h.
DMF/DMSO (v/v 5:1).
DMF/DMSO (v/v 3:1).
[b]
[c]
[d]
[e]
Scheme 1. Copper-catalyzed treatment of 2-bromo-N-p-tolylbenzamide (3) (A), N-(2-bromophenyl)-4-methylbenzamide (5)
(B), N-p-tolylbenzamide (7) (C) or (2-bromophenyl)acetamide (9) (D) with cyanamide under the standard conditions.
480
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 477 – 482

Copper-Catalyzed Domino Synthesis of BenzimidazoACTHNUTRGNEU[GN 2,1-b]quinazolin-12(6H)-ones
Scheme 2. Possible mechanism for the copper-catalyzed domino synthesis of benzimidazoACTHNUTRGNE[NUG 2,1-b]quinazolin-12(6H)-ones.
expensive CuI/l-proline as the catalyst/ligand system,
and readily available substituted 2-bromo-N-(2-halo-
phenyl)benzamides and cyanamide as the starting ma-
terials, and the corresponding benzimidazoquinazo-
line derivatives were obtained in moderate to good
yields. The method is tolerant towards functional
groups in the substrates, and it should attract much at-
tention in organic chemistry and medicinal chemistry.
A. A. C. C. Pais, F. J. B. Veiga, Pharm. Res. 2007, 24,
377; d) Y. Yamamoto, H. Mizuno, T. Tsuritani, T. Mase,
J. Org. Chem. 2009, 74, 1394; e) D. J. Skalitzky, J. T.
Marakovits, K. A. Maegley, A. Ekker, X.-H. Yu, Z.
Hostomsky, S. E. Webber, B. W. Eastman, R. Almassy,
J. Li, N. J. Curtin, D. R. Newell, A. H. Calvert, R. J.
Griffin, B. T. Golding, J. Med. Chem. 2003, 46, 210;
f) C. Fischer, S. Shah, B. L. Hughes, G. N. Nikov, J. L.
Crispino, R. E. Middleton, A. A. Szewczak, B. Munoz,
M. S. Shearman, Bioorg. Med. Chem. Lett. 2011, 21,
773; g) A. Asagarasu, T. Matsui, H. Hayashi, S. Tamao-
ki, Y. Yamauchi, K. Minato, M. Sato, J. Med. Chem.
2010, 53, 7549; h) S. Yoshida, T. Aoyagi, S. Harada, N.
Matsuda, T. Ikeda, H. Naganawa, M. Hamada, T. Take-
uchi, J. Antibiot. 1991, 44, 111; i) S. Johne, Prog. Drug
Res. 1982, 26, 259; j) S. Johne, Prog. Chem. Org. Nat.
Prod. 1984, 46, 159.
Experimental Section
General Procedure for Copper-Catalyzed Synthesis of
BenzimidazoACHTUNGTRENNUNG[2,1-b]quinazolin-12(6H)-ones
An oven-dried Schlenk tube containing a stir bar was
charged with CuI (0.05 mmol, 10 mg), 2-bromo-N-(2-bromo-
phenyl)benzamide (0.5 mmol), cyanamide (1 mmol, 42 mg),
l-proline (0.1 mmol, 12 mg), K2CO3 (2 mmol, 276 mg), and
DMSO (2 mL). The Schlenk tube was capped with a Teflon
screw cap and then evacuated and backfilled with nitrogen
(3 cycles). The Schlenk tube was sealed and put into a pre-
heated oil bath at 1208C or 1308C. After stirring for 24 h,
the reaction mixture was allowed to cool to room tempera-
ture, DMSO was removed under rotary evaporation and the
residue was purified by column chromatography on silica
gel to provide the desired product.
[2] a) A. W. White, R. Almassy, A. H. Calvert, N. J. Curtin,
R. J. Griffin, Z. Hostomsky, K. Maegley, D. R. Newell,
S. Srinivasan, B. T. Golding, J. Med. Chem. 2000, 43,
4084; b) N. H. Hauel, H. Nar, H. Priepke, U. Ries, J.
Stassen, W. Wienen, J. Med. Chem. 2002, 45, 1757.
[3] J. VelIk, V. Baliharova, J. Fink-Gremmels, S. Bull, J.
Lamka, L. Skalova, Res. Vet. Sci. 2004, 76, 95 and refer-
ences cited therein.
[4] M. Ulusoy, C. Zafer, C. Ozsoy, C. Varlikli, T. Dittrich,
B. Cetinkaya, S. Icli, Dyes. Pigm. 2010, 84, 88.
[5] S. W. Tsang, Y. Tao, Z. H. Lu, J. Appl. Phy. 2011, 109,
023711.
[6] a) N. A. Santagati, E. Bousquet, A. Spadaro, G. Ronsis-
valle, Farmaco. 1999, 54, 780; b) R. P. Dickinson, A. W.
Bell, C. A. Hitchcock, S. Narayana-Swami, S. J. Ray, K.
Richardson, P. F. Troke, Bioorg. Med. Chem. Lett. 1996,
6, 2031; c) S.-I. Nagai, S. Takemoto, T. Ueda, K. Mizu-
tani, Y. Uozumi, H. Tokuda, J. Heterocycl. Chem. 2001,
38, 1097.
Acknowledgements
The authors wish to thank the National Natural Science
Foundation of China (Grant Nos. 20972083, 21172128) and
the Ministry of Science and Technology of China
(2012CB722600) for financial support.
[7] J. Bartroli, E. Turmo, M. Alguero, E. Boncompte,
M. L. Vericat, L. Conte, J. Ramis, M. Merlos, J. Garcia-
Rafanell, J. Forn, J. Med. Chem. 1998, 41, 1869.
[8] S. K. Kashaw, V. Gupta, V. Kashaw, P. Mishra, J. P.
Stables, N. K. Jain, Med. Chem. Res. 2010, 19, 250.
[9] V. Jatav, P. Mishra, S. Kashaw, J. P. Stables, Eur. J. Med.
Chem. 2008, 43, 135.
[10] M. M. Aly, Y. A. Mohamed, K. A. M. El-Bayouki,
W. M. Basyouni, S. Y. Abbas, Eur. J. Med. Chem. 2010,
45, 3365.
References
[1] a) M. Boiami, M. Gonzalez, Mini-Rev. Med. Chem.
2005, 5, 409; b) M. Sabat, J. C. L. M. J. Vanrens, T. A.
Brugel, J. Maier, A. Golebiowski, B. De, V. Easwaran,
L. C. Hsieh, R. L. Walter, M. J. Mekel, A. Evdokimov,
M. J. Janusz, Bioorg. Med. Chem. Lett. 2006, 16, 5973;
c) A. Figueiras, J. M. G. Sarraguca, R. A. Carvalho,
Adv. Synth. Catal. 2012, 354, 477 – 482
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
481

Daoshan Yang et al.
FULL PAPERS
[11] S. N. Meyyanathan, M. Ramu, B. Suresh, Med. Chem.
Res. 2010, 19, 993.
[12] W. M. Welch, F. E. Ewing, J. Huang, F. S. Menniti, M. J.
Pagnozzi, K. Kelly, P. A. Seymour, V. Guanowsky, S.
Guhan, M. R. Guinn, D. Critchett, J. Lazzaro, A. H.
Ganong, K. M. Devries, T. L. Staigers, B. L. Chenard,
Bioorg. Med. Chem. Lett. 2001, 11, 177.
[13] a) N. Dias, J. F. Goosens, B. Baldeyrou, A. Lansiaux, P.
Colson, A. Di Salvo, J. Bernal, A. Turnbull, D. Min-
cher, C. Bailly, Bioconjugate Chem. 2005, 16, 949; b) L.
Dalla Via, O. Gia, S. Marciani Magno, A. Da Settimo,
A. M. Marini, G. Primofiore, F. Da Settimo, S. Salerno,
El Farmaco 2001, 56, 159.
Chem. Res. 2008, 41, 1450; f) F. Monnier, M. Taillefer,
Angew. Chem. 2009, 121, 7088; Angew. Chem. Int. Ed.
2009, 48, 6954; g) H. Rao, H. Fu, Synlett 2011, 745, and
references cited therein.
[20] a) C. Huang, Y. Fu, H. Fu, Y. Jiang, Y. Zhao, Chem.
Commun. 2008, 6333; b) D. Yang, H. Fu, L. Hu, Y.
Jiang, Y. Zhao, J. Org. Chem. 2008, 73, 7841; c) X. Liu,
H. Fu, Y. Jiang, Y. Zhao, Angew. Chem. 2009, 121, 354;
Angew. Chem. Int. Ed. 2009, 48, 348; d) D. Yang, H.
Liu, H. Yang, H. Fu, L. Hu, Y. Jiang, Y. Zhao, Adv.
Synth. Catal. 2009, 351, 1999; e) F. Wang, H. Liu, H.
Fu, Y. Jiang, Y. Zhao, Org. Lett. 2009, 11, 2469; f) J.
Lu, X. Gong, H. Yang, H. Fu, Chem. Commun. 2010,
46, 4172; g) X. Yang, H. Fu, R. Qiao, Y. Jiang, Y. Zhao,
Adv. Synth. Catal. 2010, 352, 1033; h) X. Gong, H.
Yang, H. Liu, Y. Jiang, Y. Zhao, H. Fu, Org. Lett. 2010,
12, 3128; i) C. Wang, S. Li, H. Liu, Y. Jiang, H. Fu, J.
Org. Chem. 2010, 75, 7936.
[14] W. H. W. Lunn, R. W. Harper, R. L. Stone, J. Med.
Chem. 1971, 14, 1069.
[15] a) C. W. Bird, Tetrahedron 1965, 21, 2179; b) C. W.
Bird, M. Kapilli, Tetrahedron 1987, 43, 4621.
[16] A. A. Fadda, H. M. Refat, M. E. A. Zaki, E. Monir,
Synth. Commun. 2001, 31, 3537.
[17] R. D. Carpenter, K. S. Lam, M. J. Kurth, J. Org. Chem.
2007, 72, 284.
[18] I. Nakamura, Y. Yamamoto, Chem. Rev. 2004, 104,
2127.
[19] For recent reviews on copper-catalyzed cross-couplings,
see: a) K. Kunz, U. Scholz, D. Ganzer, Synlett 2003,
2428; b) S. V. Ley, A. W. Thomas, Angew. Chem. 2003,
115, 5558; Angew. Chem. Int. Ed. 2003, 42, 5400; c) I. P.
Beletskaya, A. V. Cheprakov, Coord. Chem. Rev. 2004,
248, 2337; d) G. Evano, N. Blanchard, M. Toumi,
Chem. Rev. 2008, 108, 3054; e) D. Ma, Q. Cai, Acc.
[21] a) R. Martin, M. R. Rivero, S. L. Buchwald, Angew.
Chem. 2006, 118, 7237; Angew. Chem. Int. Ed. 2006, 45,
7079; b) R. Martꢂn, C. H. Larsen, A. Cuenca, S. L.
Buchwald, Org. Lett. 2007, 9, 3379; c) B. Zou, Q. Yuan,
D. Ma, Angew. Chem. 2007, 119, 2652; Angew. Chem.
Int. Ed. 2007, 46, 2598; d) D. Ma, Q. Cai, Acc. Chem.
Res. 2008, 41, 1450; e) G. Evindar, R. A. Batey, J. Org.
Chem. 2006, 71, 1802; f) F. Bonnaterre, M. Bois-Chous-
sy, J. Zhu, Org. Lett. 2006, 8, 4351; g) G. Altenhoff, F.
Glorius, Adv. Synth. Catal. 2004, 346, 1661.
[22] J. A. Bleda, P. M. Fresneda, R. Orenes, P. Molina, Eur.
J. Org. Chem. 2009, 2490.
482
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 477 – 482