Copper-catalyzed sequential Ullmann N-arylation and aerobic oxidative C-H amination: A convenient route to indolo[1,2-c]quinazoline derivatives

Article abstract of DOI:10.1021/ol3016435

An efficient synthesis of indolo[1,2-c]quinazoline derivatives has been developed by copper-catalyzed sequential Ullmann N-arylation and aerobic oxidative C-H amination. The protocol uses readily available 2-(2-halophenyl)-1H-indoles and (aryl)methanamines as the starting materials to afford indolo[1,2-c]quinazolines, which are the core units of hinckdentine A.

Full text of DOI:10.1021/ol3016435

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Copper-Catalyzed Sequential Ullmann
N-Arylation and Aerobic Oxidative CÀH
Amination: A Convenient Route to
Indolo[1,2-c]quinazoline Derivatives
Peng Sang,† Yongju Xie,† Jianwei Zou,*,†,‡ and Yuhong Zhang*,†,§
Department of Chemistry, Zhejiang University, Hangzhou 310027, China,
Ningbo Institute of Technology, Zhejiang University, Ningbo 315104, China,
and State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, China
jwzou@nit.zju.edu.cn; yhzhang@zju.edu.cn
Received June 14, 2012
ABSTRACT
An efficient synthesis of indolo[1,2-c]quinazoline derivatives has been developed by copper-catalyzed sequential Ullmann N-arylation and aerobic
oxidative CÀH amination. The protocol uses readily available 2-(2-halophenyl)-1H-indoles and (aryl)methanamines as the starting materials to
afford indolo[1,2-c]quinazolines, which are the core units of hinckdentine A.
Polyheterocycles are frequently found in bioactive
natural products and have been intensively studied as drug
candidates.1 Accordingly, substantial attention has been
focused on the complementary approach to the synthesis
of polyheterocycles over the past decades.2 In recent years,
domino reactions have emerged as powerful tools for the
synthesis of polyheterocycles3 and reaction sequences that
involve direct CÀH activation are especially attractive
since such processes preclude the presence of additional
functionalities in the substrate.4
The indolo[1,2-c]quinazoline is a very important poly-
heterocycle. It is the core skeleton of the marine alkaloid
hinckdentine A (Figure 1),5 and its derivatives have shown
interesting biological and pharmacological activities.
† Department of Chemistry, Zhejiang University.
‡ Ningbo Institute of Technology, Zhejiang University.
§ Lanzhou University.
(1) (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893. (b) DeSimone, R. W.; Currie, K. S.; Mitchell, S. A.; Darrow,
J. W.; Pippin, D. A. Comb. Chem. High Throughput Screen. 2004, 7, 473.
(2) For selected examples, see: (a) Sreenivas, D. K.; Ramkumar, N.;
Nagarajan, R. Org. Biomol. Chem. 2012, 10, 3417. (b) Ohno, H.; Iuchi,
M.; Kojima, N.; Yoshimitsu, T.; Fujii, N.; Tanaka, T. Chem.;Eur. J.
2012, 18, 5352. (c) Kunz, T.; Knochel, P. Angew. Chem., Int. Ed. 2012,
51, 1958. (d) Zhou, Y.; Li, J.; Ji, X.; Zhou, W.; Zhang, X.; Qian, W.;
Jiang, H.; Liu, H. J. Org. Chem. 2011, 76, 1239. (e) Sun, C.-L.; Gu, Y.-F.;
Huang, W.-P.; Shi, Z.-J. Chem. Commun. 2011, 47, 9813. (f) Kumar,
A. S.; Nagarajan, R. Org. Lett. 2011, 13, 1398. (g) Lai, J.-J.; Salunke,
(4) For some recent examples, see: (a) Xu, H.; Fu, H. Chem.;Eur. J.
2012, 18, 1180. (b) Wang, X.; Jin, Y.; Zhao, Y.; Zhu, L.; Fu, H. Org. Lett.
2012, 14, 452. (c) Lu, J.; Jin, Y.; Liu, H.; Jiang, Y.; Fu, H. Org. Lett. 2011,
13, 3694. (d) Jordan-Hore, J. A.; Johansson, C. C. C.; Gulias, M.; Beck,
E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 16184. (e) Tsang,
W. C. P.; Munday, R. H.; Brasche, G.; Zheng, N.; Buchwald, S. L.
J. Org. Chem. 2008, 73, 7603. (f) Tsang, W. C. P.; Zheng, N.; Buchwald,
S. L. J. Am. Chem. Soc. 2005, 127, 14560. (g) Smith, M. R. J. Am. Chem.
Soc. 2011, 133, 3684. (h) Daugulis, O. Top. Curr. Chem. 2010, 292, 57.
(i) Ding, S.; Shi, S.; Jiao, N. Org. Lett. 2010, 12, 1540. (j) Bellina, F.;
Rossi, R. Tetrahedron2009, 65, 10269. (k) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. Chem. Rev. 2010, 110, 624. (l) Ackermann, L. Chem. Rev.
2011, 111, 1315. (m) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111,
1215.
D. B.; Sun, C.-M. Org. Lett. 2010, 12, 2174. (h) Garcıa-Fortanet, J.;
´
Kessler, F.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 6676. (i) Ohno,
H.; Iuchi, M.; Fujii, N.; Tanaka, T. Org. Lett. 2007, 9, 4813.
(3) For selected examples, see: (a) Yang, D.; Wang, Y.; Yang, H.;
Liu, T.; Fu, H. Adv. Synth. Catal. 2012, 354, 477. (b) Xu, W.; Jin, Y.; Liu,
H.; Jiang, Y.; Fu, H. Org. Lett. 2011, 13, 1274. (c) Xu, W.; Fu, H. J. Org.
Chem. 2011, 76, 3846. (d) Cai, S.; Wang, F.; Xi, C. J. Org. Chem. 2012,
77, 2331. (e) Liao, Q.; Zhang, L.; Li, S.; Xi, C. Org. Lett. 2010, 13, 228.
(f) Mahendar, L.; Krishna, J.; Gopi Krishna Reddy, A.; Venkat
Ramulu, B.; Satyanarayana, G. Org. Lett. 2012, 14, 628. (g) Jiang, M.;
Li, J.; Wang, F.; Zhao, Y.; Zhao, F.; Dong, X.; Zhao, W. Org. Lett.
2012, 14, 1420. (h) Saifuddin, M.; Agarwal, P. K.; Kundu, B. J. Org.
Chem. 2011, 76, 10122. (i) Ackermann, L.; Althammer, A. Angew.
Chem., Int. Ed. 2007, 46, 1627. (j) Tietze, L. F. Chem. Rev. 1996, 96, 115.
(5) Blackman, A. J.; Hambley, T. W.; Picker, R.; Taylor, W. C.;
Thirasana, N. Tetrahedron Lett. 1987, 28, 5561.
r
10.1021/ol3016435
XXXX American Chemical Society

For example, certain derivatives of indolo[1,2-c]quinazoline
present cataleptogenic activity,6 and some show excellent
antibacterial as well as antifungal properties that make
them promising drug candidates for Ampicillin and
Ketoconazole.7
The effect of solvents was also investigated, and DMSO
was the optimal solvent (compare entries 4 and 10À13).
Other solvents such as DMF, ethylene glycol, dioxane, and
toluene furnished the product in poor yields (Table 1,
entries 10À13). We attempted different reaction tempera-
tures, and 110 °C was optimal (Table 1, entries 14À15).
Under a nitrogen atmosphere, only a small amount of 3a
was obtained.
Table 1. Optimization of Reaction Conditionsa
Figure 1. Hinckdentine A.
Currently, indolo[1,2-c]quinazolines are synthesized
in two steps.7 First, the condensation between 2-(o-
aminophenyl)indoles and arylaldehydes affords the corre-
sponding Schiff bases, which were further purified by
recrystallization. Second, the prepared Schiff base is sub-
jected to KMnO4 to reflux in acetone to give the indolo-
[1,2-c]quinazolines. We envisioned that the oxidative CÀH
amination strategy,4,8 which was pioneered by Buchwald
in 2005,4f might be probed in the construction of the
pyrimidine cycle in indolo[1,2-c]quinazolines. In these
transformations, palladium catalysts together with stoi-
chiometric or excess amounts of copper or silver salts have
been used predominantly. Herein, we report a copper-
catalyzed method for the synthesis of indolo[1,2-c]-
quinazoline derivatives by the use of readily available
2-(2-halophenyl)-1H-indoles via a sequential Ullmann
coupling reaction and CÀH amination. Notably, this
transformation uses air rather than metal salts as the
oxidant without the use of any ligands or additives.
temp
yield
(%)b
entry
cat.
base
solvent
(°C)
1
CuI
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Na2CO3
K3PO4
K2CO3
K2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
110
110
110
110
110
110
110
110
110
110
110
36
46
34
61
53
0
2
CuBr
CuCl
3
4
Cu(OAc)2
5
CuCO3 Cu(OH)2
3
6
À
7
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
18
54
22
34
18
8
9
10
11
ethylene
glycol
12
13
14
15
16
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
dioxane
toluene
DMSO
DMSO
DMSO
110
110
90
0
12
49
56
9c
130
110
Our initial attempt started with the reaction of 2-(2-
bromophenyl)-1H-indole and benzylamine with 3 equiv of
K2CO3 (relative to the amount of 2-(2-bromophenyl)-1H-
indole) as the base and DMSO as the solvent at 110 °C by
the use of CuI as the catalyst. To our delight, it afforded
fused heterocyclic product 3a in 36% yield (Table 1, entry 1).
Screening of the copper catalysts (Table 1, entries 1À5)
revealed that Cu(OAc)2 was optimal to give the product 3a
in 61% yield (Table 1, entry 4). A relatively lower yield was
obtained when the reaction was carried out by the use of
a Reaction conditions: 2-(2-bromophenyl)-1H-indole (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).
We next studied the generality of this copper-catalyzed
domino reaction under the optimized conditions [using
10 mol % of Cu(OAc)2 as the catalyst, 3 equiv of K2CO3 as
the base, and DMSO as the solvent]. As shown in Table 2,
most of the substrates examined provided moderate to
good yields. For substituted 2-(2-halophenyl)-1H-indoles,
the aryl iodides showed higher reactivity than the corre-
sponding bromides (Table 2, entries 1À19). The electronic
properties of the substituents in the indole ring exerted a
very limited influence over the reactivity (Table 2, entries
10À19). Functional groups, including methyl, flouride,
and chloride, could be tolerated in this domino transfor-
mation. The selective amination in the presence of a
chloride functionality provided a useful handle for further
cross-coupling reactions (Table 2, entries 15 and 16).
The scope of arylmethanamines was also examined as
shown in Table 2. Both electron-rich and -deficient aryl-
methanamines participated in the reaction smoothly to
afford the desired products (Table 2, entries 1À4, 11À18).
CuCO3 Cu(OH)2 as the catalyst (Table 1, entry 5). No
3
reaction was observed in the absence of the copper catalyst
(Table 1, entry 6). It was found that empolying K2CO3 as
the base showed the best activity (compare entries 4, 7À9),
while other bases such as Cs2CO3 and K3PO4 were less
effective (Table 1, entries 7 and 9). A relatively lower yield was
obtained when employing Na2CO3 as a base (Table 1, entry 8).
(6) (a) Duncan, R. L. Ger. Ofen. 2,051,961 (April 29, 1971).
(b) Grinev, A. N.; Kurilo, G. N.; Cherkasova, A. A.; Mashkovskii,
M. D.; Andreeva, N. I.; Sokolov, I. K. Khim.-Farm. Zh. 1978, 12, 97(Russ).
(7) Rohini, R.; Muralidhar Reddy, P.; Shanker, K.; Hu, A.; Ravinder,
V. Eur. J. Med. Chem. 2010, 45, 1200.
(8) (a) Kumar, R. K.; Punniyamurthy, T. RSC Adv. 2012, 2, 4616.
(b) Youn, S. W.; Bihn, J. H.; Kim, B. S. Org. Lett. 2011, 13, 3738. (c) Li,
Y.; Xie, Y.; Zhang, R.; Jin, K.; Wang, X.; Duan, C. J. Org. Chem. 2011,
76, 5444.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Scope of the Indolo[1,2-c]quinazolines Synthesisa
a Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Cu(OAc)2 (0.02 mmol), K2CO3 (0.6 mmol), DMSO (2 mL) under air. b Isolated yield. c Y = Br.
d 24 h reaction time.
Org. Lett., Vol. XX, No. XX, XXXX
C

The naphthyl-substituted methanamines were tolerated in
this process to provide the corresponding indolo[1,2-c]-
quinazoline derivatives 3e and 3l. Importantly, various
heteroaromatic methanamines are compatible with this
domino reaction to give the desired products. It was found
that the reactivity of thiophen-2-ylmethanamine showed a
better reactivity than furan-2-ylmethanamine and pyridin-
3-ylmethanamine (3fÀ3h).
Scheme 1. Control Experiments
Notably, 2-(2-bromophenyl)-1H-benzo[d]imidazole par-
ticipated in the reaction easily with benzylamine to afford
the benzimidazoquinazoline derivative 3s in moderate
yield (Table 2, entry 20). Benzimidazoquinazoline deriva-
tives are valuable substrates with various biological activ-
ities and exhibit a wide range of therapeutic activities,
such as anticancer,9 antiviral,10,11 antimicrobial,12 anti-
inflammatory,10,13 and anticonvulsants.14 Thus, we also
provided an alternative approach for the benzimidazoqui-
nazoline derivatives.
Control experiments for the mechanism studies were
carried out as shown in Scheme 1. We found that this
copper-catalyzed domino reaction was partially inhabited
under a nitrogen atmosphere to afford mainly N-benzyl-
2-(1H-indol-2-yl)aniline 4a (eq 1). Only a trace of cycliza-
tion products 3a and 5a was detected by HRMS (eq 1 and
Supporting Information). These results reveal that the
copper-catalyzed domino reaction may first undergo an
Ullmann-type coupling between 2-(2-halophenyl)-1H-in-
doles and (aryl)methanamines. In contrast, under air
atmosphere, 3a was obtained, and 4a or 5a was not
detected (eq 1), indicating that the subsequent cyclization
and aromatization require oxygen as the oxidant. We
treated 4a under standard conditions, and 3a was afforded
in 81% yield (eq 2). No reaction was observed in the
absence of the copper catalyst (eq 2). Again, under a
nitrogen atmosphere, only a small amount of 3a was
obtained (eq 2). We treated 6a under standard conditions,
and 3a was afforded in 84% yield (eq 3). Further studies to
elucidate the detailed reaction mechanism are ongoing in
our laboratory.
In summary, we have developed a simple and efficient
copper-catalyzed method for the synthesis of indolo[1,2-c]-
quinazoline derivatives. The protocol uses environmen-
tally friendly air as the oxidant, cheap Cu(OAc)2 as the
catalyst, and readily available 2-(2-halophenyl)-1H-indoles
and (aryl)methanamines as the starting materials without
the use of ligands. The accessibility and generality of this
process make it highly valuable in view of the medicinal
importance of these polyheterocycles.
(9) Dalla Via, L.; Gia, O.; Marciani Magno, S.; Da Settimo, A.;
Marini, A. M.; Primofiore, G.; Da Settimo, F.; Salerno, S. Il Farmaco
2001, 56, 159.
(10) Spasov, A. A.; Yozhitsa, I. N.; Bugaeva, L. I.; Anisimova, V. A.
Pharm. Chem. J. 1999, 33, 232.
Acknowledgment. We gratefully acknowledge the
National Basic Research Program of China (No.
2011CB936003) and NSFC (No. 21072169) for their
financial support.
ꢀ
(11) Fernandez, B.; Castellano, J.; Redondo, M. Eur. Pat. Appl. 1989,
331, 093.
(12) Insuasty, B. A.; Torres, H.; Quiroga, J.; Abonia, R.; Rodriguez,
R.; Nogueras, M.; Sanchez, A.; Saitz, C.; Alvarez, S. L.; Zacchino, S. A.
J. Chil. Chem. Soc. 2006, 51, 927.
Supporting Information Available. The experimental
procedure and spectroscopic data (1H NMR, 13C NMR,
and HRMS) for the products. This material is available
free of charge via the Internet at http://pubs.acs.org.
(13) Galarcei, G. D.; Foncea, R. E.; Edwards, A. M.; Pessoamahana,
H.; Mahana, C. D. P.; Ebenspergeri, R. A. Biol. Res. 2008, 41, 43.
(14) Vostrova, L. N.; Voronina, T. A.; Karaseva, T. L.; Gernega,
ꢀ
S. A.; Ivanov, E. I.; Kirichenko, A. M.; Totrova, M. Y. Pharm. Chem. J.
1986, 20, 404.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX