A facile copper-catalyzed one-pot domino synthesis of 5,12-dihydroindolo[2, 1- b ]quinazolines

Article abstract of DOI:10.1021/ol3001624

A domino synthesis of 5,12-dihydroindolo[2,1-b]quinazoline derivatives via copper-catalyzed Ullmann-type intermolecular C-C and intramolecular C-N couplings is reported. Good yields of various 5,12-dihydroindolo[2,1-b] quinazoline derivatives were obtained. Reaction scopes, limitations, and the reaction mechanism are discussed.

Full text of DOI:10.1021/ol3001624

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1420–1423
A Facile Copper-Catalyzed
One-Pot Domino Synthesis
of 5,12-Dihydroindolo[2,1-b]quinazolines
Min Jiang,† Jian Li,† Feng Wang,† Yichao Zhao,† Feng Zhao,† Xiaochun Dong,*,† and
Weili Zhao*,†,‡
School of Pharmacy, Fudan University, Shanghai, 201203, P. R. China, and
Key Laboratory for Special Functional Materials of the Ministry of Education,
Henan University, Kaifeng, 475004, P. R. China
xcdong@shmu.edu.cn; zhaoweili@fudan.edu.cn
Received January 19, 2012
ABSTRACT
A domino synthesis of 5,12-dihydroindolo[2,1-b]quinazoline derivatives via copper-catalyzed Ullmann-type intermolecular CÀC and intra-
molecular CÀN couplings is reported. Good yields of various 5,12-dihydroindolo[2,1-b]quinazoline derivatives were obtained. Reaction scopes,
limitations, and the reaction mechanism are discussed.
The 1,2,3,4-tetrahydropyrimido[1,2-a]indole and indolo-
[2,1-b]quinazoline skeletons exist in the core structures of
several biologically active compounds and natural pro-
ducts such as 5-HT4 receptor antagonists A,1 antimicrobial
active compounds B,2 antimalarial candidates C,3 and
anticancer agent tryptanthrin, respectively.4
The known methods for the synthesis of 1,2,3,4-tetra-
hydropyrimido[1,2-a]indole and indolo[2,1-b]quinazoline
have suffered from limitations such as limited availability
of starting materials, harsh reaction conditions, and poor
overall yield of the multistep synthesis.5,6 It is highly desir-
able to develop an efficient synthetic method and expand the
structure diversity for current medicinal chemistry needs.
Over the past years, copper-catalyzed coupling reactions
in CÀC, CÀheteroatom bond formation have achieved
remarkable progress.7,8 Many types of heterocycles have
(5) (a) Portnov, Y. N.; Golubeva, G. A.; Kost, A. N. Khim. Geterotsikl.
Soedin. 1972, 61. (b) Portnov, Y. N.; Golubeva, G. A.; Kost, A. N.; Volkov,
V. S. Khim. Geterotsikl. Soedin. 1973, 647. (c) Coppola, E. M.; Hardtmann,
G. E. J. Heterocycl. Chem. 1979, 16, 769.
(6) (a) De la Mora, M. A.; Cuevas, E.; Muchowski, J. M. Tetrahedron
Lett. 2001, 42, 5351. (b) Sutherland, J. K. Chem. Commun. 1997, 325.
(c) Yang, L.-J.; Yan, S.-J.; Chen, W.; Lin, J. Synthesis 2010, 3536.
(d) Xia, Z.; Wang, K.; Zheng, J.; Ma, Z.; Jiang, Z.; Wang, X.; Lv, X. Org.
Biomol. Chem. 2012, 10, 1602.
(7) For recent reviews on copper-catalyzed Ullmann-type couplings,
see: (a) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954.
(b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400.
(c) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450. (d) Evano, G.;
Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054. (e) Liu., Y.; Wan,
J.-P. Org. Biomol. Chem. 2011, 9, 6873. (f) Surry, D. S.; Buchwald, S. L.
Chem. Sci. 2010, 1, 13. (g) Rao, H.; Fu, H. Synlett 2011, 6, 745. (h) Das,
P.; Sharma, D.; Kumar, M.; Singh, B. Curr. Org. Chem. 2010, 14, 754.
(i) Evano, G.; Toumi, M.; Coste, A. Chem. Commun. 2009, 45, 4166.
(j) Cacchi, S.; Fabrizi, G.; Goggiamani, A. Org. Biomol. Chem. 2011,
9, 641.
† Fudan University.
‡ Henan University.
(1) (a) Gaster, L. M.; Wyman, P. A. WO93/018036, 1993. (b) Gaster,
L. M.; Wyman, P. A. US5852014, 1998.
(2) Grandolini, G.; Ambrogi, V.; Perioli, L.; Giannangeli, M.; Jovicevic,
L.; Rossi, V. Farmaco. 1997, 52, 679.
(3) Bhattacharjee, A. K.; Hartell, M. G.; Nichols, D. A.; Hicks, R. P.;
Stanton, B.; Van Hamont, J. E.; Milhous, W. K. Eur. J. Med. Chem.
2004, 39, 59.
(4) (a) Camargo, L. T. F. M.; Sena, M. M.; Camargo, A. J. SAR
QSAR Environ. Res. 2009, 20, 537. (b) Jao, C.-W.; Lin, W.-C.; Wu,
Y.-T.; Wu, P.-L. J. Nat. Prod. 2008, 71, 1275. (c) Sharma, V. M.;
Prasanna, P. Bioorg. Med. Chem. Lett. 2002, 12, 2303.
r
10.1021/ol3001624
Published on Web 03/06/2012
2012 American Chemical Society

been constructed via copper-catalyzed domino processes;
attractively, some tricyclic and tetracyclic systems, e.g.
imidazoindolone, pyrrolo[1,2-a]quinoxaline, pyrrolo[2,1-a]-
isoquinoline, pyrido[1,2-a]benzimidazole, and 4-oxo-indeno-
[1,2-b]pyrroles, have also been constructed.9,10 We are
interested in a copper-catalyzed domino process for effi-
cient synthesis of indole fused heterocycles.
Table 1. Optimization of the Coupling of N-(2-Bromobenzyl)-2-
iodoaniline with Malononitrilea
For various fused N-heterocycles prepared through
Ullmann-type domino coupling precesses,9 an activating
group (carbonyl or its equivalent) was generally employed
to speed-up the coupling process.7c,g,9aÀ9l Very recently,
Ma’s group reported an efficient cascade synthesis of
phenothiazine from a nonactivated system.9m However,
two attempted syntheses for 2-amino indole from a non-
activated system failed.8g,9l Herein we report a copper-
catalyzed domino synthesis of 5,12-dihydroindolo[2,1-b]-
quinazoline derivatives from nonactivated starting material.
For the model reaction, N-(2-bromobenzyl)-2-iodoani-
line (1a) and malononitrile (2a) were adopted, and the
reaction was screened by using 10 mol % CuI, 20 mol %
ligand, and 3.0 equiv of K2CO3 in DMSO at 90 °C under
argon. From various ligands (L1ÀL12, Table 1) screened,
trans-4-OH-L-proline (L1) which was reported to promote
CÀC coupling at À45 °C8a was identified to be the
yield
entry
catalyst
ligand
base
solvent
(%)b
1
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Cu
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
L12
L1
À
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
DBU
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
71
41
58
70
52
32
40
42
24
18
49
23
51c
30
20d
37
66
61
67
18
62
17
22
18
0
2
(8) For copper-catalyzed Ullman-type CÀC and CÀN bond forma-
tion: (a) Xie, X.; Chen, Y.; Ma, D. J. Am. Chem. Soc. 2006, 128, 16050.
(b) Yip, S. F.; Cheung, H. Y.; Zhou, Z.; Kwong, F. Y. Org. Lett. 2007, 9,
3469. (c) Xie, X.; Cai, G.; Ma, D. Org. Lett. 2005, 7, 4693. (d) Mino, T.;
Yagishita, F.; Shibuya, M.; Kajiwara, K.; Shindo, H.; Sakamoto, M.;
Fujita, T. Synlett 2009, 15, 2457. (e) Jiang, Y.; Wu, N.; Wu, H.; He, M.
Synlett 2005, 18, 2731. (f) Okuro, K.; Furuune, M.; Miura, M.; Nomura,
M. J. Org. Chem. 1993, 58, 7606. (g) Yang, X.; Fu, H.; Qiao, R.; Jiang,
Y.; Zhao, Y. Adv. Synth. Catal. 2010, 352, 1033. (h) Wang, F.; Liu, H.;
Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2009, 11, 2469. (i) Chen, Y.; Wang,
Y.; Sun, Z.; Ma, D. Org. Lett. 2008, 10, 625. (j) Wang, B.; Lu, B.; Jiang,
Y.; Zhang, Y.; Ma, D. Org. Lett. 2008, 10, 2761. (k) Shafir, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742. (l) Klapars, A.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421. (m)
Altman, R. A.; Anderson, K. W.; Buchwald, S. L. J. Org. Chem. 2008,
73, 5167. (n) Wang, D.; Ding, K. Chem. Commun. 2009, 45, 1891. (o) Lv,
X.; Bao, W. J. Org. Chem. 2007, 72, 3863. (p) Chen, Y.-J.; Chen, H.-H.
Org. Lett. 2006, 8, 5609. (q) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y.
Chem.;Eur. J. 2006, 12, 3636. (r) Lu, H.; Li, C. Org. Lett. 2006, 8, 5365.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
CuBr
CuCl
Cu2O
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
(s) Minatti, A.; Buchwald, S. L. Org. Lett. 2008, 10, 2721. (t) Martın, R.;
´
Larsen, C. H.; Cuenca, A.; Buchwald, S. L. Org. Lett. 2007, 9, 3379. (u)
Chen, D.; Wang, Z.; Bao, W. J. Org. Chem. 2010, 75, 5768.
(9) Recent examples for N-heterocycles construction via copper-
catalyzed domino process: (a) Diao, X.; Xu, L.; Zhu, W.; Jiang, Y.;
Wang, H.; Guo, Y.; Ma, D. Org. Lett. 2011, 13, 6422. (b) Xu, H.; Fu, H.
Chem.;Eur. J. 2012, 18, 1180. (c) Liu, T.; Wang, R.; Yang, H.; Fu, H.
Chem.;Eur. J. 2011, 17, 6765. (d) Xu, S.; Lu, J.; Fu, H. Chem. Commun.
2011, 47, 5596. (e) Lu, J.; Gong, X.; Yang, H.; Fu, H. Chem. Commun.
2010, 46, 4172. (f) Cai, Q.; Li, Z.; Wei, J.; Fu, L.; Ha, C.; Pei, D.; Ding, K.
Org. Lett. 2010, 12, 1500. (g) Xu, W.; Jin, Y.; Liu, H.; Jiang, Y.; Fu, H.
Org. Lett. 2011, 13, 1274. (h) Lu, J.; Fu, H. J. Org. Chem. 2011, 76, 4600.
(i) Vaillard, V. A.; Rossi, R. A.; Martin, S. E. Org. Biomol. Chem. 2011,
9, 4927. (j) Zou, B.; Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46,
2598. (k) Liu, X.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem., Int. Ed.
2009, 48, 348. (l) Kobayashi, K.; Komatsu, T.; Yokoi, Y.; Konishi, H.
Synthesis 2011, 764. (m) Ma, D.; Geng, Q.; Zhang, H.; Jiang, Y. Angew.
Chem., Int. Ed. 2010, 49, 1291.
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMAc
NMP
Dioxane
DME
0
trace
a Reaction conditions: N-(2-bromobenzyl)-2-iodoaniline (1 mmol),
malononitrile (1.2 mmol), catalyst (0.1 mmol), ligand (0.2 mmol),
base (3 mmol), solvent (2 mL), 90 °C, 16 h, under argon in sealed tube.
b Isolated yield. c 70 °C. d CuI (0.02 mmol), L1 (0.04 mmol).
(10) Recent examples for copper-catalyzed polycyclic systems con-
struction: (a) Malakar, C. C.; Schmidt, D.; Conrad, J.; Beifuss, U. Org.
Lett. 2011, 13, 1972. (b) Cai, Q.; Zhou, F.; Xu, T.; Fu, L.; Ding, K. Org.
Lett. 2011, 13, 340. (c) Barange, D. K.; Tu, Y.-C.; Kavala, V.; Kuo, C.-W.;
Yao, C.-F. Adv. Synth. Catal. 2011, 353, 41. (d) Wu, Z.; Huang, Q.;
Zhou, X.; Yu, L.; Li, Z.; Wu, D. Eur. J. Org. Chem. 2011, 5242. (e)
Wang, Z.-J.; Yang, J.-G.; Yang, F.; Bao, W. Org. Lett. 2010, 12, 3034. (f)
Verma, A. K.; Kesharwani, T.; Singh, J.; Tandon, V.; Larock, R. C.
Angew. Chem., Int. Ed. 2009, 48, 1138. (g) Yuen, J.; Fang, Y.-Q.;
Lautens, M. Org. Lett. 2006, 8, 653.
optimum ligand (entries 1À12, Table 1). A diminished
yield was obtained at 70 °C (entry 13, Table 1). Without
ligand, the yield was poor (entry 14, Table 1). A low
catalyst loading was not effective either (entry 15, Table 1).
Other copper sources, e.g. Cu, CuBr, CuCl, and Cu2O,
were found to be less effective (entries 16À19, Table 1).
Org. Lett., Vol. 14, No. 6, 2012
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Table 2. Copper-Catalyzed Domino Synthesis of 5,12-Dihydroindolo[2,1-b]quinazoline Derivativesa
a Reaction conditions: 1 (1 mmol), malononitrile (1.2 mmol), CuI (0.1 mmol), trans-4-OH-L-Proline (0.2 mmol), K2CO3 (3 mmol), DMSO (2 mL),
90 °C, 16 h, under argon, sealed tube. b Isolated yield. c 2-(Methylsulfonyl)acetonitrile. d 2-(Phenylsulfonyl)acetonitrile. e Diethyl cyanomethylphosphonate.
Among the base selected, K2CO3 was the best (com-
pare entry 1 with entries 20À22, Table 1). For solvent
selection, DMSO was found to be much better than
DMF and DMAc (entries 23 and 24, Table 1). NMP,
1,4-dioxane, or DME was not suitable (entries 25À27,
Table 1).
The reaction scope was then examined under the opti-
mized conditions, and the results are summarized in Table 2.
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Org. Lett., Vol. 14, No. 6, 2012

Scheme 1. Reaction Passway Identification
Scheme 2. Proposed Reaction Mechanism
Direct condensation of amine (1a) to 2a did not seem to
happen under various conditions. Reaction of N-benzyl-2-
iodoaniline (4) with 2a produced 2-amino-1-benzyl-1H-in-
dole-3-carbonitrile (5) in 79% yield. Meanwhile, reaction of
N-(2-bromobenzyl)aniline (6) with 2a presumably generated
product 7 in 15% yield. The combination of N-benzyl-2-
iodoaniline (4) with N-(2-bromobenzyl)aniline (6) and 2a
(4:6:2a = 1:1:1.2) gave product 5 as the only isolated product
in 62% yield. These results suggest that insertion of Cu into the
CÀI bond plays a major role in the reaction. Reaction of
N-(2-bromobenzyl)-2-iodoaniline (1a) and 2a at room tempera-
ture for 16 h allowed us to isolate the corresponding intermediate
8in 34% yield and recover 60% of 1a via flash chromatography,
which clearly suggests that the reaction initially takes place
through Cu insertion into the CÀI bond. Intermediate 8 was
heated to 90 °C for 16 h under standard conditions, targeting
product 3a, which was obtained in 83% yield after purification.
Based on the above discussions, a reaction mechanism
is proposed as shown in Scheme 2. Copper-catalyzed
Ullmann-type intermolecular CÀC coupling produces 9,
and then base-promoted intramolecular nucleophilic attack
generates 10 which tautomerizes to give 11. Copper-catalyzed
intramolecular CÀN coupling provides the target products 3.
In summary, we have developed a facile and efficient
one-pot domino synthesis of 5,12-dihydroindolo[2,1-
b]quinazoline derivatives via copper-catalyzed Ullmann-
type intermolecular CÀC and intramolecular CÀN cou-
plings under mild conditions. The protocol displays a wide
functional group compatibility and provides economical
and practical advantages over the previous methods.
For ortho-iodo aniline substrates, electron-donating para-
methoxy and methyl groups afforded good isolated yields
of the desired products (entries 2 and 3, Table 2); however,
meta-methyl substitution provided a diminished yield
(entry 4, Table 2). The substitution of fluoro, chloro, or
trifluoromethyl only resulted in moderate yields (entries 5À9,
Table 2). In comparison, an electron-withdrawing ester
group and cyano substituent led to good production of the
desired compounds (entries 10À12, Table 2). For a strong
electron-withdrawing counterpart, even ortho-bromo aniline
is active enough for the cascade reaction. While nitro sub-
stitution resulted in a good yield of product, the pyridine
system only gave an acceptable yield of the desired com-
pound (entries 13 and 14, Table 2). For the substituents at
the ortho-bromide benzyl moiety, it is noteworthy that
both electron-withdrawing and -donating groups led to good
yields of the desired products (entries 15À18, Table 2).
However, a pyridine species gave a lower yield (entry 19,
Table 2). Furthermore, other types of acetonitrile substituted
with electron-withdrawing groups of ÀCO2Me, ÀSO2Me,
ÀSO2Ph, and ÀPO(OEt)2 were also investigated in such a
copper-catalyzed domino process (entries 20À22, Table 2).
While ÀSO2Me provided a good yield of the product,
ÀSO2Ph and ÀPO(OEt)2 substitutions led to less satisfied
results. Unfortunately, ÀCO2Me failed to afford the target
product under the same conditions (not shown in Table 2).
For mechanistic studies, control experiments were car-
ried out under standard conditions as shown in Scheme 1.
Acknowledgment. This work was supported by the Na-
tional Natural Science Foundation of China (20872026),
the Hi-Tech Research and Development Program of China
(863 Plan, 2009AA02Z308), and Shanghai Pujiang Talent
Plan Project (09PJD008). We are also grateful to Roche
Pharma Research and Early Development China for support.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
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