Copper-catalyzed synthesis of quinoxalines with o-phenylenediamine and terminal alkyne in the presence of bases

Article abstract of DOI:10.1021/ol201664x

A novel way of synthesizing quinoxalines efficiently through cyclization of o-phenylenediamine and terminal alkyne by Cu(II) and bases is developed. This reaction proceeds smoothly to give the products in moderate to good yields.

Full text of DOI:10.1021/ol201664x

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4514–4517
Copper-Catalyzed Synthesis of
Quinoxalines with o-Phenylenediamine
and Terminal Alkyne in the Presence of
Bases
Wen Wang, Yongwen Shen, Xu Meng, Mingming Zhao, Yongxin Chen, and Baohua
Chen*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Gansu
Lanzhou 730000, P. R. China, and Key Laboratory of Nonferrous Metal Chemistry and
Resources Utilization of Gansu Province, Lanzhou, 730000, P. R. China
chbh@lzu.edu.cn
Received June 21, 2011
ABSTRACT
A novel way of synthesizing quinoxalines efficiently through cyclization of o-phenylenediamine and terminal alkyne by Cu(II) and bases is
developed. This reaction proceeds smoothly to give the products in moderate to good yields.
Quinoxalines play an important role in the area of
nitrogen-containing heterocycles as they are useful inter-
mediates of other organic cyclic compounds1 and are
useful dyes.2 In addition, their derivatives possess signifi-
cant biological activities including antiviral, antibacterial,
and anti-inflammatory.3 The quinoxalines are also well-
known in the pharmacological industry.4 During the last
decades, many methods have been developed for the
preparation of quinoxalines.5 Most of them utilized o-
phenylenediamine and alkyne, which is oxidized to dike-
tone (Scheme 1).6 Numerous oxidants and catalytic sys-
tems for this process have been reported: DMSO/PdX2,7
PdCl2/CuCl2/PEG,8 KMnO4/NaHCO3,9 SO3/dioxane,10
I2/DMSO,11 O2/Cu,12 and Ga(OTf)3.13 Although they
are efficient methods for quinoxalines, most of them make
use of elevated temperature, prolonged reaction time, toxic
oxidants, and functionalized substrates. Here we devel-
oped a novel method to synthesize quinoxalines with o-
phenylenediamine and phenylacetylene catalyzed by Cu-
(1) Dailey, S.; Feast, J. W.; Peace, R. J.; Sage, I. C.; Till, S.; Wood,
E. L. J. Mater .Chem. 2001, 11, 2238.
(2) (a) Brock, E. D.; Lewis, D. M.; Yousaf, T. I.; Harper, H. H. The
Procter and Gamble Co. WO9951688, 1999. (b) Sonawane, N. D.;
Rangnekar, D. W. J. Heterocycl. Chem. 2002, 39, 303.
(OAc)2 H2O in the presence of bases.
3
(3) (a) Schutz, H. Benzodiazepines; Springer: Heidelberg, 1982. (b)
Landquist, J. K. In Comprehensive Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 1, pp 166ꢀ170.
(c) Seitz, L. E.; Suling, W. J.; Reynolds, R. C. J. Med. Chem. 2002, 45,
5604. (d) Kim, Y. B.; Kim, Y. H.; Park, J. Y.; Kim, S. K. Bioorg. Med.
Chem. Lett. 2004, 14, 541. (e) He, W.; Meyers, M. R.; Hanney, B.; Spada,
A.; Blider, G.; Galzeinski, H.; Amin, D.; Needle, S.; Page, K.; Jayyosi,
Z.; Perrone, H. Bioorg. Med. Chem. Lett. 2003, 13, 3097.
(4) Lindsley, C. W.; Zhao, Z.; Leister, W. H.; Robinson, R. G.;
Barnett, S. F.; Defeo- Jones, D.; Jones, R. E.; Hartman, G. D.; Huff,
J. R.; Huber, H. E.; Duggan, M. E. Bioorg. Med. Chem. Lett. 2005, 15,
761.
(6) (a) Katritzky, A. R.; Zhang, D.; Kirichenko., K. J. Org. Chem.
2005, 70, 3271. (b) Merkul, E.; Dohe, J.; Gers, C.; Rominger, F.; Muller,
T. J. J. Angew. Chem., Int. Ed. 2011, 50, 2966.
(7) Mousset, C.; Provot, O.; Hamze, A.; Brion, J.-D.; Alami, M.
Tetrahedron 2008, 64, 4287.
(8) Chandrasekhar, S.; Kesava Reddy, N.; Praveen Kumar., V.
Tetrahedron Lett. 2010, 51, 3623.
(9) Deng, X.; Mani, N. S. Org. Lett. 2006, 8, 269.
(10) Rogatchov, V. O.; Filimonov, V. D.; Yusubov, M. S. Synthesis
2001, 1001.
(11) Bhosale, R. S.; Sarda, S. R.; Ardhapure, S. S.; Jadhav, W. N.;
Bhusare, S. R.; Pawar, R. P. Tetrahedron Lett. 2005, 46, 7183.
(12) Zhang, C.; Jiao, N. J. Am. Chem. Soc. 2010, 132, 28.
(13) Cai, J.; Zou, J. P.; Pan, X. Q.; Zhang, W. Tetrahedron Lett. 2008,
49, 7386.
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Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; p 157. (b)
Woo, G. H. C.; Snyder, J. K.; Wan, Z. K. Prog. Heterocycl Chem. 2002,
14, 279.
r
10.1021/ol201664x
Published on Web 08/01/2011
2011 American Chemical Society

Table 2. Reactions of o-Phenylenediamine 1a with Various
Terminal Alkynesa
Scheme 1
Treatment of a toluene solution of o-phenylenediamine
1a (0.25 mmol) with phenylacetylene 2a (1 mmol) in the
presenceof Cu(OAc)2 H2O (10mol %, basedonthe molar
3
amount of 1a), Cs2CO3 (0.75 mmol), and 4-dimethylami-
nopyridine (DMAP, 0.75 mmol) at 70 °C for 8 h gave the
corresponding quinoxaline 3a in a yield of 86%. Three
Table 1. Screening of Reaction Conditions for Synthesis of
Quinoxalines with 1a and 2aa
entry
catalyst
base
Cs2CO3
yieldb (%)
1
2
Cu(OAc)2 H2O
42
86
64
55
59
0
3
Cu(OAc)2 H2O
DMAP þ Cs2CO3
Et3N þ Cs2CO3
TMDEA þ Cs2CO3
pyridine þ Cs2CO3
DMAP
3
3
Cu(OAc)2 H2O
3
4
Cu(OAc)2 H2O
3
5
Cu(OAc)2 H2O
3
6
Cu(OAc)2 H2O
3
7
Cu(OAc)2 H2O
DMAP þ Na2CO3
DMAP þ KOH
52
46
35
79c
86e
43
34f
3
8
Cu(OAc)2 H2O
3
9
Cu(OAc)2 H2O
DMAP þ K3PO4
DMAP þ Cs2CO3
DMAP þ Cs2CO3
DMAP þ Cs2CO3
DMAP þ Cs2CO3
3
10
11
12
13
Cu(OAc)2 H2O
3
Cu(OAc)2 H2Od
3
CuCl2
Cu(PPh3)3Br
a All of the reactions were carried out in tubes using 0.25 mmol of 1a,
1 mmol of 2a, 10 mol % of catalyst, and 3 equiv of each base in the
solvent at 70 °C for 8 h. b Isolated yields. c For 24 h. d 20 mol % catalyst.
e The reaction was carried out at 100 °C. f Protected by N2.
a All of the reactions were carried out in sealed tubes using 0.25 mmol
of 1, 1 mmol of 2, 10 mol % of Cu(OAc)2 H2O, and 3 equiv of each base
3
in toluene at 70 °C for 8 h. b Isolated yields.
equivalents of DMAP was employed in this reaction to
get the best yield. Pyridine, Et3N, and tetramethylethyle-
nediamine (TMEDA) were tested (Table 1, entries 1ꢀ5),
but the yields did not increase evidently. However, this
reaction did not work in the absence of inorganic base.
Among various inorganic bases tested, Na2CO3, KOH,
and K3PO4 were all effective, albeit affording the products
with diminished yields, and Cs2CO3 turned out to be the
best one (Table 1, entries 6ꢀ9). The screening experiments
essentially ineffective in this reaction. When the reaction
was conducted at a lower temperature, it proceeded
smoothly with a lower yield, and a higher reaction tem-
perature did not increase the yield (Table 1, entry 11).
Further inspection of the reaction conditions reveals that
the reaction proceeded efficiently in solvents such as
CH3CN, THF, benzene, 1,4-dioxane, and ethyl alcohol,
whereas they were less efficient compared with toluene.
To investigate the scope of the reaction, a variety of
different substituted o- phenylenediamines and phenylace-
tylenes were subjected to the standard reaction conditions.
The corresponding quinoxalines were obtained in moder-
ate to good yields as shown in Table 2. First, a variety of
also showed that increasing the amount of Cu(OAc)2 H2O
3
did not enhance the yield and even prolonged the reaction
time to 24 h (Table 1, entry 10). The effects of different
copper sources were also examined, and Cu(OAc)2 H2O
3
showed the highest activity (Table 1, entries 11ꢀ13). Other
catalysts such as FeCl3 and AlCl3 were found to be
Org. Lett., Vol. 13, No. 17, 2011
4515

Table 3. Reactions of Substituted o-Phenylenediamine with
Terminal Alkynesa
Figure 1. X-ray structure of 3ab.
We also explored the mechanism of the reaction. When
the product of homocoupling of 2a was used as a substrate,
3a was not observed. Unactivated alkyne such as diphe-
nylacetypene did not react either. On the basis of the
experiments mentioned above, a plausible mechanism
was proposed as shown in Scheme 2. The proposed
initiated complex A would lose Hþ and Cu2þ to give B,
which was attacked by a second equivalent of alkyne to
form C after losing another Hþ and Cu2þ, and a precursor
of quinoxaline D was obtained. Next, D could be easily
aromatized to the target compound quinoxaline 3aa by
air.14 We will focus on the systematic investigation in
future studies.
a All of the reactions were carried out in sealed tubes using:
0.25 mmol of 1, 1 mmol of 2, 10 mol % of Cu(OAc)2 H2O, and 3 equiv
Scheme 2. Proposed Mechanism
3
of each base in toluene at 70 °C for 8 h. b Isolated yields.
aromatic alkynes were efficient, although those ones bear-
ing electron-rich groups generated the products with mod-
erate yields (Table 2, entries 1ꢀ7). This reaction was not
limited to aromatic alkynes; aliphatic alkynes were also
tested, and it turned out that they could react with 1a to
give quinoxalines smoothly (Table 2, entries 8 and 9).
Next, the reaction scope of o-phenylenediamine was
studied (Table 3). Those compounds bearing an electron-
donating group formed the products in good yields. The
chloro and bromo moieties on o-phenylenediamine were
all well tolerated under these reaction conditions but
afforded the target products with lower yields (Table 3,
entries 1ꢀ5). Notably, regioselectivities were observed in
this transformation. Substrates substituted by CH3, Cl, or
Br groups gave a mixture of regioisomers. The combined
yields ranged from 30 to 89%, and the ratio of isomers varies
In conclusion, we have developed a copper-catalyzed
method for synthesis of quinoxaline by using o-phenyle-
nediamine and terminal alkyne. This method uses simple
available substrates and can proceed successfully with a
one-step synthetic procedure, and the reaction conditions
were relatively mild.
1
from 2.0:1 to 1.2:1. Confirmed by H NMR, 13C NMR,
HMBC, and HRMS, reaction involving 4-methylbenzene-
1,2-diamine can be highly regioselective with 3ba as product.
Thus, we assume the favorable isomer would be 3.
All products displayed spectroscopic data in agreement
with the expected quinoxaline, and the structure was
further confirmed by X-ray data (Figure 1).
(14) (a) Zhou, L.; Shi, Y.; Xiao, Q,; Liu, Y. z.; Ye, F.; Zhang, Y.;
Wang, J. B. Org. Lett. 2011, 13, 968. (b) Tetsuya Hamada, Ye, X.; Stahl,
S. S. J. Am. Chem. Soc. 2008, 130, 833. (c) Xiao, Q.; Xia, Y.; Li, H.;
Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2011, 50, 1114.
4516
Org. Lett., Vol. 13, No. 17, 2011

Acknowledgment. We are grateful for support of the
project by the Scientific Research Foundation for the State
Education Ministry (No.107108) and the Project of Na-
tional Science Foundation of P. R. China (No. J0730425).
Supporting Information Available. Experimental de-
tails, spectra, and X-ray data (CIF). This material is
available free of charge via the Internet at http://pubs.
acs.org.
Org. Lett., Vol. 13, No. 17, 2011
4517