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Chemistry Letters Vol.37, No.3 (2008)
First Example of Cu(OTf)2-catalyzed Synthesis of Quinoxalines
from ꢀ-Diazoketones and Aryl 1,2-Diamines
J. S. Yadav,Ã B. V. Subba Reddy, Y. Gopala Rao, and A. V. Narsaiah
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
(Received December 13, 2007; CL-071385; E-mail: yadavpub@iict.res.in)
ꢀ-Diazoketones undergo smooth coupling with aryl 1,2-
certainly be useful in generating combinatorial libraries for drug
discovery.
The ready availability, relative stability, and facile decom-
diamines in the presence of 10 mol % of copper(II) triflate to
provide the corresponding 2-alkyl- or 2-aryl-quinoxalines in ex-
cellent yields with high selectivity. Rh2(OAc)4 is also found to
be an equally effective catalyst for this transformation. It is a
new and alternative approach for the preparation of biologically
well-defined quinoxaline derivatives.
position of ꢀ-diazocarbonyl compounds under thermal, photo-
chemical, acid, base, and transition-metal catalytic conditions
make them useful intermediates in organic synthesis.10 Interest-
ingly, ꢀ-diazoketones undergo a variety of transformations such
as cyclopropanation, aziridine formation, ylide formation, C–H
and X–H insertion reactions and cyclization reactions.11 These
reactions are chemoselective, which allow new carbon–carbon
and carbon–hetero atom bond formation under mild condi-
tions.12 However, there have been no reports on the coupling
of ꢀ-diazoketones with aryl 1,2-diamines to generate biological-
ly potent quinoxaline derivatives.
In this article, we report a novel method for the synthesis of
quinoxalines via the coupling of aryl 1,2-amines and ꢀ-diazoke-
tones using a catalytic amount of copper(II) triflate under mild
reaction conditions. Accordingly, treatment of diazoacetophe-
none (1) with o-phenylenediamine (2) in the presence of
10 mol % of Cu(OTf)2 in dichloroethane (DCE) at 80 ꢀC afford-
ed 2-phenylquinoxaline (3a) in 94% yield (Scheme 1).
This result provided the incentive for further study of
reactions with other ꢀ-diazocarbonyl compounds. Interestingly,
various ꢀ-diazoketones reacted smoothly with several aryl 1,2-
diamines to give the corresponding 2-alkyl- or 2-aryl-quinoxa-
lines derivatives as the products of nitrogen insertion. Both
aromatic and aliphatic diazoketones participated well in this
conversion (Table 1). In all cases, the reactions proceeded
efficiently in the presence of 10 mol % of Cu(OTf)2 at 80 ꢀC in
dichloroethane and the products were obtained in high to excel-
lent yields. No side product arising from a Wolff rearrangement
was observed under these reaction conditions. Other side prod-
ucts such as ꢀ-keto-O-triflates (the products of OTf insertion)
arising from Cu(OTf)2, were not detected under these condi-
tions. The effects of various copper salts such as Cu(OAc)2,
Cu(BF4)2, and Cu(acac)2 were tested for this conversion.
Of these catalysts, Cu(OTf)2 was found to be the most
effective. As solvent, dichloroethane gave the best conversion.
Alternatively, 5 mol % of Rh2(OAc)4 was found to be an equally
effective catalyst for this transformation. Other Lewis acids such
as Yb(OTf)3, Sm(OTf)3, and In(OTf)3 failed to give the desired
products. Similarly, Brønsted acids such as Montmorillonite
K10 and heteropoly acids also did not give the expected product.
The reaction may proceed via an initial formation of imine fol-
lowed by N–H insertion, which would result in the formation of
Quinoxaline derivatives have received considerable interest
from the pharmaceutical industry because of their interesting
therapeutic properties such as antiviral, antibacterial, anti-in-
flammatory, anti-protozoaval, and as kinase inhibitors.1 They
have also been evaluated as anticancer, anthelmintic agents, an-
tifungal and insecticidal agents.2 In addition, quinoxaline nu-
cleus is a part of several antibiotics such as echinomycin, levo-
mycin, and actinomycin which are known to inhibit the growth
of gram-positive bacteria and active against various transplanta-
ble tumors.3 Besides this, they have found applications as dyes,
electroluminescent materials, organic semiconductors, cavi-
tands, chemically controllable switches, and DNA cleaving
agents.4,5 Since they display a broad spectrum of biological
properties, they are considered as privileged structures in combi-
natorial drug discovery. Drug formulations containing quinoxa-
lines such as Lamprene are currently available (Figure 1). Con-
sequently, a variety of methods have been developed for the syn-
thesis of quinoxalines, which include condensation of aryl 1,2-
diamines with 1,2-ketones, oxidative cyclization of ꢀ-hydroxy
ketones with 1,2-diamines, cyclization–oxidation of phenacyl
bromides with 1,2-diamines, oxidative coupling of epoxides
with ene-1,2-diamines.6–9 However, many of these methods suf-
fer from several drawbacks such as the use of strong oxidizing
agents, expensive metal catalysts, harsh reaction conditions,
and also the yields are far from satisfactory. Therefore, the de-
velopment of simple, convenient, and general approach would
Cl
N
N
N
Cl
N
H
Clofazimine (Lamprene for leprosy)
N
O
Cl
MeO
MeO
N
N
N
N
O
OH
O
N
NH2
NH2
Cu(OTf)2
N
X
O
+
H
N2
Me
BMS-238497 (Kinase inhibitor)
Me
XK-469 (anticancer)
N
ClCH2CH2Cl, 80 °C
1
3a
2
Figure 1. Structures of Lamprene, BMS-238497, and XK-469.
Scheme 1. Preparation of 2-phenylquinoxaline (3a).
Copyright Ó 2008 The Chemical Society of Japan
Yadav
