Angewandte
Chemie
DOI: 10.1002/anie.201408522
Heterocycles
Synthesis of Highly Functionalized Polycyclic Quinoxaline Derivatives
Using Visible-Light Photoredox Catalysis**
Zhi He, Minwoo Bae, Jie Wu, and Timothy F. Jamison*
Abstract: A mild and facile method for preparing highly
functionalized pyrrolo[1,2-a]quinoxalines and other nitrogen-
rich heterocycles, each containing a quinoxaline core or an
analogue thereof, has been developed. The novel method
features a visible-light-induced decarboxylative radical cou-
pling of ortho-substituted arylisocyanides and radicals gener-
ated from phenyliodine(III) dicarboxylate reagents and exhib-
its excellent functional group compatibility. A wide range of
quinoxaline heterocycles have been prepared. Finally, a tele-
scoped preparation of these polycyclic compounds by integra-
tion of the in-line isocyanide formation and photochemical
cyclization has been established in a three-step continuous-
flow system.
process involving the in-line isocyanide formation by using
a continuous-flow microreactor system reveals its potential in
sustainable pharmaceutical production.
Inspired by the recent development of constructing of
phenanthridine derivatives through the use of biaryl isocya-
nides as radical acceptors which could undergo reaction
cascades involving C-radical addition with subsequent homo-
lytic aromatic substitution (HAS), oxidation, and deprotona-
tion,[3] we were curious if a similar strategy could be employed
to construct pyrrolo[1,2-a]quinoxalines or other heterocycle-
fused quinoxaline derivatives. Given that visible-light-
induced photoredox catalysis has proven to be a powerful
approach to generate C radicals under mild reaction condi-
tions,[4] we decided to investigate the synthesis of 4-alkylated
heterocycle-fused quinoxalines from ortho-heterocycle-sub-
stituted arylisocyanides by a photoredox decarboxylative
radical cyclization, using phenyliodine(III) dicarboxylates as
an easily accessible and environmentally friendly source of
alkyl radicals.[5]
We opted to investigate the photoredox transformation by
using module substrates 1-(2-isocyanophenyl)-1H-pyrrole
(1a) and phenyliodine(III) dicyclohexanecarboxylate (2a)
(Table 1). The iridium complex [fac-Ir(ppy)3] was chosen as
the photocatalyst. When a solution of 1a and 2a in DMF was
irradiated with a household 26 W compact fluorescent bulb in
the presence of only 1 mol% of [fac-Ir(ppy)3] for 5 hours, the
desired pyrrolo[1,2-a]quinoxaline product 3a was obtained
smoothly in excellent yield (Table 1, entry 1). In contrast,
negative results were observed in the absence of the metal
A
mong subclasses of quinoxaline derivatives, pyrrolo[1,2-
a]quinoxalines or analogues with similar fusion of other
nitrogen-rich five-membered heterocycles have been found in
a variety of complex compounds displaying interesting
biological activities, and have therefore received particular
attention in the pharmaceutical industry.[1] However, only
a few procedures for the preparation of pyrrolo[1,2-a]quin-
oxalines or other heterocycle-fused analogues thereof are
described in the literature.[2] For instance, Kobayashi and co-
workers recently reported the preparation of aminoalkyl or
hydroxyalkyl pyrrolo[1,2-a]quinoxalines from iminium salts
and aldehydes or ketones.[2f,g] Although conducted under
ambient temperature, these methods are somewhat limited in
functional-group compatibility because of the need for
catalysis by strong and corrosive Lewis acids.
Herein, we describe a novel synthetic method in which 4-
alkylated pyrrolo[1,2-a]quinoxaline derivatives and other
nitrogen-rich heterocycle-fused analogues thereof are effi-
ciently obtained from ortho-heterocycle-substituted aryliso-
cyanides by employing visible-light induced decarboxylative
radical cyclization under ambient conditions. The method-
ology demonstrates excellent functional-group tolerance,
which enables preparation of a wide range of highly
functionalized polycyclic quinoxalines. Further incorporation
of the photochemical reaction in a three-step telescoping
Table 1: Reaction conditions evaluation.[a]
Entry
Photocatalyst
Additives
Solvent
Yield [%][b]
1
[fac-Ir(ppy)3]
–
–
–
–
–
DMF
DMF
DMF
MeCN
MeCN
DMF
DMF
73
0
0
32
65
70
71
2[c]
3[d]
4
[fac-Ir(ppy)3]
[fac-Ir(ppy)3]
[Ir(dtbbpy)(ppy)2]PF6
[fac-Ir(ppy)3]
[fac-Ir(ppy)3]
5
6
7
–
[*] Dr. Z. He, M. Bae, Dr. J. Wu, Prof. Dr. T. F. Jamison
Department of Chemistry, Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
H2O[e]
Et3N[e]
E-mail: tfj@mit.edu
[a] Unless stated otherwise, the reaction was carried out with 1a
(1.0 equiv), 2a (1.5 equiv), and photocatalyst (1 mol%) in the indicated
solvent and irradiated with 26 W compact fluorescent lamp for 5 h.
[b] Yield of isolated product. [c] The reaction was irradiated in the
absence of metal catalysts. [d] The reaction was carried out under dark.
[e] 5.0 equiv of additives was added. DMF=N,N-dimethylformamide,
ppy=phenyl pyridine.
[**] We are grateful to the Novartis-MIT Center for Continuous
Manufacturing for financial support. We thank several colleagues at
Novartis (Dr. Berthold Schenkel, Dr. Gerhard Penn, Dr. Benjamin
Martin, and Dr. Jçrg Sedelmaier) for insightful discussions.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!