Synthesis of indolo [1,2-a ]quinoxalines via a Pd-catalyzed regioselective C - H olefination/cyclization sequence

Article abstract of DOI:10.1021/ol203275b

A highly efficient approach to indolo [1,2-a]quinoxaline derivatives through a Pd-catalyzed regioselective C - H olefination/cyclization sequence has been developed. This transformation has a wide range of substrates with various functional groups, and th

Full text of DOI:10.1021/ol203275b

ORGANIC
LETTERS
2012
Vol. 14, No. 3
740–743
Synthesis of Indolo [1,2-a]Quinoxalines
via a Pd-Catalyzed Regioselective CꢀH
Olefination/Cyclization Sequence
Liang Wang,† Wei Guo,† Xiao-Xiao Zhang,† Xu-Dong Xia,† and Wen-Jing Xiao*,†,‡
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079,
China, and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
wxiao@mail.ccnu.edu.cn
Received December 8, 2011
ABSTRACT
A highly efficient approach to indolo [1,2-a]quinoxaline derivatives through a Pd-catalyzed regioselective CꢀH olefination/cyclization sequence
has been developed. This transformation has a wide range of substrates with various functional groups, and the corresponding heterocyclic
products were obtained in good yields.
Indole/pyrrole-fused heterocycles are widely present
in a large number of natural products as well as drug
candidates and medicinal chemistry lead compounds.1
Among this plethora of compounds, indole/pyrrole-fused
quinoxaline derivatives have always constituted a subject
of great interest due to their intriguing structures and
remarkable biological activities (Figure 1). For instance,
indolo [1,2-a]quinoxaline A exhibits promising antifungal
activities in vitro against the phytopathogenic fungi and
B is identified as a potential inhibitor of VEGFR-3
kinase cells.2 In addition, 6-FQXPT, a compound bearing
a pyrrolo [1,2-a]quinoxaline unit, has been recognized to
be the second generation non-nucleoside reverse transcrip-
tase inhibitor (NNRTI).3 Therefore, the development of
novel and highly efficient methods to construct these fused
heterocyclic architectures is highly desirable for drug
discovery.
Over the past decade, the transition-metal-catalyzed
direct CꢀH activation strategy has become a powerful
† Central China Normal University.
‡ Chinese Academy of Sciences.
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r
10.1021/ol203275b
Published on Web 01/18/2012
2012 American Chemical Society

protocol for the construction of complex molecules.4 In this
context, cascade CꢀH oxidative olefination/cyclization
the privileged indole and pyrrole scaffolds is still rare but
highly desirable.
As part of our ongoing program on heterocycle-oriented
methodology development, we describe herein a highly
regioselective CꢀH olefination/cyclization sequence of
N-aryl-substituted indoles/pyrroles and electron-withdraw-
ing olefins for the synthesis of a series of novel indole/fused
heterocycle derivatives.9,10
Table 1. Optimization of Reaction Conditions for the CꢀH
Olefination/Cyclisation Sequencea
Figure 1. Representative examples of indole/pyrrole-fused
quinoxaline derivatives.
processes have been widely used to efficiently generate
structurally diverse heterocyclic compounds.5,6 In the
1990s, Miura and co-workers reported their pioneer-
ing work on Pd-catalyzed cascade CꢀH olefination
and CꢀX bond (X = N, O) formation utilizing phenol,
benzoic acid and benzene sulphonamide.7 More recently,
related examples of Pd- and Rh-catalyzed cascade CꢀH
olefination/cyclization reactions via the cleavage of aro-
matic CꢀH bonds of amides or benzoic acids have been
successfully developed by Yu, Glorius, Li, and others.8
Despite these advances, the application of such a cascade
CꢀH oxidative olefination/cyclization methodology to
temp
yield
(%)b
entry
catalyst
Pd(OAc)2
(°C)
base
NaOAc
1
100
100
100
100
100
100
100
100
110
120
110
110
110
110
110
110
58
53
54
39
49
51
18
38
76
71
71
70
75
72
82
76
2
Pd(TFA)2
PdCl2
NaOAc
3
NaOAc
4
Pd(PPh3)2Cl2
Pd(CH3CN)2Cl2
Pd(PhCN)2Cl2
Pd2dba3
NaOAc
5
NaOAc
6
NaOAc
7
NaOAc
8
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
NaOAc
9
NaOAc
10
11
12
13
14
15c
16d
NaOAc
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LiOAc
KOAc
CsOAc
CsOPiv
NaOAcþLiOAc
CsOAcþLiOAc
a Unless noted, reactions were performed with 1a (0.20 mmol),
2a (0.40 mmol), Cu(OAc)2 (0.30 mmol), base (0.45 mmol), and Pd-catalyst
(10 mol %) in DMF (2.0 mL) at the indicated temperature. b Isolated
yield. c NaOAc (0.45 mmol) and LiOAc (0.45 mmol). d CsOAc (0.45 mmol)
and LiOAc (0.45 mmol).
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Org. Lett., Vol. 14, No. 3, 2012
741

Gratifyingly, the use of Pd(OAc)2 (10 mol %) and
Cu(OAc)2 as the catalytic system together with a stoichio-
metric amount of NaOAc as the base at 100 °C in DMF
resulted in the formation of the desired indole [1,2-a]
quinoxaline 3a in 58% yield (Table 1, entry 1). The
structure of 3a was unambiguously established by X-ray
crystallographic analysis (Figure 2). Encouraged by this
result, we continued to optimize reaction conditions to
further improve the chemical yield. Screening of catalysts
indicated that Pd(OAc)2 displayed the highest catalytic
activity toward the formation of 3a (Table 1, entries 1ꢀ8).
Table 2. Pd-Catalyzed CꢀH Olefination/Cyclization Sequencea
yield
(%)b
entry
R1
R2
product
1
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
82
80
81
88
71
88
75
90
87
82
68
66
65
73
83
2
4-Me
5-Me
6-Me
5-BnO
5,6-(MeO)2
6-F
3
4
5
6
7
3g
3h
3i
8
6-Cl
H
9
4-Me
10
11
12
13
14
15
H
4,5-(Me)2
4-Cl
3j
H
3k
3l
H
4-CF3
4-CO2Me
4-Me
H
3m
3n
3o
6-Cl
3-Me
H
a Unless noted, reactions were performed with 1a (0.20 mmol), 2a
(0.40 mmol), Cu(OAc)2 (0.30 mmol), NaOAc (0.45 mmol), LiOAc (0.45 mmol),
and Pd(OAc)2 (10 mol %) in DMF (2.0 mL) at 110 °C. b Isolated yield.
Figure 2. X-ray crystal structure of 3a.
The reaction temperature had a significant effect on the
reaction efficiency, and the yield was drastically increased
to 76% when the reaction was carried out at 110 °C (entry
9). Various bases such as LiOAc, KOAc, CsOAc, and
CsOPiv were found to be effective for this cascade CꢀH
olefination/cyclization (entries 11ꢀ14). Finally, the yield
of the product was further improved to 82% when a
mixture of NaOAc and LiOAc was used in the reaction
system (entry 15).
Table 2, a number of alkyl and alkyoxyl substituents
can be incorporated on the indole or benzene ring at
various positions without significant loss in reaction
efficiency (Table 2, entries 2ꢀ6 and 9ꢀ10, R1,2 = Me,
MeO, or BnO). It is well-known that fluorine can affect
the biological activity of compounds. As revealed in
entries 7 and 12, we successfully utilized fluoro-substi-
tuted substrates in this cascade reaction.11 Of note, a
chloro group on the indole or phenyl ring of the sub-
strate, which was well-tolerated in the current reaction
system, could also be used for further transformation
(entries 8 and 9). Notably, the catalytic system proved to
be tolerant of valuable electrophilic functional groups,
such as esters (entry 13). Additionally, the current catalytic
system was not restricted to the use of monosubstituted
substrates, but also allowed for efficient oxidative cycliza-
tion of different disubstituted N-arylation of indoles (entries
6 and 14). Perhaps more importantly, substrate 1o not only
demonstrated that steric interactions were well-tolerated but
also showed excellent regioselectivity in our cascade catalytic
system (entry 15).
With the optimal conditions in hand, we then investi-
gated the scope of this transformation using different
N-aryl-substituted indole derivatives. As summarized in
(11) For selected reviews, see: (a) Shimizu, M.; Hiyama, T. Angew.
€
Chem., Int. Ed. 2005, 44, 214. (b) Muller, K.; Faeh, C.; Diederich, F.
Science 2007, 317, 1881. (c) Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A.
Chem. Rev. 2011, 111, 455.
(12) Selected examples of oxidative olefinations: (a) Weissman, H.;
Song, X.; Milstein, D. J. Am. Chem. Soc. 2001, 123, 337. (b) Boele,
M. D. K.; van Strijdonck, G. P. F; de Vries, A. H. M.; Kamer, P. C. J.; de
Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2002, 124,
1586. (c) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J.
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J. Am. Chem. Soc. 2005, 127, 4156. (e) Beck, E. M.; Grimster, N. P.; Hatley,
R.; Gaunt, M. J. J. Am. Chem. Soc. 2006, 128, 2528. (f) Cai, G.; Fu, Y.;
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Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254. (h) Houlden,
Subsequently, a variety of electron-deficient terminal
alkenes were examined. Scheme 1 shows that reactions of
N-aryl-substituted indole 1a with several acrylates 2pꢀ2w
proceeded smoothly and efficiently to produce the corre-
sponding products in generally good yields. Methyl vinyl
ketone 3s and N,N-dimethylacrylamide 3t were also found
to be competent coupling partners. Other olefins, such as
vinyl Sulphone, vinyl phosphonate, and vinyl cyanide,
ꢀ
C. E.; Bailey, C. D.; Ford, J. G.; Gagne, M. R.; Lloyd-Jones, G. C.;
Booker-Milburn, K. I. J. Am. Chem. Soc. 2008, 130, 10066. (i) Wrtz, S.;
€
Rakshit, S.; Neumann, J. J.; Droge, T.; Glorius., F. Angew. Chem., Int.
Ed. 2008, 47, 7230. (j) Wang, D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q.
Science 2010, 327, 315. (k) Morimoto, K.; Hirano, K.; Satoh, T.; Miura,
M. Org. Lett. 2010, 12, 2068. (l) Ng, K.-H.; Chan, A. S. C.; Yu, W.-Y.
J. Am. Chem. Soc. 2010, 132, 12862. (m) Patureau, F. W.; Glorius, F.
J. Am. Chem. Soc. 2010, 132, 9982. (n) Huang, C.; Chattopadhyay, B.;
Gevorgyan, V. J. Am. Chem. Soc. 2011, 133, 12406.
742
Org. Lett., Vol. 14, No. 3, 2012

Scheme 1. Pd-Catalyzed CꢀH Olefination/Cyclization
Scheme 3. Proposed Reaction Pathway
Sequencea,b
a Unless noted, reactions were performed with 1a (0.20 mmol), 2a
(0.40 mmol), Cu(OAc)2 (0.30 mmol), NaOAc (0.45 mmol), LiOAc
(0.45 mmol), and Pd(OAc)2 (10 mol %) in DMF (2.0 mL) at 110 °C.
bIsolated yield.
Scheme 4. Experiment for Kinetic Isotope Effects
could also participate in this CꢀH olefination/cyclization
sequence, albeit with poor reactivity.
Interestingly, we were pleased tofind that the indole core
could be successfully extended to pyrrole-derived systems.
For example, N-aryl-substituted pyrrole 1x smoothly re-
acted with n-butyl acrylate 2a affording the corresponding
cyclized product in 60% yield (Scheme 2).
labeled 1a at the 2-position of the indole ring (H/D = 1)
(Scheme 4).13 It was observed that the reaction did not
exhibit kinetic isotope effects (kH/kD = 1.0), which may
imply that CꢀH bond cleavage at the C2 position of the
indole is not involved in the rate-determining step of the
overall catalytic process.
Scheme 2. Pd-Catalyzed CꢀH Olefination/Cyclization Se-
quence Reaction of a Pyrrole
In summary, we have developed an efficient Pd-
catalyzed highly regioselective CꢀH olefination and
cyclization sequence of N-aryl-substituted indoles and
electron-withdrawing olefins. The reaction is applic-
able to a wide range of substrates with various func-
tional groups affording the corresponding indole/
pyrrole-fused quinoxaline derivatives in moderate to
good yields. Application of this reaction to the pre-
paration of biologically relevant compounds is cur-
rently underway.
On the basis of these preliminary results, a plausible
mechanism is illustrated in Scheme 3. We envisioned that
an initial intermediate I could be generated by PdꢀN bond
formation with the aid of a base. Selective activation of the
CꢀH bondatthe 2-positionofthe indole ringformeda six-
membered palladium (II) intermediate. Then, palladacycle
II could smoothly undergo the FujiwaraꢀMoritani pro-
cess with electron-deficient alkenes to provide the CꢀH
olefination intermediate V.12 Subsequently, intramolecu-
lar cyclization through CꢀN bond formation gave the
final product.
Acknowledgment. We are grateful to the National Science
Foundation of China (Nos. 21072069 and 21002036) and the
National Basic Research Program of China (2011CB808603)
for support of this research.
Intermolecular kinetic isotope effects were readily ob-
tained through a competition experiment of deuterium-
Supporting Information Available. Experimental pro-
cedures and compound characterization data including
X-ray crystal data (CIF) for 3a. This material is available
free of charge via the Internet at http://pubs.acs.org.
(13) (a) Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc. 2005, 127,
4156. (b) Shibahara, F.; Yamaguchi, E.; Miura, T. Chem. Commun.
2010, 2471. (c) Kim, J. Y.; Cho, S. H.; Joseph, J.; Chang, S. Angew.
Chem., Int. Ed. 2010, 49, 9899. (d) Zhao, X.; Wu, G.; Zhang, Y.; Wang, J.
ꢀ
J. Am. Chem. Soc. 2011, 133, 3296. (e) Gomez-Gallego, M.; Sierra, M. A.
Chem. Rev. 2011, 111, 4857.
Org. Lett., Vol. 14, No. 3, 2012
The authors declare no competing financial interest.
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