Gold-catalyzed cascade C-C and C-N bond formation: Synthesis of polysubstituted indolequinones and pyrroles

Article abstract of DOI:10.1016/j.tetlet.2013.08.100

The combination of Ph₃PAuCl and AgOTf was proven to be an efficient catalyst for the cascade C-C and C-N bond formation reactions from enamines and bromoquinones or nitroolefins. This protocol affords a straightforward method for the synthesis of polysubstituted indolequinones and pyrroles in good yields.

Full text of DOI:10.1016/j.tetlet.2013.08.100

Tetrahedron Letters 54 (2013) 5898–5900
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Gold-catalyzed cascade C–C and C–N bond formation: synthesis of
polysubstituted indolequinones and pyrroles
Ablimit Abdukader a,b, Qicai Xue a, Aijun Lin a, Ming Zhang a, Yixiang Cheng a, Chengjian Zhu a,
⇑
a School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210093, China
b School of Chemistry and Chemical Engineering, Xinjiang University, Urumqi 830046, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The combination of Ph3PAuCl and AgOTf was proven to be an efficient catalyst for the cascade C–C and C–
N bond formation reactions from enamines and bromoquinones or nitroolefins. This protocol affords a
straightforward method for the synthesis of polysubstituted indolequinones and pyrroles in good yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 30 June 2013
Revised 15 August 2013
Accepted 24 August 2013
Available online 31 August 2013
Keywords:
Gold catalysis
Cascade reaction
Pyrrole
Indolequinone
Enamine
Introduction
complex I (Scheme 2) to give the corresponding 3a in 24% yield
in CH2Cl2 at 60 °C (Table 1, entry 1). Other Au(III) catalysts (II, III)
Gold catalysis has emerged as a frontier research area in organic
chemistry, owing to its excellent reactivity, compatibility with
aqueous medium, and mild reaction conditions.1 As our continued
interests in gold-catalysis,2 herein we report an efficient, conver-
gent, and general procedure for the synthesis of polysubstituted
indolequinones and pyrrole analogues through domino C–C and
C–N bond forming process based on the catalysis of gold.3
Five-membered nitrogen containing heterocycles, such as poly-
substituted indolequinones and pyrroles present privileged skele-
tons frequently existed in a broad range of natural products and
biologically important molecules (Scheme 1),4 also as the key
intermediates for the synthesis of functional materials.5 Conse-
quently, developing benign, eco-friendly, and practical synthetic
methods for the synthesis of these important heterocyclic scaffolds
with simple substrates remains a continued strong demand.6
showed similar low catalytic activity (Table 1, entries 2 and 3).
The utilization of Ph3PAuCl instead of the Au(III) catalysts resulted
in an increased yield (Table 1, entry 4). To our delight, the coupling
reaction provided the desired product in a satisfied yield (78%)
under the catalysis of the combination of Ph3PAuCl and AgOTf,
while using AgOTf as a single catalyst offered 3a only in 17% yield
(Table 1, entries 6 and 7). The reaction did not proceed as efficiently
as CH2Cl2 with other solvents, such as CH3CN, MeOH, THF, hexane,
and toluene (Table 1, entries 8–12). Other bases such as K3PO4,
t-BuOK, and Cs2CO3 were also evaluated, and no improved results
O
O
NH2
NH2
Ph(4-NO2)
O
S
N
O
O
O
O
O
O
O
H2N
Me
MeO
H2N
OMe
Results and discussion
Me
N
NH
N
N
H
Me
In our initial study of the synthesis of polysubstituted
indolequinones,7 the cascade C–C and C–N bond formation reaction
of 2-bromo-naphthalene-1,4-dione 1a with enamine 2a was
selected as model reaction. The results are summarized in Table 1.
The cascade reaction could occur under the catalysis of Au(III)
A
B
C
OH
OH
Me
Me
O
Me
COOH
N
Ph
N
H
HOOC
N
Me
O
Ph
Ph(4-F)
E
D
⇑
Corresponding author.
E-mail address: cjzhu@nju.edu.cn (C. Zhu).
Scheme 1. Some drugs containing indolequinones and pyrrole substructures.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.100

A. Abdukader et al. / Tetrahedron Letters 54 (2013) 5898–5900
5899
Table 1
With the optimized reaction conditions in hand (Table 1, entry
6), we investigated the scope of this protocol (Table 2). It was
found that electron-donating as well as electron-withdrawing
groups on the aromatic rings of enamines were compatible under
the reaction conditions, and offered the desired product 3a–d in
moderate to good yields. When alkyl-substituted b-enamino esters
were tested in the reaction, better transformations were obtained
even at room temperature (Table 2, 3e–h). To our delight, this reac-
tion can also tolerate a broad substituent range of b-enamino ke-
tones (Table 2, 3i–l) (Scheme 2).
The optimization of reaction conditions for the synthesis of indolequinonea
O
O
O
OEt
Me
Ph
Br
NH
O
N
Me
OEt
Ph
O
O
1a
3a
2a
Entry
Catalyst
Solvent
Base
Yieldb
1
2
3
4
5
6
7
8
I
II
III
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
MeOH
THF
Hexane
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
t-BuOK
Cs2CO3
K2CO3
24
16
18
43
13
78
17
35
13
<10
23
28
45
51
63
52
To further illustrate the generality of our method using gold(I)
as catalyst for the tandem C–C and C–N bond forming process,
we applied this protocol to the synthesis of polysubstituted pyr-
roles with a series of nitroolefins.3 Initially, treatment of 2a with
Ph3PAuCl
Bu4NAuCl4
Ph3PAuCl + AgOTf
AgOTf
Ph3PAuCl + AgOTf
Ph3PAuCl + AgOTf
Ph3PAuCl + AgOTf
Ph3PAuCl + AgOTf
Ph3PAuCl + AgOTf
Ph3PAuCl + AgOTf
Ph3PAuCl + AgOTf
Ph3PAuCl + AgOTf
Ph3PAuCl + AgOTf
9
Table 3
10
11
12
13
14
15
16c
Scope of the reaction for the synthesis of polysubstituted pyrrolesa,b
O
R2
Ph3PAuCl
AgOTf
MeOH
R1
Ar
NH
O
NO2
Me
Ar
N
Me
R2
R1
a
Reaction conditions: 1a (0.50 mmol), 2a (0.55 mmol), solvent (2.0 mL), catalyst
4
5
2
(5 mol %), base (1.5 mmol), 60 °C, 5 h.
b
Isolated yield (%).
2 mol % catalyst was used.
O
O
O
O
c
OEt
Me
OEt
Me
OEt
Me
Ph(4-Br)
OEt
Me
Ph
Ph
Ph
Ph
N
N
N
N
Table 2
Scope of the reaction for the synthesis of indolequinonesa
Ph
Ph(4-Me)
Ph(4-OMe)
5c
, r.t., 90%
5a
5b
, r.t., 93%
, r.t., 89%
5d, r.t., 83%
O
O
O
O
R2
Me
O
O
O
O
Ph3PAuCl
R1
Br
OEt
Me
Np-2
OMe
Me
OMe
Me
OEt
Me
NH
O
AgOTf
Ph
Ph
Ph
Ph
K2CO3
CH2Cl2
R2
O
N
Me
R1
O
1a
N
N
N
N
2
3
Ph(4-OMe)
Ph(4-Cl)
, r.t., 81%
Ph(4-Cl)
5e, r.t., 85%
5f, r.t., 86%
5g, r.t., 83%
5h
O
O
O
O
OEt
O
O
OEt
Me
OEt
Me
O
O
O
O
Me
Me
Ph(4-Me)
Me
Me
Ph(4-OMe)
Me
Me
Ph(4-Br)
Me
Me
Me
Ph
Ph
Ph
Ph
N
N
N
Ph
Ph(4-Cl)
Ph(4-OMe)
O
O
N
N
N
N
3b
3c
,
3a, 5 h, 60°C, 78%
, 5 h, 60°C, 68%
5 h, 60°C, 56%
O
Ph
O
O
O
5i
5j
5k
, 60°C, 86%
, 60°C, 89%
, 60°C, 86%
5l, 60°C, 91%
O
OEt
Me
O
OEt
Me
Bu-n
OEt
O
O
O
O
Me
OEt
OEt
Me
Me
N
N
N
Ph
Ph
Ph
Ph
Ph(4-Br)
Me
O
O
O
Me
N
Me
N
Me
Me
3d, 7 h, 60°C, 61%
3f, 5 h, r.t., 94%
3e, 5 h, r.t., 87%
N
N
O
Me
5n, r.t., 85%
Bu-n
5o, r.t., 89%
Me
O
O
O
O
Ph(4-Cl)
5m, 60°C, 90%
O
OEt
Me
Me
Me
OMe
Me
5p
, 60°C, 90%
O
O
O
O
N
N
N
OEt
OEt
Me
OEt
Me
Bn
Me
Me
2-
Np
O
Ar
O
Ph
O
S
Me
Me
N
Ph(4-Br)
3g
3i, 5 h, r.t., 88%
, 6 h, r.t., 91%
3h, 5 h, r.t., 85%
Me
Bu-n
N
Ph
N
N
O
O
O
O
O
O
Me
Me
Me
Me
Me
Me
Ph
b
5q
5r
5s
, 60°C, 87%
, r.t., 85%
, r.t., 83%
5t, r.t., 84%
N
N
N
O
O
O
O
OEt
Me
OEt
Me
OEt
Me
Ph(4-OMe)
OEt
Bu-n
Bn
Ph(4-OMe)
3l
, 9 h, 60°C, 65%
O
O
O
Ar
Ar
Ar
Ar
3k
3j, 5 h, r.t., 88%
, 7 h, r.t, 92%
Me
N
N
N
N
a
Reaction conditions: 1a (0.5 mmol), 2 (0.55 mmol), Ph3PAuCl (5 mol %), AgOTf
(5 mol %), K2CO3 (1.5 mmol), CH2Cl2 (2.0 mL), rt or 60 °C. Yields are for the isolated
Ph(4-OMe)
Ar = Ph(4-OPh)
5v
Ph(4-OMe)
Ar = Ph(4-NO2)
5w
Ph(4-OMe)
Ar = Ph(4-OMe)
5u
Ar = Ph(4-Cl)
5x, r.t., 75%
products.
, r.t., 80%
, r.t., 78%
, r.t., 68%
were obtained (Table 1, entries 13–15).8 Further studies indicated
that reducing the catalyst loading to 2% affected its catalytic effi-
ciency (Table 1, entry 16).
a
Reaction conditions: 4 (0.50 mmol), 2 (0.55 mmol), Ph3PAuCl (1 mol %), AgOTf
(1 mol %), MeOH (2.0 mL), rt or 60 °C, 8 h. Yields are for the isolated products.
b
Ar = 1,3,5-(OMe)3Ph.

5900
A. Abdukader et al. / Tetrahedron Letters 54 (2013) 5898–5900
ronmentally benign process, as well as the broad substrate scope,
O
low catalyst loading, and good yields make this protocol very prac-
tical. Further studies for the detailed mechanism and exploration of
gold-catalyzed tandem reactions for the synthesis of biologically
important compounds are underway in our laboratory.
N
Au Cl
Cl
AuCl4
Cl
N
N
N
N
O
Au
Au
Cl
Cl
Cl
Cl
Ι
ΙΙ
ΙΙΙ
Acknowledgments
Scheme 2. Gold-complexes.
We gratefully acknowledge the National Natural Science Foun-
dation of China (21172106, 21074054), the National Basic Research
Program of China (2010CB923303) and the Research Fund for the
Doctoral Program of Higher Education of China (20120091110010)
for their financial support.
R1
NH
O
Ph3PAuCl
AgOTf
Ar
O2N
Me
R2
R2
2
4
O
O
O
R2
R2
Ar
O2N
Ar
Ar
N
Supplementary data
O
Me
Me
Me
N
HO
N
HN
R1
HN
R1
HO
R1
8
Supplementary data (Experimental details and the characteriza-
tion data.) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2013.08.100.
6
7
OH
5
- H2O
- HNO
References and notes
Scheme 3. Proposed reaction mechanism for the synthesis of polysubstituted
pyrroles.
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The mechanism for the cascade reaction is not certainly clear.
On the basis of literatures,9 a plausible mechanism for the synthe-
sis of polysubstituted pyrroles is proposed in Scheme 3. In the
presence of Ph3PAuCl and AgOTf,10 conjugate addition of 2 to 4
gives Michael adduct 6. Subsequently, 6 tautomerizes into the
intermediate 7, then attacked by the nitrogen atom to form 8. Fi-
nally, the elimination of water and nitroxyl molecules affords the
desired product 5.
Conclusions
We have demonstrated a facile and mild preparation of polysub-
stituted indolequinone and pyrrole compounds. The combination of
Ph3PAuCl and AgOTf was proven to be an efficient catalyst for the
cascade C–C and C–N bond formation reactions from enamines
and bromoquinones or nitroolefins. The safe, convenient, and envi-
10. Wang, D.; Cai, R.; Sharma, S.; Jirak, S.; Thummanapelli, S.; Akhmedov, N.;
Zhang, H.; Liu, X.; Petersen, J.; Shi, X. D. J. Am. Chem. Soc. 2012, 134, 9012.