Copper-catalyzed cascade double C3-indolations of 3-diazoindolin-2-imines with indoles: Convenient access to 3,3-diaryl-2-iminoindoles

Article abstract of DOI:10.1021/acs.orglett.5b00089

Symmetrical 3,3-diaryl-2-iminoindoles were prepared from 3-diazoindolin-2-imines and indoles via a copper-catalyzed cascade arylation/dehydrogenative cross-coupling process. By controlling the molar ratio of reactants and the operation procedure, 3-aryl-2-aminoindoles and asymmetrical 3,3-diaryl-2-iminoindoles could be approached.

Full text of DOI:10.1021/acs.orglett.5b00089

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Cascade Double C3-Indolations of 3‑Diazoindolin-
2-imines with Indoles: Convenient Access to 3,3-Diaryl-2-
iminoindoles
Zao Du, Yanpeng Xing, Ping Lu,* and Yanguang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
S
* Supporting Information
ABSTRACT: Symmetrical 3,3-diaryl-2-iminoindoles were prepared from 3-diazoindolin-2-imines and indoles via a copper-
catalyzed cascade arylation/dehydrogenative cross-coupling process. By controlling the molar ratio of reactants and the operation
procedure, 3-aryl-2-aminoindoles and asymmetrical 3,3-diaryl-2-iminoindoles could be approached.
ndole and its derivatives are privileged structures in natural
products, bioactive pharmaceutics, and organic optoelec-
tronic materials. Integration of three indoles in a single
molecule is of interest to scientists not only because of the
interesting architecture but also due to the indole’s unique
property (Figure 1). For example, trisindoline, isolated from
The traditional synthetic route to symmetrical 3,3′-diary-
loxindole is the Friedel−Crafts approach (Scheme 1, route a),
starting from isatin and electron-rich arenes through iterative
electrophilic aromatic substitutions, which was created by
Baeyer and Lazarus at the end of the 19th century.3 Klumpp
and Olah investigated the influence of the acid strength on this
process and also produced asymmetrical 3,3-diaryloxindoles by
the reaction of isatin with a mixture of aromatics.4 This
approach was modified by Nicolaou et al. and applied in the
total synthesis of diazonamide A, in which the construction of a
C3 quaternary stereocenter of indole with two different aryls
was a challenging task.5
I
Transition-metal-catalyzed direct C3-arylation of indole was
developed for the preparation of 3-arylindole (Scheme 1, route
b).6 Sammakiain employed this method for the synthesis of
asymmetrical 3,3-diaryloxindoles7 and natural product diazo-
namide A.8 Palladium-catalyzed dearomative C3-arylation of
indole, which furnished spiroindolenine derivatives with an all-
carbon quaternary stereocenter at C3 of the indole ring, was
reported by You’s group.9
Figure 1. Privileged structures of 3,3′-diaryloxindole and C(3a)-
arylpyrroloindoline.
As one of the important intermediates in modern organic
synthesis, diazo compounds could be directly arylated through
C−H insertion. The acid or transition-metal-catalyzed arylation
of 3-diazooxindoles with electron-rich arenes took place on the
C-3 position of indoles to give 3-aryloxindoles with high
regioselectivity (Scheme 1, route c).10 Based on this kind of
metal carbene intermediates, Hu’s11 and Gong’s groups12 also
synthesized various 3,3′-bisindoles with an all-carbon quater-
the culture of Vibrio sp. that is a bacteria separated from the
fresh marine sponge Hyrtiosaltum, presents antibiotic activity.1
Idiospermuline, a representative of many biologically active
cyclotryptamine alkaloids, is a highly toxic component of
idiospermum seeds, preventing animals from eating them.2
Structures of these bioactive compounds all share a similar
structure of 3,3′-diaryloxindole or 3-arylindole substructure
with an all-carbon quaternary stereocenter. With regard to the
preparation of such privileged structures, many efficient
methodologies have been developed.
Received: January 16, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00089
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Literature Reported Methods in the Preparation
Table 1. Optimization of the Reaction Conditions
of 3,3′-Diarylindole and 3-Arylindole
b
entry
catalyst
Cu(OTf)2
solvent
temp (°C) time (h) yield (%)
1
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
toluene
THF
CH3CN
DMF
DMSO
DCE
DCE
DCE
DCE
DCE
DCE
DCE
50
50
50
50
50
50
50
50
50
50
50
50
50
80
50
35
35
35
rt
8
81
2
Cu(acac)2
Cu(NO3)2·3H2O
CuCl2·2H2O
Cu(OAC)2·H2O
CuBr2
8
64
3
8
66
4
8
54
5
8
63
6
36
36
8
18
7
Cu2O
40
8
CuOTf
78
9
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
8
76
10
11
12
13
14
15
16
17
18
19
20
8
64
8
trace
trace
trace
60
8
8
8
24
24
16
8
86
98
65
32
36
24
79
c
35
58
nary center though a rhodium- or ruthenium-catalyzed three-
component reaction of 3-diazooxindoles with indole, and
electrophiles. More recently, we developed a convenient and
economic method to construct 3,3′-bisindoles through Ar−H
insertion of α-imino rhodium carbenes derived from 3-
diazoindolin-2-imines (Scheme 1, route d).13a As part of our
ongoing commitment to α-imino metal carbenes,13 here we
would like to report a copper-catalyzed cascade double
arylation of 3-diazoindolin-2-imines, furnishing symmetrical
and asymmetrical 3,3-diaryl-2-imino-indoles.
To begin with, the reaction between 1-methyl-1H-indole
(1a) and 3-diazoindolin-2-imine (2a) was carried out in the
presence of Cu(OTf)2 in dichloroethane (DCE) at 50 °C for 8
h under an oxygen atmosphere. Fortunately, 3,3-diarylindolin-
2-imine (3a) was isolated in 81% yield. The reaction
regioselectively occurred on the 3-position of 1-methyl-1H-
indole (1a) without the contaminant of that on the 2-position.
The structure of 3a was confirmed by the single crystal analysis
of its analog (3s).14 By screening other Cu(II) catalysts,
Cu(OTf)2 was found to be optimal (Table 1, entries 1−6).
Meanwhile Cu(I) also catalyzed the reaction to some extent,
with CuOTf giving a comparable yield (Table 1, entries 7 and
8). As to the solvent used, polar aprotic solvents (CH3CN,
DMF, and DMSO) were not suitable in comparison with DCE,
toluene, and THF. Among these, DCE provided the highest
yield (Table 1, entries 1, 9−13). By screening the reaction
temperature and reaction time (Table 1, 14−19), the optimal
reaction temperature and reaction time were found to be 35 °C
and 24 h, respectively (Table 1, entry 16). When the reaction
was conducted under an air atmosphere, a dramatically
decreased yield was observed (Table 1, entry 20).
a
Reaction conditions: 1a (0.2 mmol), 2a (0.1 mmol), catalyst (0.005
b
c
mmol), solvent (1 mL), O2. Isolated yield. In air.
corresponding products 3a−f were obtained in 57%−98%yields
(Table 2, entries 1−6). When the R1 was an electron-
withdrawing group, such as Boc (1g) or Ts (1h), the desired
product was not detected although 2a was completely
consumed in each case (Table 2, entries 7 and 8). Substituted
groups on 5-, 6-, 7-positions of indoles could be either electron-
donating or -withdrawing. Thus, 3,3-diarylindolin-2-imines 3g−
m were prepared in yields between 60% and 93% (Table 2,
entries 9−15). 1,2-Dimethyl-1H-indole (1p), with methyl
blocked at the 2-position of indole, provided the desired
product 3n in excellent yield (Table 2, entry 16). 1-Ethyl-1H-
pyrrolo[2,3-b]pyridine (1q) could react at higher temperature
to give 3o (Table 2, entry 17).
As shown in Table 3, the R4 group in the benzene ring of 3-
diazoindolin-2-imines 2 could be altered from hydrogen,
methyl, methoxy, to nitro. In these cases, the substituent effect
is not apparent in comparison with that on indoles 1. The R6
group in sulfonyl could be either aliphatic or aromatic, such as
methyl, phenyl, p-methylphenyl, p-methoxyphenyl, p-chloro-
phenyl, and p-nitrophenyl.
In the case where R5 is tert-butyl (2i), the diarylation reaction
generated the deprotected product 3y in 78% yield (Scheme 2).
It is noticeable that 3y could not be directly prepared from the
unprotected 3-diazoindolin-2-imine and 1-methylindole (1a).
In order to understand the reaction mechanism, a condition-
controlled reaction between indoles 1 and 3-diazoindolin-2-
imine (2a) in an equivalent molar ratio was performed under
nitrogen at room temperature for 3 h. As shown in Table 4, 3-
arylindolin-2-amines 4a−g were isolated in 65%−95% yields.
Further arylation of the monoarylated compounds 4c and 4g
with indoles was achieved under oxygen conditions, furnishing
With the optimized reaction conditions (Table 1, entry 16),
we tested the substrate diversity (Table 2). Beginning with the
alternation of substituents on indole, the R1 group on the
nitrogen of indole could be alkyl, aryl, benzyl, and allyl. The
B
DOI: 10.1021/acs.orglett.5b00089
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Scope of Indoles
Scheme 2. Formation of the Deprotected Product 3y
a
Table 4. Formation of 3-Arylindolin-2-amines 4
b
entry
1 (X/R1/R2/R3/R4)
product
yield (%)
1
2
3
4
5
6
7
1a (CH/Me/H/H/H)
1j (CH/Me/H/MeO/H)
1m (CH/Me/H/H/Cl)
1o (CH/Et/H/MeO/H)
1p (CH/Me/Me/H/H)
1q (N/Et/H/H/H)
4a
4b
4c
4d
4e
4f
73
71
87
70
86
c
65
1r (CH/Me/H/Br/H)
4g
95
a
Reaction conditions: 1 (0.2 mmol), 2a (0.2 mmol), DCE (2 mL),
b
Cu(OTf)2 (0.01 mmol), N2, room temperature, 3 h. Isolated yields.
c
50 °C, 24 h.
asymmetrical 3,3-diarylindolin-2-imines 5a−c in excellent yields
(Scheme 3).
Scheme 3. Formation of 3,3-Diarylindolin-2-imines 5
a
Reaction conditions: 1 (0.4 mmol), 2 (0.2 mmol), DCE (2 mL),
b
Cu(OTf)2 (0.01 mmol), O2, 35 °C, 24 h. Isolated yields refer to 2.
c
d
e
50 °C. rt. 70 °C, 6 h.
a
Table 3. Scope of 3-Diazoindolin-2-imines
b
entry
2 (R4/R5/R6)
2b (H/Me/Me)
product
yield (%)
1
2
3
4
5
6
7
8
9
3p
3q
3r
90
84
95
2c (H/Me/Ph)
2d (H/PhCHCH/Tol)
2e (5-NO2/Me/Tol)
2f (H/Me/p-MeOC6H4)
2g (6-MeO/Bn/Tol)
2h (5-Me/Bn/Tol)
c
3s
3t
80
80
98
98
95
99
3u
3v
3w
3x
Based on these results and our previous finding in 3-
diazoindolin-2-imine chemistry,11,15 we postulated a working
mechanism for this transformation (Scheme 4). In the presence
of the copper catalyst, copper-carbene A16 is formed in situ
from 3-diazoindolin-2-imine during the process. Addition of
electron-rich indole on electrophilic copper-carbene species
leads to the formation of intermediate B. If one more
2i (H/Me/p-ClC6H4)
2j (H/Me/p-NO2C6H4)
a
Reaction conditions: 1 (0.4 mmol), 2 (0.2 mmol), DCE (2 mL),
b
Cu(OTf)2 (0.01 mmol), O2, 35 °C, 24 h. Isolated yields refer to 2.
c
50 °C.
C
DOI: 10.1021/acs.orglett.5b00089
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Organic Letters
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equivalent electron-rich arene existed in the reaction media, the
intermediate B provided an electrophilic site and reacted. Thus,
3,3-diarylindolin-2-imines 3 were afforded. If the reaction
between 2 and 1 preformed stoichimetrically, the intermediate
B underwent metal−H exchange to result in the formation of
the monoarylated products 4. The monoarylated compounds 4
could react with the copper catalyst to generate B via an
electrophilic metalation pathway and provide asymmetrical 3,3-
diarylindolin-2-imines 5 when a different arene was used.
In conclusion, we developed a novel and efficient synthesis of
3,3-diaryl-2-iminoindoles via copper-catalyzed reactions of 3-
diazoindolin-2-imines and indoles. The cascade process
involves a C−H insertion of arene on the electron-deficient
α-imino copper carbene which was derived from the copper-
catalyzed decomposition of 3-diazoindolin-2-imine and a
copper-catalyzed dehydrogenative cross-coupling. When the
reaction was carried out step-by-step, asymmetrical 3,3-diaryl-2-
iminoindoles could be prepared by sequentially feeding
different arenes.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for all new
compounds, and crystallographic information file (CIF) for
compound 3s. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: pinglu@zju.edu.cn.
*E-mail: orgwyg@zju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge financial support from the National Natural
Science Foundation of China (Nos. 21472164 and 21472173).
■
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D
DOI: 10.1021/acs.orglett.5b00089
Org. Lett. XXXX, XXX, XXX−XXX