Rh(III)-catalyzed selective C7-H functionalization of indolines with 1,3-enynes enables access to six-membered 1,7-fused indolines

Article abstract of DOI:10.1016/j.tetlet.2021.153065

We described herein a Rh(III)-catalyzed C7-selective C–H activation/annulation of indolines with 1,3-enynes to efficiently access various privileged 1,7-fused indolines bearing an all-carbon quaternary stereogenic carbon center. Notably, the resulting pro

Full text of DOI:10.1016/j.tetlet.2021.153065

Tetrahedron Letters 72 (2021) 153065
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Tetrahedron Letters
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Rh(III)-catalyzed selective C7-H functionalization of indolines with 1,3-
enynes enables access to six-membered 1,7-fused indolines
Yunkai Shi a,b, Chao Chen b,e, Yaxi Yang b,c,d, Bing zhou b,c,d,
⇑
a Institute of Pharmaceutical Research and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
b State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
c University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China
d School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
e Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong New District, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
We described herein a Rh(III)-catalyzed C7-selective CAH activation/annulation of indolines with 1,3-
enynes to efficiently access various privileged 1,7-fused indolines bearing an all-carbon quaternary stere-
ogenic carbon center. Notably, the resulting products can be readily transformed into 1,7-fused indoles,
further widening the C-7 derivatization of indoles and highlighting the synthetic utility of this
methodology.
Received 4 March 2021
Revised 29 March 2021
Accepted 5 April 2021
Available online 8 April 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
CAH activation
1,7-Fused indoline
Enynes
Introduction
1,3-Enynes, are important compounds in organic chemistry and
have been utilized as a C1, C2 or C3 annulation synthon in the tran-
The indoles and indolines are common fragments in numerous
bioactive natural products, pharmaceutically important com-
pounds, other functional molecules and even marketed drugs [1].
Among them, 1,7-fused indolines are particularly noteworthy
owing to their great potential in pharmaceuticals and agrochemi-
cals (Fig. 1) [2]. Therefore, the development of catalytic and practi-
cal methods to efficiently access various 1,7-fused indolines, is
highly desirable and of prime synthetic value.
sition-metal-catalyzed CAH functionalizations [6]. In this context,
given the importance of 1,7-fused indolines and with our continu-
ing interest in the transition-metal-catalyzed CAH functionaliza-
tion [7], we herein reported a Rh(III)-catalyzed C7-selective CAH
activation/annulation of indolines with 1,3-enynes to efficiently
access various privileged six-membered 1,7-fused indolines bear-
ing an all-carbon quaternary stereogenic carbon center.
The transition metal-catalyzed CAH functionalizations have
advantages over traditional protocols because substrate preactiva-
tion is unnecessary [3,4]. In this regard, it would be highly desir-
able and attractive if we can take advantage of selective C7-H
fuctionalization/annulation of indolines with proper coupling part-
ners to directly access a variety of 1,7-fused indolines. Recently,
some elegant examples of transition-metal-catalyzed C7-H func-
tionalization/annulation of indolines with different coupling part-
ners have been disclosed by several groups and us [5], including
alkynes, alkenes, allylic alcohols, and carbon monoxide. Despite
significant progress, the development of catalytic synthetic meth-
ods to expand the range of products and access structurally more
complex and diverse 1,7-fused indolines, is still highly desirable.
Results and discussion
We commenced our study with the coupling of N-methoxycar-
bamoyl-protected indoline (1a) and 1,3-enynes (2a) in the pres-
ence of [Cp*RhCl2]2 (5 mol %) and various additives (200 mol %)
in 1,4-dioxane at 70 ℃ for 48 h (Table 1, entries 1–4). Cu(OAc)2
was identified as the best additive, affording the 3a in 20% yield
(entry 1). Next, a screening of the solvent proved THF to be the
optimal choice (entries 5–9), giving 3a in 37% yield. The prepared
Rh (III) precursor Cp*Rh(CH3CN)3(SbF6)2 led to a higher yield (entry
10). Increasing the reaction temperature to 85℃ further improved
the reaction efficiency (entry 11) but a higher reaction temperature
(100 ℃) decreased the yield (entry 12). Other catalyst system
proved ineffective in this reaction (entries 13–15). This annulation
reaction did not occur in the absence of the rhodium catalyst and
the oxidant Cu(OAc)2 (entries 16 and 17).
⇑
Corresponding author.
E-mail addresses: zhoubing@simm.ac.cn, zhoubing2012@hotmail.com (B. zhou).
https://doi.org/10.1016/j.tetlet.2021.153065
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

Y. Shi, C. Chen, Y. Yang et al.
Tetrahedron Letters 72 (2021) 153065
Fig. 1. Representative bioactive 1,7-fused indolines.
With the optimized reaction conditions in hand, the substrate
scope of indolines was investigated. As shown in Scheme 1, indo-
lines containing both electron-donating(3b À g) and withdrawing
(3h À j) groups proceeded smoothly in this transformation to give
the corresponding six-membered 1,7-fused indolines in moderate
to good yields. Moreover, substitutions at the C2– (3b), C3– (3c,
d), C4- (3e), C5- (3f À j) and even C6- (3k and 3l) position were tol-
erated. The structure of 3j was unambiguously conformed by an X-
ray crystallographic analysis (CCDC 2067486). Of special impor-
tance, indolines bearing chloro (3i) and bromo (3j) functional
groups were also compatible with this catalytic system, thus offer-
ing the opportunity for further transformations, for example, the
metal-catalyzed cross-coupling reactions. To our delighted, tri-
cyclic hexahydrocarbazole (3m) were also fully applicable to this
catalytic system. Notably, the C2-substitution gave an excellent
diastereomeric selectivity (3b and 3m). Carbazole failed to deliver
the desired product 3n.
[a]
Scheme 1. Substrate scope of indolines[a]
Reaction conditions: 1 (0.2 mmol, 1.0
equiv), 2 (0.3 mmol, 1.5 equiv), Cp*Rh(CH3CN)3(SbF6)2 (5 mol %) and Cu(OAc)2
(200 mol %) in THF (2.0 mL) for 48
chromatography.
h at 85 °C; yield isolated by column
with 1a, furnishing the desired products 4b-i in moderate to good
yield, although the reaction efficiency decreased with a bulky sub-
stituent (4h and 4i).
The scope of enynes was also explored (Scheme 2). 1,3-enynes
with various alkyl, cycloalkyl and aryl groups coupled smoothly
Table 1
Reaction optimization[a]
.
Entry
catalyst
additive
T[℃]
solvent
yield of 3a (%)
1
2
3
4
5
6
7
8
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
Cu(OAc)2
Zn(OAc)2
AgSbF6
70
70
70
70
70
70
70
70
70
70
85
100
70
70
70
70
70
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
DCE
EtOH
DMSO
DMF
THF
THF
THF
THF
THF
THF
THF
THF
20
11
0
9
37
0
12
0
0
52
70
46
0
AgF2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
–
9
[Cp*RhCl2]2
10
11
12
13
14
15
16
17
Cp*Rh(CH3CN)3(SbF6)2
Cp*Rh(CH3CN)3(SbF6)2
Cp*Rh(CH3CN)3(SbF6)2
[Ru(p-cymene)Cl2]2
[Rh(COD)Cl]2
[Cp*IrCl2]2
0
0
0
0
–
Cp*Rh(CH3CN)3(SbF6)2
[a]
Conditions: 1a (0.1 mmol), 2a (0.15 mmol), catalyst (5 mol %) and additive (200 mol %) in Solvent (1 mL) for 48 h. Yield isolated by column chromatography.
2

Y. Shi, C. Chen, Y. Yang et al.
Tetrahedron Letters 72 (2021) 153065
[a] [a]
Scheme 2. Substrate scope of various enynes
Reaction conditions: 1
A preliminary mechanistic pathway is postulated for the Rh(III)-
(0.2 mmol, 1.0 equiv), 2 (0.3 mmol, 1.5 equiv), Cp*Rh(CH3CN)3(SbF6)2 (5 mol %),
and Cu(OAc)2 (200 mol %) in THF (2.0 mL) for 48 h at 85 °C; yield isolated by column
chromatography.
catalyzed of indoline C-7 C À H activation/annulation with enynes
(Scheme 4)[6f]. First,
a Rh(III)-catalyzed reversible C-7 C–H
cleavage occurs to give rhodacycle A upon proton abstraction.
Insertion of enynes to the carbon À rhodium bond of A affords
the eight-membered rhodacycle B. Then, the Rh(III) alkenyl
intermediate undergoes d-hydrogen elimination to produce the
Rh(III) enallene hydride intermediate C. Subsequent hydride
insertion into the allene middle carbon gives the g3 allyl D.
The synthetic utility of this method was further highlighted by
its successful conversion of 1,7-fused indoline 3a into 1,7-fused
indole 5 (Scheme 3). Moreover, reduction of 3a with 10% Pd/C
under H2 afforded product 6 in 81% yield. In addition, a Diels–Alder
reaction of 3a with N-phenylmaleimide proceeded smoothly to
give product 7 in 67% yield.
Nucleophilic attack of the
p–allylrhodium moiety of D delivers
the product 3 and the Rh(I) species, which can be reoxidized to
For a preliminary mechanistic study, H/D exchange experi-
ments were performed. A significant H/D scrambling was observed
at the C7-position of indoline when 1l was reacted with Cp*Rh
(CH3CN)3(SbF6)2 catalyst in THF and D2O (eq 1). Moreover, in the
presence of 2a, a similar H/D scrambling was observed in the re-
isolated 1l (eq 2). Together, these results indicated the reversibility
of the CAH activation. Next, competition experiments using an
equimolar mixture of electronically differentiated indolines
revealed that CAH activation was slightly kinetically favored for
electron-rich indolines (eq 3).
Rh(III) by Cu(OAc)2.
Conclusions
In summary, we have developed a Rh(III)-catalyzed selective C-
7 C À H activation/annulation of indolines with 1,3-enynes. This
robust transformation proceeds with a broad functional group tol-
erance under mild reaction conditions, affording a variety of priv-
ileged 1,7-fused indolines bearing an all-carbon quaternary
stereogenic carbon center.
Scheme 3. Synthetic applications of annulation products.
Scheme 4. Proposed Mechanism.
3

Y. Shi, C. Chen, Y. Yang et al.
Tetrahedron Letters 72 (2021) 153065
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Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgements
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This work is financially supported by National Natural Science
Foundation of China (No. 81973166), Youth Innovation Promotion
Association (2017333) and Science and Technology Commission of
Shanghai Municipality (18431907100).
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