Stereoselective Synthesis of Vinylcyclopropa[ b]indolines via a Rh-Migration Strategy

Article abstract of DOI:10.1021/acs.orglett.0c02071

A mild rhodium catalytic system has been developed to synthesize vinylcyclopropa[b]indolines through cyclopropanation of indoles with vinyl carbenoids generated from ring opening of cyclopropenes in situ. By employing a Rh-migration strategy, the products can be obtained with good to excellent E:Z ratios (≤99:1) and complete diastereoselectivity (≤99:1). This method is easy, has a low catalyst loading, and works for a broad range of functionalities.

Full text of DOI:10.1021/acs.orglett.0c02071

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Letter
Stereoselective Synthesis of Vinylcyclopropa[b]indolines via a Rh-
Migration Strategy
Pan Guo, Wangbin Sun, Yu Liu, Yong-Xin Li, Teck-Peng Loh,* and Yaojia Jiang*
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ABSTRACT: A mild rhodium catalytic system has been developed
to synthesize vinylcyclopropa[b]indolines through cyclopropana-
tion of indoles with vinyl carbenoids generated from ring opening
of cyclopropenes in situ. By employing a Rh-migration strategy, the
products can be obtained with good to excellent E:Z ratios (≤99:1)
and complete diastereoselectivity (≤99:1). This method is easy, has
a low catalyst loading, and works for a broad range of
functionalities.
ndole skeletons exist as key building blocks in drugs, natural
1
Iproducts, and biologically active molecules.
As an
important branch of indole derivatives, cyclopropane-fused
indolines such as Lundurine A−D exhibit significant
antibacterial, phytotoxic, anticancer, and antifungal activities.2
Transition metal-catalyzed cyclopropanation of indoles with
carbene precursors is recognized as one of the most reliable
methods for constructing cyclopropane-fused indolines and
related complex molecules.3 However, compared to well-
developed aryl/alkyl carbenoids generated from N-tosylhy-
drazones and diazo compounds, the reactions involving vinyl
carbenoids have still hardly been explored.4 In 2019, the Sun
group disclosed silver-catalyzed cyclopropanation of indoles
with vinyl diazoacetates to build up monosubstituted
vinylcyclopropa[b]indolines.4g Despite this progress, some
significant remaining challenges should be noted: (1) the
competitive reactions of carbenic and vinylogous reactivities
for metal vinyl carbene species,5 (2) the control of chemo-
selectivity of cyclopropantion versus C−H insertion and [3+2]
annulation,6 and (3) building up trisubstituted olefine-installed
cyclopropa[b]indolines and controlling their E:Z selectivity.4g,7
Cyclopropenes are unique carbene precursors8 featuring
atom economy and non-exposure character that are widely
used in X−H insertion,9 C−H insertion,10 cyclopropanation,11
and coupling reactions.12 We envisioned that employing a
disubstituted vinyl carbene complex that is formed from
cyclopropene ring opening in situ with a rhodium catalyst to
react with indoles may access trisubstituted vinylcyclopropa-
[b]indolines (Figure 1).13 The E:Z selectivity could be
potentially controlled by the judicious choice of the N-
protecting group of indoles. Herein, we reported an efficient
method for synthesize vinylcyclopropa[b]indolines through
cyclopropanation of steric N-sulfonyl indoles with vinyl
carbenoids. The products installing a variety of functionalities
Figure 1. Construction of vinylcyclopropa[b]indolines.
could be prepared with good to excellent E:Z ratios (≤99:1)
and complete diastereoselectivity.14
Received: June 23, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02071
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
a
Table 1. Optimization of Cyclopropanation Conditions
Scheme 1. Reactions of Different Substituted Indoles with
Cyclopropene
a
b
c
entry
R
metal catalyst
yield (%)
3:3′
1
2
3
Ac
Boc
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
72
28
35
30
43
64
−
61:39
91:9
70:30
74:26
99:1
79:21
−
86:14
85:15
93:7
94:6
97:3
97:3
tBuCO
PhCO
PhSO2
PhSO2
PhSO2
PhSO2
PhSO2
PhSO2
ArSO2
SG
4
5
6
7
8
9
10
11
12
d
ZnBr2
Cu(OAc)2
AgOAc
e
e
9
Rh2(OPiv)4
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
79
70
79
74
92
f
13
SG
a
Unless otherwise noted, reactions were carried out using 1 (0.20
mmol, 1.0 equiv), 2a (0.60 mmol, 3.0 equiv), and a catalyst (1 mol %)
in CH2Cl2 (0.1 M, 1 mL) at 25 °C for 5 h. Abbreviations: OAc,
acetyl; OPiv, trimethyl acetate; Boc, tert-butyloxycarbonyl; ArSO2,
2,4,6-trimethylbenzenesulfonyl; Rh2(esp)2, bis[rhodium(α,α,α′,α′-
tetramethyl-1,3-benzenedipropionic acid)]; SG, 2,4,6-triisopropylben-
b
c
zenesulfonyl. Isolated yields. The E:Z selectivity was determined by
d
e
1H NMR analysis. With 20 mol % catalyst. With 10 mol % catalyst.
2a (0.80 mmol, 4.0 equiv).
f
Indoles are well-known to preferentially undergo cyclo-
propanation under the circumstances in which the N
substituent is an electron-withdrawing group.15 In the
beginning, we explored cyclopropanation of N-acetyl indole
1 with cyclopropene 2a in the presence of Rh2(OAc)4 to
achieve vinylcyclopropa[b]indolines 3 (Table 1, entry 1). The
desired vinylcyclopropane-fused indolines 3 were obtained in
72% yield albeit in low E:Z ratio (61:39) (Table 1, entry 1).
To increase the E:Z selectivity, we examined other N-
substituted indoles with more steric electron-withdrawing
groups. The results showed that the benzenesulfonyl group
gave better stereoselectivity compared to those for other
substituents albeit in moderate yield (43%) (Table 1, entries
2−5). Then various metal catalysts, including Cu, Ag, Zn, and
Rh, were screened. Compared to ZnBr2, for which the yield
improved to 64% with 79:21 selectivity (Table 1, entry 6),
copper and silver catalysts were inactive with respect to this
reaction system (Table 1, entries 7 and 8, respectively).
Surprisingly, in sharp contrast with Rh2(OAc)4, the different
anions of Rh(II), including Rh2(OPiv)4 and Rh2(esp)2, could
significantly increase the E:Z selectivity (≤93:7) and
maintained good yields (Table 1, entries 9 and 10,
respectively). We further explored more steric sulfonyl
substituents with installing methyl and isopropyl groups. The
results revealed that the N-triisopropylbenzenesulfonyl indole
achieved the best result with an E:Z selectivity of 97/3 and a
yield of 74% (Table 1, entries 11 and 12). The optimized
reaction condition was finally carried out with N-triisopro-
pylbenzenesulfonyl indole 1a and cyclopropene 2a with 1 mol
% Rh2(esp)2 at room temperature, and the vinylcyclopropa-
[b]indolines 3aa could be observed in 92% yield and 97:3 E:Z
selectivity. The geometries of products 3aa and 3aa′ were
analyzed by 1H NMR and NOSEY (see the Supporting
a
Unless otherwise noted, the reactions were carried out using 1 (0.20
mmol), 2a (4.0 equiv), and Rh2(esp)2 (1 mol %) in CH2Cl2 (0.1 M,
2.0 mL) at 25 °C for 5−12 h. Isolated yields and E:Z ratios were
determined by H NMR analysis.
1
Information), and 3pa (CCDC 1997886) and 3pa′ (CCDC
1997855) were further determined by a single-crystal X-ray
structure (Scheme 1 and the Supporting Information).
Under the optimized reaction conditions, the substrate
scope of indoles was then studied (Scheme 1). In general, a
plethora of functionalized indoles 1 could be smoothly reacted
with cyclopropene 2a to provide the vinylcyclopropa[b]-
indolines in promising yields, high stereoselectivity, and
complete diastereoselectivity. Screening different methyl-
substituted positions of indoles revealed that 5- and 6-methyl
substitutions generated the desired cyclopropanes in good
yields (82% and 83%, respectively) and E:Z ratios of ≤97:3
(3ca and 3da, respectively). 4-Methyl-substituted indole
achieved a similar high stereoselectivity (96:4) but with a
decreased yield (47%) (3ba). The indoles with different
halogen groups (F, Cl, Br, and I) all performed well to give
yields from 71% to 92% and E:Z ratios of ≤99:1 (3ea−3ka). It
is worth mentioning that the obtained halide vinylcyclopropa-
B
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Scheme 2. Reactions of Indole with Different Substituted
Cyclopropenes
Scheme 3. Proposed Reaction Pathway
a
the same catalytic system (Scheme 2). Aryl-substituted
cyclopropenes bearing p- and m-methyl groups were screened
and produced the corresponding indolines in moderate to
good yields with excellent E:Z selectivity (3ac and 3ad). o-
Methyl substitution occurred successfully with a promising
yield (58%), but the stereoselectivity decreased (3ab). We
supposed that it might be a weak steric effect of the aryl group
and rhodium complex involved in the reaction. Thus, o-Cl
substitution was further investigated, and the results were
similar to those of an o-methyl substitution with a 61% yield
and a 42:58 E:Z ratio (3ae). The reaction worked efficiently
with a broad range of m- and p-aryl halides (F, Cl, Br, and CF3)
with excellent yields (79−99%) and E:Z ratios of ≤95:5 (3af−
3aj). The reaction with a bulky group such as naphthalene
proceeded well to provide the desirable vinylcyclopropane
product with excellent selectivity (>99:1) and 43% yield (3ak).
The E:Z selectivity then deteriorated with alkyl-substituted
cyclopropenes with substituents that were larger than a methyl
group (3al−3an). Ethyl and butyl groups gave good yields and
slightly decreased selectivities (3al and 3am, respectively),
while isopropyl gave a 46% yield and a 50:50 E:Z ratio (3an).
The long alkyl chain also showed poor selectivity (only 53:47)
and a 51% yield, which may be due to the loss of the steric
effect of the methyl and alkyl chain (3ao). We also explored
symmetrically substituted cyclopropenes under the same
reaction conditions. The trisubstituted olefine product could
be obtained in 45% yield (3ap) when diphenyl-substituted
cyclopropene 2p was employed. The use of cyclic alkyl-
substituted cyclopropanes 2q and 2r gave yields of 85% and
49%, respectively (3aq and 3ar, respectively).
A plausible reaction pathway is then proposed according to
the obtained results (Scheme 3). In the beginning, cyclo-
propene 2a opens the ring in situ to generate rhodium complex
A in the presence of catalytic Rh2(esp)2.17 Complex A then is
nucleophilically attacked by indole 1a to form a zwitterion
complex B. Because it is difficult to control the stereoselectivity
at the carbene formation step and additional steps, the high
E:Z stereoselectivity obtained for the vinylcyclopropa[b]-
indoline could be explained by CC bond equilibration of
the rhodium allyl complex B and complex C. After rhodium
migration, the newly formed C−C bond rotates,18 and finally,
the equilibrated species C cyclizes to the thermodynamically
stable E isomer 3aa as a major product.
a
Unless otherwise noted, the reactions were carried out using 1 (0.20
mmol), 2a (4.0 equiv), and Rh2(esp)2 (1 mol %) in CH2Cl2 (0.1 M,
2.0 mL) at 25 °C for 5−12 h. Isolated yields and E:Z ratios was
determined by H NMR analysis.
1
[b]indolines can potentially further be functionalized into
other useful indoline substrates by cross-coupling reactions,
such as Suzuki and Heck reaction.16 The electronic effect was
then examined by installing electron-donating and electron-
withdrawing groups at the phenyl position of indoles. While
electron-rich substituted indole (6-MeO) gave a 77% yield and
a 93:7 E:Z ratio (3la), electron-deficient groups such as
-CO2Me (3ma and 3na) and -NO2 (3oa) resulted in yields
that fluctuated from 32% to 73%. Furthermore, 1H-pyrrolo-
[2,3-b]pyridine smoothly underwent the process to provide
3pa in moderate yield and good stereoselectivity. Finally,
indoles substituted at position 2 or 3 were explored to generate
the corresponding vinylcyclopropa[b]indolines with a quater-
nary carbon center (3qa and 3ra).
Subsequently, we explored the different substituted cyclo-
propenes to further study the generality of this method under
In summary, we described a practical and efficient approach
for preparing trisubstituted vinylcyclopropa[b]indolines with
C
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complete diastereoselectivity and a high E:Z ratio. The
reactions require a low Rh(II) catalyst loading under mild
and neutral conditions. We believed the reaction involves an
Rh-migration step to control the E:Z selectivity through sp3
C−C bond rotation. The method works for a broad spectrum
of functionalities to construct trisubstituted vinylcyclopropa-
[b]indoline derivatives.
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02071.
Experimental procedures and NMR spectra for new
compounds (PDF)
Accession Codes
CCDC 1997855 and 1997886 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
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Yaojia Jiang − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech University,
Nanjing 211816, China; orcid.org/0000-0003-0695-0069;
Email: iamyjjiang@njtech.edu.cn
Teck-Peng Loh − Division of Chemistry and Biological
Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637616;
orcid.org/0000-0002-2936-337X; Email: teckpeng@
ntu.edu.sg
Authors
Pan Guo − Institute of Advanced Synthesis, School of Chemistry
and Molecular Engineering, Nanjing Tech University, Nanjing
211816, China
Wangbin Sun − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech University,
Nanjing 211816, China
Yu Liu − Institute of Advanced Synthesis, School of Chemistry
and Molecular Engineering, Nanjing Tech University, Nanjing
211816, China
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02071
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge funding from the National
Natural Science Foundation of China (21971112) and the
Starting Funding of Research (39837107) from Nanjing Tech
University.
D
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