Sulfinate and Carbene Co-catalyzed Rauhut–Currier Reaction for Enantioselective Access to Azepino[1,2-a]indoles

Article abstract of DOI:10.1002/anie.201810879

A carbene and sulfinate co-catalyzed intermolecular Rauhut–Currier reaction between enals and nitrovinyl indoles is disclosed. The carbene catalyst activates the enal and the sulfinate co-catalyst activates the nitrovinyl indole. Both activation processes are realized via the formation of covalent bonds between the catalysts and substrates to generate catalyst-bound intermediates. The dual catalytic reaction affords azepino[1,2-a]indole products with excellent stereoselectivity. Our study demonstrates the unique involvement of sulfinate as an effective nucleophilic catalyst in activating electron-deficient alkenes for asymmetric reactions. This dual catalytic approach should also encourage future explorations of both sulfinate and carbene catalysts for new reactions.

Full text of DOI:10.1002/anie.201810879

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Accepted Article
Title: Sulfinate and Carbene Co-catalyzed Rauhut-Currier Reaction for
Enantioselective Access to Azepino[1,2-a]indole
Authors: XINGXING WU, Liejin Zhou, Rakesh Maiti, Chengli Mou, Lutai
Pan, and Yonggui Robin Chi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810879
Angew. Chem. 10.1002/ange.201810879
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10.1002/anie.201810879
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Sulfinate and Carbene Co-catalyzed Rauhut-Currier Reaction for
Enantioselective Access to Azepino[1,2-a]indole
Xingxing Wu,† Liejin Zhou,† Rakesh Maiti, Chengli Mou, Lutai Pan,* and Yonggui Robin Chi*
Abstract: A carbene and sulfinate co-catalyzed intermolecular
Rauhut-Currier reaction between enals and nitrovinyl indoles is
disclosed. The carbene catalyst activates the enal and the sulfinate
co-catalyst activates the nitrovinyl indole. Both activation processes
are realized via the formation of covalent bonds between catalysts
and substrates to generate the catalyst-bound intermediates. The
dual catalytic reaction affords azepino[1,2-a]indole products with
excellent stereo-selectivities. Our study demonstrates the unique
involvement of sulfinate as effective nucleophilic catalyst in activating
electron-deficient alkenes for asymmetric reactions. The dual catalytic
approach shall also encourage future explorations of both sulfinate
and carbene catalysts for new reactions.
The dimerization of two electron-deficient alkenes, known as
Rauhut-Currier reaction, is an important method to prepare
functional molecules bearing an unsaturated carbon-carbon
bond.[1] This reaction is typically realized through the use of a
nucleophilic organocatalyst to activate one of the alkenes (1) to
form a nucleophilic zwitterionic species that subsequently reacts
with
a second electron-deficient alkene (2) (Figure 1a).
Phosphines and amines are two types of mostly-studied catalysts
for the Rauhut-Currier reactions.[2] Thiols (from cysteine) and
thiolates have also been demonstrated by Miller, Murphy and
Moore as nucleophilic catalysts.[3] These catalysts are found
effective for enantioselective processes mostly in intramolecular
reactions, as reported by Miller, Xiao, Enders and Sasai, Zhang
and others.[4] When moving from intramolecular reactions to
intermolecular versions, both chemical reactivities and
enantioselectivities become much more challenging.[5] The
incorporation of a second catalyst to simultaneously activate the
electrophile 2 therefore provides a promising strategy to achieve
efficient Rauhut-Currier reactions. For example, the groups of Shi
and Feng have used amines as co-catalysts to activate
unsaturated ketones or aldehydes (via iminium formation) as
electrophiles in enantioselective Rauhut-Currier reactions.[6]
Our laboratory is interested in using N-heterocyclic carbene
(NHC) to activate aldehydes and carboxylic esters for efficient
asymmetric synthesis of functional molecules.[7,8] Here we
demonstrate that the merge of a sulfinate and an NHC catalyst
readily allows for catalytic intermolecular Rauhut-Currier
Figure 1. Rauhut-Currier reaction and bioactive molecules containing
azepino[1,2-a]indoles. SI = Supporting Information.
reactions to generate azepino[1,2-a]indole scaffold with high
enantioselectivities (Figure 1b). Briefly, the addition of a sulfinate
catalyst to a nitroalkene substrate (1a) generates intermediate I
bearing a nucleophilic carbon.[9] Simultaneously in the same
system, the reaction of an NHC catalyst with α-bromoenal (2a)
generates the α,β-unsaturated acyl azolium intermediate II.[10,11]
Michael-type addition of intermediate I to II followed by a few
processes (see Supporting Information for a complete pathway)
eventually leads to product 3a with both sulfinate and NHC
catalysts regenerated. The optically enriched products from our
catalytic reactions contain an azepino[1,2-a]indole moiety that is
widely found as a core scaffold in natural products and bioactive
functional molecules (Figure 1c).[12] In our approach, the chemical
reactivity is enabled by both catalysts cooperatively, and the
enantioselectivity is controlled by the chiral NHC catalyst. Notably,
in previous cooperative NHC catalysis,[13] the other catalyst is
typically non-covalent catalyst such as Lewis/Brønsted acid,[14a-f]
hydrogen-bond donor.[14g-h] In our dual catalytic approach, both
NHC and the sulfinate catalysts activate the substrates via
covalent bond formations.[15] Our study constitutes the first
[*]
Dr. X. Wu,[+] Dr. L. Zhou,[+] R. Maiti, Prof. Dr. Y. R. Chi, Division of
Chemistry & Biological Chemistry, School of Physical &
Mathematical Sciences, Nanyang Technological University,
Singapore 637371 (Singapore)
E-mail: robinchi@ntu.edu.sg
C. Mou, Prof. Dr. L. Pan, Guiyang College of Traditional Chinese
Medicine, Guizhou (P.R.China).
E-mail: ltpan@sina.cn
These authors contritubuted equally to this work.
[+]
Supporting information for this article is available on the WWW
under http://www.angewandte.org.
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10.1002/anie.201810879
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success in using NHC to activate the electrophilic partner for
enantioselective Rauhut-Currier reactions. Additionally, our work
shall encourage further explorations of sulfinates (including the
chiral variants) as potentially versatile nucleophilic catalysts for
other asymmetric reactions.
Based on our dual activation design, we began the investigation
by using nitrovinylindole 1a and bromoenal 2a as the model
substrates (Table 1). It is known that NHC catalyst can react with
bromoenal 2a to generate the α,β-unsaturated acyl azolium
intermediate that can behave as an electrophilic component.[10]
1). We next found the use of DMAP as the co-catalyst could afford
product 3a with around 8% yield (entry 2). Further optimizations
with DMAP as the co-catalyst did not lead to significant
improvement.
Inspired by pioneering studies from Murphy, Moore and Miller,[3]
we then turned to evaluate thiol-based nucleophilic catalysts
(entry 3). Unfortunately, the use of thiol or thiophenol as the co-
catalyst failed to afford product 3a (entry 3). Analysis of the
reaction (entry 3) indicated that these co-catalysts reacted with
acyl azolium intermediate (II, Figure 1b) to form the corresponding
To generate a nucleophilic partner for the Rauhut-Currier reaction, thioester adduct. We hypothesized that the sulfinate as the co-
we first studied several commonly used amine and phosphine
catalysts to activate nitrovinylindole 1a. The model reaction was
performed at 45 oC with A[16a] as an NHC pre-catalyst, Cs2CO3 as
a base, and DCM as the solvent. No product (3a) was observed
while the nitroalkene 1a was fully consumed when DABCO, NMI,
PMe3, or Ph2PMe was used as the co-catalyst to activate 1a (entry
catalyst should prevent the undesired pathway for thioester
formation. To our great delight, the use of PhSO2Na as a co-
catalyst resulted in 3a with a very encouraging 49% yield (entry
4). We next found that the use of benzenesulfinic acid as the
precursor provided a slight increase in the product yield (54%,
entry 5), probably due to a better solubility of the in situ generated
sulfinate salt in the reaction. To achieve an optimal
enantioselectivity, several amino-indanol-derived NHCs were
examined. We found the bromo-substituted pre-catalyst B[16b,c]
afforded 3a in 63% yield and 96:4 er (entry 6). The pre-catalyst
C[16b,c] substituted with nitro group did not perform as well as B
(entry 7). K2CO3 could be used as a base, while organic base Et3N
was not effective (entries 9-10). Control experiments without
either NHC pre-catalyst (B) or sulfinate pre-co-catalyst (PhSO2H)
did not provide any desired product, with the starting materials (1a
and 2a) remained mostly unconsumed in both reactions (entries
11 and 12). These results (entries 11-12) strongly supported that
simultaneous dual activations were critical for the transformation.
Finally, we were pleased to find that with 15 mol% of pivalic acid
(tBuCO2H) as an additive,[14e] 3a was obtained in an acceptable
yield (70%) and 98:2 er (entry 13).
Table 1. Optimization of the Reaction Conditions.[a]
Entry
1
NHC
Base
Co-Cat.
3a Yield [%][b]
e.r.
A
Cs2CO3
DABCO, NMI, PMe3, or Ph2PMe as co-cat.,
no product 3a was observed
With optimized reaction conditions in hand (Table 1, entry 13),
we next explored the generality of the reaction. Initially, we
studied the scope of bromoenal 2 (Table 2). A diverse set of
substituents (OCH3, CH3, halogens etc) at the para-, meta- or
ortho-position of the β-phenyl group of enals were well tolerated
and the corresponding annulation products (3a-k) were obtained
with good yields and excellent er values. The β-phenyl group of
2a could be replaced with heteroaryl units, such as furyl (3m) and
thienyl (3n) substituents. Moreover, the enal bearing further
transferable alkenyl group was also compatible in this reaction,
giving product 3o in 63% yield and 96:4 er. Notably, substrates
possessing electron-withdrawing group (F, Cl, Br, NO2 and
CO2Me) at the para-position of the β-phenyl group delivered the
corresponding products in low yields, probably due to the
relatively strong reactivity of the enals. In these cases, removal of
the pivalic acid additive from the optimal conditions gave better
results (3d-h). Unfortunately, this protocol was not applicable for
β-alkyl bromoenal substrates (please see SI for more details).
The scope of nitrovinylindole 1 by using enal 2a as the model
substrate was also investigated (Table 3). Various substituents
(e.g. methyl, chloro, bromo) and substitution patterns on the
indole aromatic ring were compatible in the catalytic reactions. As
a technique note, when electron-withdrawing substituents (Cl, Br)
were placed on the vinylindoles (1), the reactions were performed
in CHCl3 as the solvent with the absence of pivalic acid additive
in order to achieve good yields and high er values (3s-t, 3v-w).
Additionally, nitrovinylpyrrole was also screened in our reaction to
2
A
A
A
A
B
C
B
B
B
−
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
DMAP
8
90:10
3
PhSH or nPrSH (See SI), no product
4
PhSO2Na
PhSO2H
PhSO2H
PhSO2H
PhSO2Na
PhSO2H
PhSO2H
PhSO2H
−
49
70:30
70:30
96:4
88:12
96:4
93:7
−
5
54
6
63
7
61
8
55
9
45
10
11
12
13[c]
Et3N
−
Cs2CO3
Cs2CO3
Cs2CO3
−
−
B
B
−
−
PhSO2H
71 (70)[d]
98:2
[a] Reaction conditions: 1a (0.07 mmol, 1.4 equiv), 2a (0.05 mmol, 1.0 equiv),
NHC (20 mol%), co-cat. (30 mol%), base (2.0 equiv), 4 Å MS (50 mg), CH2Cl2
(0.04 M) at 45 oC, 16 h. [b] Yield estimated via 1H NMR analysis of crude
reaction mixture, based on 2a, by using 1,3,5-trimethoxybenzene as an internal
standard. [c] 15 mol% of Pivalic acid was added, and reaction completed within
3 h. [d] Isolated yield within parentheses.
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10.1002/anie.201810879
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deliver the corresponding product 3y in 58% yield and a moderate
er (84:16 er), probably because of the weak steric interaction with
NHC catalyst owing to the inherent smaller size of pyrrole.
triazole structure is widely found as a core moiety of biological
agents and can be employed as ligands in synthetic chemistry.[17]
Table 2. Substrate scope of bromoenals 2.[a]
Scheme 1. Synthetic transformations of product 3a
In summary, we have developed a new dual catalytic activation
approach that employ NHC and benzenesulfinate as the catalysts.
For the first time we demonstrate the unique involvement of
benzenesulfinate as an effective catalyst for enantioselective
Rauhut-Currier reactions. Both catalysts activate the
corresponding substrates via covalent bond formations. The key
reaction step involves two in situ generated catalyst-bound
intermediates (a PhSO2-bound and an NHC-bound intermediate).
Our dual catalytic reaction allows for access to azepino[1,2-
a]indoles in excellent enantioselectivities. Ongoing studies
include asymmetric reaction development by designing new chiral
sulfinate catalysts, and rapid synthesis and activity evaluation of
medicinally relevant molecules.
[a] Reaction conditions were as in Table 1, entry 13, unless otherwise specified.
Isolated yields (after SiO2 chromatography purification) based on the enal 2.
[b] Reactions performed at 50 oC. [c] No pivalic acid was added.
Table 3. Substrate scope of vinylindoles 1.[a]
Acknowledgements
We thank Dr. Yongxin Li (NTU) and Dr. Rakesh Ganguly for
assistance with X-ray structure analysis; We acknowledge
financial supports by Singapore National Research Foundation
(NRF-NRFI2016-06), the Ministry of Education of Singapore
(MOE2013-T2-2-003; MOE2016-T2-1-032; RG108/16), A*STAR
Individual
Research
Grant
(A1783c0008),
Nanyang
Technological University, Singapore; Guizhou Province First-
Class Disciplines Project (YiLiu Xueke Jianshe Xiangmu)-
GNYL(2017)008, and Guiyang College of Traditional Chinese
Medicine, China.
[a] Unless otherwise noted, reaction conditions were as in Table 1, entry 13.
Isolated yields based on enal 2a. [b] Reactions performed at 50 oC. [c] CHCl3
was used instead of CH2Cl2. [d] No pivalic acid was added.
Keywords: azepino[1,2-a]indole • N-heterocyclic carbene •
Rauhut-Currier reaction • cooperative catalysis • organocatalysis
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10.1002/anie.201810879
Angewandte Chemie International Edition
COMMUNICATION
Layout 2:
COMMUNICATION
Xingxing Wu, Liejin Zhou, Rakesh Maiti,
Chengli Mou, Lutai Pan,* and Yonggui
Robin Chi*
Page No. – Page No.
Sulfinate and Carbene Co-catalyzed
Rauhut-Currier Reaction for
Enantioselective Access to
Azepino[1,2-a]indole
Cooperative: A carbene and sulfinate co-catalyzed intermolecular Rauhut-Currier
reaction provides an efficient method for access to azepino[1,2-a]indoles with
excellent stereo-selectivities. The sulfinate was found to be a unique and effective
nucleophilic catalyst in activating nitrovinyl indoles for the Rauhut-Currier reaction.
This article is protected by copyright. All rights reserved.