Carbene-Catalyzed Reductive Coupling of Nitrobenzyl Bromide and Nitroalkene via the Single-Electron-Transfer (SET) Process and Formal 1,4-Addition

Article abstract of DOI:10.1021/acs.orglett.6b03792

A carbene-catalyzed reductive 1,4-addition of nitrobenzyl bromides to nitroalkenes is disclosed. The reaction proceeds via a carbene-enabled single-electron-transfer process that generates radicals as key intermediates. The present study expands the potentials of carbene catalysis and offers unusual transformations for common substrates in organic synthesis.

Full text of DOI:10.1021/acs.orglett.6b03792

Letter
pubs.acs.org/OrgLett
Carbene-Catalyzed Reductive Coupling of Nitrobenzyl Bromide and
Nitroalkene via the Single-Electron-Transfer (SET) Process and
Formal 1,4-Addition
Yuhuang Wang,† Yu Du,† Xuan Huang,† Xingxing Wu,† Yuexia Zhang,† Song Yang,‡
and Yonggui Robin Chi*,†,‡
†Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
‡Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural
Bioengineering, Ministry of Education, Guizhou University, Huaxi District, Guiyang 550025, China
S
* Supporting Information
ABSTRACT: A carbene-catalyzed reductive 1,4-addition of nitrobenzyl
bromides to nitroalkenes is disclosed. The reaction proceeds via a carbene-
enabled single-electron-transfer process that generates radicals as key
intermediates. The present study expands the potentials of carbene catalysis
and offers unusual transformations for common substrates in organic synthesis.
ingle-electron-transfer (SET) radical activations provide
NHC-mediated benzoin reactions.6 Our laboratory reported
Sunique opportunities for unusual transformations not readily NHC-mediated reductive self-coupling of nitroalkenes, in which
key radical intermediates were verified via EPR (electron
paramagnetic resonance) experiments.7 Rovis8 and our labo-
ratory9 independently reported homoenolate-derived radical
intermediates for the NHC-mediated β-carbon functionalization
of enals. Very recently, we have realized carbene-mediated
generation of radical intermediates from nitro-benzyl bromides
for formal 1,2-addition to activated ketones.10
Here we report formal 1,4-addition of nitro-benzyl bromide
(1a) to nitroalkene (2a) via NHC-mediated SET as a key process
(Scheme 1b). Aldehyde (3) is used as a reductant that transfers
one electron to the nitro-benzyl bromide substrate (via a Breslow
adduct formed between 3 and NHC catalyst) to eventually form
a nitrobenzyl radical as a key intermediate. The reductive 1,4-
addition product (4a) constitutes a formal polarity inversion11
for the benzylic carbon of 1a, in which the initially electrophilic
benzylic carbon is catalytically converted to a nucleophilic
reactive carbon.
Key results of condition optimization using nitrobenzyl
bromide 1a and nitroalkene 2a as the model substrates are
summarized in Table 1. With aryl aldehyde 3 as a formal
reductant and CH3OH as a reagent and solvent, triazolium NHC
catalyst C112 was found to mediate the formation of the 1,4-
reductive coupling product 4a in 81% yield (entry 1).13 The N-
pentafluorobenzyl (C6F5) substituent in catalyst C1 was
important for this reaction, as the use of the corresponding N-
mesityl or N-phenyl NHC catalysts led to much poorer yields of
4a (see Supporting Information (SI)). A few N-C6F5 substituted
triazolium NHC catalysts that could mediate this reaction to give
4a with 21%−69% yields are shown in entries 2−4. Evaluating
accessible from conventional electron-pair reactions (e.g.,
reactions between nucleophiles and electrophiles).1,2 In recent
years, N-heterocyclic-carbenes (NHCs) as organic catalysts have
received considerable attention in synthetic chemistry.3 It is also
known that the oxidative decarboxylation of pyruvate to form
acetyl-CoA in living systems is mediated by thiamine
pyrophosphate (TPP/Vitamin B1) with carbene as the active
catalytic site.4 This biological reaction catalyzed by Vitamin B1
involves both electron-pair-transfer and SET processes. It is
therefore reasonable to expect that in synthetic chemistry, NHCs
shall be able to mediate a large set of transformations that include
SET radical reactions. Somewhat unfortunately, to date most of
the reactions mediated by NHCs are developed based on
electron-pair transfers as the key processes (Scheme 1a).3 NHC-
mediated SET radical reactions are much less developed. In this
challenging direction, Studer’s oxidation of aldehydes to esters by
using TEMPO as an oxidant is believed to go through a SET
process.5 Recent mechanistic studies from Rehbein suggest that
both radical and electron-pair-transfer pathways operate in the
Scheme 1. NHC-Catalyzed 1,4-Addition via SET Process
Received: December 20, 2016
© XXXX American Chemical Society
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a b c
, ,
Table 1. Condition Optimization
Scheme 2. Examples of Nitrobenzyl Bromides
a
entry
NHC, mol %
base
solvent (mL)
yield (%)
1
2
3
4
5
6
C1, 10
C2, 10
C3, 10
C4, 10
C1, 10
C1, 10
C1, 10
C1, 10
C1, 5
DIEA
DIEA
DIEA
DIEA
K2CO3
DBU
CH3OH (1)
CH3OH (1)
CH3OH (1)
CH3OH (1)
CH3OH (1)
CH3OH (1)
toluene (1)
CH3OH (2)
CH3OH (2)
CH3OH (2)
81
21
55
69
53
68
76
91
c
7
DIEA
DIEA
DIEA
DIEA
DIEA
8
b
9
92(87)
10
11
C1, 1
63
no NHC
CH3OH (2)
no reaction
a
1
Yield (based on 2a) was estimated via H NMR analysis using 1,3,5-
a
b
Reaction conditions same as those in Table 1, entry 9. Isolated yield.
b
trimethoxybenzene as an internal standard. Isolated yield in
parentheses. 10 equiv CH3OH was used.
c
1
For 4c, 4e−4j, 4m, dr between 1.1:1 and 1.2:1, determined via H
c
NMR.
a b
,
Scheme 3. Examples of Nitroalkenes
the effects of bases showed that DIEA was an optimal choice
(entries 1, 5, 6; see SI). Toluene could also be used as a solvent
(entry 7). We then found that the reaction yield could be
improved when the reaction concentration was reduced (entry
8). The loading of the NHC catalyst could be reduced to 5 mol %,
affording product 4a in 87% yield (entry 9). The use of 1 mol %
NHC catalyst could still afford 4a in 61% yield (entry 10). The
NHC catalyst was required to enable the SET process for the
reaction to proceed, as no product (4a) could be obtained when
NHC was absent (entry 11).
With acceptable conditions in hand, we next evaluated the
generality of this reaction. We first studied the scope of the
nitrobenzyl bromides by using nitro-styrene 2a as a model
substrate (Scheme 2). para-Nitrobenzyl bromide with two
substituents on the benzylic carbon worked very effectively,
giving the corresponding 1,4-addition products (4a−d) in 76−
87% yields. Nitrobenzyl bromide with one substituent on the
benzylic carbon was then studied (4e−j). The substituent could
be alkyl (4e, f), aryl (4g), and allyl (4h) units. The carboxylic
ester group (e.g., 4j) could also be tolerated. The simplest p-
nitrobenzyl bromide reacted as well, leading to 4k in 53% yield.
The nitro group could be placed on the ortho-position of the
benzyl ring (4l, m) without affecting the reaction outcomes. The
relatively low yields for 4k and 4l are likely due to the relatively
low stability of benzyl radicals bearing no substituents on the
benzylic carbon.14
We then evaluated the scope of the nitroalkenes by using 1a as
a model nitrobenzyl bromide substrate (Scheme 3). By placing
various substituents on the 4-position of the phenyl ring of the
nitrostyrene, increasing the amount of 1a and aldehyde 3 from
1.5 to 2.0 equiv was necessary for complete conversion of the
nitroalkene substrates (6f−g). The presence of an unprotected
alcohol in the substrate did not affect the reaction yield (6h).
Installing various substituents at the meta- or ortho-positions on
the phenyl ring of the nitrostyrene substrates led to desired
a
b
c
Reaction condition as in Table 1, entry 9. Isolated yield. 0.2 mmol
of 1a, 0.2 mmol of 3 were used.
products with satisfactory yields as well (6i−o); substrates with
ortho-unsaturated substituents did not give any cyclization
products (6m−o). Finally, the phenyl ring of 2a could be
replaced with naphthyl or heteroaryl groups (6p−b). The use of
β-alkyl nitroalkene substrates examined in our studies did not
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Scheme 4. Proposed Reaction Pathways
lead to desired products. In these cases, the nitrobenzyl bromides
were reduced, and the nitroalkene largely remained unchanged.
The plausible pathways leading to the formation of the formal
1,4-addition product were illustrated in Scheme 4. Reduction of
nitrobenzyl bromide 1a by Breslow intermediate A leads to
radical cation intermediate B and benzyl bromide-derived radical
anion intermediate C. The release of a Br− from radical anion C
leads to benzylic radical intermediate D. In one possible pathway
(possible pathway #1), 1,4-addition of the benzylic radical (D) to
nitroalkene 2a leads to radical intermediate E. Similar 1,4-
addition of a carbon-centered radical to a Michael acceptor is a
known process.15 This radical intermediate (E) undergoes one
further SET reduction to form anion intermediate F. Protonation
of F leads to final product 4a. During this SET redox process (E
to F), the Breslow intermediate-derived radical cation inter-
mediate B is further oxidized to azolium ester intermediate G that
is then trapped by CH3OH to form ester 5. Alternatively
(possible pathway #2), the benzylic radical intermediate D may
be further reduced to the corresponding benzylic anion
intermediate H. A nucleophilic addition (electron-pair reaction)
of H to nitroalkene 2a furnishes intermediate F that is then
converted to 4a after protonation.
Scheme 5. Control Experiments for Mechanistic Insights
To further understand the reaction pathways, we performed
multiple experiments (Scheme 5). The nitro (NO2) group on the
benzyl bromide is required for the NHC-mediated generation of
radical intermediates (C and D, Scheme 4), as replacing the NO2
group with other electron-withdrawing units (such as Br, CF3,
COOMe, 7a−c) led to no formation of the corresponding
reductive coupling product 8 (Scheme 5a). Placing the nitro
group on the meta-position of the benzyl bromide also led to no
reaction (7d). Replacing the bromide (Br) with other leaving
groups (such as Cl, OTs, 9a−b) led to an identical product with
similar yields (Scheme 5b), suggesting that the leaving group (Br,
Cl, or OTs) has little influence on the SETprocess that transfers
one electron from Breslow intermediate A (e.g., to 1a) to form
the radical anion intermediate (e.g., C). Similar leaving groups
have been used in the electrochemical process for benzylic radical
formations.16 In our earlier studies of NHC-mediated self-
couplings of nitroalkenes,7 the formation of a nitroalkene-
derived radical anion initiates the subsequent coupling reactions.
In the present work, our experiments suggest that it is not the
addition of nitroalkene-derived radical anion to nitrobenzyl
bromide that leads the formation of 4a. For example, when
dibromoethyl-4-nitrobenzene (10) was used to replace 1a as the
substrate, the corresponding reductive coupling product 12 was
not formed (Scheme 5c). These results (Scheme 5c) suggest
that, in our present catalytic reaction (Table 1), addition of a
nitroalkene-derived radical anion to nitrobenzyl bromide
unlikely occurred. Additional discussions on this mechanistic
aspect are provided in the SI.
We also performed experiments to evaluate the feasibility of
possible pathway #2 (Scheme 5). The use of 13 to react with 2a
in the presence of various bases failed to produce 4a (Scheme
5d). This observation (Scheme 5d) suggests that, under our
condition with CH3OH as the solvent, the ionic pathway
(addition of H to nitrostyrene 2a, Scheme 4, possible pathway
#2) is likely unfavorable. When 4-nitrobenzyl bromide 14a or
14b was used as the substrate, identical results were obtained
with the formation of product 15a and 15b in 32% and 18%
yields respectively (Scheme 5e). In particular, 15a derived from a
secondary carbon was formed in a higher yield than 15b that was
formed from the corresponding primary carbon. These results
(Scheme 5e) suggest that the reaction likely goes through the
radical pathway (possible pathway #1, Scheme 4), although the
ionic pathway (possible pathway #2) cannot be completely ruled
out. Moreover, there is a third possibility of direct coupling of
two radicals.17 Although we cannot completely exclude this
possibility, we feel this pathway is unlikely, because the result of
using 10 as a nitrobenzyl bromide (Scheme 5c), and in all our
reactions of reaction scope study, the nitroalkene reductive self-
coupling products7 were not observed, suggesting that a
C
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nitroalkene-derived radical anion intermediate was not formed in
significant concentration in our reactions.
The reductive coupling products from our reactions could
undergo further transformations by using simple conditions. For
example, 4a could be reduced to the corresponding diamine 16 in
96% yield (Scheme 6). Catalytic reaction product 4j−a (one
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radical intermediate as the key process. A formal 1,4-addition of
the benzylic carbon to the nitroalkene furnishes the final product.
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ASSOCIATED CONTENT
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■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03792.
Experimental procedures and spectral data for all new
compounds; crystallographic data for 4a (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: robinchi@ntu.edu.sg.
ORCID
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(13) The structure of 4a was confirmed via X-ray crystallographic
analysis (CCDC 1485928).
Yonggui Robin Chi: 0000-0003-0573-257X
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support by the Singapore National
Research Foundation (NRF-NRFI2016-06), the Ministry of
Education of Singapore (MOE2013-T2-2-003), Nanyang
Technological University (NTU, Singapore), China’s Ministry
of Education, National Key program for Basic Research (No.
2010CB 126105), Thousand Talent Plan (700059143302), and
National Natural Science Foundation of China (No. 21132003;
No. 21472028) and support by the Guizhou Province Returned
Oversea Student Science and Technology Activity Program,
Science and Technology of Guizhou Province, and Guizhou
University.
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DOI: 10.1021/acs.orglett.6b03792
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