N -heterocyclic carbene organocatalytic reductive β,β-coupling reactions of nitroalkenes via radical intermediates

Article abstract of DOI:10.1021/ol5027415

An unprecedented N-heterocyclic carbene catalytic reductive β,β-carbon coupling of α,β-nitroalkenes, by using an organic substrate to mimic the one-electron oxidation role of the pyruvate ferredoxin oxidoreductase (PFOR) in living systems, has been develo

Full text of DOI:10.1021/ol5027415

Letter
pubs.acs.org/OrgLett
N‑Heterocyclic Carbene Organocatalytic Reductive β,β-Coupling
Reactions of Nitroalkenes via Radical Intermediates
Yu Du,† Yuhuang Wang,† Xin Li,‡ Yaling Shao,† Guohui Li,*,‡ Richard D. Webster,*,†
and Yonggui Robin Chi*,†
†Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
‡State key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457
Zhongshan Rd, Dalian 116023, P. R. China
S
* Supporting Information
ABSTRACT: An unprecedented N-heterocyclic carbene catalytic reduc-
tive β,β-carbon coupling of α,β-nitroalkenes, by using an organic substrate
to mimic the one-electron oxidation role of the pyruvate ferredoxin
oxidoreductase (PFOR) in living systems, has been developed. The
reaction goes through a radical anion intermediate generated under a
catalytic redox process. For the first time, the presence of radical anion
intermediate in NHC organocatalysis is observed and clearly verified.
through SET redox processes via NHC-bound radical
intermediate similar to II as illustrated in Figure 1.6
hiamine pyrophosphate (TPP), a thiamine (vitamin B1)
Tderivative and a cofactor of enzymes, catalyzes the
oxidative decarboxylation of pyruvate to form acetyl-CoA and
CO2 in living systems.1 These oxidative catalytic reactions,
enabled by pyruvate ferredoxin oxidoreductase (PFOR), are
believed to proceed via single-electron transfer (SET)/radical
processes.2,3 In synthetic chemistry, thiamine and related
imidazolium and triazolium-based organocatalysts have been
explored for a large set of reactions such as Benzoin4 and
Stetter reactions5 via electron-pair transfer processes. However,
a direct mimicking of Nature’s radical process for reaction
development received rare success.6 Inspired by the TPP-
mediated SET process of decarboxylation, here we report the
first organocatalytic biomimetic β-carbon reductive coupling of
nitroalkenes. In this reaction, nitroalkene undergoes a one-
electron reduction process to form a reactive radical anion
intermediate, and aldehyde is used as the reducing agent. The
nitroalkene behaves as an oxidant, mimicking the role of PFOR
in the TPP-dependent living systems.
We envisioned that the carbene-mediated SET processes
could be developed for useful reactions other than the
biological oxidative decarboxylation (Figure 1a) and the
previously evaluated aldehyde to acid/ester conversions. More
specifically, we hypothesized that when an (electron-deficient)
alkene is used as a one-electron oxidant (by mimicking the role
of PFOR in the living systems), the resulting alkene-derived
radical might be modulated for interesting reactions. Nitro-
alkenes, with electron-deficient carbon−carbon double bonds,
are commonly used as Michael acceptors in nucleophilic/
electrophilic (electron pair transferring) reactions. A further
survey of the literature9 showed the feasibility of nitroalkenes
behaving as a single-electron remover in the presence of metal
reductants and under the enzymatic9c or electrochemical9g
reduction environments. We thus chose α,β-unsaturated
nitroalkenes (e.g., 2 in Figure 1b) as model substrates to
develop NHC-mediated biomimetic coupling reactions via a
SET process.
The SET enzymatic catalytic pathway that inspired our
design is illustrated in Figure 1a. Key steps of this enzymatic
reaction include two single-electron oxidation steps that
convert the Breslow intermediate (I) to a carboxylic acid
derivative. The PFOR (briefed as [Fe4S4]2+ in Figure 1a) serves
as an oxidant to remove one electron from the TPP-bound
intermediate (I and II). In small molecule organocatalysis
involving N-heterocyclic carbenes (NHCs), oxidation of
aldehydes (via Breslow intermediates similar to I) to carboxylic
acids and acid derivatives have been studied by several
groups.7,8 In particular, Studer and co-workers used TEMPO
as an oxidant to convert aldehydes to esters presumably
Briefly, an aldehyde molecule (e.g., 1) may be used as a
formal reductant to react with a NHC catalyst to generate
Breslow intermediate I (Figure 1b). Removal of one electron
from the Breslow intermediate I by nitroalkene 2 forms a
nitroalkene-derived anionic radical intermediate III. During the
formation of III, the Breslow intermediate I is oxidized to II
that then undergoes a subsequent oxidation to form NHC-
bound ester intermediate IV. The radical intermediates (III)
combine to form a β,β-reductive coupling product 3 after
Received: September 17, 2014
Published: October 24, 2014
© 2014 American Chemical Society
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a
Table 1. Condition Optimization
3a yield (%)
b
c
entry
NHC
aldehyde
dl + meso
dl
3a dr
1
A
B
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
∼5
10
17
94
13
14
85
58
75
<5
2
8
3
C
D
E
14
66
9
4
5
71:29
d
6
F
12
62
38
51
d
7
G
D
D
D
72:28
70:30
71:29
8
9
10
a
Unless otherwise noted, reactions were carried out at 0 °C using 1
(0.2 mmol), 2a (0.3 mmol), catalyst (0.02 mmol), DIEA (0.04 mmol),
1
and 2 mL of MeOH. Yields and dr were determined via H NMR
b
c
d
analysis. Isolated yields of dl-3a. dr refers to dl over meso.10 No
enantioselectivity.
the NHC catalyst. We further evaluated the effects of the
aldehyde reductant using the optimal NHC catalyst D (entries
8−10, also see the Supporting Information for more details).
Benzaldehyde 1b was less effective than the electron-deficient
aryl aldehyde 1a, leading to 3a with 58% yield. The use of
heteroaryl aldehyde 1c could afford 3a in 75% yield, and alkyl
aldehydes (such as 1d) were completely ineffective. In addition,
we observed significant differences in using different alcohols
(see the Supporting Information): the more hindered and less
acidic 2-propanol and ethanol were less effective and afforded
the reaction products in lower yields.
In these reactions, the diastereomeric ratio (dr) of product
3a is approximately 2.5:1. dl-3a is the major isomer that
dissolves well in common solvents such as MeOH or CH2Cl2.
In contrast, meso-3a is less soluble and tends to precipitate.
Similar trends were observed for other coupling products using
other β-aryl substituted nitroalkenes (Figure 2).
The scope of the β,β-reductive coupling reactions was then
examined. We first studied nitroalkenes with a β-aryl
substituent using the optimal condition developed above
(Table 1, entry 4). The use of nitroalkenes bearing an
electron-donating moiety at the para-position of the aryl
substituent led to high yields of the reductive coupling products
3b and 3c (Figure 2). Placing electron-withdrawing groups on
the β-aryl substituents was also well tolerated (3d−g), and β-
naphthyl-substituted nitroalkene worked fine as well (3h).
These reactions gave moderate values of diastereoselectivity.
Heteroaryl (e.g., furyl, thienyl) analogues also worked well,
providing products (3i−l) with high yields. Interestingly, β,β′-
disubstituted α,β-unsaturated nitroalkene could also work
Figure 1. TPP-mediated enzymatic transformation and its biomimetic
application in small molecule organocatalysis.
protonation. The NHC-bound ester intermediate IV is attacked
by a methanol molecule to form an ester, with the generation of
the NHC catalyst that can initiate another reaction cycle
(Figure 1b). The overall reaction in converting nitroalkene 2 to
the β,β-coupling product 3 is further shown as an equation in
Figure 1c.
Key results in searching for suitable NHC catalysts, proper
aldehyde reductants, and optimal reaction conditions are shown
in Table 1. Since the active catalytic component in Nature’s
TPP is a thiazolium group, we initially chose thiazolium A as a
NHC precatalyst. Nitrostyrene 2a was chosen as a model
substrate to develop the proposed coupling reactions.
Evaluation of aldehyde reductants revealed that the use of the
electron-deficient aryl aldehyde 1a could lead to an encouraging
formation of the proposed nitroalkenes β,β-coupling product
3a (Table 1, entry 1).
During this reaction, the aldehyde substrate 1a was oxidized
and trapped by methanol (used as solvent) to form the
corresponding ester, as isolated in our experiments. Further
evaluations on the NHC catalysts (entries 2−5) showed that
triazolium-based catalyst D bearing an N-C6F5 group was
effective in mediating the formation of 3a with 94% yield (entry
4). Chiral triazolium NHC catalysts F and G could also mediate
this reaction, but without any observed enantioselectivity
(entries 6−7). The lack of enantioselectivities partially supports
the formation of the coupling product 3a via a radical
intermediate (III, Figure 1b) that is not covalently bonded to
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yields. For example, in the formation of 3q (66% yield), the
competing Stetter product was formed with 20% yield (in
comparison, when aldehyde 1a was used, 3q was formed in
12% yield and the corresponding Stetter product was formed in
52% yield.).
To understand the reaction mechanism, we moved to detect
and analyze the radical intermediates proposed in our reaction.
Fortunately we detected the radical anion derived from β-
isopropyl nitroethylene 2p using EPR spectroscopy (Figure 3).
Figure 3. (Black line) EPR spectrum of the anionic radical derived
from β-isopropyl nitroethylene obtained in methanol at 22( 2) °C.
(Red line) Simulated spectrum based on hyperfine coupling constants
of 1N = 13.025 G, 1Ha = 8.775 G, 1Hb = 2.80 G, 1Hc = 6.375 G and
6H = 0.275 G, with a line width of 0.15 G.
A postulated pathway is further illustrated in Scheme 1. The
catalytically generated radical anion III underwent a 1,4-
Scheme 1. Postulated Pathway
Figure 2. Substrate scope. (a) Unless otherwise noted, yields are
isolated total yields; dr (dl over meso)11 were determined via 1H NMR
analysis. (b) Based on isolated dl and meso-3h (slight dissolves in
DMSO). (c) Yields obtained when 1a was used as the model aldehyde.
addition to a nitroalkene 2 to form intermediate V. This
intermediate (V) underwent another SET reduction process
and 2-fold protonations to furnish the nitroalkene dicoupling
product 3. The Breslow intermediate-derived radical cation II
underwent a deprotonation process and a SET oxidation step
to eventually form an acyl azolium intermediate IV that was
subsequently captured by alcohol. This proposed pathway is
consistent with an electrochemical ECE mechanism (electron
transfer-chemical reaction-electron transfer) for reductive β,β-
dimerization of activated olefins.13 Another possible pathway is
a direct radical anion combination to form the dicoupling
product, which cannot be ruled out at this moment.
In summary, we have developed the first NHC organo-
catalytic reductive β,β-coupling reaction of nitroalkenes. The
reactions proceed through a SET process mimicking Nature’s
TPP-mediated oxidative decarboxylation of pyruvates. Nitro-
alkenes, unlike their frequent use in electron-pair-transfer
reactions, participate in the reactions as one-electron acceptors.
Aldehydes act as reducing agents. This NHC-catalyzed SET
under the standard conditions to afford the reductive coupling
product 3n bearing two adjacent quaternary carbon centers. We
have tried two different nitroalkenes (e.g., 2b and 2d) together
in order to synthesize nonsymmetric coupling products but
only obtained inseparable complex mixtures.
We then evaluated nitroalkenes with β-alkyl substituents.
The conditions (e.g., with aldehyde 1a as a reductant) used for
β-aryl nitroalkenes were ineffective for the reductive coupling
product formations (Figure 2, yields given in parentheses). In
these cases (3o−r), the corresponding Stetter reaction
products12 between aldehyde and nitroalkenes (nitroalkenes
behaving as Michael acceptors) were obtained as the major
adducts. Fortunately, by using heteroaryl aldehyde 1c as the
reductant, the desired nitroalkenes reductive coupling products
(3o−r) could be obtained in moderate yields. The competing
Stetter reactions were still observed, but with much lower
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(6) Guin, J.; De Sarkar, S.; Grimme, S.; Studer, A. Angew. Chem., Int.
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procedure is expected to significantly expand the scope of
organocatalysis for new reaction developments. Detailed
mechanistic studies via experimental and computational
approaches are being pursued in our laboratories and will be
communicated in due course.
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carboxylic acids and acid derivatives, see: (a) Chow, K. Y.-K.; Bode, J.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Chem. 2011, 76, 3016−3023. (j) Zhao, J.-F.; Muck-Lichtenfeld,
̈
AUTHOR INFORMATION
Corresponding Authors
C.; Studer, A. Adv. Synth. Catal. 2013, 355, 1098−1106. (k) Delany, E.
G.; Fagan, C.-L.; Gundala, S.; Zeitler, K.; Connon, S. J. Chem.
Commun. 2013, 49, 6513−6515.
■
*E-mail: ghli@dicp.ac.cn.
*E-mail: webster@ntu.edu.sg.
*E-mail: robinchi@ntu.edu.sg.
(8) Reviews of oxidative NHC catalysis: (a) Knappke, C. E. I.;
Imami, A.; Jacobi von Wangelin, A. ChemCatChem 2012, 4, 937−941.
(b) De Sarkar, S.; Biswas, A.; Samanta, R. C.; Studer, A. Chem.Eur. J.
2013, 19, 4664−4678.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support for this work was provided by the
Singapore National Research Foundation and Nanyang
Technological University (NTU). We thank Dr. Y. Li and
Dr. R. Ganguly (NTU) for X-ray structure analysis.
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