Visible-Light-Driven N-Heterocyclic Carbene Catalyzed γ- and ?-Alkylation with Alkyl Radicals

Article abstract of DOI:10.1002/anie.201909017

The merging of photoredox catalysis and N-heterocyclic carbene (NHC) catalysis for γ- and ?-alkylation of enals with alkyl radicals was developed. The alkylation reaction of γ-oxidized enals with alkyl halides worked well for the synthesis γ-multisubstituted-α,β-unsaturated esters, including those with challenging vicinal all-carbon quaternary centers. The synthesis of ?-multisubstituted-α,β-γ,δ-diunsaturated esters by an unprecedented NHC-catalyzed ?-functionalization was also established.

Full text of DOI:10.1002/anie.201909017

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Visible-Light-Driven N-Heterocyclic Carbene-catalyzed γ- and ε-
Alkylation with Alkyl Radicals
Authors: Lei Dai, Zi-Hao Xia, Yuan-Yuan Gao, Zhong-Hua Gao, and
Song Ye
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201909017
Angew. Chem. 10.1002/ange.201909017
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10.1002/anie.201909017
Angewandte Chemie International Edition
RESEARCH ARTICLE
Visible-Light-Driven N-Heterocyclic Carbene-catalyzed - and -
Alkylation with Alkyl Radicals
Lei Dai, Zi-Hao Xia, Yuan-Yuan Gao, Zhong-Hua Gao*, and Song Ye*
Abstract: The merging of photoredox catalysis and N-heterocyclic
carbene (NHC) catalysis for - and -alkylation of enals with alkyl
radicals was developed. The alkylation reaction of -oxidized enals
with alkyl halides worked well for the synthesis -multisubstituted-
,-unsaturated esters, including those with challenging vicinal all-
carbon quaternary centers. The synthesis of -multisubstituted-,-
-diunsaturated esters via unprecedented NHC-catalyzed -
functionalization was also established.
cooperative photoredox catalysis with amine catalysis,[16]
Brønsted acid catalysis[17] are very successful. In 2012, Rovis et
al. reported the first example of NHC/photo co-catalyzed
umpolung addition of aldehydes to in situ generated iminium.[18]
In this paper, we report an NHC/photo co-catalyzed - and -
alkylation of enals with simple alkyl radicals (Scheme 1, reaction
g), which features readily available starting materials, good
functional group compatibility and construction of vicinal all-
carbon quaternary centers.
Introduction
Over the past decades, N-heterocyclic carbenes (NHCs) have
been demonstrated as powerful organocatalysts[1] for the
umpolung of aldehydes and enals via Breslow intermediate,[2]
homoenolate[3] and dienolate[4] to react with strong electrophiles
with sp2 carbon, such as active ketones and imines. However,
NHC-catalyzed reaction with weak electrophiles with sp3 carbon,
such as alkyl halides, for the construction of C(sp3)-C(sp3) is
highly challenging. Recently, the NHC-catalyzed reaction
through radical process showed great potential owing to its high
activity (Scheme 1),[5] including esterification of aldehydes via
two consecutive single electron oxidation (reaction a),[6] -
hydroxylation of enals with oxygen radical (reaction b),[7] the
homo/cross-coupling of homoenolate and its radical (reaction
c),[8] and the cross coupling of homoenolate and enolate radicals
(reaction d).[9] Sun et al. reported an elegant NHC-catalyzed -
dihalomethylenation with trichloromethyl and tribromomethyl
radicals (reaction e),[10] and Nagao and Ohmiya et al. reported
the decarboxylative alkylation of aldehydes via alkyl radicals
(reaction f).[11] These NHC-catalyzed reactions with specific
oxygen or functionalized carbon-centered radicals promoted us
to explore general NHC-catalyzed C(sp3)-C(sp3) bond formation
with simple alkyl radicals.
The visible-light-driven photoredox catalysis is very useful to
generate radical intermediates,[12] and the cooperative
photocatalysis provides unique approaches for various
invaluable chemical transformations.[13] For example, transition
metal/photo-catalyzed C(sp2)-C(sp3)[14] and C(sp3)-C(sp3)[15]
bonds formation were developed by MacMillan et al. The
Scheme 1. NHC-catalyzed reactions with radicals. NHC = N-heterocyclic
carbine, [O] = single electron oxidant, hv = visible light irradiation.
[a]
L. Dai, Z.-H. Xia, Y.-Y. Gao, Dr. Z.-H. Gao, Prof. Dr. S. Ye
Beijing National Laboratory for Molecular Sciences, CAS Key
Laboratory of Molecular Recognition and Function, CAS
Research/Education Center for Excellence in Molecular Sciences,
Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190, China.
Results and Discussion
The NHC-catalyzed model reaction of -oxidized enal 1a and
iodoacetonitrile 2a was investigated under visible light irradiation
(Table 1). Although the reaction with thioazolium preNHC 5a
gave no desired product (entry 1), we are encouraged to find
that the reaction with imidazolium preNHC 5b afforded product
3a in 12% yield with exclusive -regioselectivity (entry 2). It is
interesting that N-phenyl triazolium preNHC 5c and 5d gave no
E-mail: gaozh@iccas.ac.cn
songye@iccas.ac.cn
L. Dai, Z.-H. Xia, Y.-Y. Gao, Prof. Dr. S. Ye
[b]
University of Chinese Academy of Sciences, Beijing 100049,China
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201909017
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RESEARCH ARTICLE
or only trace product (entries 3 &4), the N-mesityl preNHCs 5e-
5g showed promising yields (entries 5-7). These data implies
that the benefit of bulky substituent of the catalyst. Thus, the
sterically hindered tetracyclic preNHC 5h[19] was tested, which
resulted in dramatically improvement of the yield (70%).
Screening of the bases revealed that inorganic bases (K2CO3
and Cs2CO3) worked better than commonly used organic bases
such as DBU, DIPEA and DABCO (entries 8-13), and the
reaction in the presence of CsOAc afforded product 3a in 86%
isolated yield with exclusive -regioselectivity (entry 14).
With the optimized conditions in hand, the scope of the
reaction was investigated (Table 2). It was found that -aryl
enals bearing electron-withdrawing and electron-donating
groups were all tolerated and gave the desired -alkylation
products 3b-3l in good yields with exclusive -regioselectivity.
The ortho-substituted (2-Me, 2-vinyl), ortho, meta-disubstituted
(2,4-dimethyl) or ortho, meta, para-trisubstituted (2,4,6-trimethyl)
aryl groups showed no significant negative effect on the reaction
(3i-3l). The reaction of the enals with -2-naphthyl gave the
corresponding product (3m) in 85% yield. Then the compatibility
of functional groups was then explored. It was found that silyl
ether (3n), primary alcohol (3o), alkenes (3h, 3j, 3p) and even
alkyne (3q) were all well tolerated to afford the desired products
in moderate to excellent yields. It is noteworthy that the reaction
of enals with additional C-C double or triple bond, which is
effective radical acceptor, occurred exclusively at the -position
of enal rather than the additional unsaturated C-C bonds.
Besides the primary cyanomethyl radical, secondary and tertiary
cyanoalkyl radicals (3r-3t) were also successfully applied for the
reaction, giving the desired -cyanoalkylation products in high
yields. Alkyl enals with various substituents (isopropyl,
cyclohexyl, allyl etc.) at the  position were also tested to give
the products 3u-3z in good yields. Additionally, the
alkoxylcarbonylmethyl and tertiary cyanoalkyl radicals (3y-3z)
went smoothly, giving the desired products in moderate yields.
Table 1: Optimization of the Reaction Conditions.a
The construction of all-carbon quaternary center (ACQC) is
very challenging in organic synthesis.[20] Although some
successful strategies for the construction of ACQCs have been
developed over the past decades, new methods with good
scope and functional group tolerance are still highly desired.[16b]
Gratifyingly, -dialkylated enals were all tolerated for the reaction,
giving the corresponding products (3aa-3ad) bearing ACQC in
good yields. The reaction with various alkyl radical precursors
(primary and secondary cyanoalkyl, ester-alkyl, benzyl radicals)
afforded the target compounds (3ae-3ak) bearing ACQC in
moderate to good yields. The catalytic construction of molecules
with vicinal ACQCs is extremely challenging in organic synthesis.
We were happy to find that the photo/NHC co-catalyzed cross
coupling of -dialkylenals and tertiary radical precursors alkyl
electrophiles worked well for the construction of vicinal ACQCs
(Table. 3). The reaction of -dialkyl enals (methyl, n-butyl, and
allyl) with tertiary cyanoalkyl radicals (methyl, cyclohexyl, and
cyclopentyl) gave the products (3al-3ap) in good yields. Various
other types of tertiary alkyl radicals derived from benzyl, esters,
and malonates worked for the reaction to give the desired
products (3aq-3as) in moderate to good yields. Interestingly, -
alkylmalonate radicals (methyl, benzyl, allyl) gave the cross
coupling products (3as-3az) in good to excellent yields. The
multifunctionalized compound 3ay, bearing a vicinal diallyl
ACQC affords many possible transformations for the access of
complex molecules in organic synthesis.
entry
preNHC
base
yield (%)b
1
5a
5b
5c
5d
5e
5f
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
DBU
0
2
12
0
3
4
trace
15
21
12
70
0
5
6
7
5g
5h
5h
5h
5h
5h
5h
5h
8
9
10
11
12
13
14
DIPEA
DABCO
K2CO3
Cs2CO3
CsOAc
0
0
37
52
86
aGeneral conditions: 1a (0.5 mmol), 2a (0.2 mmol), PC 4a (2 mol%), preNHC 5
(20 mol%), base (2.0 equiv.), MeOH (40 μl), DCE (2 mL), 32W CFL, 24h, 25
oC under nitrogen protection. bIsolated yields.
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Table 2: Reaction scopea
aAll reactions were performed on a 0.3 mmol scale. For each compound the isolated yield is given in percent. * 2a (X = I) was used, ** 2b (X = Br) was used;
Ɨdiastereomeric ratio (dr) were determined by 1H NMR spectroscopy of raw product. EWG = electron-withdrawing group; DCE = 1, 2-dichloroethane; CFL =
compact fluorescent light.
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Table 3: Construction of vicinal all-carbon quaternary centersa
a All reactions were performed on a 0.3 mmol scale. * 2a (X = I) was used, ** 2b (X = Br) was used
Table 4: NHC-catalyzed -functionalizationa
aAll reactions were performed on a 0.3 mmol scale. * 2a (X = I) was used, ** 2b (X = Br) was used.
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NHC-catalyzed
remote
functionalization
of
carbonyl
catalyst to give the corresponding multisubstituted cyclohexene
9 in 87% yield (Scheme 3b).
compounds is a challenge.[21] Our group reported the first
example of NHC-catalyzed  functionalization of acyl chloride[4a]
in 2011. Chi et al. reported the pioneering NHC-catalyzed [4c]
-
Several control experiments were carried out to clarify the
reaction mechanism (Scheme 4). The reaction in the absence of
light, photocatalyst, or NHC gave no or only trace desired
product (Scheme 4a). The reaction was totally inhibited when
the radical scavenger of 2,2,6,6-tetramethylpiperidine N-oxyl
radical (TEMPO) was added, while the radical coupling adduct
between cyanomethyl radical and TEMPO was detected by high
resolution mass spectrum (HR-MS) (Scheme 4b). The reaction
of enal 1ba and 1bb, bearing a cyclopropyl group at the 
position, with iodoacetonitrile gave the desired products 3ba and
3bb in 82% and 86% yield respectively without the formation of
ring-opening product 3ba' and 3bb', which suggests the non-
involvement of the -radical generated from enals (Scheme 4c).
and [22]-functionalization of enals or dienals. To the best of our
knowledge, there is no example for NHC-catalyzed -
functionalization.[23] To address this problem, we designed a
series of peroxidized enals bearing vinyl or 1-propenyl
substituents at the

position which may deliver -
functionalization products via trienolate intermediate (Table 4).
We were happy to find that the reaction of enal 6a bearing vinyl
substituent at the  position with iodoacetonitrile under our
optimized condition gave the desired product 7a in 56% yield
with the exclusive -selectivity. Different alkyl radical precursors
(primary, secondary and tertiary alkyl radicals) were all tolerated,
giving the corresponding products (7b-7f) in good to excellent
yields. Enal 6b bearing 1-propenyl substituents were also
investigated to give the corresponding products (7g-7j) in
moderate to good yields.
Scheme 2. Primitive results of enantioselective reaction
Promising enantioselectivities are observed when chiral
NHC precursor 5i was used as the catalyst for synthesis of chiral
3a* and 3az* with vicinal ACQCs (Scheme 2).
Scheme 4. Mechanism studies.
The plausible mechanism is depicted in Figure 1. The alkyl
radical I is generated from alkyl halide via photocatalysis, which
reacts with the dienolate intermediate[4b] II, generated from -
oxidized enals via NHC catalysis, to give homoenolate radical III.
The following single-electron transfer (SET) oxidation of
homoenolate radical III by the radical cation IV of photocatalyst
affords ,-unsaturated acyl azolium intermediate V and finishes
the photocatalytic cycle. The acyl azolium intermediate V is
trapped by methanol as the nucleophile to give the final product
-alkylated-,-unsaturated esters 3 and regenerates the NHC
catalyst.
Scheme 3. Further transformations.
The resulting product with multifunctional groups present
opportunities for many further chemical transformations. For
example, the hydrogenation of compound 3b under Pd/C
followed by selective reduction of cyano group by NiCl2/NaBH4
and lactamization gave 7-membered lactam 8 in 67% overall
yield (Scheme 3a). Compound 3ay bearing vicinal diallyl ACQCs
was subjected to ring-closed metathesis using Grubb’s II
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Figure 1. Proposed mechanism.
S. Ye conceived and directed the project. L. Dai designed and
performed most of experiments. Z.-H, Xia, Y.-Y. Gao., Z.-H. Gao
performed the experiments. All the authors analyzed the data. L.
Dai, Z.-H. Gao and S. Ye wrote the manuscript.
Conclusion
The - and -alkylation of enals with simple alkyl radicals via the
merging of photoredox and NHC catalysis was developed. The
Keywords: photocatalysis • N-heterocyclic carbene •
reaction features operational simplicity, exclusive
 or -
cooperative catalysis • remotealkylation • quaternary carbon
regioselectivity, well tolerance of functional groups and efficient
construction of challenging vicinal all carbon quaternary centers.
The combination of alkyl radical via photocatalysis and
dienolate/trienolate intermediates via NHC catalysis is the key
step for the reaction.
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Acknowledgements
We are grateful for the financial support from the Natural
Science Foundation of China (Nos 21425207, 21521002,
21672216, 21702208, 21831008), and the Chinese Academy of
Sciences is greatly acknowledged.
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RESEARCH ARTICLE
Lei Dai, Zi-Hao Xia, Yuan-Yuan Gao,
Zhong-Hua Gao*, and Song Ye*
Page No. – Page No.
Visible-Light-Driven N-Heterocyclic
Carbene-catalyzed - and -Alkylation
with Alkyl Radicals
Text for Table of Contents
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