Organocatalytic Three-Component 1,2-Cyanoalkylacylation of Alkenes via Radical Relay

Article abstract of DOI:10.1021/acs.orglett.0c03907

Here, we report an unprecedented regioselective, intermolecular 1,2-cyanoalkylacylation of feedstock alkenes with readily available oxime esters and aldehydes by N-heterocyclic carbene (NHC) organocatalysis. The crux of this success is the exquisite control over the radical relay process by an NHC organocatalyst. This protocol offers a general platform for diversity-oriented synthesis of valuable ketonitriles under mild, transition-metal-free, and redox-neutral conditions and highlights its potential in the late-stage functionalization of pharmaceutical architectures and natural products.

Full text of DOI:10.1021/acs.orglett.0c03907

pubs.acs.org/OrgLett
Letter
Organocatalytic Three-Component 1,2-Cyanoalkylacylation of
Alkenes via Radical Relay
Yu Gao, Yusheng Quan, Zhenjiang Li,* Luoyu Gao, Zhihao Zhang, Xin Zou, Rui Yan, Yuanyuan Qu,
and Kai Guo*
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ABSTRACT: Here, we report an unprecedented regioselective,
intermolecular 1,2-cyanoalkylacylation of feedstock alkenes with readily
available oxime esters and aldehydes by N-heterocyclic carbene (NHC)
organocatalysis. The crux of this success is the exquisite control over the
radical relay process by an NHC organocatalyst. This protocol offers a
general platform for diversity-oriented synthesis of valuable ketonitriles
under mild, transition-metal-free, and redox-neutral conditions and
highlights its potential in the late-stage functionalization of pharmaceutical architectures and natural products.
he direct transformation of commodity chemicals into
value-added products plays a vital role in chemical
Scheme 1. Motivation and Synthetic Strategy
T
synthesis. Multicomponent reactions, a powerful method to
accomplish this goal, enable a rapid buildup of molecular
complexity and diversity through simultaneously coupling
three or more starting materials.1 An attractive subset of these
reactions is three-component vicinal dicarbofunctionalization
of simple feedstock alkenes, which forges two consecutive
carbon−carbon (C−C) bonds across the π-systems in one pass
and would allow for a rapid influx of carbon frameworks’
complexity.2 Recently, considerable progress has been achieved
within this domain via transition-metal catalysis or metal-
laphotoredox catalysis.2−4 Radical relay in this context has
arisen as a prominent strategy to add a challenging sp3-
hybridized carbon component onto the alkene through a
single-electron transfer (SET)-mediated pathway, retarding
problematic side reactions inherent to the two-electron
character of the traditional transmetalation.5 Notwithstanding,
the types of carbon-based coupling partners are still limited
and a fully organocatalytic version of this dicarbofunctionaliza-
tion reaction remains elusive.
Owing to their unique reactivity profile, iminyl radicals have
emerged as versatile reactive intermediates with wide
applications in synthetic organic chemistry.6 Stimulated by
the seminal work of Zard,7 readily available cycloketone oxime
derivatives have recently been harnessed as precursors of
iminyl radicals by reductive or oxidative SET. Such reactive
open-shell nitrogen-centered radicals are susceptible to under-
going a β-scission process,6a providing translocated carbon-
centered radicals (cyanoalkyl radicals), which can further be
trapped by a portfolio of synthetically useful radical acceptors
(Scheme 1A). Following this line, a range of impressive
transformations have been developed to install valuable
cyanoalkyl components onto structurally diverse mole-
cules.6d,8−10 Most of these dedicated efforts, however, were
somewhat limited to the two-component mode, enabling the
formation of one single C−C or C−heteroatom linkage
Received: November 25, 2020
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© XXXX American Chemical Society
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A

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a
(Scheme 1A). In contrast, three-component intermolecular
cyanoalkylcarbofunctionalization of alkenes, which would
efficiently forge two C−C bonds and rapidly achieve high
levels of molecular complexity, remains challenging and more
underdeveloped. One prominent challenge is an unwanted
competitive two-component reaction. Recently, elegant works
from the group of Xiao and Chen revealed the viability of 1,2-
cyanoalkylaryllation11 and 1,2-cyanoalkylalkynylation12 of
alkenes through a photoinduced, copper-catalyzed radical
relay (Scheme 1B). Nevertheless, vicinal cyanoalkylacylation
of alkenes, to the best of our knowledge, is still unexplored to
date. Given the ubiquity and paramount importance of
carbonyl group in almost every facet of chemical science,13
as well as the prevalence of cyanoalkyl moieties in many
natural products and pharmaceuticals,14 an efficient and
modular method for 1,2-cyanoalkylacylation of alkenes would
be highly desirable.
Enlightened by recent striking radical transformations
mediated by N-heterocyclic carbene (NHC),15−17 we envi-
sioned that the merging of iminyl radical chemistry with NHC
organocatalysis might provide a new opportunity for
accomplishment of vicinal cyanoalkylacylation of alkenes with
widely available aldehydes. In this regard, we became intrigued
by the reducing enolate form of Breslow intermediate, which
can form a persistent radical intermediate through single-
electron oxidation as reported in the pioneering studies of
Fukuzumi group (Scheme 1C).18 Building on this knowledge,
recently, the Ohmiya group used redox-active carboxylic esters
as SET oxidants to fulfill the 1,2-alkylacylation of alkenes via
NHC-catalyzed radical relay.19 Prompted by this elegant study,
fluoroalkyl reagents20 and Katritzky pyridinium salts21 were
subsequently identified as viable SET oxidants by other groups.
Despite these venerable advances, in contrast to NHC-enabled
electron-pair-transfer reactions,22 the realm of NHC catalyzed
radical transformations is still in its infancy,15b especially with
respect to vicinal alkene dicarbofunctionalization. Herein, we
report an unprecedented protocol for the intermolecular
radical 1,2-cyanoalkylacylation of alkenes with oxime esters
and aldehydes through NHC organocatalysis in a completely
regioselective fashion (Scheme 1D). This modular method
grants a rapid, flexible access to densely functionalized versatile
ketonitrile architectures under mild, transition-metal-free, and
redox-neutral conditions.
Our investigations commenced by reacting O-(tert-butox-
ycarbonyl) oxime 1a with styrene 2a and 4-chlorobenzalde-
hyde 3a in the presence of the NHC catalyst. An abbreviated
outline of optimization studies is provided in Table 1. In its
optimal manifestation, a 79% yield of the three-component
coupling product, ζ-keto nitrile 4aaa, was obtained from 1a
(0.15 mmol), 2a (0.2 mmol), and 3a (0.1 mmol) using 1.5
equiv of Cs2CO3 in concert with the N-2,6-diisopropylphenyl-
substituted cycloheptane-fused thiazolium precatalyst C1 (10
mol %) in DCM at 60 °C (entry 1). The acyl and γ-cyanoalkyl
fragments were incorporated into the α and β positions of
styrene, respectively, in an exclusively regioselective fashion. A
small quantity of the byproduct 5aa was observed due to the
competitive two-component cross-coupling of 1a and 3a.
The screening of NHC catalysts unveiled that both the
backbone and the N-substituent of the NHC precursors were
essential for the reaction efficiency (Table 1, entries 2−4). The
reaction saw an obvious decrease in yield when conducted
using NHC precursors possessing a cyclohexane or dimethyl
backbone or a smaller N-mesityl group. Switching the R group
Table 1. Optimization of the Reaction Conditions
yield
(4aaa, %)
yield
b
b
entry deviation from standard conditions
(5aa, %)
1
2
3
4
5
none
79
56
55
45
64
14
10
11
15
18
C2 instead of C1
C3 instead of C1
C4 instead of C1
1a′ (R = 4-CF3C6H4CO) instead of
1a
6
7
1a′′ (R = C6F5CO) instead of 1a
using Li2CO3, Na2CO3, K2CO3, or
K3PO4
40
<15
15
<5
8
9
DBU instead of Cs2CO3
NEt3 instead of Cs2CO3
NMM instead of Cs2CO3
using pyridine or 2,6-lutidine
1.0 equiv of Cs2CO3
ratio of 1a:2a:3a = 2:2:1
ratio of 1a:2a:3a = 1.2:2:1
ratio of 1a:2a:3a = 1.5:1.5:1
no NHC catalyst
10
32
10
0
48
56
62
42
0
0
9
0
10
11
12
13
14
15
16
17
0
10
18
14
18
0
no base
0
0
a
Reaction conditions: 1a (0.15 mmol), 2a (0.2 mmol), 3a (0.1
mmol), C1 (10 mol %), and Cs2CO3 (0.15 mmol) in DCM (1.0 mL)
at 60 °C for 12 h under Ar. Yield determined by H NMR analysis
using 1,3,5-trimethoxybenzene as an internal standard. Boc = tert-
butyloxycarbonyl, DBU = 1,8-diazabicyclo[5.4.0]-7-undecene. NMM
= N-methylmorpholine.
b
1
of O-acyl oxime from Boc to 4-(trifluoromethyl)benzoyl or
perfluorobenzoyl rendered an erosion in the reactivity (entries
5 and 6). The specific identity of the base proved critical
(entries 7−11), as did the choice of the solvent system (see the
Supporting Information for details). Attempts to reduce the
equivalent of Cs2CO3 employed led to lower yields (entry 12).
Further refinement of the molar ratio of 1a and 2a to 3a did
not boost the product yield (entries 13−15). As speculated,
control studies confirmed that the NHC catalyst and base were
indispensable to this vicinal alkene dicarbofunctionalization
reaction (entries 16 and 17).
With an optimized set of conditions established, the scope of
this NHC organocatalytic three-component cyanoalkylacyla-
tion of alkenes was then explored (Scheme 2). The initial focus
was on evaluating alkene diversity. Aside from 2a, vinyl arenes
bearing either electron-withdrawing or -donating substituents
on the phenyl ring could all engage in this dicarbofunction-
alization reaction and furnish the desired ζ-keto nitriles in
moderate to good yields (4aba−4aga). Chloro-substituents at
the meta- and ortho-position of styrene were well tolerated
under the standard conditions (4afa and 4aga). Naphthyl-,
thiophene-, and pyridine-substituted olefins also proved to be
competent coupling partners (2h−2k) for the facile assembly
B
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Finally, the scope of cycloketone oxime esters was
assessed.24 Nonsymmetrical cyclobutanone oxime ester 1b
furnished the desired product 4bja in 75% yield, where C−C
bond cleavage occurred at the sterically more demanding site
with complete selectivity. On the other hand, the mono-
substituted, symmetrical cyclobutanone oxime esters with
functionalities including ester (1c), phenyl (1d), and
carbamate (1e) smoothly reacted, providing synthetically
useful quantities of the corresponding products (4cja, 4dja,
and 4eja). In the case of 3,3-disubstituted O-acyl oxime ester
1f bearing a Boc-protected medicinally prevalent piperidine
core, the three-component cyanoalkylacylation product 4fja
was obtained in 65% yield. However, less-strained O-acyl
oximes such as 1g derived from cyclopentanone did not
function well, giving the target product 4gaa in low yield.
The merit of this organocatalytic protocol was further
magnified by late-stage functionalization of drug derivatives
and natural products (Scheme 3). A derivative of fenofibrate 2l
Scheme 2. Scope of the NHC-Catalyzed Three-Component
Cyanoalkylacylation of Alkenes
a
Scheme 3. Late-Stage Functionalization of Drug Derivatives
a
and Natural Products
a
Standard reaction conditions: 1 (0.3 mmol), 2 (0.4 mmol), 3 (0.2
mmol), C1 (10 mol %), and Cs2CO3 (0.3 mmol) in DCM (2.0 mL)
at 60 °C for 12 h under Ar; isolated yields based on 3 are given.
b
c
d
Oxime ester 1a′ instead. Using 20 mol % C1. Diastereomeric ratio
a
e
is 2.5:1 determined by 1H NMR analysis. Diastereomeric ratio is 1:1
determined by H NMR analysis.
Conditions as Table 1, entry 1; 0.1 mmol scale; isolated yields based
b
on 3 are given. Diastereomeric ratio is 17:1 determined by 1H NMR
1
c
analysis. Diastereomeric ratio is 1:1 determined by 1H NMR analysis.
d
Using 20 mol % C1.
of ζ-keto nitriles 4aha−4aka with yields ranging from 50% to
69%. To showcase the scalability of this method, a 6.0 mmol
scale reaction of 3a was conducted, and the target product
4aaa could be furnished in 56% yield on a 1.05 g scale, albeit
with a higher catalyst loading.23 However, the present catalytic
system is nonproductive for aliphatic alkenes.
Next, the amenability toward aldehydes was examined. A
multitude of pendant functionalities in the aromatic aldehydes,
encompassing halides (4aac and 4aah), nitro group (4aad),
ester (4aae), and ether (4aag), were left unscathed. Electronic
effects can be observed for para-substituted aromatic aldehydes
(4aad vs 4aag). 2-Naphthaldehyde featuring an aromatic fused
ring can also be enlisted (4aai). Furthermore, heteroaromatic
rings such as thiophene and benzofuran were tolerated in the
dicarbofunctionalization process, as exemplified by 4aaj and
4aak. Unfortunately, attempts to leverage aliphatic aldehydes
as acyl donors were met with failure.
bearing a pendent alkene was amenable to cyanoalkylacylation
under the standard reaction conditions, affording the drug-like
compound 4alj in good yield. A vinylarene installed on the
skeleton of a well-known nonsteroidal anti-inflammatory drug,
indomethacin, reacted smoothly with oxime ester 1a and
aldehyde 3j to give the target product 4amj in useful yield.
Beyond these drug-like molecules, derivatives of estrone 2n,
carbohydrate 2o, and peptide 2p bearing functionalities such as
ketone, ester, acetal, and amide were also apt to furnish good
yields of the cyanoalkylacylated products (4ana, 4aoa, and
4apa), which would be otherwise difficult to prepare by other
methods. As such, this modular approach shows promise in
accelerating drug discovery.
To shed light on the putative reaction pathway, several
mechanistic experiments were conducted (Scheme 4). In the
C
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C−C single bond cleavage generates the translocated
cyanoalkyl radical B, which can further add onto alkene 2 to
render the secondary radical C. In the next step, the resultant
radical C undergoes radical−radical cross-coupling with the
persistent ketyl radical III,19,20a,25 giving the species IV (path
a). Finally, the intermediate IV would engage in facile
elimination to furnish the desired ketonitrile product 4 and
regenerate the NHC, thereby completing this organocatalytic
cycle. On the other hand, radical C might undergo addition to
the enolate form of the Breslow intermediate II to form
another possible NHC-bound radical intermediate V. Then,
SET from intermediate V to 1a produces intermediate IV and
a new radical A, respectively (path b).26
Scheme 4. Mechanistic Investigations
In conclusion, we have developed an intermolecular, three-
component 1,2-cyanoalkylacylation of alkenes with easily
accessible oxime esters and aldehydes enabled by NHC
organocatalysis. This emerging modular protocol enjoys mild,
redox-neutral, and transition-metal-free conditions, exhibits
broad compatibility of substrate scope and functional groups,
and highlights its potential in the late-stage diversification of
pharmaceutical architectures and natural products. The NHC
organocatalyst gives exquisite control over the radical relay
pathway involving reductive generation of iminyl radicals/
radical transposition by C−C bond cleavage/radical addition/
radical−radical cross-coupling sequence, thus enabling regio-
selective formation of C(sp3)−C(sp3) and C(sp3)−C(sp2)
bonds in a single step. This work not only offers a general
method for the efficient and flexible assembly of diversely
functionalized valuable ketonitriles from simple building blocks
but also expands the repertoire of NHC catalyzed radical-
mediated alkene dicarbofunctionalization.
presence of 2.0 equiv of radical traps TEMPO or PhSeSePh,
the standard reaction of 1a, 2a, and 3a was completely
inhibited (Scheme 4A). Notably, the radical-trapping product
PhSe-(CH2)3CN (5) was isolated in 83% yield. This is
indicative of the intermediacy of a cyanoalkyl radical in this
transformation. Furthermore, the radical clock reaction with
vinyl cyclopropane 6 under the standard conditions furnished
the rearranged coupling product 7 in 48% yield, which is in
agreement with a radical relay pathway (Scheme 4B).
Based on the experimental results aforementioned, a
mechanistic rationale for this 1,2-cyanoalkylacylation of
alkenes via NHC organocatalyzed radical relay is outlined in
Scheme 5. Initially, NHC combines with the aldehyde 3 to
ASSOCIATED CONTENT
■
sı
* Supporting Information
Scheme 5. Proposed Catalytic Cycle for the NHC-Catalyzed
Cyanoalkylacylation of Alkenes
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03907.
Experimental details and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Zhenjiang Li − College of Biotechnology and Pharmaceutical
Engineering and State Key Laboratory of Materials-Oriented
Chemical Engineering, Nanjing Tech University, Nanjing
211816, P. R. China; orcid.org/0000-0002-1100-7297;
Email: zjli@njtech.edu.cn
Kai Guo − College of Biotechnology and Pharmaceutical
Engineering and State Key Laboratory of Materials-Oriented
Chemical Engineering, Nanjing Tech University, Nanjing
211816, P. R. China; orcid.org/0000-0002-0013-3263;
Email: guok@njtech.edu.cn
Authors
Yu Gao − College of Biotechnology and Pharmaceutical
Engineering, Nanjing Tech University, Nanjing 211816, P. R.
China
Yusheng Quan − College of Biotechnology and Pharmaceutical
Engineering, Nanjing Tech University, Nanjing 211816, P. R.
China
Luoyu Gao − College of Biotechnology and Pharmaceutical
Engineering, Nanjing Tech University, Nanjing 211816, P. R.
China
afford a neutral Breslow intermediate I. Then, the enolate form
of the Breslow intermediate II, produced by deprotonation,
would act as a competent single-electron reductant and
undergo facile SET with cyclobutanone oxime ester 1a. This
process results in the formation of a persistent aldehyde-
derived ketyl radical III and a cyclic iminyl radical A,
respectively. Subsequent fast ring opening of A via homolytic
D
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S.; Khanal, N.; Basnet, P.; Lebrun, R. W.; Giri, R. Ni-Catalyzed
Regioselective Alkylarylation of Vinylarenes via C(sp3)−C(sp3)/
C(sp3)−C(sp2) Bond Formation and Mechanistic Studies. J. Am.
Chem. Soc. 2018, 140, 9801−9805. (g) Zhao, X.; Tu, H.-Y.; Guo, L.;
Zhu, S.; Qing, F.-L.; Chu, L. Intermolecular selective carboacylation
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Zhihao Zhang − College of Biotechnology and Pharmaceutical
Engineering, Nanjing Tech University, Nanjing 211816, P. R.
China
Xin Zou − College of Biotechnology and Pharmaceutical
Engineering, Nanjing Tech University, Nanjing 211816, P. R.
China
Rui Yan − College of Biotechnology and Pharmaceutical
Engineering, Nanjing Tech University, Nanjing 211816, P. R.
China
Yuanyuan Qu − College of Biotechnology and Pharmaceutical
Engineering, Nanjing Tech University, Nanjing 211816, P. R.
China
́
(j) Shu, W.; García-Domínguez, A.; Quiros, M. T.; Mondal, R.;
́
Cardenas, D. J.; Nevado, C. Ni-Catalyzed Reductive Dicarbofunction-
Complete contact information is available at:
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alization of Nonactivated Alkenes: Scope and Mechanistic Insights. J.
Am. Chem. Soc. 2019, 141, 13812−13821. (k) KC, S.; Dhungana, R.
K.; Khanal, N.; Giri, R. Nickel-Catalyzed α-Carbonylalkylarylation of
Vinylarenes: Expedient Access to γ,γ-Diarylcarbonyl and Aryltetralone
Derivatives. Angew. Chem., Int. Ed. 2020, 59, 8047−8051. (l) Tu, H.-
Y.; Wang, F.; Huo, L.; Li, Y.; Zhu, S.; Zhao, X.; Li, H.; Qing, F.-L.;
Chu, L. Enantioselective Three-Component Fluoroalkylarylation of
Unactivated Olefins through Nickel-Catalyzed Cross-Electrophile
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The support of this work by the National Natural Science
Foundation of China (U1463201 and 21522604), the National
Key Research and Development Program of China
(2017YFC1104802), the Natural Science Foundation of
Jiangsu Province, China (BK20150031), the Jiangsu National
Synergetic Innovation Center for Advanced Materials
(SICAM), the Priority Academic Program Development of
Jiangsu Higher Education Institutions (PAPD), and the Top-
Notch Academic Programs Project of Jiangsu Higher
Education Institutions (TAPP) is gratefully acknowledged.
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