A Visible-Light-Driven Iminyl Radical-Mediated C?C Single Bond Cleavage/Radical Addition Cascade of Oxime Esters

Article abstract of DOI:10.1002/anie.201710618

A room-temperature, visible-light-driven N-centered iminyl radical-mediated and redox-neutral C?C single bond cleavage/radical addition cascade reaction of oxime esters and unsaturated systems has been accomplished. The strategy tolerates a wide range of O-acyl oximes and unsaturated systems, such as alkenes, silyl enol ethers, alkynes, and isonitrile, enabling highly selective formation of various chemical bonds. This method thus provides an efficient approach to various diversely substituted cyano-containing alkenes, ketones, carbocycles, and heterocycles.

Full text of DOI:10.1002/anie.201710618

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Visible Light-Driven Iminyl Radical-Mediated C-C Single Bond
Cleavage/Radical Addition Cascade of Oxime Esters
Authors: Wen-Jing Xiao, Xiao-Ye Yu, Jia-Rong Chen, Peng-Zi Wang,
Meng-Nan Yang, and Dong Liang
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201710618
Angew. Chem. 10.1002/ange.201710618
Link to VoR: http://dx.doi.org/10.1002/anie.201710618
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10.1002/anie.201710618
Angewandte Chemie International Edition
COMMUNICATION
Visible Light-Driven Iminyl Radical-Mediated C-C Single Bond
Cleavage/Radical Addition Cascade of Oxime Esters
Xiao-Ye Yu, Jia-Rong Chen,* Peng-Zi Wang, Meng-Nan Yang, Dong Liang, and Wen-Jing Xiao*
Abstract: A room temperature, visible light-driven N-centered iminyl
radical-mediated and redox-neutral C-C single bond cleavage/radical
addition cascade reaction of oxime esters and unsaturated systems
has been accomplished. The strategy tolerates a wide range of
O-acyl oximes and unsaturated systems such as alkenes, silyl enol
ethers, alkynes, and isonitrile, enabling highly selective formation of
various chemical bonds. This protocol thus provides an efficient
approach to various diversely substituted cyano-containing alkenes,
ketones, carbocycles and heterocycles.
facile assembly of structurally diverse N-containing arenes and
pyrrolines by radical cyclizations.[9] These pioneering works also
built up a powerful platform for invention of iminyl radical-initiated
cascade reactions and inert C(sp3)-H bond activation.[10] More
recently, the groups of Studer and Leonori developed a novel
photocatalytic cycle for SET oxidation of α-imino-oxy propionic
acids to form iminyl radicals, respectively, allowing for a more
broadly applicable polyfunctionalized N-heterocycle synthesis.[11]
The Zard group pioneered the use of cyclobutanone
sulfenylimines and carboxymethyl oximes as iminyl radical
precursors to trigger C-C bond cleavage using stiochiometric
radical initiators or UV irradiation.[12] Employing this method, Zard
et al. developed an elegant sequential ring opening/addition of
cyclobutanone oximes and methyl acrylate.[12c] Recently, the
groups of Uemura,[13a] Selander,[13b] Shi[8g] and Guo[13c] disclosed
Ir-, Fe-, Cu-, and Ni-catalyzed iminyl radical-mediated ring
opening of cyclobutanone oximes at elevated temperature,
respectively (Scheme 1B). Drawing inspiration from these works,
we contemplated that iminyl radicals such as those derived from
cyclobutanone oxime esters by visible light photocatalysis, might
enable cleavage of C-C single bonds under mild conditions. Such
an approach would then allow us to devise novel catalytic radical
cascade reactions for the rapid generation of molecular
complexity.[14,15] Herein, we describe how this concept was
translated into experimental reality, leading to a new iminyl
radical-mediated C-C single bond cleavage/radical addition
cascade of oxime esters and unsaturated systems (Scheme 1C).
Nitrogen-centered radicals (NCRs) have become the focus of
intense research efforts over the past few decades given their
versatile reactivity in C-N bond forming reactions and great
potential in the synthesis of nitrogen-containing compounds.[1] To
overcome the drawbacks inherent to the traditional NCR-based
radical reactions, chemists have recently developed many state
of the art methods by visible light photocatalysis.[2] Employing the
redox properties of photocatalysts, a variety of NCR species
could be formed in a controlled way under very mild conditions,
thus enabling easy construction of various C-N bonds (Scheme
1A).[3] Recently, Knowles[4a] and Rovis[4b,c] independently applied
photogenerated
amidyl
radicals
to
remote
activation/functionalization of inert C(sp3)-H bonds by a hydrogen
atom transfer process.[5] Despite these significant advances, the
exploration of photogenerated NCRs in activation/cleavage of the
inert C-C single bonds is still underdeveloped; most of the known
methods are highly dependent on transition metal catalysis and
elevated reaction temperature.[6,7] Therefore, accomplishing such
strategy would create unique opportunities to significantly
streamline the construction of versatile carbon skeletons.
A: Visible light photocatalytic generation of NCRs and reactivity modes
visible light
R1
R1
N
R2
C-N bond formation
photoredox catalysis
N
R3
C-H bond activation
Iminyl radicals are one of the most important classes of NCRs
and can be easily formed from readily available and stable oxime
derivatives via thermolysis, UV irradiation, transition metal
catalysis, or using oxidant. Because of their favorable kinetics
and synthetic potential of the imino group in products, such
radical class has been extensively explored in N-heterocycle
synthesis and hydrogen atom abstraction. [8] In this context, Yu
and Leonori first recently disclosed that O-acyl oximes and O-aryl
oximes could be conveniently transformed into the corresponding
iminyl radicals by photoredox catalyzed single electron transfer
(SET) reduction under mild reaction conditions, thus enabling
SET reduction or oxidation
R2
C-C bond cleavage
(challenging)
NCRs
B: Previous works: generation of iminyl radicals and C-C bond cleavage
LG
N
Zard (ref. 12)
n-Bu3SnH, AIBN or UV
-carbon
elimination
N
CN
R3
R3
Uemura, Selander, Shi, Guo
(ref. 8g, 13), [Ir], [Fe], [Cu], or [Ni]
R1 R2
R1 R2
R1 R2
O
Zard's work
O
CH2CN
O
N
NEt3
OMe
SPy
S
O
N
500 W tungsten lamp
77%
CO2Me
C: This work, NCR-mediated C-C single bond cleavage/radical addition cascade
C(sp3)-C(sp2)
C(sp3)-C(sp3)
OR
N
R1
R2
N
Nu
N
[*]
X.-Y. Yu , Prof. Dr. J.-R. Chen, P.-Z. Wang, M.-N. Yang, D. Liang,
Prof. Dr. W.-J. Xiao
R3
R3
R3
n
n
n
R
N=C
R1 R2
R1 R2
R1 R2
R
R
CCNU-uOttawa Joint Research Centre, Hubei International Scientific
and Technological Cooperation Base of Pesticide and Green
Synthesis, Key Laboratory of Pesticides & Chemical Biology Ministry
of Education, College of Chemistry, Central China Normal University,
152 Luoyu Road, Wuhan, Hubei 430079, China
• C-C single bond cleavage
• redox neutral, mild condtions
nitrile-containing
alkenes, ketones,
carbocycles, heterocycles
• easily accessible starting materials
• divergent synthesis of organic skeletons
E-mail: chenjiarong@mail.ccnu.edu.cn; wxiao@mail.ccnu.edu.cn
Prof. Dr. W.-J. Xiao
State Key Laboratory of Applied Organic Chemistry, Lanzhou
University, Lanzhou 730000, China
Scheme 1. Visible light-driven photocatalytic generation of NCRs and reaction
design. SET = single electron transfer. NCR = nitrogen-centered radical.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201710618
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COMMUNICATION
On the basis of our ongoing research on NCRs[14] and the
unique reactivity of oximes,[8,16] we first selected O-acyl oxime 1a
as iminyl radical precursor to trigger C-C single bond cleavage,
and 1,1-diphenyl ethylene 2a as radical acceptor (Table 1).[17]
Extensive screening of typical photocatalysts showed that use of
fac-[Ir(ppy)3] as the photocatalyst and Cs2CO3 as the base gave
rise to a clean reaction under irradiation of 7 W blue LEDs at
ambient temperature, probably owing to its superior reduction
capacity in its excited state (E1/2IV/*III= -1.73 V vs. SCE).[18] The
C(sp3)-C(sp2) coupling product, 6,6-diphenylhex-5-enenitrile 3aa,
was obtained in 81% yield (entry 1), confirming the feasibility of
our designed iminyl radical-mediated C-C single bond
cleavage/radical addition cascade. Then, a brief evaluation of the
reaction media revealed that DMF was still the best choice; other
solvents such as CH3CN, THF and CHCl3 significantly diminished
the yield (entries 2-4). Pleasingly, in the presence of Na2CO3 as
the base, the yield could be increased to 89% (entry 5); and a
91% yield of 3aa was finally obtained when the reaction was
performed at a concentration of 0.1 M (entry 6). Notably, the
base is critical to the reaction efficiency; without the base, only a
65% yield was obtained. When the model reaction was carried
out without photocatalyst or visible light irradiation, no desired
product was detected and large amounts of starting materials
remained unreacted (entries 8-9). These results confirmed that
the observed reactivity can be attributed to the visible light-driven
photocatalytic activation. The reaction still proceeded smoothly
with comparable results, even when using sunlight as the light
source. Notably, we also found that acyl moiety on the oxime was
essential for the reaction with p-trifluoromethylbenzoate 1a being
superior to its analogs (Scheme S1).[17]
3ga-3ia in 60-70% yields. In addition, both oxetan-3-one and
1-Cbz-3-azetidinone derived O-acyl oximes 1j and 1k
participated in the reaction very well to deliver products 3ja and
3ka with high yields. As demonstrated in the cases of
nonsymmetrical cyclobutanone derived acyl oximes 1l-1n with
methyl, allyl and benzyl groups at the 2-position, our mild
photocatalytic system also demonstrated good reaction
efficiency, and allowed the C-C single bond cleavage to occur
exclusively at the more hindered position, furnishing the products
3la-3na in 61-76% yields. Once again, the reaction of
benzocyclobutenone-derived substrate 1o proved to be suitable
for the reaction with 3oa being formed as the sole product in 82%
yield. Notably, the scalability of this protocol was demonstrated
by a 5.98 mmol (1.54 g) reaction of 1a to react with 2a, which
also proceeded smoothly to give product 3aa in 82% yield (1.2
g).[17] In contrast to transition metal-catalyzed ring opening of
cyclobutanone oximes,[13] a range of less-strained O-acyl oximes
1p-1s
derived
from
camphor,
cyclopentanone,
and
cyclohexanone could participate in this reaction very well to give
the desired products 3pa-3sa in 45-70% yields. These results
demonstrated the advantages of this protocol. Notably, all of
these O-acyl oximes can be readily prepared from commercially
available cyclic ketones or alkenes by routine manipulation
according to the literature procedure.[12,13,19]
Table 2: Scope of the O-acyl oximes.[a,b]
Table 1: Optimization of the reaction conditions.[a]
Entry
Base
Solvent
Conc.
Yield [%][b]
1
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
Na2CO3
-
DMF
CH3CN
THF
(0.05 M)
(0.05 M)
(0.05 M)
(0.05 M)
(0.05 M)
(0.10 M)
(0.10 M)
(0.10 M)
(0.10 M)
81
73
15
10
89
91
65
0
2
3
4
CHCl3
DMF
DMF
DMF
DMF
DMF
5
6
7[c]
8[d]
9[e]
Na2CO3
Na2CO3
0
[a] Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), fac-Ir(ppy)3 (2 mol%),
base (0.2 mmol), solvent, 7 W blue LEDs, at room temperature. [b] Isolated
yield after flash chromatography. [c] Without base. [d] Without photocatalyst. [e]
Without visible light irradiation. ppy
N,N-dimethylformamide.
=
2-phenylpyridine. DMF
=
With the optimal conditions established, we first evaluated the
substrate scope by the reaction between range of
a
[a] Reaction conditions: 1 (0.3 mmol), 2a (0.45 mmol), fac-Ir(ppy)3 (2 mol%),
Na2CO3 (0.60 mmol), and DMF (3.0 mL) at rt for 12 h under irradiation of 7 W
blue LEDs. [b] Isolated yields after flash chromatography. [c] Gram-scale
reaction: 1a (1.54 g, 5.98 mmol), 2a (1.62 g, 9.0 mmol), fac-Ir(ppy)3 (1 mol%),
Na2CO3 (1.27 g, 12 mmol), and DMF (60 mL) at rt for 12 h under irradiation of 7
W blue LEDs.
representative O-acyl oximes 1 and 2a on 0.3 mmol scale (Table
2). In addition to 1a, symmetric monosubstituted O-acyl oximes
1b-1f bearing various functional groups such as ester, cyano,
ether, protected amine and phenyl substituents at the 3-position
were well tolerated to afford the expected products 3ba-3fa in
62-80% yields. Moreover, the reactions of disubstituted
substrates 1g-1h also proceeded smoothly to give products
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COMMUNICATION
Isolated yields after flash chromatography. [c] Performed at -10 oC. [d]
Determined by 1H NMR analysis of the crude mixture.
Encouraged by these results, we continued to investigate the
substrate generality with a range of 1,1-disubstituted alkenes
under the standard conditions. As highlighted in Table 3, the
substitution patterns and electronic characteristics of the
1,1-disubstituted alkenes have no obvious effect on the reaction.
For example, a set of alkenes 2b-2d with electron-donating (Me,
NMe2) or electron-withdrawing (F) groups at the para-position of
the phenyl ring reacted nicely with 1a, furnishing the desired
products 3ab-3ad with yields ranging from 70% to 90% (Table
3a). Interestingly, the reactions with α-methyl styrenes 2d-2g and
α-methyl 2-vinylnaphthalene 2h proceeded smoothly to deliver
terminal alkenes 3ae-3ah as the major products with 52-60%
yields, most of which can be easily separated from their minor
linear isomers by column chromatography (Table 3b).
Biologically important coumarin 2i bearing electron-poor alkene
moiety could also react well with 1a to give product 3ai in 52%
yield. To our delight, a wide range of readily accessible silyl enol
ethers could also be utilized as coupling partners. Under the
standard conditions, a variety of α-aryl and α-heteroaryl silyl enol
ethers 4a-4e with electron-rich or electron-poor groups on the
phenyl ring all reacted well, allowing high-yielding introduction of
synthetically important ketone moiety into the final nitrile
products 5aa-5ea (Table 3c). Notably, the sterically encumbered
α,β-unsaturated cyclic ketone-derived silyl enol ether 4f also
readily participated in the reaction to form product 5af in 70%
yield.
Though the alkyl radicals formed after C-C bond cleavage
are nucleophilic, their addition to the styrenes and silyl enol
ethers should be facilitated by the subsequent SET oxidation of
the resultant benzylic radical intermediates.[13] However,
attempts to couple simple styrenes with O-acyl oxime 1a failed to
give the expected products, probably because of the high
reactivity of the resultant benzylic radical intermediate.[17]
To further explore the potential of our protocol, we attempted
to apply this photocatalytic system to series of aryl alkynes that
are easily accessible and robust feedstocks (Table 4).
Surprisingly, phenylacetylene derivatives 7a-7b reacted with
3-phenyl or 2-benzyl-substituted O-acyl oximes 6a-6c through a
C-C single bond cleavage/formal radical [4+2] cycloaddition
cascade.
A range of densely functionalized carbocycles,
nitrile-containing 1,2-dihydronaphthalenes 8, were then isolated
in generally good yields (51-75%). These results also implied
that iminyl radical-mediated formation of the radical
intermediates 6-A and 6-B should be involved in these reactions.
Table 4: Scope of the alkynes.[a,b]
CN
R1
OR
R2
fac-Ir(ppy)3 (2 mol%)
Na2CO3 (2.0 equiv)
N
+
R2
7 W blue LEDs, DMF
degas, rt, 12 h
R1
or
Ar
Ph
R
CN
6
7a, R = H
Table 3: Scope of the alkenes and silyl enol ethers.[a,b]
7b, R = Br
R1 = H or Me; R2 = H or Bn
R = p-CF3C6H4CO
8
Ar
[a] 6 (0.3 mmol), 7 (0.45 mmol), fac-Ir(ppy)3 (2 mol%), Na2CO3 (0.60 mmol),
and DMF (3.0 mL) at rt for 12 h under irradiation of 7 W blue LEDs. [b] Isolated
yields after flash chromatography.
Inspired by the inherent redox property of the above reactions,
we speculated that other unsatured systems with a suitable
reactive pendant might also be employed to trap the O-acyl
oxime-derived radical species, thus enabling assembly of more
complex and biologically important heteocycles. Then, we
investigated several transformations to highlight the synthetic
potential of this methodology. For example, the O-acyl oxime 1a
derived C-radical interemediate could undergo a radical addition
and cyclization cascade reaction with 2-isocyanobiphenyl 9 to
give the valuable phenanthridine 10 in 70% yield (Scheme 2a).[20]
When employing CH3CN as the solvent, radical-mediated
cascade reactions of 1a with 11 or 13 also proceeded smoothly
to give the corresponding significant heterocycles, oxindole 12
and isobenzofuran-1-one oxime 14 in 69% and 81% yields,
[a] 1a (0.3 mmol), 2 or 4 (0.45 mmol), fac-Ir(ppy)3 (2 mol%), Na2CO3 (0.60
mmol), and DMF (3.0 mL) at rt for 12 h under irradiation of 7 W blue LEDs. [b]
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10.1002/anie.201710618
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respectively (Scheme 2b-2c). Moreover, 1a could undergo a
facile radical cascade reaction with β,γ–unsaturated hydrazone
15 to form CN-containing dihydropyrazole 16 in moderate yield,
providing a complementary approach for pyrazoline synthesis.
Notably, all of these reactions proceeded through a redox-neutral
process without using any external oxidant. With cyano and
alkene groups as versatile handles, we selected several key
transformations to highlight the potential of product 3aa.[17]
On the other hand, we carried out a series of Stern-Volmer
quenching and electrochemical experiments with substrates 1a,
2a, and 3a, which revealed that O-acyl oxime 1a can more
effectively quenched the excited state of photocatalyst
fac-Ir(ppy)3 (Figures S1-S3).[17] It was found that the reaction
proceeded smoothly upon light irradiation, but no further
conversion was detected without the light source (Figure S2).
Moreover, we determined the quantum yield of the model
reaction of 1a and 2a to be 0.48. A value below unit suggests that
the reaction should proceed by a catalytic redox cycle rather than
by a radical chain process (Scheme S2).[17] Taking the reaction of
1a and 2a as an example, we finally proposed a plausible
mechanism as shown in Figure 1. The reaction begins with the
visible light-induced SET reduction of O-acyl oxime 1a by the
excited state photocatalyst *fac-Ir(ppy)3, generating the iminyl
+
radical 1a-A and oxidizing state fac-Ir(ppy)3 . Then, the iminyl
radical 1a-A undergoes a ring-opening by homolytic C-C single
bond cleavage to form a highly reactive cyanoalkyl radical 1a-B.
Addition of 1a-B to 1,1-diphenyl ethylene 2a produces carbon
radical 1a-C that are more stabilized and relatively less reactive.
Subsequently, the radical 1a-C was oxidized to carbocation
+
intermediate 1a-D by the oxidizing fac-Ir(ppy)3 species with
regeneration of ground-state fac-Ir(ppy)3, closing the
photocatalytic cycle. Finally, 1a-D undergoes
a
facile
base-mediated deprotonation to provide the alkene product 3aa.
Notably, as for the reactions of other unsaturated systems, such
as alkynes, 2-isocyanobiphenyl, and N-aryl acrylamide, another
radical addition would ensue after the addition step of cyanoalkyl
radical 1a-B. In the cases of benzamide 13 and β,γ–unsaturated
hydrazone 15, the corresponding carboncations were trapped by
their nucleophilic moiety to form the corresponding heterocyclic
prodcuts. It should be noted that all of these reactions proceed
through a redox-neutral process, thus avoiding using external
oxidant.
Scheme 2. Exploration of other unsaturated systems.
Scheme 3. Mechanistic studies.
To gain some insights into the mechanism, we then performed
a series of control experiments with the model substrates 1a and
2a. In the presence of 2.0 equiv of radical quenchers including
TEMPO and PhSeSePh, complete suppression of the model
reaction was observed; instead, the radical trapping products 21
and 22 were obtained in 18% and 58% yields, respectively
(Scheme 3a). These results implied that iminyl radical-mediated
C-C single bond cleavage and formation of cyanoalkyl radical
might be involved in the process.[17] In addition, subjecting of 1a
and radical clock substrate 1-(1-cyclopropylvinyl)benzene 23 to
our standard conditions afforded the normal coupling product
24a in 32% yield; meanwhile, we isolated a 30% yield of 24b,
which was formed through a cyanoalkyl-based sequential radical
addition/ring-opening/cyclization process via an intermediate
23-A (Scheme 3b).[22] Thus, this radical clock experiment also
indicated the involvement of radical intermediates in our
transformation.
Figure 1. Proposed reaction pathway.
In summary, we have developed a visible light-driven iminyl
radical-mediated C-C single bond cleavage/radical addition
cascade reaction of oxime esters and unsaturated systems. This
mild, general and redox-neutral protocol enables constructing
various C(sp3)-C(sp2) and C(sp3)-C(sp3) bonds, thus providing an
efficient approach to a wide range of diversely functionalized
cyano-containing
heterocycles.
alkenes,
ketones,
carbocycles
and
Acknowledgements
We are grateful to the NNSFC (21472058, 21472057, 21622201
and 21232003), the Science and Technology Department of
Hubei Province (2016CFA050 and 2017AH047), and the
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10.1002/anie.201710618
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COMMUNICATION
Program of Introducing Talents of Discipline to Universities of
[11] a) H. Jiang, A. Studer, Angew. Chem. Int. Ed. 2017, 56, 12273-12276;
Angew. Chem. 2017, 129, 12441-12444; b) J. Davies, N. S. Sheikh,
D. Leonori, Angew. Chem. Int. Ed. 2017, 56, 13361–13365; Angew.
Chem. 2017, 129, 13546–13550; while our work was under revision,
Leonori et al. reported that α-imino-oxy propionic acids-derived
iminyl radical could also enable C-C and C-H cleavage by a
photocatalytic reductive quenching cycle, see: c) E. M. Dauncey, S.
P. Marcillo, J. J. Douglas, N. S. Sheikh, D. Leonori, Angew. Chem.
Int. Ed. 2017, doi: 10.1002/anie.201710790.
China (111 Program, B17019) for support of this research.
Conflict of interest
The authors declare no conflict of interest.
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[13] a) T. Nishimura, T. Yoshinaka, Y. Nishiguchi, Y. Maeda, S. Uemura,
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[14] For our recent works on the NCR chemistry, see: a) X.-Q. Hu, J.-R.
Chen, Q. Wei, F.-L. Liu, Q.-H. Deng, A. M. Beauchemin, W.-J. Xiao,
Angew. Chem. Int. Ed. 2014, 53, 12163-12167; Angew. Chem. 2014,
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[15] Zhou has recently reported a photoredox iminyl radical-mediated
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[17] See the Supporting Information for more details.
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Keywords: photoredox catalysis • iminyl radicals • N-centered
radicals • nitriles • heterocycles
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10.1002/anie.201710618
Angewandte Chemie International Edition
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N-Radicals
Xiao-Ye Yu, Jia-Rong Chen,* Peng-Zi
Wang, Meng-Nan Yang, Dong Liang,
and Wen-Jing Xiao*
Page No. – Page No.
Visible Light‐Driven Iminyl Radical‐Mediated
C‐C Single Bond Cleavage/Radical Addition
Cascade of Oxime Esters
A room temperature, visible light-driven N-centered iminyl radical-mediated
and redox-neutral C-C single bond cleavage/radical addition cascade reaction
of oxime esters and unsaturated systems has been accomplished. The strategy
tolerates a wide range of O-acyl oximes and unsaturated systems such as
alkenes, silyl enol ethers, alkynes, and isonitrile, enabling highly selective
formation of various chemical bonds. This protocol thus provides an efficient
approach to various diversely substituted cyano-containing alkenes, ketones,
carbocycles and heterocycles.
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