Photoinduced, Copper-Catalyzed Radical Cross-Coupling of Cycloketone Oxime Esters, Alkenes, and Terminal Alkynes

Article abstract of DOI:10.1021/acs.orglett.9b01529

A photoinduced, copper-catalyzed three-component radical cross-coupling of cycloketone oxime esters, alkenes, and terminal alkynes is described for the first time. Key to the success of this process was the integration of photoinduced iminyl radical-mediated C-C bond cleavage with the conceptual simplicity of copper-catalyzed radical cross-coupling. This protocol provides access to cyanoalkyl-containing propargylic compounds in good yields.

Full text of DOI:10.1021/acs.orglett.9b01529

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Photoinduced, Copper-Catalyzed Radical Cross-Coupling of
Cycloketone Oxime Esters, Alkenes, and Terminal Alkynes
Jun Chen, Bin-Qing He, Peng-Zi Wang, Xiao-Ye Yu, Quan-Qing Zhao, Jia-Rong Chen,*
and Wen-Jing Xiao
CCNU-uOttawa Joint Research Centre, Key Laboratory of Pesticides & Chemical Biology Ministry of Education, College of
Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, China
S
* Supporting Information
ABSTRACT: A photoinduced, copper-catalyzed three-component
radical cross-coupling of cycloketone oxime esters, alkenes, and
terminal alkynes is described for the first time. Key to the success of
this process was the integration of photoinduced iminyl radical-
mediated C−C bond cleavage with the conceptual simplicity of
copper-catalyzed radical cross-coupling. This protocol provides
access to cyanoalkyl-containing propargylic compounds in good
yields.
n recent years, the combination of transition-metal catalysis
Zard on iminyl radical-mediated β-C−C bond cleavage of
Iand radical chemistry has been established as a robust and cyclobutanone sulfenylimine and carboxymethyl oximes,14 the
generation of cyclic iminyl radicals from cycloketone oxime
derivatives and manipulation has recently attracted extensive
research interest from the synthetic community (Scheme 1B).
The vast majority of the known methodologies falls into four
different categories according to the reaction modes of
cyanoalkyl radicals: (1) direct addition to an unsaturated
system,15 (2) cascade addition to unsaturated systems/
oxidation/addition by nucleophiles,16 (3) SET oxidation/
addition by nuleophiles,17 and (4) reductive18 or oxidative19
radical trap. Thus, a wide array of differently functionalized
valuable nitriles can be obtained. Surprisingly, application of a
cyanoalkyl radical or another carbon-centered radical formed
by its addition to alkene in the RCC reaction has been less
explored.20 Based on our continuous interest in NCR
chemistry,21 we recently disclosed that a visible-light photo-
redox catalyst or copper catalysis enabled facile conversion of
cycloketone oxime esters to iminyl radicals and their C−C
bond cleavage.20a Mechanistic studies suggested that a benzylic
radical was involved as the key intermediate formed upon
addition of a cyanoalkyl radical to styrene. Thus, we wonder if
we can develop radical cross-coupling of cycloketone oxime
esters, alkenes, and alkynes through a cross-coupling between
such a benzylic radical and in-situ-formed copper acetylide
complex (Scheme 1C). Given the synthetic and biological
significance of both nitrile and alkyne moieties, the products of
this protocol should be of great interest to chemists. As
illustrated in the proposed pathway, however, several
competitive side reactions need to be considered, such as
direct reductive HAT of radical A or its direct coupling with
alkynes, reductive HAT of radical B, its oxidation to ketone, or
powerful method toward construction of diverse C−C and C−
heteroatom bonds under mild conditions.1 In particular, such
transition-metal-catalyzed radical cross-coupling (RCC) allows
construction of ubiquitous alkyl−alkyl bonds from various
electrophiles and nucleophiles in a controlled manner that have
been the most challenging to realize using traditional cross-
coupling.2 For instance, a number of important studies of Fu
revealed that nickel catalysis enabled the use of a wide
spectrum of primary, secondary, and tertiary alkyl halides as
radical precursors, thus rendering their efficient coupling with
various carbon- and heteroatom-based nucleophiles.2,3
Building on these inspiring works, many groups devoted a
great deal of effort to develop other radical precursor types to
achieve a broader range of coupling partners and functional
group compatibility. A wide variety of redox-active aliphatic
carboxylic acids and their derivatives,4 alkylborons and
alkylsilicons,5 sulfones,6 as well as alkyl (hetero)arenes,7 and
vinyl (hetero)arenes,8−11 can be converted to the relevant alkyl
radicals via SET, HAT, or radical addition (Scheme 1A).
Subsequent capture of such radical species by a nucleophile-
derived metal complex (Nu-M) led to incorporation of diverse
nucleophilic partners at the sp3-hybridized carbon centers via
high-valent organometallic intermediates. Remarkably, several
recent works of Zhang,8 Liu,9 and Liu10 demonstrated that a
benzylic radical, formed by addition of CF3, CN, and N-
centered radicals to styrenes, could be trapped by an active
Cu(II)-nucleophile species. These three-component cross-
couplings provide useful access to 1,2-difunctionalization of
alkenes. Despite these impressive advances, the scope of
functionalized radical precursors and nucleophiles is still
limited. As a versatile class of nitrogen-centered radicals
(NCRs),12 iminyl radicals have found extensive application in
organic synthesis.13 Particularly, stimulated by the discovery of
Received: May 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01529
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Radical Cross-Coupling of Alkyl Radicals and
Reaction Development with Oxime Derivatives
Table 1. Condition Optimization
b
entry
oxime ester
[Cu] catalyst
ligand (x)
yield (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a′
1a′
1a′
1a′
1a′
CuCl
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
-
L1 (15)
L1 (15)
L2 (15)
L3 (15)
L4 (15)
L5 (15)
L3 (20)
L3 (20)
L3 (20)
L3 (20)
-
52
58
52
61
25
53
63
74 (71)
56
trace
trace
trace
c
d
9
10
11
CuI
CuI
e
12
L3 (20)
a
1a or 1a′ (0.6 mmol), 2a (0.2 mmol), 3a (0.6 mmol), copper salt
(10 mol %), ligand (x mol %), and K2CO3 (0.6 mmol, 3.0 equiv) in
DMF (2.0 mL) at 30 °C under irradiation of 7 W blue LEDs for 10 h.
b
Yields were determined by GC analysis using biphenyl as an internal
c
d
standard. Isolated yield within the parentheses. Without visible-light
irradiation, 24 h. Without base.
e
β-elimination to Heck-type product. Notably, in their recent
work on copper-catalyzed trifluoromethylalkynylation of
styrenes with trimethoxysilyl-substituted alkynes, Liu et al.
found that a simple terminal alkyne is not a suitable
substrate.9c With these points in mind, we hypothesized that
fine-tuning the rate of each intermediate generation by a
rational combination of reaction parameters would probably
allow us to solve these challenges.
improve the efficiency. The results of entries 3−7 indeed
demonstrated obvious ligand effects, and use of 4,4′-di-tert-
butyl-2,2′-bipyridine (dtbbpy) (L3) (20 mol %) gave 4a in
63% yield (entry 7). We found that structural modification of
the acyl moiety on the oxime also had remarkable effects on
the reaction. Replacement of p-trifluoromethylbenzoate in 1a
with p-methoxylbenzoate (1a′) resulted in a significant
increase of yield, with 4a isolated in 71% yield (entry 8).
Without visible-light irradiation, the yield of 4a decreased
significantly even after prolonged reaction time. In a series of
control experiments without copper, ligand, or base, no desired
product was detected, confirming the significance of these
parameters (entries 10−12). Notably, the use of a super-
stoichiometric amount of a base should facilitate the in situ
formation of the Cu(II) acetylide species prior to the radical
trapping step.23
With the optimal conditions established, we first investigated
the generality of this cross-coupling by reacting 1a′ and 3a
with a representative array of alkenes (2) (Scheme 2A).
Notably, most of them are inexpensive and commercially
available feedstock materials. For instance, the catalytic system
tolerated well a range of neutral styrene (2b) and its derivatives
(2c−h) bearing electron-donating (e.g., Ph, OMe, OAc) or
electron-withdrawing (e.g., Bpin, Br, CO2Me) substituents at
the para-position of the aromatic ring. The expected products
(4b−h) were obtained with yields ranging from 36 to 76%. To
show the scalability of this process, a gram-scale reaction of 2c
Drawing inspiration from the recent wide use of copper salts
as photocatalysts in organic synthesis,22 we first examined the
feasibility of the model reaction of cyclobutanone oxime ester
(1a), 2-vinylnaphthalene (2a), and phenylacetylene (3a) in a
ratio of 1:1.5:2 in DMF under visible-light-driven copper
catalysis conditions (Table 1).23 Despite the formation of the
desired cross-coupled product (4a), a significant amount of
side products SP-1 to SP-4 were detected. These side products
resulted from the self-coupling of substrates 1a and 3a or the
intermolecular two-component coupling among 1a, 2a, and 3a.
To our delight, when using 2a as a limiting reagent, a
combination of CuCl (10 mol %) as a catalyst and 4,4′-
dimethoxy-2,2′-bipyridine (L1) (15 mol %) as a ligand led to a
cleaner reaction system, furnishing product (4a) in 52% yield
(entry 1). A further brief screening of copper salts revealed that
CuI is superior to CuCl and increased the yield to 58% (entry
2). The suitable ligand might modulate the reactivity of the
photoexcited copper acetylide complex and thus suppress the
competitive reactions. Thus, with CuI in hand, we then
evaluated a range of ligands (L2−L4) in order to further
B
DOI: 10.1021/acs.orglett.9b01529
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a b
,
conditions. As highlighted in Scheme 3A, a representative set
of aryl alkynes having various electron-rich (tBu, Me, OMe) or
Scheme 2. Substrate Scope of the Alkenes
a b
,
Scheme 3. Substrate Scope of the Alkynes
a
b
c
Refer to footnote a of Scheme 2. Isolated yields. 1.0 mmol scale.
Determined by chiral HPLC analysis on a chiral stationary phase.
d
electron-deficient (Br) functional groups at the para-, meta-, or
ortho-position of the phenyl ring worked smoothly to afford
the corresponding products (5a−g) in 52−82% yields. The
fused aromatic group substituted alkynes such as 2-
ethynylnaphthalene (3h) and 1-ethynylpyrene (3i) were also
well tolerated to give 5h and 5i in moderate to good yields. In
addition to aryl alkynes, thiophene alkynes (3j and 3k) and
ethynylferrocene (3l) also proved to be suitable substrates in
this process (5j−l). Notably, a range of diversely functionalized
aliphatic terminal alkynes such as ((prop-2-yn-1-yloxy)-
methyl)benzene (3m), 2-methylbut-3-yn-2-ol (3n), and but-
3-yn-1-ol (3o) also performed well in the reaction with
satisfactory yields of 5m−o and excellent chemoselectivity; no
C−O coupling products were observed along with 5n and 5o.
Pleasingly, in the case of complex substrates, such as bioactive
ethynyl estradiol (3p) and diacetone-D-glucose-derived alkyne
(3q), the reaction worked smoothly without detrimental effect
on the stereochemistry, leading to good yields of 5p and 5q
(Scheme 3B). To display the scalability of this protocol, a 1.0
mmol scale reaction of alkyne 3d was also carried out, and
product 5d could still be obtained in 75% yield.
Finally, the substrate scope with respect to cycloketone
oxime esters was explored (Scheme 4). Again, the current
catalytic system demonstrated broad substrate and high
functional group compatibility. For example, the reaction
tolerated well a diverse range of symmetric, monosubstituted
cyclobutanone oxime esters (1b−f) with biologically relevant
functionality, including esters, cyano, phenyl, and benzyloxy
groups at the 3-position, leading to the cross-coupled products
6b−f with 53−71% yields (Scheme 4A). Nonsymmetric
cyclobutanone oxime ester (1g) could also participate in the
reaction smoothly to produce 6g in 66% yield. Moreover, the
sterically very demanding substrates such as 1h and 1i also
proved to be suitable for the reaction and resulted in the
corresponding products 6h and 6i in 54% and 41% yields,
a
1a′ (0.6 mmol), 2a (0.2 mmol), 3a (0.6 mmol), CuI (10 mol %), L3
(20 mol %), and K2CO3 (0.6 mmol) in DMF (2.0 mL) at 30 °C
b
c
under irradiation of 7 W blue LEDs for 10 h. Isolated yields. Gram-
d
scale reaction. Determined by 1H NMR analysis of the crude
e
mixture. Determined by chiral HPLC analysis on a chiral stationary
phase.
was performed, and product 4c could be obtained in 57% yield
with 1.2 g.23 As shown in the synthesis of 4i−k, the
substitution pattern and steric hindrance of the phenyl ring
have no obvious effect on the reaction outcome. Moreover, 2-
vinylnaphthalene (2l) and heteroayl-substituted alkene (2m)
were also well accommodated in the reaction, producing 4l and
4m in 61% and 55% yields, respectively. Remarkably, the
current reaction system could be further successfully extended
to a series of biologically relevant compounds and
pharmaceutical-derived alkenes (Scheme 2B). Alkenes (2n−
p) that contain a simple amino acid, estrone, and febuxostat
scaffolds as well as gibberellic-acid-derived alkene (2q) all
participated in the cross-coupling reaction efficiently to give
the corresponding products (4n−q) with good yields. Thus,
our protocol should be of potential application for late-stage
functionalization of drug and drug-like compounds. Finally, we
also examined several electron-deficient alkenes, such as
acrylates 2r−s, α,β-unsaturated ketone 2t, and diethoxyphos-
phinylethene 2u under the standard conditions. Unfortunately,
in all of these cases, lots of cyclobutanone oxime ester 1a′
remained, and no desired cross-coupling products were
detected; instead, two-component coupling side products SP-
1 were observed with 10−20% NMR yields (Scheme 2C).23
Next, we continued to examine the scope of the alkynes (3)
by reacting them with 1a′ and 2d under the standard
C
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To indentify the active metal species that might be involved
in the process, we further utilized EPR spectroscopy to
investigate the redox process between CuI catalyst and
cyclobutanone oxime ester 1a′ (see Figure S1 in the
Supporting Information).23 It was found that, upon addition
of 1a′, the solution of CuI/dtbbpy/2a/3a in DMF showed
obvious Cu(II) singals, which is in good agreement with Lei’s
study.24 Moreover, we measured redox potentials of the
ground states of 1a′ (Eredox = −2.18 V vs SCE in DMF), CuI/
dtbbpy (Eredox = −2.31 V vs SCE in DMF), CuI/phenyl-
acetylide (Eredox = −0.89 V vs SCE in DMF), and CuI/dtbbpy/
phenylacetylide (Eredox = −2.82 V vs SCE in DMF). These
results showed that SET oxidation by the complexes of CuI/
dtbbpy and CuI/dtbbpy/phenylacetylide is thermodynamically
feasible, while the complex of CuI/phenylacetylide alone could
not reduce 1a′. Finally, we studied the UV/vis spectra of the
complexes of CuI/dtbbpy and CuI/dtbbpy/phenylacetylide.
As expected, there is significant absorption above 400 nm for
these complexes (see Figure S3 in the Supporting Informa-
tion). Therefore, visible-light irradiation could result in
generation of a photoexcited triplet Cu(I) complex and
subsequently facilitate the cross-coupling process.22d,e
Scheme 4. Substrate Scope of the Cycloketone Oxime
Esters
a b
,
a
b
c
Refer to footnote a of Scheme 2. Isolated yields. Determined to be
1
1:1 d.r. by H NMR analysis of the crude mixture, unless otherwise
noted. Determined by chiral HPLC analysis on a chiral stationary
phase. Addition of fac-Ir(ppy)3 (2 mol %).
On the basis of these experimental results and related
literature,22,24 we proposed a possible mechanism as shown in
Scheme 6. First, iminyl radical species 1a′-A was generated
d
e
respectively (Scheme 4B). Notably, the current protocol can
also be successfully extended to bicyclic ketone derived oxime
esters 1j and 1k with the desired products 6j and 6k being
formed in good yields (Scheme 4C). Finally, it was found that
less strained, five- and six-membered cyclic ketone and
camphor-derived oxime esters 1l and 1m were also compatible
with the reaction in the presence of photocatalyst fac-Ir(ppy)3
(2 mol %), while resulting in moderate yields of 6l and 6m
(Scheme 4D).
Scheme 6. Proposed Reaction Mechanism
To gain some insight into the mechanism, we first carried
out several control experiments with model substrates 1a′, 2a,
and 3a (Scheme 5a). When adding stoichiometric amounts of
Scheme 5. Mechanistic Experiments
through a SET reduction of substrate 1a′ by the photoexcited
complex [Cu(I)]* (path a) and its ground state [Cu(I)]
complex (path b), with release of an oxidized [Cu(II)] complex.
Then, a regioselective C−C bond β-scission of iminyl radical
species 1a′-A occurs to form cyanoalkyl radical 1a′-B, which
can be quickly captured by alkene 2a to generate a new,
relatively more stable alkyl radical 1a′-C. Subsequently, radical
species 1a′-C can be intercepted by the [Cu(II)]/phenyl-
acetylide complex that is generated in situ by transmetalation
between the initially formed [Cu(II)] and 3a, providing high-
valent [Cu(III)] species 1a′-D. Finally, reductive elimination of
intermediate 1a′-D gives rise to the final cross-coupling
product 4a, regenerating the [Cu(I)] catalyst.
Overall, we have developed a visible-light-driven, copper-
catalyzed three-component radical cross-coupling of cyclo-
ketone oxime esters, alkenes, and terminal alkynes. The
protocol is distinguished by mild conditions, broad substrate
scope, and high functional group tolerance, providing access to
structurally diverse cyanoalkyl-containing propargylic com-
pounds.
radical traps TEMPO and PhSeSePh, the desired reaction was
completely inhibited, and the relevant radical trapping
products 7 and 8 could be detected. Furthermore, the reaction
with radical clock substrate 9 gave rise to ring-opening product
10 in 78% yield, which should result from a radical cross-
coupling of radical intermediate 9-B with phenylacetylene (3a)
(Scheme 5b). These observations indicated the radical
property of the cross-coupling process and the involvement
of cyanoalkyl radical 1a’-B and benzylic radical such as 9-A.
D
DOI: 10.1021/acs.orglett.9b01529
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Organic Letters
Letter
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chenjiarong@mail.ccnu.edu.cn.
ORCID
Jia-Rong Chen: 0000-0001-6054-2547
Wen-Jing Xiao: 0000-0002-9318-6021
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the NNSFC (21622201, 91856119,
21820102003, and 21772053), the Science and Technology
Department of Hubei Province (2016CFA050 and
2017AHB047), and the Program of Introducing Talents of
Discipline to Universities of China (111 Program, B17019) for
support of this research.
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E
DOI: 10.1021/acs.orglett.9b01529
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
eaav9713. (j) Zhang, Q.; Liu, Y.; Wang, T.; Zhang, X.; Long, C.; Wu,
Y.-D.; Wang, M.-X. J. Am. Chem. Soc. 2018, 140, 5579.
(23) See the Supporting Information for more details.
(24) Tang, S.; Liu, Y.; Gao, X.; Wang, P.; Huang, P.; Lei, A. J. Am.
Chem. Soc. 2018, 140, 6006.
F
DOI: 10.1021/acs.orglett.9b01529
Org. Lett. XXXX, XXX, XXX−XXX