Copper-Catalyzed Radical Cross-Coupling of Oxime Esters and Sulfinates for Synthesis of Cyanoalkylated Sulfones

Article abstract of DOI:10.1002/cctc.201901695

Sulfones and alkylnitriles play a significant role in both organic and medicinal chemistry, as versatile synthetic building blocks and privileged pharmacophores in many natural products and bioactive compounds. Herein, a room-temperature, copper-catalyzed radical cross-coupling of redox-active cycloketone oxime esters and sulfinate salts is described for the first time. Key to the success of this process involves catalytic generation of a cyclic iminyl radical and ensuing ring-opening C?C bond cleavage. The resultant cyanoalkyl radical is then engaged in cross-coupling with nucleophilic sulfinate to form cyanoalkylated sulfones.

Full text of DOI:10.1002/cctc.201901695

Communications
DOI: 10.1002/cctc.201901695
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Copper-Catalyzed Radical Cross-Coupling of Oxime Esters
and Sulfinates for Synthesis of Cyanoalkylated Sulfones
Xue-Song Zhou,[a] Ying Cheng,[a] Jun Chen,[a] Xiao-Ye Yu,[a] Wen-Jing Xiao,[a, b] and
Jia-Rong Chen*[a]
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nates as nucleophiles,[7] however, the substrate scope of electro-
Sulfones and alkylnitriles play a significant role in both organic
philic coupling partners is still quite limited and harsh
conditions (e.g., elevated temperature) are typically required.
Due to the readily availability of diverse radical precursors,
transition-metal-catalyzed radical cross-coupling (RCC) has
recently been established as a promising and enabling tool for
assembly of a wide variety of CÀ C and C-heteroatom bonds
under mild conditions.[8]
and medicinal chemistry, as versatile synthetic building blocks
and privileged pharmacophores in many natural products and
bioactive compounds. Herein, a room-temperature, copper-
catalyzed radical cross-coupling of redox-active cycloketone
oxime esters and sulfinate salts is described for the first time.
Key to the success of this process involves catalytic generation
of a cyclic iminyl radical and ensuing ring-opening CÀ C bond
cleavage. The resultant cyanoalkyl radical is then engaged in
cross-coupling with nucleophilic sulfinate to form cyanoalky-
lated sulfones.
Owing to their distinct electronic properties and structural
features, alkylnitriles also play an important role in many fields
of applications. A large number of biologically active natural
products (e.g., C and D) and pharmaceuticals contain such
structural motifs (e.g., F, piritramide, treatment of postoperative
pain) (Figure 1).[9] The nitrile group also serves as versatile
synthetic building block in organic chemistry, because it can be
easily transformed into many other important functional groups
through routine manipulation.[10] Numerous approaches toward
their synthesis have been developed. In particular, the explora-
tion of efficient methods for synthesis of nitriles without use of
metal- or metalloid-bound cyanide sources have been a subject
of increasing interest.[11] Considering the importance of both
sulfone and alkylnitrile groups, it would be highly desirable to
develop new synthetic methods to construct novel molecules
that contain such both structural motifs. We surmised that
incorporation the features of both cyanoalkyl and sulfonyl
motifs into a single scaffold would probably lead to a new class
of compounds, and such molecular hybridization[12] would also
be highly desirable for exploring new biologically relevant
chemical space.[13]
Sulfones are a valuable class of pharmaceutically relevant motifs
due to their wide profile of biological activities,[1] such as
bicalutamide (A, treatment of prostate cancer)[2] and mesotrione
(B, herbicide)[3] (Figure 1). Moreover, the sulfonyl groups have
also been considered as chemical chameleons with versatile
synthetic applications in organic chemistry.[4] Not surprisingly, a
large number of preparative methods have been developed for
the construction of structurally diverse sulfones.[5] The vast
majority of the classical methods falls into four categories,
including oxidation of sulfides/sulfoxides, aromatic sulfonyla-
tion, alkylation/arylation of sulfinates, and radical addition to
alkenes/alkynes. Recently, sulfur dioxide-based multicomponent
reaction[6] as well as metal-catalyzed coupling of sulfinates and
sulfonyl halides have also emerged as intriguing alternatives to
the traditional processes. Despite some impressive advances
achieved in transition-metal-catalyzed cross-coupling of sulfi-
Drawing the inspiration from the pioneering works of
Forrester[14] and Zard[15] on the chemistry of iminyl radicals, we
[a] X.-S. Zhou, Dr. Y. Cheng, J. Chen, X.-Y. Yu, Prof. W.-J. Xiao, Prof. J.-R. Chen
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
Hubei 430079 (P. R. China)
E-mail: chenjiarong@mail.ccnu.edu.cn
Homepage: http://www.jrchen-group.com
[b] Prof. W.-J. Xiao
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
345 Lingling Road
Shanghai 200032 (P. R. China)
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cctc.201901695
Figure 1. Examples of compounds containing sulfone and alkylnitrile moi-
eties.
This manuscript is part of the Special Issue on New Concepts in Homo-
geneous Catalysis.
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Table 1. Exploring reaction conditions.[a]
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Entry
[Cu] catalyst
Ligand
Solvent
Yield [%][b]
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8
Cu(OAc)2
Cu(CH3CN)4PF6
CuI
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L1
L1
–
DMF
DMF
DMF
DMF
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73
60
40
79
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49
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84
0
CuCN
Scheme 1. Generation of iminyl radicals from cycloketone oxime esters by
SET-reduction strategy and application to CÀ C bond cleavage/functionaliza-
tion.
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
–
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
9
10
11
12[c]
13[c]
14[c]
15[c,d]
have recently developed a visible light-driven SET-reduction
strategy, which enables facile conversion of cycloketone oxime
esters to iminyl radicals, and subsequent ring-opening CÀ C
bond cleavage to give cyanoalkyl radicals.[16] With the suitable
radical acceptors, a range of CÀ C bond-forming radical reactions
were developed, providing access to diversely functionalized
nitriles (Scheme 1a). Many other research groups have also
been involved in this active area, and significantly expanded
the coupling partners, allowing installation of diverse function-
alities at the sp3-hybridized carbon.[17–21] Despite these impres-
sive advances, however, the radical cross-coupling of readily
available nucleophilic sulfinates with cycloketone oxime esters
is still unexplored.[16f,21] Thus, the implementation of this
protocol would provide access potentially useful compounds
that contain both sulfone and alkylnitrile moieties (Scheme 1b).
Building on our recent work on visible light-driven, copper-
catalyzed cross-coupling of oxime esters,[16d] we initially exam-
ined the feasibility of the model reaction of cyclobutanone
oxime ester 1a and sodium sulfinate 2a under copper catalysis
and visible light irradiation (Table 1).[22] To our delight, using Cu
(OAc)2 as catalyst and 4,–4’-dimethoxy-2,2’-bipyridine (L1) as
ligand in DMF under visible light irradiation, the reaction indeed
worked smoothly, giving the cross-coupled product 3aa in 65%
yield (entry 1). A brief examination of commonly used copper
catalysts revealed that Cu(CH3CN)4PF6 proved to be superior to
others, leading to a 73% yield of 3aa (entry 2). When using
DMSO as the solvent, the yield could be further improved to
79% (entry 5). The redox properties of the copper complexes
can be easily tuned by the structural variation of ligands.[23]
Thus, with Cu(CH3CN)4PF6 as catalyst and DMSO as reaction
media, we further screened several other N,N-bidentate ligands
(L2-L7) as ligands; the outcomes of entries 6–11 disclosed
obvious ligand effects; and ligand L1 was still the best
candidate. When changing the ratio of two components 1a and
2a to 1.5:1, 3aa was obtained in 84% yield (entry 12).
Interestingly, the control experiments without copper catalyst,
ligand L1 or visible light irradiation confirmed that the current
reaction should proceed through a copper catalytic process
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
67
83
L1
[a] Reaction Conditions: 1a (0.2 mmol), 2a (0.2 mmol), [Cu] catalyst
°
(0.02 mmol, 10 mol%), solvent (2.0 mL), 7 W blue LEDs, Ar, 30 C, 10 h, [b]
Yields were determined by 1H NMR spectroscopy with 1,3,5-trimethox-
ybenzene as an internal standard, [c] Using 1a (0.3 mmol) and 2a
(0.2 mmol), [d] Without visible light irradiation. DMF=N,N-dimeth-
ylformamide.
(entry 13), and visible light irradiation is not necessary
(entry 15).[24] Accordingly, a catalytic system consisting of Cu
(CH3CN)4PF6, L1, and DMSO is the optimum system for this
cross-coupling reaction, giving 3aa in 83% yield (entry 15).
With the above standard conditions established, we first
investigated the substrate scope by reacting 1a with a
representative set of sodium (hetero)aryl sulfinates 2 on a
0.4 mmol scale. As highlighted in Table 2A, the catalytic system
proved to be tolerant of a wide range of differently substituted
sodium sulfinates. For example, in the cases of sodium aryl
t
sulfinates 2a–h with either electron-donating (e.g., Me, Bu,
OMe) or electron-withdrawing (e.g., F, Cl, Br, NO2) substituents
at the para-position of the phenyl ring, all of the reactions
proceeded smoothly to furnish the corresponding products
3aa–ah with 51–77% yields. As shown in the reactions of 2i--
2k, variation of the substitution pattern and steric hindrance on
the phenyl ring has no obvious influence on the reaction
efficiency; while very sterically demanding 2l led to moderate
yield of 3al. Furthermore, the reactions of the fused aromatic
and heteroaromatic group substituted sulfinates 2m and 2n as
well as simple heteroarene substituted substrate 2o also
participated in the cross-coupling reaction very well, affording
3am-ao in good yields. The structure of product 3af was also
ambiguously determined by X-ray crystallographic analysis,
confirming the CÀ S bond formation in the reaction.[25]
Notably, the current catalytic system could also be success-
fully extended to sodium alkyl sulfinates (Table 2B). For
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Table 2. Scope with respect to sodium sulfinates.[a,b]
Table 3. Scope with respect to cycloketone oxime esters.[a,b]
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[a] 1a (0.6 mmol), 2 (0.4 mmol), Cu(CH3CN)4PF6 (0.04 mmol, 10 mol%), L1
°
(0.04 mmol, 10 mol%), DMSO (4.0 mL), Ar, 30 C, 4–10 h, [b] Yield of
isolated product after flash chromatograph, [c] 1a/2=1:2. [d] 0.2 mmol
scale, [e] With L8 shown in Table 3 as ligand in DMF.
instance, sodium benzyl sulfinate 2p reacted well with O-acyl
oxime 1a, giving product 3ap in 60% yield. Sodium methane-
sulfinate 2q and sodium ethanesulfinate 2r were also coupled
well with O-acyl oxime 1b to give 3bq and 3br in fair yields,
when using L8 as ligand in DMF. However, under the current
conditions, sodium trifluoromethyl sulfinate proved to be not
suitable for the reaction.
Next, we turned our attention to evaluation of the general-
ity of the cross-coupling reaction by using a range of cyclo-
ketone oxime esters 1b–g (Table 3). Under the standard
conditions, a significant amount of side-product, the original
cycloketone precursors, such as 1b’ were typically formed
together with the desired products. Upon minor modification of
the conditions, we found that a combination of Cu(CH3CN)4PF6
and 1,10-phenanthroline, and a 1:2 ratio of substrates 1 to 2
could lead to much cleaner reaction. Substrate 1b reacted well
with sodium sulfinates 2a, 2b and 2f, giving the corresponding
products with moderate yields. A range of monosubstituted
substrates with 2-naphthyl, ester, and benzyloxy groups at the
3-position also proceed to be suitable for the reaction, giving
the cross-coupled products 3ca, 3da and 3ea in 20–47% yields.
Substrate 1f with a nitrogen heterocycle was well tolerated to
form the desired product 3fa. Surprisingly, in the case of
oxetan-3-one derived oxime ester 1g, we did not detect any
[a] 1 (0.4 mmol), 2 (0.8 mmol), Cu(CH3CN)4PF6 (0.04 mmol, 10 mol%), L8
°
(0.04 mmol, 10 mol%), DMF (4.0 mL), Ar, 30 C, 10 h, [b] Yield of isolated
product after flash chromatograph, [c] 0.2 mmol scale, [d] Purified by
preparative HPLC.
expected product 3ga; instead, the side-product 3ga’ was
isolated in 18% yield, which should result from the cross-
coupling between cyanoalkyl radical and carboxylate anion. In
case of camphor-derived oxime ester 1h, we did not detect any
amount of the expected ring-opening/cross-coupling product;
instead, the product (–)-camphorsulfonylimine 4 resulting from
the NÀ S bond forming reaction was isolated as the sole
product.[25,26] As for the reaction of the five-membered cyclic
ketone-derived oxime ester 1i and 2a, despite complete
consumption of 1i, the reaction only gave rise to complex
mixture and no desired product was detected under standard
conditions. It was found that the reaction of 1j of 2a resulted in
only trace amount of desired product 3ja. Our preliminary
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efforts to achieve asymmetric version of the reaction of 1j by
using chiral bisoxazoline L9 met failure either, resulting a trace
amount of 3ja together with side products 1j-A and 1j-B.[22]
To further demonstrate the practicality of the protocol, a
gram-scale reaction of 1a and 2f was also evaluated under the
standard conditions (Scheme 2a). The reaction proceeded well
To confirm the redox states of the copper catalyst that
might be engaged in the reaction, we then used the EPR
technique to explore the possible redox process between Cu
(CH3CN)4PF6 and substrates 1a and 2a in the presence or
without ligand L1 (Figure 2). As shown in Figure 2a and 2b, the
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Scheme 2. Synthetic applications.
to give the desired product 3af in 67% yield. With the nitrile
group as a synthetically versatile handle, several diversifications
of the thus-obtained cyanoalkylated sulfone 3af were per-
formed. For instance, 3af could undergo methanolysis to give
methyl ester 5 in 76% yield (Scheme 2b).[27] Moreover, product
3af could be easily transformed into N-tert-butylated acetamide
6
in 80% yield through
a
modified Ritter reaction
(Scheme 2c).[16d]
In order to gain some insight into the mechanism, we first
carried out several control experiments with model substrates
1a and 2a by addition of variable amounts of radical scavenger,
TEMPO (Scheme 3). It was found that the addition of TEMPO
Figure 2. EPR spectra (X brand, 9.8 GHz, rt). [Cu]=Cu(CH3CN)4PF6. Exp. 1: Cu
(CH3CN)4PF6 (0.02 mmol), DMSO (2.0 mL); Exp. 2: Cu(CH3CN)4PF6 (0.02 mmol),
1a (0.3 mmol), DMSO (2.0 mL); Exp. 3: Cu(CH3CN)4PF6 (0.02 mmol), L1
(0.02 mmol), DMSO (2.0 mL); Exp. 4: Cu(CH3CN)4PF6 (0.02 mmol), L1
(0.02 mmol),1a (0.3 mmol), DMSO (2.0 mL).
Scheme 3. Radical trapping experiments with TEMPO.
has substantial effect on the reaction; the formation of desired
product 3aa was entirely inhibited in the presence of 3.0
equivalents of TEMPO. The ESI-HRMS analysis of these reaction
mixtures suggested formation of cyanoalkyl radical trapping
adduct 7. These outcomes suggested the radical nature of this
process and involvement of cyanoalkyl radical 1a-B.
addition of substrate 1a to the solutions of Cu(CH3CN)4PF6 and
Cu(CH3CN)4PF6/L1 in DMSO instantly resulted in obvious CuII
signals, which are in agreement with the literature.[28] In sharp
contrast, no characteristic signal was observed in the solution of
Cu(CH3CN)4PF6/L1/2a; and further addition of 1a to such
solution led to appearance of CuII signals (Figure 2c). Taken
together, these results suggested that an SET process should
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lated sulfones.[30] Current interest in our laboratory is toward
extension of this protocol to other nucleophiles.
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Acknowledgements
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We are grateful to the NNSFC (91856119,21971081, 21622201,
21820102003, and 21772053), the Science and Technology Depart-
ment of Hubei Province (2016CFA050 and 2017AHB047), and the
Program of Introducing Talents of Discipline to Universities of
China (111 Program, B17019) for the support of this research.
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Conflict of Interest
The authors declare no conflict of interest.
Keywords: copper · cross-coupling · nitrogen radicals · oxime
esters · sulfones
Scheme 4. Proposed mechanism.
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occur between 1a and CuI complex, thus enabling generation
of the corresponding iminyl radical by NÀ O bond fragmenta-
tion.
On the basis of the above experimental results, a plausible
reaction mechanism involving a CuI/CuII/CuIII-based catalytic
cycle was then proposed (Scheme 4). First, a SET reduction of
oxime ester 1a by LCuI complex occurred, followed by
fragmentation to afford cyclic iminyl radical 1a-A and oxidized
[Cu(II)] complex. Next, cyclic iminyl radical 1a-A undergoes
regioselective ring-opening CÀ C bond cleavage to form
cyanoalkyl radical 1a-B. Meanwhile, a transmetalation event
between the originally formed LCu(I) complex and nucleophilic
sodium sulfinate 2a occurred to give LCu(II)SO2Ar2 species. At
this point, cyanoalkyl radical 1a-B was intercepted by
LCuIISO2Ar2 species to furnish the high-valent Cu(III) complex 1a-
C. Ultimately, a reductive elimination of 1a-C complex resulted
in the cross-coupled product 3aa with regeneration of [Cu(I)]
catalyst. At the current stage, we could not rule out the
following two alternative pathways. It should be noted that the
trap of the cyanoalkyl radical 1a-B could also proceed through
two other pathways: (1) the out-sphere direct ligand-transfer
(path b) and (2) SET-oxidation of the cyanoalkyl radical 1a-B by
the Cu(II) complex to a carbon cation that can be trapped by
the nucleophilic sulfinate anion (path c).[29] Remarkably, the
reaction is a redox-neutral process and does not require any
external oxidant.
In conclusion, we have developed a room-temperature,
copper-catalyzed radical cross-coupling of redox-active cyclo-
ketone oxime esters and sulfinate salts for the first time. This
protocol features broad substrate scope, good functional group
tolerance, and mild reaction conditions, providing practical
access to structurally diverse and potentially useful cyanoalky-
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These are not the final page numbers!

Communications
COMMUNICATIONS
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X.-S. Zhou, Dr. Y. Cheng, J. Chen, X.-
Y. Yu, Prof. W.-J. Xiao, Prof. J.-R.
Chen*
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Copper-Catalyzed Radical Cross-
Coupling of Oxime Esters and Sul-
finates for Synthesis of Cyanoalky-
lated Sulfones
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Cu-catalyzed radical reactions:
of a cyclic iminyl radical and ensuing
ring-opening CÀ C bond cleavage. The
resultant cyanoalkyl radical is then
engaged in cross-coupling with nucle-
ophilic sulfinate to form cyanoalky-
lated sulfones.
Herein, a room temperature, copper-
catalyzed radical cross-coupling of
redox-active cycloketone oxime esters
and sulfinate salts is described for the
first time. Key to the success of this
process involves catalytic generation