Copper-Catalyzed Synthesis of gem-Bisarylthio Enamines under Redox-Neutral Conditions

Article abstract of DOI:10.1002/adsc.201900035

An efficient approach for the construction of gem-bisarylthio enamines via coupling of oxime acetates with diaryl disulfides is developed. This process involved copper-catalyzed N?O/S?S bond cleavages and formation of two new C?S bonds. A broad range of s

Full text of DOI:10.1002/adsc.201900035

Title: Copper-Catalyzed Synthesis of gem-Bisarylthio Enamines under
Redox-Neutral Conditions
Authors: Jiabin Ni, Xiaokang Mao, and Ao Zhang
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10.1002/adsc.201900035
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Copper-Catalyzed Synthesis of gem-Bisarylthio Enamines
under Redox-Neutral Conditions
Jiabin Ni,a,b Xiaokang Mao,a,c Ao Zhang*,a,b,d
a
CAS Key Laboratory of Receptor Research, and the State Key Laboratory of Drug Research, Shanghai Institute of
Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
E-mail: aozhang@simm.ac.cn
College of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China
Department of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai 200444, China
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
b
c
d
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
this copper-catalyzed oxidative coupling system thus
leading to arylthio substituted ketones.
Abstract: An efficient approach for the construction of
gem-bisarylthio enamines via coupling of oxime acetates
with diaryl disulfides is developed. This process involved
copper-catalyzed N-O/S-S bond cleavages and formation of
two new C-S bonds. A broad range of substrates with
diverse functional groups were tolerated.
Keywords: copper; oxime acetates; disulfides; redox-
neutral; gem-bisarylthio enamines
Transition-metal-catalyzed reactions using ketone
oxime esters as internal oxidants have attracted more
and more attention in organic synthesis.[1]
Specifically, oxime acetates represent a class of
useful synthons that are widely applied in the field of
transition-metal-catalyzed
oxime
N-O
bond
transformations.[2,3] In general, the conversion of
oxime acetates triggered by transition-metals occurs
through iminyl radical intermediates, which are then
converted to carbon radicals or metal-enamine
intermediates.1f Recently, such radical transformation
strategy[4] using copper as the catalyst and oxime
acetates as substrates has been achieved by the Jiang
group[2b,d] and Lei group[2c] (Scheme 1a). In these
cases, copper-catalyzed radical cross-couplings of
oxime acetates with sodium sulfonates[2b] or
phosphine oxides[2c] were accomplished. More
recently, the Jiang group[2d] further reported a copper-
catalyzed α-C(sp3)-H bond acylation of oxime
acetates with α-oxocarboxylic acids to afford
enamine products that are generally unstable and
readily rearranged to imine tautomers.
Scheme 1. Cu-catalyzed C(sp3)-H oxidative coupling of
oxime acetates.
To our surprise, we found that treatment of
acetophenone O-acetyl oxime with diphenyl disulfide
under Cu catalysis provided an unexpected gem-
bisphenylthio enamine, which represents a unique
and barely reported thio-containing architecture
(Scheme 1b).[6,7] A literature research disclosed that
there was only one report (Scheme 2) ever describing
the formation of such gem-bisarylthio enamines[8] by
the Davis group, who found that the sulfenamide
enolate equivalent II which were prepared by
treatment of sulfenime I with LDA, could react with
diaryl disulfides to afford the α-arylthiosulfenimine
III, together with the gem-bisarylthio enamine IV as
Inspired by the Jiang group and Lei group’s
elegant work in copper-catalyzed oxidative coupling
of oxime acetates and in view of the limited
structures bearing the arylthio function, we
envisioned that an arylthio radical[5] generated from
diaryl disulfides might react with oxime acetates in
1
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10.1002/adsc.201900035
Advanced Synthesis & Catalysis
a side product. Although this was reported in 1980,
the harsh reaction conditions restricted it for further
investigation. Herein, we report a copper-catalyzed
method allowing for rapid and efficient construction
of gem-bisarylthio enamines from oxime acetates and
diarylthio disulfides.
15
CuI
Reactions were carried out by using 1a (0.10 mmol), 2a
(0.20 mmol), Cu catalyst (20 mol%), additive (0.10 mmol),
NaI
MeCN
83[e]
[a]
solvent (1.0 ml), 90oC, N2, 16h.
Isolated yield.
1
[b]
[c]
mmol scale. [d] CuI(10 mol%). [e] 2a (0.10 mmol).
To validate the optimum reaction condition in
entry 11, a 1.0 mmol-scale reaction was performed
and compound 3a was produced in 85% yield,
demonstrating the good scalability of this protocol.
Therefore, the optimum reaction condition was
determined as those in entry 11.
Scheme 2. Reported Synthesis of gem-bisarylthio
enamines.
Table 2. Reactions with various oxime acetates.[a,b]
Initially, we commenced our investigation using
acetophenone oxime acetate (1a) and diphenyl
disulfide (2a) as model substrates (Table 1). Among
the copper(I) salts, CuI showed the best catalytic
reactivity, giving 45% yield of the gem-bisphenylthio
enamine product 3a,[9] while CuCl, CuBr and CuOAc
showed lower reactivity (entries 1-4). In addition,
commonly used copper(II) salts such as Cu(OAc)2
and Cu(TFA)2 did not catalyze this conversion
(entries 5 and 6). Subsequently, different solvents
such as toluene, 1,4-dioxane, DCE and DMF were
screened, but no improvements were obtained (entries
7-10). Pleasantly, the yield of 3a was significantly
enhanced to 95% in the presence of 1 equiv of NaI
(entry 11).[10] Replacement of NaI with KI provided
inferior result (entry 12). In addition, reducing the
loading of CuI to 10 mol % slightly decreased the
yield (entry 13). It was found that the absence of CuI
catalyst led to no product (entry 14). Furthermore,
when one equivalent of 2a was used, the yield 3a was
decreased to 83% (entry 15).
Table 1. Optimization of Reaction Conditions.[a]
[a]
Reactions were carried out by using 1 (0.10 mmol), 2a
(0.20 mmol), CuI (0.02 mmol, 20 mol%), NaI (0.10 mmol),
MeCN (1.0 ml), 90oC, N2, 16h. [b] Isolated yield.
Entry [Cu]
Additive Solvent
Yield[%][b]
With the optimized reaction conditions in hand, we
then evaluated the versatility and limitations of the
current copper-catalyzed synthesis of gem-bisarylthio
enamines by using various oxime acetates 1 (Table 2).
Generally, this reaction proceeded smoothly and gave
the desired products 3 in good to excellent yields.
Acetophenone oxime acetates bearing a variety of
para- or meta-substituents that are either electron-
donating groups (Me, tBu, MeO) or electron-
withdrawing groups (F, Cl, Br, CF3, NO2) showed
good compatibility, and the corresponding products
3b-l were obtained in 73-99% yields. The tolerance
of fluoro, chloro and bromo groups provides a
complementary platform for further synthetic
transformations via classic cross-coupling reactions.
It is worth noting that the disubstituted acetophenone
1
2
3
4
5
6
7
8
CuCl
CuBr
CuI
CuOAc
Cu(OAc)2
Cu(TFA)2
CuI
/
/
/
/
/
/
/
/
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
PhMe
1,4-
dioxane
DCE
DMF
MeCN
MeCN
MeCN
MeCN
0
0
45
Trace
0
Trace
0
9
CuI
9
CuI
CuI
CuI
CuI
CuI[d]
/
/
/
21
10
11
12
13
14
7
NaI
KI
NaI
NaI
95(85[c])
85
90
0
2
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10.1002/adsc.201900035
Advanced Synthesis & Catalysis
oxime acetates were suitable substrates, and the
corresponding products were obtained in 96% and
90% yields (3m, 3n) respectively. Notably, the ortho-
substituted substrate 1o was converted to the
corresponding product 3o as well in 99% yield,
implying that the steric hindrance had little effect on
the reaction. Also 1-acetylnaphthalene oxime acetate
was found to be a suitable substrate for this reaction,
affording the desired product 3p in 98% yield.
Furthermore, a series of oxime acetates containing a
heterocyclic component, including furan (1q),
thiophene (1r, 1s), benzothiophene (1t), and pyridine
(1u), took part in this reaction smoothly to generate
the desired products 3q-u in 59-85% yields. More
appealingly, the oxime acetate of 4-phenylbut-3-en-2-
one was also transformed to the corresponding
product 3v in 82% yield, indicating the double bond
in the substrate has no effect on either copper
chelation or radical attack. In addition,
methylcyclohexyl ketone oxime acetate also
participated in the reaction very well and the
corresponding product 3w was obtained in 59% yield.
or ortho-position also reacted smoothly with substrate
1a and provided corresponding products 4e−f in good
yields. It is worth noting that the reaction tolerates
3,5-dichlorophenylthio substituent (4g), which are
handy synthetic tools for further functionalization to
complex molecules. Besides aromatic disulfides, the
heteroaromatic disulfides such as 2,2′-dithienyl
disulfide showed good reactivity, and the heteroarene
substituted product 4h was obtained in 61% yield. At
last, alkyl disulfides (BnSSBn) was explored in this
method. But the result (4i) shows that the alkyl
disulfide was incompatible, which may result from
the unstable alkylthio radical. We also tested the
reactivity of PhSeSePh, but no reaction (N.R.)
occurred (4j), suggesting that selenation was
incompatible in current reaction system.
Inspired by this unique coupling reaction, we
explored its transformations (Scheme 5).[11]
Hydrolysis of 3a with 1M HCl gave 1-phenyl-2,2-
bis(phenylthio)ethan-1-one 5 in 68% yield, which
could be used for further functional transformations
such as ketone-reduction by NaBH4 or nucleophilic
addition by Grignard reagent or oxidation of sulfides,
thus leading to compounds 6-8 in 70-85% yields.
Furthermore, the bis(phenylsulfonyl) methine of 8
could be halogenated to generate quaternary products
9-11 in 67-96% yields (Scheme 3a). In addition, the
classic Suzuki coupling strategy was used for further
functionalization of 3g, and the corresponding
coupling product 12 was obtained in 76% yield
(Scheme 3b).
Table 3. Reactions with various diaryl disulfides.[a,b]
[a]
Reactions were carried out by using 1a (0.10 mmol), 2
(0.20 mmol), CuI (0.02 mmol, 20 mol%), NaI (0.10 mmol),
MeCN (1.0 ml), 90oC, N2, 16h. [b] Isolated yield.
Scheme 3. Transformations of 3a and 3g.
For a thorough evaluation of the utility of this
protocol, we then turned our attention to investigate
the scope of diaryl disulfides 2. Irrespective of the
nature of the substituents and their position in the
arene ring, the disulfides were well suited for the
present transformation, affording satisfactory yields
of the desired products 4a-h (Table 3). Diaryl
disulfides with Me-, MeO-, Cl- and NO2- substituents
at the para-position efficiently participated in the
reaction, rendering corresponding gem-bisarylthio
enamines products 4a−d in 80−90% yields. Diaryl
disulfides with substituent such as fluoro at the meta-
To gain more insight into the mechanism of this
transformation, a series of control experiments were
performed (Scheme 4). First, we envisioned that only
one phenylthio group would be stalled if 2-methyl-1-
phenylpropan-1-one (1x) was used as the substrate.
As expected, although quite sluggish, the reaction of
1x with 2a afforded 13 in 39% yield as the major
product (Scheme 4a). Second, the reaction of oxime
with only one alpha-methyl group under standard
conditions could also produce one arylthio-equipped
3
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10.1002/adsc.201900035
Advanced Synthesis & Catalysis
ketone in 9% yield, which means the steric effect of
methyl group inhibit the second C-S bond formation
(Scheme 4b). Subsequently, we added radical
scavengers,
such
as
2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) and 1,4-benzoquinone (BQ)
to our standard reaction (Scheme 4c). We found that
this conversion was partially inhibited, giving product
3a in significantly reduced yield (14-30%), indicating
that both a radical process and an organometallic
pathway might be involved in this transformation,
phenomena similar to that in Jiang’s report.[12]
Scheme 5. Proposed reaction mechanism.
Scheme 4. Mechanistic studies.
In conclusion, we have developed a copper-
catalyzed oxidative cross-coupling of oxime acetates
with diaryl disulfides leading to a unique class of
gem-bisarylthio enamines in high yields. This process
involves copper-catalyzed N-O/S-S bond cleavage
and formation of two new C-S bonds. This
transformation possesses a broad substrate scope with
good functional group compatibility.
Based on the experiments above and the literature
reports,[2,3,5] a plausible reaction mechanism is
proposed in Scheme 5. The mechanism may involve
organo-copper(III) species as the key intermediates.
First, the copper(III) intermediate A was formed by
oxidative addition of 1 to Cu(I).[13] Meanwhile, an
arylthio radical and an arylthio anion were generated
from diaryl disulfide 2 by Cu(I) in a single-electron-
transfer reaction.[5] Alternatively, iodine ions were
oxidized by Cu(II) to generate I2, which reacted with
2a to yield ArSI. Then ArSI underwent homolytic
cleavage to afford arylthio radicals.[14] Subsequent
coordination of arylthio anion to A formed the
intermediate B that was then tautomerized to the
copper(III) species D.[2b] Reductive elimination of
CuX from the intermediate D afforded the key
intermediate E. Attack of a second equivalent of
arylthio radical to the intermediate E formed the
radical intermediate F, which then underwent a single
electron transfer to generate a carbocation species G.
The gem-bisaryl enamines 3 or 4 were finally formed
from intermediate G via a β-H abstraction by ArS- or
AcO-.
Experimental Section
General procedure for the synthesis of gem-bisarylthio
enamines. To an oven-dried 10 mL sealed tube was added
substrate 1 (0.10 mmol), diaryl disulfides 2 (0.20 mmol),
CuI (3.8 mg, 0.020 mmol), NaI (15 mg, 0.10 mmol) and
acetonitrile (1.0 mL) under a nitrogen atmosphere. The
mixture was stirred for 16 h at 90 oC. The mixture was then
cooled to room temperature, and concentrated in vacuo.
The desired product gem-bisarylthio enamines 3 and 4
were purified by silica-gel column chromatography in
moderate to good yields.
Acknowledgements
This work was supported by grants from Chinese NSF (81430080,
81773565). Supporting from the National Program on Key Basic
Research Project of China (2015CB910603), and Key Program
of the Frontier Science (QYZDJ-SSW-SMC002) of the Chinese
Academy of Sciences, National Science & Technology Major
Project “ Key New Drug Creation and Manufacturing
Program”，China (2018ZX09711002-006), and the Shanghai
Commission of Science and Technology (16XD1404600) is also
highly appreciated.
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10.1002/adsc.201900035
Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201900035
Advanced Synthesis & Catalysis
COMMUNICATION
Copper-Catalyzed Synthesis of gem-Bisarylthio
Enamines under Redox-Neutral Conditions
Adv. Synth. Catal. Year, Volume, Page – Page
Jiabin Ni, Xiaokang Mao, Ao Zhang*
6
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