Copper-catalyzed coupling of oxime acetates with sodium sulfinates: An efficient synthesis of sulfone derivatives

Article abstract of DOI:10.1002/anie.201311217

Sulfone derivatives are important synthetic intermediates. However, the general method for their preparation is through traditional coupling reaction: the alkylation of sodium sulfinates with phenacyl halides. Based on our previous work on sodium sulfinates and oxime acetates, we herein report a novel method for sulfone derivatives by oxidative coupling with sodium sulfinates and oxime acetates using copper as catalyst. The sulfonylvinylamine products could be formed in excellent yields. Upon hydrolysis by silica gel in CH ₂Cl₂, β-ketosulfones could also be efficiently constructed. Various sulfonylvinylamines and β-ketosulfones were obtained in good to excellent yields under the optimized reaction conditions. Mechanistic studies indicated that this transformation involved copper-catalyzed N-O bond cleavage, activation of a vinyl sp² C-H bond, and C-S bond formation. The oxime acetates act as both a substrate and an oxidant, thus the reaction needs no additional oxidants or additives. Copper brings us together: The title reaction involves copper-catalyzed N-O bond cleavage, activation of a vinyl sp² C-H bond and C-S bond formation; it uses simple oxime acetates and sodium sulfinates to synthesize sulfonylvinylamine products without the need for additional oxidants or additives. Upon hydrolysis, useful β-ketosulfones are obtained.

Full text of DOI:10.1002/anie.201311217

Angewandte
Chemie
DOI: 10.1002/anie.201311217
Synthetic Methods
Copper-Catalyzed Coupling of Oxime Acetates with Sodium
Sulfinates: An Efficient Synthesis of Sulfone Derivatives**
Xiaodong Tang, Liangbin Huang, Yanli Xu, Jidan Yang, Wanqing Wu, and Huanfeng Jiang*
Abstract: Sulfone derivatives are important synthetic inter-
mediates. However, the general method for their preparation is
through traditional coupling reaction: the alkylation of sodium
sulfinates with phenacyl halides. Based on our previous work
on sodium sulfinates and oxime acetates, we herein report
a novel method for sulfone derivatives by oxidative coupling
with sodium sulfinates and oxime acetates using copper as
catalyst. The sulfonylvinylamine products could be formed in
excellent yields. Upon hydrolysis by silica gel in CH2Cl2, b-
ketosulfones could also be efficiently constructed. Various
sulfonylvinylamines and b-ketosulfones were obtained in good
to excellent yields under the optimized reaction conditions.
oxidant are redox neutral, and do not need stoichiometric
external oxidants; oxime is one such internal oxidant.[8]
Traditionally, oximes are used for constructing amides and
nitriles, and for the development of metal catalysis, oxime
derivatives have been applied to Pd-,[9a,b] Rh-,[9c–e] Fe-,[9f,g] and
Cu-catalyzed[9h-j] reactions. Among which, copper not only
shows good catalytic activity, but also is one of the most
readily available metals.
b-Ketosulfones important synthetic intermediates, which
have been widely used in the construction of natural products,
such as lycopodine alkaloid,[10] polyfunctionalized 4H-
pyrans,[11] quinolines,[12] vinyl sulfones, among others. They
can be easily transformed into the corresponding alkynes,[13]
epoxy sulfones, and b-hydoxysulfones. They are also used in
antifungal and antibacterial drugs, and are potent nonnucleo-
side inhibitors. owing to their good reactivity and synthetic
utility, numerous methods have been reported for their
preparation.[14] The general method is a traditional coupling:
the alkylation of sodium sulfinates with phenacyl halide
(Scheme 1a). However, they often have drawbacks, such as
Mechanistic studies indicated that this transformation involved
2
À
copper-catalyzed N O bond cleavage, activation of a vinyl sp
À
À
C H bond, and C S bond formation. The oxime acetates act
as both a substrate and an oxidant, thus the reaction needs no
additional oxidants or additives.
O
xidative coupling has emerged as an attractive and
challenging method to construct carbon–carbon and
carbon–heteroatom bonds, an eco-friendly and green
method.[1] This strategy has been realized by many kinds of
catalysts, such as enzymes, organocatalysts, transition
metals,[2] among others. Transition-metal-catalyzed oxidative
coupling reactions, generally with the use of oxidants, have
successfully been developed and applied in laboratory and
industrial chemical syntheses;[3] these have many advantages,
such as simplifying reaction steps, reducing waste, and
maximizing resource efficiency. However, it also faces some
challenges: the late transition metal catalysts are expensive
and toxic, and stoichiometric amounts of oxidants, such as
PhI(OAc)2, H2O2, and copper salts, are needed. Therefore,
the first-row transition metals, especially copper[4] and iron,[5]
have received more and more attention recently, owing to
their availability, low cost, low toxicity, and ease of use. To
solve the oxidant problem, green oxidants such as O2[6] or an
internal oxidant[7] are used. Reactions that use an internal
Scheme 1. Traditional coupling and oxidative coupling reactions.
OTs=para-toluenesulfonate.
prolonged reaction times, the use of expensive reagents,
multistep syntheses, and the limitations of phenacyl halide.
The biggest problem is the limitations of the reaction
substrates. Therefore, it is meaningful and challenging to
develop new methods that use new reagents and go through
a new mechanism to obtain b-ketosulfones. Based on our
previous work with sodium sulfinates (Scheme 2a),[15a] oxime
acetates (Scheme 2b),[15b] and copper-catalyzed carbon–het-
eroatom bond and carbon–carbon bond construction,[15c–f] we
wondered whether we could construct b-ketosulfones through
oxidative coupling using copper as a catalyst and green
oxidants such as O2 or an internal oxidant (Scheme 1b).
Herein, we report a copper-catalyzed synthesis of sulfone
derivatives from oxime acetates and sodium sulfinates
(Scheme 2c). The oxime acetates are used as an internal
oxidant; external oxidants are not necessary. To the best of
our knowledge, it is the first example of the construction of b-
[*] X. Tang, L. Huang, Y. Xu, J. Yang, Dr. W. Wu, Prof. Dr. H. Jiang
School of Chemistry and Chemical Engineering, South China
University of Technology
E-mail: jianghf@scut.edu.cn
Homepage: http://www2.scut.edu.cn/ce/lshxyjzx/links.html
[**] This work was supported by the National Basic Research Program of
China (973 Program) (2011CB808600), the National Natural
Science Foundation of China (21172076), the Guangdong Natural
Science Foundation (10351064101000000), and the Fundamental
Research Funds for the Central Universities (2014ZP0004 and
2014ZZ0046).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201311217.
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respectively, with toluene giving the best result for this
reaction. Thus, the optimized catalytic system for this copper-
catalyzed coupling reaction was: 1a (0.5 mmol), 2a
(0.5 mmol), Cu(OAc)2 (10 mol%), in toluene at 1008C
under N2 for 6 h.
With the optimized reaction conditions in hand, we then
explored the scope of the substrates (Scheme 3). The products
3aa, 3ja, 3ka, 3la, and 3ta were isolated in good to excellent
yields (72–92%). A single crystal of product 3ta was obtained
Scheme 2. Copper catalyzed coupling reactions.
ketosulfones and b-sulfonylvinylamines by transition-metal-
À
catalyzed direct C S bond formation through oxidative
2
À
coupling with vinyl sp C H bonds using internal oxidant.
Our initial investigations of this copper-catalyzed cou-
pling of oxime acetates with sodium sulfinates focused on
acetophenone oxime acetate (1a) with sodium p-toluenesul-
finate (2a) in the presence of CuI in toluene at 1008C under
N2. We were excited that the desired product 3aa could be
detected in 77% yield (Table 1, entry 1). The screening of
Scheme 3. Preliminary substrate screen. All reactions were performed
with 1 (0.5 mmol), 2a (0.5 mmol), Cu(OAc)2 (10 mol%), in toluene
(2 mL) at 1008C under N2 for 6 h. Yields shown are of isolated
products.
Table 1: Impact of reaction parameters on the coupling of oxime acetate
with sodium sulfinate.[a]
by slow crystallization from a mixture of petroleum ether and
ethyl acetate, and its structure was confirmed by single-crystal
X-ray analysis.[16] Owing to the intramolecular hydrogen
bonding between the sulfone groups and amine, the enamine
has a Z alkene geometry. To the best of our knowledge, very
few methods have been developed to construct b-sulfonylvi-
nylamines.[17,18]
Entry
Catalyst
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
CuI
CuBr
CuCl
Cu(OTf)2
CuBr2
CuCl2
Cu(OAc)2
none
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
77
82
85
80
82
84
95 (92)
0
62
As b-ketosulfones are important synthons, we decided to
take b-ketosulfones as our final product (catalytic reaction
followed by hydrolysis), to explore this transformation
(Scheme 4). Various oxime acetates could couple with
sodium p-tolylsulfinate to form sulfonylvinylamine, which
was transformed into b-ketosulfones after hydrolysis. Differ-
ent para-substituted acetophenone oxime acetates could be
converted into the corresponding b-ketosulfones in good to
excellent yields (4aa–4ia), and electron-withdrawing groups
did not show a positive effect on our reaction. When using the
ortho-substituted acetophenone oxime acetates (F and OMe)
as the substrates, the corresponding products were formed in
73% and 94% yields, respectively (4ma–4na). When the
meta position is substituted with CH3, F, Cl, or Br, the
products were obtained in 89%, 75%, 81%, and 70% yields,
respectively (4oa–4ra). The substrates 3’,4’-dimethylaceto-
phenone, propiophenone, and n-butyrophenone oxime ace-
tates also gave good yields of b-ketosulfones 4sa–4va.
Heteroaromatic substrtates such as thiophene oxime acetate
could give 4wa in 78% yield. Unfortunately, alkyl oxime
acetates were not suitable for our reaction. 3ja, 3ka, 3la, and
3ta could also not undergo the hydrolysis process to afford
9
10
11
12
1,4-dioxane
DMF
DMSO
81
76
87
[a] Unless otherwise noted, all reactions were performed with 1a
(0.5 mmol), 2a (0.5 mmol), and catalyst (10 mol%), in 2 mL solvent at
1008C for 6 h. [b] Yields determined by GC analysis; value in parenthesis
is the yield of the isolated product. Ac=acetyl, Tf=trifluoromethane-
sulfonyl.
different copper salts, such as CuBr, CuCl, Cu(OTf)2, CuBr2,
CuCl2, and Cu(OAc)2, revealed that 3aa could be formed in
good yields (entries 2–7). Cu(OAc)2 was found to be the best
and the yield could reach 95%. Other metal species such as
AgCl, NiCl2, MnCl3, PdCl2, and CoCl2 did not show any
catalytic activity, and no product was formed without metal
catalysts (entry 8). Different solvents were also examined
(entries 9–12). When 1,2-dichloroethane (DCE), 1,4-dioxane,
N,N-dimethylformamide (DMF), and DMSO were used as
solvents, the yields of 3aa were 62%, 81%, 76%, and 87%,
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thalenesulfinate could also transform into the corresponding
products in 81% and 76% yields (4ah–4ai). We are excited
that aliphatic sulfinic acid sodium salts were also good starting
materials, and the desired products were formed in good
yields (4aj–4al).
To investigate the reaction mechanism, several experi-
ments were performed. When the radical scavenger 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) was added to our
reaction, no product was detected, which indicated that
a radical pathway might be involved [Eq. (1)]. However,
when we tried to use 1,1-diphenylethylene to trap the radical
in the presence or absence of oxime acetates, the yields of the
radical coupling products were very low [Eqs. (2) and (3)].
Scheme 4. Substrate scope of various oxime acetates. All reactions
were performed with 1 (0.5 mmol), 2a (0.5 mmol), Cu(OAc)2
(10 mol%), in toluene (2 mL) at 1008C under N2 for 6 h, followed by
stirring in CH2Cl2 with silica gel at room temperature overnight. Yields
shown are of isolated products.
the corresponding b-ketosulfones under the same conditions.
When stronger acids such as hydrochloric acid and acetic acid
were used, the corresponding ketones were formed.
Based on the optimization study, the scope of the sodium
sulfinates was also studied; the results are summarized in
Scheme 5. The nature of the sulfinic acid sodium salts did not
have a great effect on the results. However, the electron-
donating groups were advantageous to the reaction. When
sodium benzenesulfinate was used as substrate, the corre-
sponding product 4ab was formed in 93% yield. Various para-
substituted sodium benzenesulfinates such as those bearing F,
Cl, Br, CF3, or OMe groups afforded the products 4ac–4ag in
good yields. Sodium 2-chlorobenzenesulfinate and 2-naph-
Therefore, we could not overlook an organometallic pathway
in this transformation. The plausible mechanisms that ration-
alize the observed results are shown in Scheme 6. One
proposed mechanism is that acetophenone oxime acetate
1 was easily converted into copper enamide intermediate 2 by
the copper catalyst and another CuII was obtained in this
Scheme 5. Substrate scope of various sodium sulfinates. All reactions
were performed with 1a (0.5 mmol), 2 (0.5 mmol), Cu(OAc)2
(10 mol%), in toluene (2 mL) at 1008C under N2 for 6 h, followed by
stirring in CH2Cl2 with silica gel at room temperature overnight. Yields
shown are of isolated products.
Scheme 6. Studies on the reaction mechanism for the copper-cata-
lyzed coupling of oxime acetates with sodium sulfinates
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cess and released CuI. The final product 8 is the tautomeric
form of intermediate 7 (path a). Another possible mechanism
might involve organo-copper(III) intermediates. First, inter-
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[16] CCDC 965756 (3ta) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. A single crystal of product
3ta is in Supporting Information.
À
mediate 4 was formed by oxidative addition of the N O bond
of 1 to CuI.[9i,j] Coordination of sodium sulfinates to 4 formed
intermediate 5 and simultaneously released NaOAc. Then,
intermediate 6 was obtained after tautomerization and the
CuIII species activated the vinyl C H. Finally, the desired
À
product 8 was generated from reductive elimination of
intermediate 6 (path b).[20]
In conclusion, we have developed a novel method for the
synthesis of sulfone derivatives through the copper-catalyzed
coupling of oxime acetates with sodium sulfinates. This
À
process involves copper-catalyzed N O bond cleavage, acti-
2
À
À
vation of a vinyl sp C H bond, and C S bond formation. The
present method employs simple oxime acetates and sodium
sulfinates to synthesize sulfonylvinylamine products. Upon
hydrolysis, useful b-ketosulfones are also obtained. Oxime
acetates act not only as a substrate, but also as an oxidant, thus
the reaction needs no additional oxidants or additives.
Received: December 26, 2013
Published online: February 20, 2014
À
Keywords: C H activation · copper · cleavage reactions ·
sulfone derivatives
.
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