Copper-catalyzed aerobic oxidative N-S bond functionalization for C-S bond formation: Regio- and stereoselective synthesis of sulfones and thioethers

Article abstract of DOI:10.1002/chem.201402815

A regio- and stereoselective synthesis of sulfones and thioethers by means of Cu^I-catalyzed aerobic oxidative N-S bond cleavage of sulfonyl hydrazides, followed by cross-coupling reactions with alkenes and aromatic compounds to form the C-sp-2-S bond, is described herein. N₂ and H₂O are the byproducts of this transformation, thus offering an environmentally benign process with a wide range of potential applications in organic synthesis and medicinal chemistry. First cleave, then cross-couple: A direct Cu-catalyzed aerobic oxidative C-sp-2-H functionalization and C-S bond coupling reaction has been developed (see scheme). By slight modification of the additive, sulfonyl hydrazides could serve as sulfonation, sulfenation, or arylation reagents to undergo cross-coupling reactions with alkenes and (hetero)aromatic cycles, affording sulfones, thioethers, and biaryl compounds with high regio- and stereoselectivities (see scheme).

Full text of DOI:10.1002/chem.201402815

DOI: 10.1002/chem.201402815
Communication
&
Synthetic Methods
Copper-Catalyzed Aerobic Oxidative NÀS Bond Functionalization
for CÀS Bond Formation: Regio- and Stereoselective Synthesis of
Sulfones and Thioethers
Xianwei Li, Yanli Xu, Wanqing Wu, Chang Jiang, Chaorong Qi, and Huanfeng Jiang*[a]
cles, and reductants, and can also be used as aryl sources by
Abstract: A regio- and stereoselective synthesis of sul-
means of CÀS bond cleavage. More significantly, they could
fones and thioethers by means of CuI-catalyzed aerobic
also serve as sulfone or thioether sources by means of NÀS
and/or SÀO bond cleavage.[7] Compared to other sulfenylation/
sulfonation agents, sulfonyl hydrazides are not sensitive to air
and moisture, they are easy to prepare, and more importantly,
N2 and water are the only byproducts.
oxidative NÀS bond cleavage of sulfonyl hydrazides, fol-
lowed by cross-coupling reactions with alkenes and aro-
matic compounds to form the Csp2ÀS bond, is described
herein. N2 and H2O are the byproducts of this transforma-
tion, thus offering an environmentally benign process
with a wide range of potential applications in organic syn-
thesis and medicinal chemistry.
Recently, we have developed a copper-catalyzed aerobic oxi-
dative cross-coupling of Csp2ÀX bonds with DMSO to afford
aryl/vinyl (methyl)sulfones by means of oxidative cleavage of
the CÀS bond of DMSO[8a] (Scheme 1). A copper-catalyzed
aerobic oxidative Csp3ÀH bond functionalization of the a posi-
tion of ketone derivatives, leading to b-ketosulfones, was also
developed by our group.[8b] Lei et al. developed an elegant
oxygen-triggered oxysulfonylation of alkenes and alkynes to
furnish b-hydroxysulfones or b-ketosulfones.[8c,d] Willis et al. fur-
ther utilized their palladium-catalyzed aminosulfonylation pro-
cess in a three-component one-pot sulfone synthesis, compro-
mising of Csp2ÀX bonds, a sulfonyl unit, and an electrophilic
coupling partner.[8e,f]
Owing to concerns about reserves of fossil fuels decreasing
and environmental pollution increasing, an urgent demand for
organic chemists is to find alternative sustainable processes to
build privileged structures through selective functionalization
of unreactive CÀH bonds.[1] In this context, copper-catalyzed
aerobic oxidative functionalization of organic molecules, with
the advantage of low cost, abundance, and the versatility of
a Cu/O2 catalytic system, provide a new route towards these
targets.[2] However, great challenges still remain with respect
to synthetic scope, chemo-, regio-, and stereoselectivity; cata-
lytic systems that are capable of performing selective CÀH oxi-
dation in substrates bearing electron-rich nitrogen functional
groups are extremely scarce.
Complementary to conventional synthetic strategies, based
on CÀX bond functionalization, we envisioned that these mole-
cules could be expeditiously accessed by means of oxidative
functionalization of Csp2ÀH bonds, therefore, reducing the reli-
ance on existing functional groups. As part of our continuous
The last several decades have witnessed great advances in
transition-metal-catalyzed CÀC and CÀheteroatom (N, O, P)
bond formations,[3] however, the efficient construction of CÀS
bonds with high selectivity remains relatively unexplored,
probably owing to the deactivation of the catalyst by the
sulfur species.[4] On the other hand, sulfur-containing mole-
cules, such as sulfones and thioethers, are of great demand in
the pharmaceutical industry, in materials science, and they are
also important synthetic building blocks.[5] Despite longstand-
ing biological and synthetic interest, direct access to this im-
portant class of compounds is complicated by the lack of effi-
cient, safe, and general methods for their synthesis.[6]
Sulfonyl hydrazides are readily accessible synthetic inter-
mediates that can be used to construct hydrazones, heterocy-
[a] X. Li, Y. Xu, Dr. W. Wu, C. Jiang, Dr. C. Qi, Prof. Dr. H. Jiang
School of Chemistry and Chemical Engineering
South China University of Technology
E-mail: jianghf@scut.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402815.
Scheme 1. Copper-catalyzed aerobic oxidative Csp2ÀS bond formation.
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efforts towards dioxygen activation and copper-catalyzed aero-
bic oxidative functionalization of organic molecules,[9] herein,
we report a copper-catalyzed aerobic oxidative cross-coupling
of alkenes or aromatic compounds with sulfonyl hydrazides to
construct Csp2ÀS bonds by means of NÀS bond and/or SÀO
bond cleavage, affording vinyl sulfones and aromatic thio-
ethers. This transformation features an inexpensive catalyst,
a green oxidant from readily available starting materials, and
N2 and H2O byproducts to afford the synthetically valuable in-
termediates and privileged drug scaffolds.
Table 2. CuII-catalyzed oxidative sulfonations of alkenes.[a]
Our studies began by examining the oxidative functionaliza-
tion of styrene (1a) and p-toluene sulfonohydrazide (2a) for
CÀS bond formation, in the presence of CuCl catalyst in DMSO,
under air (Table 1, entry 1). With the use of 1,4-diazabicyclo-
Table 1. Optimization of reaction conditions.[a]
[a] Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), CuCl (5 mol%), and
LiBr (0.5 mmol) in 2.0 mL of DMSO under air, at 1008C for 12 h. Yields are
those of the isolated product.
Entry
Cu source
Additive
Yield [%]
1
2
3
4
5
6
7
8
CuCl
CuCl2
Cu(OAc)2
Cu(OTf)2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
–
DABCO
DABCO
DABCO
DABCO
phen
bpy
PPh3
LiBr
LiBr
55
23
46
38
43
naphthalene (3g), could afford the desired products in moder-
ate to high yields. The use of a heteroaromatic alkene (3n)
also led to the cross-coupling product in good yield. The com-
patibility of nitrile (3h), amide (3i), ester (3m), chloride (3e),
nitro (3 f and 3l), and trifluoromethyl (3k) functional groups
means that this oxidative cross-coupling reaction has great po-
tential for application in the late-stage modifications of ad-
vanced intermediates in medicines and materials. An electronic
effect was not evident for the alkene partners in this CÀH sul-
fonation, whereas the steric effect was critical for the reactivity.
Unfortunately, increased substitution of the alkenes was not
tolerated with the current catalytic system. However, allyl-type
alkenes could deliver the allylic-substituted sulfonation prod-
ucts in moderate yield (3t–3w). It is worth noting that for all
the CÀH sulfonation products, only trans-1,2-disubstituted vi-
nylsulfones were observed. No trace of the cis-vinyl isomer, nor
1,1-disubstituted regioisomeric sulfones have been detected.
With respect to sulfone hydrazides, various aliphatic and aro-
matic substituents were shown to be suitable cross-coupling
partners (3a, 3j, and 3o–3s) for this oxidative transformation.
Substrate 1x underwent CÀO bond cleavage[10] under the
standard conditions, affording 3x as the product. The reaction
also demonstrated great chemoselectivity when using 1y bear-
ing vinyl and allyl substituents, with 2b as the substrate, under
the standard conditions; 3y was selectively formed and the
allyl group remained intact. However, disubstituted alkene 1z
gave no desired product under the optimal conditions.
28
trace
92 (88)
trace
<10
18
9
10
11
12
LiBr
LiBr
–
trace
[a] Reaction conditions: 1a (0.5 mmol), 2a (1.5 mmol), [Cu] (10 mol%),
and additive (0.3 equiv) in 2.0 mL of solvent under O2 (1 atm), at 808C for
12 h. [b] Determined by GC analysis. Number in parentheses is yield of
isolated product. [c] Toluene was used as the solvent. [d] The reaction
was conducted under N2 atmosphere. OTf=triflate; phen=1,10-phenan-
throline; bpy=2,2’-bipyridine.
octane (DABCO) as the additive, several copper catalysts were
tested; CuCl showed superior reactivity towards this transfor-
mation (Table 1, entries 1–4). Further investigation of the addi-
tives revealed that LiBr was the best additive, whereas phos-
phorus ligands gave no desired product. It should be noted
that b-keto sulfones, recently developed by Lei et al.,[8c] were
also detected when nitrogen ligands were added to this cata-
lytic system (Table 1, entries 5 and 6). With respect to solvents,
DMSO was found to be important for this oxidative cross-cou-
pling reaction. When DMSO was replaced by toluene, product
2a could not be obtained. Control experiments suggested that
copper and air were essential to this reaction. In their absence
only trace amounts of the desired product could be detected.
With the optimized conditions in hand, we explored the
generality of this methodology and the results are summarized
in Table 2. The scope of the alkenes was first explored, and an
array of alkenes bearing electron-withdrawing and electron-do-
nating substituents on the phenyl ring (3a–3 f), as well as
Inspired by the success of developing oxidative alkene Csp2
À
H sulfonations, we wondered whether we could further ex-
plore the Csp2ÀH bond of heteroaromatic rings, which have
great synthetic potential in medicines and materials.
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Figure 1. Sulfur-containing biologically active molecules.
c are potent and selective serotonin 5-HT6-receptor (5-HT6R)
antagonists[13]
We first thought to investigate indoles[11] because of their
wide existence in nature, important biological activities, and
wide applications as pharmaceuticals and agricultural chemi-
cals. Thus, selective functionalization of the CÀH bonds of in-
doles has attracted much attention from both academia and
industry.[12] To our delight, by slight modification of the addi-
tive in this oxidative transformation (see the Supporting Infor-
mation for details), C3ÀH sulfenation of indoles 4, which un-
derwent NÀS bond cleavage, SÀO bond cleavage, and CÀS
bond formation, to obtain compounds 5 as the major product
with great regioselectivity. Trace amounts of C2ÀH sulfonation
products 5’ could also be detected (see the Supporting Infor-
mation for details). It is noteworthy that even when the reac-
tions were performed using oxidants, such as BQ (p-benzoqui-
none), DDQ (2,3-dicholro-5,6-dicyano-1,4-benzoquinone) H2O2
or K2S2O8, the yield of 5’ did not increase. As summarized in
Table 3, functional groups, such as ether (5 f) and halide (5c–
5h) groups at the C5-position of NÀH indoles could be well
tolerated in this process. Furthermore, NÀMe, C2ÀMe, C3ÀMe,
and C7ÀMe indole thioethers could also be obtained with
moderate yield.
.
The success of oxidative-functionalized indole derivatives in-
spired us to investigate a variety of electron-rich (hetero)aro-
matic rings,[14] owing to their great significance in medicines
and advanced materials. As depicted in Table 4, 1,3,5-trime-
Table 4. Oxidative sulfenation of heterocycles.[a]
The heterocyclic aromatic sulfene skeleton has proven to be
a useful building block in organic synthesis, medicinal chemis-
try, and natural-product synthesis. It exists widely in pharma-
ceutical molecules, such as enzyme inhibitors and biologically
active antagonists, which are exemplified in Figure 1. Com-
pound a is a novel, potent, and highly selective HIV-1 non-nu-
cleoside reverse transcriptase inhibitor. Compounds b and
[a] Reaction conditions:
DABCO (0.5 mmol) in 2.0 mL of DMSO under air at 1008C for 12 h.
4 (0.5 mmol), 2 (0.5 mmol), CuCl (5 mol%),
thoxybenzene 6a could be transformed into the correspond-
ing thioether in good yield. Although mesitylene 6b could un-
dergo the cross-coupling reaction with low yield, the main by-
products were oxidative homocoupling isomers.[15a] N-Hetero-
cycles, such as pyrimidine,[15b] 2-phenylpyridine,[15c] and
imidazo[1,2-a]pyridine,[15d] could all be thiolated, regioselective-
ly, in moderate yield. Furthermore, naphthols (7 f and 7g) were
good coupling partners to afford the corresponding sulfena-
tion products. The corresponding sulfamide could be detected
when b-naphthylamine was used as substrate.[16] It should be
noted that functionalized 2-naphthenols are precursors for
dyes and the synthetically valuable ligand azobisisobutyro-
nitrile (BINAP), and 1-naphthenols are important intermediates
for insecticides and pharmaceuticals. N-Phenylacetamide could
also undergo the CÀH sulfenation reaction, however, with low
efficiency.[15e]
Table 3. Substrate scope of indoles.[a]
To gain further insights into this reaction, firstly, we per-
formed experiments with the addition of a radical scavenger
(2,2,6,6-tetramethylpiperidine, TEMPO; butylated hydroxy-
toluene, BHT; and 1,4-nitrobenzene) under the optimized con-
ditions. However, the reaction proceeded with a slightly de-
[a] Reaction conditions:
DABCO (0.5 mmol) in 2.0 mL of DMSO under air, at 1008C for 12 h.
4 (0.5 mmol), 2 (0.5 mmol), CuCl (5 mol%),
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drazides 2 into 2’ takes place, with the release of N2 and H2O.
Subsequently, 2’ reacts with copper complex A to afford the
active sulfenyl cuprate, B,[18] or sulfonyl cuprate B’, which
reacts further with alkenes 1 or aromatic rings 4 to afford the
corresponding sulfones 3 or sulfenes 5, respectively, with the
addition of different additives. It was speculated that DMSO
might also serve as a co-oxidant in this process,[19] and dime-
thylsulfane was detected by GC-MS analysis. However, the pre-
cise mechanism regarding the chemoselectivity towards al-
kenes and aromatic rings, to afford sulfones or thioethers, is
not clear currently.
In summary, we have developed a copper/air catalytic
system for the regio- and stereoselective sulfonation, or sulfe-
nation, of alkenes and (hetero)aromatic cycles through NÀS
and/or SÀO bond cleavage of sulfonyl hydrazides. This trans-
formation provides a general method to afford synthetically
valuable sulfones and thioethers, and features sustainable
chemistry while utilizing sulfonyl hydrazides as the versatile
sulfur source, with N2 and water as the byproducts. Further
study the mechanism of this reaction, and efforts to develop
significant utility in a variety of synthetic applications of this
copper/air system, are the focus of current investigations.
Scheme 2. Mechanistic studies.
creased yield [Scheme 2, Eq. (1)]. These results suggested that
a radical process might not be involved in this transformation.
Furthermore, during our optimization studies for the sulfena-
tion of indoles, we observed that the addition of LiCl led to
C2-arylated product [Scheme 2, Eq. (2)]. This CÀH arylation
result not only highlighted the rich chemistry of sulfone hydra-
zides in the cross-coupling reactions, complementing the
copper-catalyzed Csp2ÀH sulfonations and sulfenations, but also
demonstrated that an RCu intermediate could be generated in
this process.
Acknowledgements
We thank the National Natural Science Foundation of China
(21172076 and 21202046), National Basic Research Program of
China (973 Program; 2011CB808600), Guangdong Natural Sci-
ence Foundation (10351064101000000 and S2012040007088),
and the Fundamental Research Funds for the Central Universi-
ties (2014ZP0004 and 2014ZZ0046) for financial support.
It is worth noting that sulfonothioate 2a’, a byproduct ob-
served in the reaction, could react with indole 2a under the
optimal conditions to afford 5a in 78% yield. Thus, we specu-
lated that 2a was the active sulfenating agent. This observa-
tion was in accordance with findings by Yang and Tian[7a] and
Cheng et al.[18a]
Although comprehensive studies are required to elucidate
the mechanistic details of the present reaction, on the basis of
the above results, a tentative mechanism for the oxidative NÀS
bond functionalizations for CÀS bond cross-coupling is pro-
posed (Scheme 3). It is envisioned that, initially, with the aid of
a copper catalyst, air oxidative decomposition of sulfonyl hy-
Keywords: CÀH functionalization
sulfones · thioethers
·
copper
·
oxygen
·
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Received: March 28, 2014
Revised: April 25, 2014
[12] a) G. W. Gribble, in Topics in Heterocyclic Chemistry: Heterocyclic Scaffolds
II: Reactions and Applications of Indoles Vol. 26, Springer, Heidelberg,
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Synthetic Methods
X. Li, Y. Xu, W. Wu, C. Jiang, C. Qi,
H. Jiang*
&& – &&
Copper-Catalyzed Aerobic Oxidative
NÀS Bond Functionalization for CÀS
Bond Formation: Regio- and
Stereoselective Synthesis of Sulfones
and Thioethers
First cleave, then cross-couple: A
lation reagents to undergo cross-cou-
pling reactions with alkenes and (heter-
o)aromatic cycles, affording sulfones,
thioethers, and biaryl compounds with
high regio- and stereoselectivities (see
scheme).
direct Cu-catalyzed aerobic oxidative
Csp2ÀH functionalization and CÀS bond
coupling reaction has been developed
(see scheme). By slight modification of
the additive, sulfonyl hydrazides could
serve as sulfonation, sulfenation, or ary-
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!