Acid Promoted Direct Cross-Coupling of Methyl Ketones with Dimethyl Sulfoxide: Access to Ketoallyl Methylsulfides and -sulfones

Article abstract of DOI:10.1021/acs.orglett.7b02753

A new strategy to prepare β-acyl allylic methylsulfides and -sulfones through acid promoted direct cross-coupling of methyl ketones with dimethyl sulfoxide (DMSO) is reported. The reaction proceeded through the nucleophilic attack of enamine intermidiates derived from ketones to in situ generated thionium ion species, followed by elimination of methanthiol to give ketoallylic methylsulfides. With the prolonged reaction time, such products could be further reacted with a methyl sulfonyl radical, which might be generated from a methylthiosulfonate species, to afford ketoallylic methylsulfones in high yields. Molecular transformations of the allylic methylsulfides were also demonstrated.

Full text of DOI:10.1021/acs.orglett.7b02753

Letter
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
pubs.acs.org/OrgLett
Acid Promoted Direct Cross-Coupling of Methyl Ketones with
Dimethyl Sulfoxide: Access to Ketoallyl Methylsulfides and -sulfones
,†
†
†
‡
Zhen-Kang Wen,* Xue-Hua Liu, Yu-Fang Liu, and Jian-Bin Chao
†School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China
‡Scientific Instrument Center, Shanxi University, Taiyuan 030006, China
*
S Supporting Information
ABSTRACT: A new strategy to prepare β-acyl allylic methylsulfides and -sulfones through acid promoted direct cross-coupling
of methyl ketones with dimethyl sulfoxide (DMSO) is reported. The reaction proceeded through the nucleophilic attack of
enamine intermidiates derived from ketones to in situ generated thionium ion species, followed by elimination of methanthiol to
give ketoallylic methylsulfides. With the prolonged reaction time, such products could be further reacted with a methyl sulfonyl
radical, which might be generated from a methylthiosulfonate species, to afford ketoallylic methylsulfones in high yields.
Molecular transformations of the allylic methylsulfides were also demonstrated.
1
rganosulfur compounds have played an important role in
organic chemistry and the drug discovery process owing to
Scheme 1. Synthetic Application of DMSO as Sulfur Source
O
their unique properties and potential pharmaceutical applica-
tions. Notably, among the US top selling drugs in 2012, about
2
2
0% of the pharmaceuticals are organosulfur compounds.
1
a−f,3
During the past decades, many methods
have been
established for synthesis of organosulfur compounds, including
Michael-type addition, nucleophilic substitution, and transition
metal catalyzed C−H functionalizaiton. However, most of these
methods need the use of odorous mercaptans, prefunctionalized
substrates, and/or the requisite expensive transition metal
catalysts. Therefore, exploration of novel and sustainable
approaches that can access multifunctional organosulfur
compounds from simple starting materials is still in great
demand.
As a cheap and commercially available polar aprotic solvent,
dimethyl sulfoxide (DMSO) has been widely used in organic
synthesis owing to its rather low cost, relative stability, and low
rarely reported. This is presumably due to the C(sp3)
nucleophiles being incompatible with the electrophilic activation6
DMSO conditions, which resulted in a number of side reactions.
4
toxicity. From a viewpoint of cost efficiency and step economy,
9
it is considered to be one of the most ideal sulfur sources for
assembly of the high-value organosulfur compounds. In this
Inspired by a recent synergistic Pd/enamine strategy for the
direct functionalization of unactivated ketones, we envisaged that
whether or not an enamine intermediate derived from a ketone
could react with the activated DMSO, this would provide a
promising chance to achieve direct cross-coupling of methyl
ketones with DMSO. Herein, we report an unprecedented acid
promoted direct cross-coupling reaction of methyl ketones with
5
context, the Pummerer rearrangement offers a straightforward
protocol for construction of functionalized thioethers, in which
DMSO served as an electrophilic −CH SCH unit, while amides,
2
3
azides, phenols, arenes, and alkenes could be employed as the
6
nuclephiles. Recently, transiton metal catalyzed introduction of
10
7
8
DMSO, which can access β-acyl allylic methylsulfides and
sulfones in high yields (Scheme 1b). The reaction proceeded
a methylthio (MeS−) or methylsulfinyl (MeSO−) group into
-
arenes or alkynes using DMSO was also documented (Scheme
with excellent functional group compatibility and a broad
1a). Despite these advances, all the above-mentioned carbon
nucleophiles are thus far largely restricted to arenes, alkenes, or
3
alkynes, whereas the direct functionalization of C(sp )−H bonds
Received: September 4, 2017
by installation of a sulfur-containing unit from DMSO has been
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02753
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
substrate scope. Significantly, this protocol will undoubtedly
provide a facile route to access valuable organosulfur compounds
from simple starting materials.
Chart 1. Substate Scope for the Reaction of Methyl Ketones
with DMSO
,
ab
We commenced our study with acetophenone (1a) as the
model substrate in DMSO/HOAc (4:1) at 120 °C. Interestingly,
when pyrolidine (A) was employed to generate the enamine
intermediate, ketoallylic methylsufide 2a was formed in 54%
yield (Table 1, entries 1−2). Further investigation showed that
Table 1. Optimization Reaction Conditions for the Coupling
Reaction of Methyl Ketone with DMSO
a
b
entry
base
additive
amine
yield (%)
1
2
3
4
5
6
7
8
9
−
−
−
−
−
−
A
A
A
A
A
A
B
C
D
A
8
54
63
74
62
63
65
0
NaOAc
NaOAc
LiOAc
KOAc
CsOAc
NaOAc
NaOAc
NaOAc
NaOAc
TsOH·H O
TsOH·H O
TsOH·H O
TsOH·H O
TsOH·H O
TsOH·H O
TsOH·H O
TsOH·H O
2
2
2
2
2
0
2
a
10
1
20
81
Conditions: The reaction was conducted with acetophenone (0.25
mmol, 1 equiv), pyrrolidine (0.25 mmol, 1 equiv), NaOAc (0.2 mmol,
2
c
1
2
a
0.8 equiv), TsOH·H O (0.25 mmol, 1 equiv), solvent = HOAc (2
2
Conditions: the reaction was conducted with acetophenone (0.25
mL), and DMSO (0.5 mL), at 150 °C for 2 h, unless otherwise noted.
mmol, 1 equiv), amine (0.25 mmol, 1 equiv), base (0.2 mmol, 0.8
b
The yields indicated were determined upon isolation.
equiv), additive (0.25 mmol, 1 equiv), solvent = HOAc/DMSO.
b
c
Isolated yield. The reaction was run for 2 h at 150 °C.
thiophene, and benzofuran; all these substrates were tolerated
and afforded the desired products in high yields (2o, 2s−x).
Remarkably, when 1a was treated with 1 equiv of pyrrolidine in
DMSO/HOAc (1:4) in the presence of 2 equiv of TsOH·H O as
2
an additive at 150 °C for 6 h, an allylic sulfone product 3a could
using NaOAc as the base could increase the yield of 2a (entry 3).
We were pleased to find that the combination of NaOAc with
11
be obtained in 60% yield (eq 1). This result led us to develop
another cascade process for the synthesis of allylic methysul-
fones.
TsOH·H O exhibited excellent reactivity, which afforded 2a in
2
74% yield (entry 4), while other bases such as LiOAc, KOAc, and
CsOAc delivered 2a in slightly lower yields (entries 5−7). Other
amines such as 2,3-dihydro-7-azaindole (B), 2-aminopyridine
(C) and L-proline (D) instead of pyrolidine resulted in low yields
or no reaction (entries 8−10). A brief examination of
temperature revealed that 2a could be isolated in 81% yield at
1
50 °C for 2 h (entry 11). Thus, the standard conditions were
As depicted in Chart 2, all of the reactions worked well and
gave the ketoallylic methylsulfone products in good to excellent
yields. The substituents at different positions (ortho-, meta-, para-
) on the phenyl ring of arylketones (3b−d) had no obvious
influence on the yields. Both electron-withdrawing and -donating
group functionalized arylketones afforded the corresponding
ketoallylic methylsulfone products in good yields (3e−h). The
current process also tolerates halogenated substrates (3i−l)
especially the bromo and iodo group, which exhibited a variety of
versatile synthetic handles in further elaboration. Notably, free
hydroxyl and amine groups were compatible in this reaction and
gave the desired products in moderate to good yields (3m, 3n).
Furthermore, other aryl and heteroaryl ketones, in particular,
naphthalene-, thiophene-, benzofuran-, furan-, thiophene-, and
pyridine-containing substrates (3o−t) were applicable to this
process and afforded the corresponding products in reasonable
yields.
established as follows: the mixture of acetophenone (0.25
mmol), DMSO (0.5 mL), NaOAc (0.8 equiv), and TsOH·H O
2
(
1 equiv) in HOAc (2 mL) was stirred for 2 h at 150 °C.
With the optimized reaction conditions in hand, we examined
the generality of this unique reaction for the synthesis of allylic
sulfur substituted α,β-unsatrurated ketone products 2 from
ketones 1 and DMSO. As shown in Chart 1, all reactions
proceeded well to provide the corresponding products in good to
excellent yields. Both electron-donating and -withdrawing group
substituted aryl ketones efficiently reacted with DMSO in good
to excellent yields (2b-d, 2f, 2g). Moreover, ortho-, meta-, and
para-substituted aryl ketones were all tolerated and provided the
desired products in high yields (2j−n). Various functional groups
such as phenyl, F, Br, Cl, and free OH also yielded the
corresponding products in high yields (2e, 2i, 2p−r). In addition,
2-naphthalene methyl ketone could react well and gave 2h in
good yield. Finally, efforts were taken to expand this protocol to
other functionalized heteroaryl ketones such as pyridine, furan,
To gain insight into the mechanism of the direct cross-
coupling of methyl ketone with DMSO, several experiments
B
DOI: 10.1021/acs.orglett.7b02753
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chart 2. Substrate Scope for the Synthesis of Keto Allylic
Methylsulfones
sulfur source in this transformation with good efficiency (eq 4).
Moreover, when TEMPO was added in the reaction conditions
to prepare ketoallylic methylsulfones, only ketoallylic methyl-
sulfide 2a was obtained and no ketoallylic methylsulfone 3a was
observed (eq 5), which indicated that the allylic methylsulfone
could be formed through a radical pathway. In addition, the
successful transformations of 2a to 3a-d , 2a-d to 3a-d (eqs 6
,
a b
3
7
4
and 7) revealed that such transformations proceeded through the
addition of a MeSO unit to the double bond of 2a along with the
2
elimination of a methylthio group (−MeS). These control
experiments suggested that the allylic methylsulfide 2a was the
key intermediate in the formation of allylic methylsulfone 3a.
Based on these observation, a plausible mechanism of present
transformation was proposed as shown in Scheme 3. Initially,
Scheme 3. Proposed Mechanism for the Reaction of Methyl
Keones with DMSO
a
Conditions: The reaction was conducted with TsOH·H O (0.25
2
mmol, 1 equiv) in a mixed DMSO (0.5 mL) and acetic acid (0.5 mL)
solvent heated at 150 °C for 10 h, and then acetophenone (0.25 mmol,
1
equiv) and pyrrolidine (0.25 mmol, 1 equiv) were added to the
b
reaction mixture at 150 °C for 1 h, unless otherwise noted. The yields
indicated were determined upon isolation.
were performed (Scheme 2). Initially, the reaction of
acetophenone (1a) with DMSO-d under the standard reaction
6
Scheme 2. Control Experiments for the Mechanism Study
DMSO was activated by acid to generate a reactive electrophilic
5
e,12
thionium ion I,
which was attacked by the enamine
intermediate derived from ketone 1a to give the bisalkylsulfur-
ized intermediate III. The following hydrolysis and elimination
of MeSH provided the ketoallylic methylsufide 2a. On the other
hand, it has been reported that a methyl sulfonyl radical
(
MeSO ) could be generated via homolysis of the S−S bond of a
2
methylthiosulfonate, which was generated from the reaction of
DMSO with acetic acid in the presence of TsOH. With a
13
prolonged reaction time, such MeSO underwent addition to the
2
double bond of the resulted allylic methylsulfide 2a, leading to
allylic methylsulfone product 3a along with the release of a
methyl mercaptan radical. This radical in turn reacted with
methylthiosulfonate to regenerate MeSO with the propagation
2
of the radical chain.
Allyllic methylsulfides as well as allylic sulfones are very
14
important and quite useful building blocks in organic synthesis.
conditions afforded the deuterated products 2a-d and 2a′-d in
Therefore, further organic transformations were conducted to
demonstrate the utility of the allylic methylsulfide products
7
10
4
9% and 37% yields, respectively (eq 2), which suggested that
DMSO may behave as a source of the CH SCH3 unit.
(Scheme 4). Treatment of 2a with TsOH·H O in DMSO/HOAc
2
2
Furthermore, 2a′ could be converted to ketoallylic methylsulfide
under N for 8 h gave the allylic acetate product 6 in 75% yield.
2
2
a (eq 3) under the standard reaction conditions, confirming that
a′ was the key intermediate in this reaction process. Other
Furthermore, the combination of 2a with 2 equiv sodium p-
toluenesulfinate in DCE/HOAc (1:1) at 150 °C for 9 h afforded
the allylic p-toluenesulfonylated product 7 in high yield.
2
sulfoxides such as phenyl methyl sulfoxide could be used as a
C
DOI: 10.1021/acs.orglett.7b02753
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Scheme 4. Transformations of the Ketoallylic Methylsufide
1
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In summary, we have developed a novel acid-promoted direct
cross-coupling reaction of methyl ketones and DMSO to prepare
β-acyl allylic methylsulfides and sulfones. High yields and wide
functional group tolerance were observed. The resulting sulfur-
containing compounds could be transformed to useful organic
synthons. We expect that these controllable processes will
provide new routes to access functionalized ketoallylic sulfides
and sulfones with versatile uses in synthetic and medicinal
applications.
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Experimental procedures, product characterizations ( H
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NMR, C NMR, HRMS), and copies of the H and C
NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
2
(
8
*
E-mail: zkwen@sxu.edu.cn.
ORCID
2
Zhen-Kang Wen: 0000-0003-1253-9583
Notes
(
Ed. 2016, 55, 2559. (b) Yang, C.; Zhang, K. F.; Wu, Z. J.; Yao, H. Q.; Lin,
A. J. Org. Lett. 2016, 18, 5332. (c) Liu, R. R.; Li, B. L.; Lu, J.; Shen, C.;
Gao, J. R.; Jia, Y. X. J. Am. Chem. Soc. 2016, 138, 5198. (d) Krautwald, S.;
Sarlah, D.; Schafroth, M. A.; Carreira, E. M. Science 2013, 340, 1065.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (21502106) and the National
Natural Science Foundation for Young Scientists of Shanxi
Province (201701D221028). We thank Prof. Yunhe Xu (USTC,
China) and Prof. Yifeng Wang (USTC, China) for valuable
discussions. We are also very grateful for the test platform
provided by Scientific Instrument Center of Shanxi University.
(e) Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 129, 11336.
(
10) During our preparation of this manuscript, a K S O mediated
2
2
8
coupling reaction between methyl ketones with dimethyl sulfoxide to
prepare β-methylthio isopropenylketones was reported; see: Liu, Y. F.;
Zhan, X.; Ji, P. Y.; Xu, J. W.; Liu, Q.; Luo, W. P.; Chen, T. Q.; Guo, C. C.
Chem. Commun. 2017, 53, 5346.
(11) We also isolated a methylthiosulfonate byproduct in this process;
further exploration suggested that an in situ generated methylthiosul-
fonate intermediate was critical to the allylic sulfone synthesis.
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Org. Lett. XXXX, XXX, XXX−XXX