Catalytic and direct methyl sulfonylation of alkenes and alkynes using a methyl sulfonyl radical generated from a DMSO, dioxygen and copper system

Article abstract of DOI:10.1039/c4sc01901f

This paper describes an efficient method to β-keto methyl sulfones and (E)-vinyl methyl sulfones using DMSO as the substrate. The methyl sulfonyl radical generated from DMSO in the presence of catalytic Cu(i) under O₂ atmosphere is believed to be involved in this reaction. Isotopic labeling and ¹⁸O₂ experiments were performed to investigate the reaction mechanism.

Full text of DOI:10.1039/c4sc01901f

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DOI: 10.1039/C4SC01901F
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ARTICLE TYPE
Catalytic and Direct Methyl Sulfonylation of Alkenes and Alkynes Using
Methyl Sulfonyl Radical Generated from DMSO, Dioxygen and Copper
System†
Yaojia Jianga and Teck-Peng Loh*a,b
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
sodium sulfinates,9 etc have been found to be useful starting
This paper describes an efficient method to β-keto methyl
materials for the generation of the corresponding sulfonyl radicals.
Recent work by Taniguchi has shown that sulfonyl radicals
35 generated from the corresponding hydrazine compounds can be
used to functionalize alkenes.10 Furthermore, Lei has also shown
that sulfonyl radicals generated from the corresponding sulfinic
acids are useful for the oxidative difunctionalization of alkenes
and alkynes.11 However, as far as we know, there has been no
40 report on the use of methyl sulfonyl radical generated from
DMSO in organic synthesis.12 Herein, we describe a novel
method for the synthesis of βꢀketo methyl sulfones and (E)ꢀvinyl
methyl sulfones from alkenes and alkynes respectively using
methyl sulfonyl radical generated from DMSO. This methyl
45 sulfonation method is found to be highly chemoꢀ and regioꢀ
selective.
sulfones and (E)-vinyl methyl sulfones using DMSO as the
substrate. The methyl sulfonyl radical generated from DMSO
10 in the presence of catalytic Cu(I) under O2 atmosphere, was
believed to be involved in this reaction. Isotopic labeling and
18O2 experiments were performed to investigate the reaction
mechanism.
Dimethyl sulfoxide (DMSO) has been used widely as solvent in
15 organic synthesis due to its rather low cost, relative stability and
low toxicity.1 On the other hand, biologists have used DMSO as a
hydroxyl radical scavenger to trap the highly reactive oxygen
species present in biological system.2 This is important since
reactive oxygen species have been implicated to be the causative
20 factors of many diseases. Detailed mechanistic studies have
revealed that DMSO reacts with the OH radical present in the
biological system to form methane, ethylene and methyl sulfonyl
radical species.3 We envisage that the methyl sulfonyl radical
species generated from DMSO using this strategy may react with
25 alkenes or alkynes to construct CꢀS bonds, generating interesting
and synthetically useful methyl sulfones (Figure 1).
As mentioned above, the hydroxyl radical has been shown to
generate the methyl sulfonyl radical. It is well known that the
highly reactive hydroxyl radical can be generated from hydrogen
50 peroxide at thermal conditions via the wellꢀknown ironꢀcatalyzed
Table 1. Optimization of reaction conditions for difunctionalization of
alkenes.a
entry
1
2
3
4
5
6
7
8
solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DCEg
catalyst
FeCl2
CuBr
CuBr
CuBr
CuBr
Cu2O
Cu(OTf).Benzene Dꢀ2
Cu(OTf)2
CuBr
additivef oxidant
yieldb
15c
27c
24c
50
Dꢀ1d
Dꢀ1d
Dꢀ1d
Dꢀ2e
Dꢀ2
H2O2
H2O2
O2
O2
O2
Figure 1. Functionalization of CꢀC unsaturated bonds.
86(82c)
54
It is important to note that sulfonyl radicals generated using
30 various sulfonyl compounds have been well studied.4 For
example, sulfonyl halides,5 selenides,6 cyanides,7 azides,8 and
Dꢀ2
O2
O2
77
36
80
64
73
5
ꢀ
Dꢀ2
Dꢀ3
Dꢀ4
Dꢀ2
Dꢀ2
ꢀ
O2
O2
O2
air
O2
O2
9
a Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University.
Singapore 637616.
10
11
12
13
CuBr
CuBr
CuBr
CuBr2/FeBr3
h
b Department of Chemistry, University of Science and Technology of
China, Hefei, Anhui 230026, P.R. China
DMSO
aConditions: 0.25 mmol 1a and 10 mol% metal catalyst with 3.0 equiv
additives were added to 1 mL 2 under oxidant (10.0 equiv H2O2 or 1 atm.
Eꢀmail: teckpeng@ntu.edu.sg; Fax: +65 6515 8229;Tel: +65 6513
8475
O2 balloon). GC yields. cIsolated yields. 20 mol% additives. 1.5 equiv
b
d
e
additives. fDꢀ1: 1,10ꢀphenanthroline; Dꢀ2: HPO(OEt)2; Dꢀ3: HPO(OMe)2;
† Electronic Supplementary Information (ESI) available: Detailed
experimental procedures analytical data, See DOI: 10.1039/b000000x/
Dꢀ4: HP(OiBu)2. 5 mmol 2 in 1 mL DCE. CuBr2 (2.5 mol%), FeBr3 (5
g
h
mol%).
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DOI: 10.1039/C4SC01901F
reactions.3b,13 Thus, our initial exploration began by reacting 35 Ortho, metaꢀ and paraꢀsubstituted phenyl alkenes (3b–3d)
styrene 1a with DMSO (2) in presence of FeCl2 and H2O2
catalytic system using 1,10ꢀphenanthroline as the ligand at 90 C
(Table 1, entry 1). To our delight, the desired 2ꢀ(methylsulfonyl)ꢀ
1ꢀphenylꢀethanone 3a could be obtained after 12 hours albeit in
worked well under our standard conditions affording the desired
products in good to excellent yields (77–84%). Sterically
hindered 2,4,6ꢀtrimethyl groups reduced the yield of the desired
product (3e, 43%). On the other hand, 4ꢀtꢀbutyl group substituted
o
5
low yield (15%). The yield improved to 27% when CuBr was 40 phenyl alkene reacted well with DMSO affording product in good
used instead of FeCl2 (Table 1, entry 2). A more common oxidant
such as O2 was also effective in this reaction, furnishing the
desired product in 24% yield (Table 1, entry 3). The yield
yield (3f). Naphthyl and heteroaryl substrates could also
participate in the reaction (3g–3h), and a diverse of halogen
substituents (F, Cl, Br) at the paraꢀposition of phenyl group could
also be well tolerated (3i–3k). It is worth to note that the chloro,
10 improved dramatically when stoichiometric diethyl phosphite was
employed as additive (Table 1, entries 4ꢀ5). Generally, copper 45 bromo, functionalities could be further functionalized in coupling
catalysts with different counterions all promoted the reaction with
fluctuating yields (see SI). Copper (I) showed more efficiency in
the reaction condition compared to copper (II) catalysts (Table 1,
15 entries 7ꢀ8). Simple substituents of phosphite like methyl, ethyl,
reactions. When alkyl substituted alkenes were used as substrates,
no reaction took place with recovery of starting material. This
negative result encouraged us to study the chemoꢀselectivity of
compound having both the alkyl and aryl substituted alkene
led to more promising results compared to bulky ones (Table 1, 50 moieties (2l). The result indicated that the alkyl substituted alkene
entries 5 and 9ꢀ10). The reaction also proceeded well under air as
oxidant with 73% yield (Table 1, entry 11). Attempts to use DCE
as solvent was unsuccessful and trace amount of product was
20 obtained (Table 1, entry 12). It is important to note that when we
moiety remained intact while the aryl substituted alkene reacted
to afford the 1ꢀ(2ꢀ(allyloxy) phenyl)ꢀ2ꢀ(methylsulfonyl)ethanone
(3l) in 75% yield. Examination of the electronic influence on the
phenyl group revealed that both of electronꢀdonating and
employed Ji’s Cu/Fe catalytic system14b in the absence of 55 electronꢀwithdrawing groups gave promising results (3m–3q).
triethylamine, the reaction was completely suppressed without
phosphorylation or sulfonylation of alkene (Table 1, entry 13).
No desired product was detected when the reaction was tested
25 using Lei’s reaction conditions (1a reacted with DMSO with
pyridine under air atmosphere, see SI).
With the optimized reaction conditions in hand, we proceeded
to survey the scope of the reaction (Table 2). Overall, the reaction
tolerated a broad range of substituted aryl alkenes to give the
30 corresponding βꢀketo methyl sulfones in good to excellent yields.
Furthermore, internal and cyclic alkenes also proceeded
efficiently to give the corresponding methyl sulfones in
promising yields (3rꢀ3s).
Although the mechanism is not fully understood, a possible
60 reaction pathway was proposed for the styrene derivatives
reacting with DMSO in CuBr/O2/HPO(OEt)2 conditions (Scheme
1). Initially, O2 is activated by the copper catalyst to form copper
complexꢀI.14 A radical process takes place, forming the metal
complexꢀII and phosphonic radicalꢀIII, respectively. One more
65 equivalent phosphite as reductant takes part in the SET (Single
Electron Transfer) process to give radical anion IV and cation V.
While V probably changes to the phosphonic radicalꢀIII by
deprotonation, copper (II) complexꢀIV generates the important
hydroxyl radical and Cu(II)ꢀOHꢀ(VI) which may be further
70 reduced by phosphite undergoing SET process to regenerate
Cu(I). As reported,3b hydroxyl radical could react with DMSO to
give several radical species, one of which is the methyl sulfonyl
radical B from demethylation of dimethyl sulfinic acid radical A.
Styrene is then attacked by radical specie B to form hydroperoxyl
75 complexꢀC, which is then oxidized to give βꢀketo methyl
sulfones.
Table 2. Substrate scope for reaction of alkenes with DMSO.a,b
O
O
S
O
R2
CuBr/O2
O
S
Me
R1
+
HPO(OEt)2/90 o
C
Me
Me
R1
R2
O
1
3
2
O
Me
O
O
O
O
S
Me
Me
Me
S
S
Me
O
O
O
Me
3b 84%
3c 77%
3d 80%
O
O
O
O
O
S
O
Me
Me
Me
S
S
O
O
O
3g 78%
3e 43%
3f 74%
O
O
O
O
O
O
Me
Me
Me
S
S
S
S
O
O
HPO(OEt)2
O2/L
O
(1)
Cu(I)
LCu(II)-O-O
LCu(II)-O-OH
+
PO(OEt)2
Cl
F
3h 75%
II
I
III
3j 65%
3i 74%
O
O
O
O
H2O
O
S
O
S
H+
SET
Me
Me
Me
III
H+
HPO(OEt)2
S
O
O
O
V
H+
O
3l 75%
PhO
Br
3k 77%
3m 75%
LCu(II)-OH
LCu(II)-O-OH
+
HPO(OEt)2
LCu(II)-OH
HPO(OEt)2
OH
O
O
O
O
O
O
Me
OH
Me
Me
IV
VII
VI
V
S
S
S
O
O
O
O
S
MeO2C
MeO
O
S
(2)
(3)
Me
Me
CH3SO2
CH4
Me
NO2
3p 52%
+
3n 68%
3o 66%
Me
Ph
Me
OH
O
O
O
O
O
2
Me
A
B
Me
O
O
S
S
Cu(II)L
O
S
Me
O
R2
O
O
O
S
F3C
O2/Cu(I)
O
O
R2 = Me: 3r 71%
R2 nPr: 3r' 50%
Me
3q 81%
3s 70%
S
Ph
O
B
Ph
=
O
1a
3a
C
aConditions: 0.25 mmol 1 and 10 mol% CuBr with 3.0 equiv HPO(OEt)2
Scheme 1. Proposed mechanism for difunctionalization of alkenes.
were stirred in 1 mL DMSO under 1 atm. O2 balloon. bIsolated yields.
2
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DOI: 10.1039/C4SC01901F
To further probe our proposed mechanism, the isotopic
labeling experiments with 18O2 and dꢀDMSO were performed.
The results demonstrated that two additional oxygen present in
ꢀessed the reaction (Table 3, entries 6ꢀ7). Finally we found that
higher temperature and small amount of water were shown to
improve the reaction efficiency compared to the reaction system
for alkenes (Table 3, entry 8, also see SI).
the product originated from 18O2 (Scheme
2 (a)) and
5
demethylation of DMSO occurred smoothly (Scheme 2 (b)).
Additionally, no product was detected when styrene was
subjected with dimethyl sulfone under the same reaction
conditions (see SI). This indicates that in the reaction system,
active methyl sulfonyl (MeSO2) radical species was involved
40
Further extension to other substrates revealed that all aryl
alkynes reacted smoothly to afford desired vinyl methyl sulfones
in good to excellent yields giving exclusively the E isomer (Table
4). Ortho and paraꢀsubstituted phenyl moieties performed well in
optimized condition irrespective of the halide (5b) or alkyl
10 rather than alkene reacting with dimethyl sulfone directly. D2O 45 substitutions (5cꢀ5d). Steric effect lowered the yield slightly
exchange experiment was also performed. No Dꢀlabelled product
was detected. Using radical scavenger reagent TEMPO, the
desired reaction was completely suppressed and only a small
amount of βꢀketo diethyl phosphonate was obtained (Scheme 2
when 1ꢀethynylꢀ2,4,5ꢀtrimethylbenzene (4e) was used as the
substrate. Fused rings (5f) as well as heterocyclic compounds (5l)
were also investigated and the corresponding vinyl methyl
sulfones were obtained in good yields, 77% and 68%,
15 (c)). Subjecting the βꢀketo diethyl phosphonate instead of the aryl 50 respectively. The results showed that both electronꢀwithdrawing
alkene to our reaction conditions did not lead to the desired
product, indicating that βꢀketo diethyl phosphonate is not the
intermediate of this reaction. On the basis of these results, we
may conclude that a DMSO/•OH radical process is most likely
20 involved in our reaction system.
(5gꢀ5i) and electronꢀdonating (5j) substitutions gave moderate to
excellent yields (63%ꢀ83%). Notably, aldehyde, an useful
functional group, could be well tolerated without oxidation to
acid. Finally, internal alkynes also worked well to give (E)ꢀ(2ꢀ
55 (methylsulfonyl)propꢀ1ꢀenꢀ1ꢀyl)benzene in 75% yield (5k).
Table 4. Substrates scope for reaction of alkynes with DMSO.a, b
O
S
R4
O
S
Me
CuBr/HPO(OEt)2/O2
R3
R3
+
O
Me
Me
R4
H2O/120 o
C
2
4
5
O
S
O
O
S
Me
Me
Me
S
O
O
O
tBu
F
5b 82%
5a 85%
5c 79%
O
Me
Me
O
S
Me
O
S
Me
Me
S
O
O
O
Scheme 2. Mechanistic studying.
Me
Me
5d 75%
5e 54%
5f 77%
Encouraged by these results, we explored the reaction with aryl
alkynes under various conditions (Table 3). Initially, we
25 employed the same reaction condition as alkenes and obtained
(E)ꢀ(2ꢀ(methylsulfonyl)vinyl)benzene 5a in moderate yield
(Table 3, entry 1). Increasing the amount of phosphite Dꢀ2
resulted in slightly decreased yield while higher temperature gave
a more positivie result (Table 3, entries 2ꢀ3). Dimetalꢀcatalysts
30 were screened however neither silver nor iron could improve the
reaction (Table 3, entries 4ꢀ5). In addition to phosphite additive,
we also examined organic base and acid but both of them surpprꢀ
O
S
O
O
S
O
S
Me
Me
Me
O
O
O2N
OHC
F3C
5g 71%
5j 80%
5h 83%
5i 63%
O
Me
O
O
S
Me
Me
S
S
O
O
O
S
Me
MeO
5l 68%
5k 75%
aConditions: 0.25 mmol 4 and 10 mol% CuBr with 3.0 equiv HPO(OEt)2
were stirred in 10 equiv H2O and 1 mL DMSO under 1 atm. O2 balloon.
60 bIsolated yields.
Table 3. Optimization of reaction conditions for sulfonylation of
alkynes.a
On the basis of these results, a reaction mechanism similar to
the alkene system is proposed as depicted in Scheme 3. Similarly,
methyl sulfonyl radical B was probably generated as shown in
35
entry catalyst
additive
yieldb
Temp (℃)
90
90
120
120
120
120
120
120
1
2
3
4
5
6
7
8
CuBr
CuBr
Dꢀ2
64
53
75
54
ꢀ
ꢀ
Dꢀ2c
CuBr
Dꢀ2
Dꢀ2
Dꢀ2
CuBr+Ag(OTf)d
d
CuBr+FeBr2
CuBr
CuBr
CuBr
Dꢀ2 +TEAe
Dꢀ2 +HOAce
Dꢀ2+ H2Of
45
88(85g)
aConditions: 0.25 mmol 4a and 10 mol% metal catalyst with 3.0 equiv Dꢀ
2 were added to 1 mL DMSO under 1 atm. O2 balloon. GC yields. c4.0
b
equiv additives. d20 mol% catalysts. e3.0 equiv additives. 10.0 equiv
f
additives. gIsolated yields.
65 Scheme 3. Proposed mechanism for methyl sulfonylation of alkynes.
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DOI: 10.1039/C4SC01901F
2003; Chapter 3 pp 60ꢀ62 and Chapter 5 pp 116ꢀ132; (d) Dimethyl
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Scheme 1, and reacted with the alkyne 4a to form complexꢀD.
Under thermal condition, the more stable intermediate
dominates. After hydrogen atom transfer, only E isomer 5a was
detected.
βꢀKeto and vinyl methyl sulfones are versatile synthetic
intermediates that are widely applied for the synthesis of
pharmaceuticals and natural products. For example, the βꢀketo
methyl sulfone could be either alkylated with allyl bromide or
diazo transferred with tosyl azide under suitable base conditions
45
50
55
60
65
E
5
10 (Scheme 4, (1) and (2)).15 It can also easily be halogenated in a
radical process to afford 2ꢀbromoꢀ2ꢀ(methylsulfonyl)ꢀ1ꢀphenylꢀ
ethanone(Scheme 4, (3)), which is a key intermediate for the
synthesis of biological active molecule 2ꢀ(methylsulfonyl)ꢀ3ꢀ
phenylꢀ5,6ꢀdihydroimidazo[2,1ꢀb]thiazole.16 The methyl sulfonyl
15 group could be well tolerated in reduction condition to afford (2ꢀ
(methylsulfonyl)ethyl)benzene in excellent yield from vinyl
methyl sulfone (Scheme 4, (4)).
70 8 N. Mantrand and P. Renaud, Tetrahedron, 2008, 64, 11860ꢀ11864.
9 (a) H. S. Li and G. Liu, J. Org. Chem., 2014, 79, 509ꢀ516; (b) R.
Chawla, A. K. Singh and L. D. S. Yadav, Eur. J. Org. Chem., 2014,
2032ꢀ2036; (c) F. Xiao, H. Chen, H. Xie, S. Chen, L. Yang and G. J.
Deng, Org. Lett., 2014, 16, 50ꢀ53; (d) A. Kariya, T. Yamaguchi, T.
75
Nobuta, N. Tada, T. Miura and A. Itoh, RSC Adv., 2014, 4, 13191ꢀ
13194; (e) Y. Xi, B. Dong, E. J. McClain, Q. Wang, T. L. Gregg, N.
G. Akhmedov, J. L. Petersen and X. Shi, Angew. Chem., Int. Ed.,
2014, 53, 4657ꢀ4661; (f) X. Tang, L. Huang, Y. Xu, J. Yang, W. Wu
and H. Jiang, Angew. Chem., Int. Ed., 2014, 53, 4205ꢀ4208.
80 10 T. Taniguchi, A. Idota and H. Ishibashi, Org. Biomol. Chem., 2011, 9,
3151ꢀ3153.
Scheme 4. Transformations of methyl sulfones.
11 (a) Q. Lu, J. Zhang, F. Wei, Y. Qi, H. Wang, Z. Liu and A. W. Lei,
Angew. Chem., Int. Ed., 2013, 52, 7156ꢀ7159; (b) Q. Lu, J. Zhang, G.
Zhao, Y. Qi, H. Wang and A. W. Lei, J. Am. Chem. Soc., 2013, 135,
20
In summary, a novel method for the synthesis of βꢀketo methyl
sulfones and (E)ꢀvinyl methyl sulfones was described. We
demonstrated a new catalytic system that involves copper,
oxygen and HPO(OEt)2 to generate the hydroxyl radical in situ
which initiates a cascade radical reaction. DMSO was activated in
85
90
11481ꢀ11485.
12 For selected recent examples of DMSO as reactant: (a) X. Jiang, C.
Wang, Y. Wei, D. Xue, Z. Liu and J. Xiao, Chem.ꢀEur. J., 2014, 20,
58ꢀ63; (b) G. Yuan, J. Zheng, X. Gao, X. Li, L. Huang, H. Chen and
H. Jiang, Chem. Commun., 2012, 48, 7513ꢀ7515; (c) Y. F. Wang, F.
L. Zhang and S. Chiba, Synthesis, 2012, 44, 1526ꢀ1534; (d) F. Luo,
C. Pan, L. Li, F. Chen and J. Cheng, Chem. Commun., 2011, 47,
5304ꢀ5306; (e) L. Chu, X. Yue and F. L. Qing, Org. Lett., 2010, 12,
1644ꢀ1647; (f) C. L. Øpstad, T. B. Melø, H. R. Sliwka and V. Partali,
Tetrahedron, 2009, 65, 7616ꢀ7619; (g) G. Yin, B. Zhou, X. Meng, A.
Wu and Y. Pan, Org. Lett., 2006, 8, 2245ꢀ2248.
25 the reaction system to afford methyl sulfonyl radical that can
functionalize both the aryl alkenes and alkynes. Isotopic labeling
and 18O2 experiments were performed to investigate the reaction
mechanism. Further studies on the mechanism of this reaction as
well as the application of this methyl sulfonyl radical for other
30 transformations will be reported in due course.
95
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Acknowledgement
We gratefully acknowledge the Nanyang Technological
University and the Singapore Ministry of Education Academic
Research Fund Tier 2: MOE2011ꢀT2ꢀ1ꢀ013 and MOE2012ꢀ
35 T2ꢀ1ꢀ014, the National Environment Agency (NEAꢀETRP
Project Ref. No. 1002 111) and University of Science and
Technology of China.
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Notes and references
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40
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