A mild and efficient synthesis of aryl sulfones from aryl chlorides and sulfinic acid salts using microwave heating

Article abstract of DOI:10.1055/s-0031-1289541

The CuCl-catalyzed coupling of aryl chlorides and sulfinic acid salts provides a simple and extremely efficient route to unsymmetrical aryl sulfones in high to excellent yields under microwave irradiation within 3-30 minutes. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289541

2750
LETTER
A Mild and Efficient Synthesis of Aryl Sulfones from Aryl Chlorides and
Sulfinic Acid Salts Using Microwave Heating
Synthesis of
Aryl
S
a
ulfones n-qin Yuan, Sheng-rong Guo*
Department of Chemistry, Lishui University, 323000 Zhejiang, P. R. of China
E-mail: guosr9609@lsu.edu.cn
Received 3 August 2011
of aryl chlorides to the corresponding sulfones under mi-
crowave irradiation (Scheme 1).
Abstract: The CuCl-catalyzed coupling of aryl chlorides and
sulfinic acid salts provides a simple and extremely efficient route to
unsymmetrical aryl sulfones in high to excellent yields under micro-
wave irradiation within 3–30 minutes.
O
O
Cl
S
base, Cu(I), NMP
MW, 5–30 min
R2
Key words: aryl chloride, microwave, sulfone, sulfinic acid salts,
quinoline, CuCl
R1
R2
SO2Na
R1
+
X
X
X = C, N, thiophene
R1 = NO2, CHO, Ac, etc.
Aryl sulfones have attracted considerable interests be-
cause of their biological activities1,2 and chemical proper-
ties,3,4 The functional group is found in numerous drugs,
including the recently developed selective cyclooxygen-
ase-2 (COX-2) inhibitor Vioxx,5 and the prostaglandin
D2(DP) antagonist MK-0524.6
R2 = 4-tolyl, Ph, cyclopropyl
Scheme 1
The reaction smoothly proceeded within a short time in
good to excellent yields in the presence of an organic base
and Cu(I) catalyst. We chose to use the relatively active 1-
chloro-4-nitrobenzene as our initial coupling partner in
combination with the commercially available sodium p-
toluenesulfinate in order to optimize the reaction condi-
tions. The coupling conditions were based on those re-
ported by others for C–X (X = N, O, S, etc.) coupling
employing microwave irradiation (Table 1).13,16 It was
demonstrated that the microwave-assisted sulfonylation
coupling reaction could produce the sulfone products in
good yields under organic base and transition-metal con-
ditions (Table 1, entries 1–11). Among the bases and sol-
vents screened, quinoline as the base and NMP as the
solvent proved to be most effective. Hence, treatment of
1-chloro-4-nitrobenzene with one equivalent of sodium
p-toluenesulfinate in the presence of copper(I) chloride
(10 mol%) and quinoline (10 mol%) in N-methylpyrrolidin-
one at 140 °C for three minutes under microwave irradia-
tion provided the product in 90% yield (Table 1, entry 9).
Although addition of CuCl did not appear to be crucial in
the model reaction (90% vs. 76% in the presence and ab-
sence of CuCl, respectively), but it turned out to be very
effective in the reactions described in Table 2 (entries 1,
6, 9, 12, 16, 20, 24, 30, 34, and 37). Generally, the pres-
ence of CuCl could promote an enhancement of 14–30%
in product yield. Although using DMSO as the solvent de-
livered the expected aryl sulfones (Table 1, entries 11–
13), it was less effective than NMP. We also tested other
solvents such as DMF, toluene, isopropanol, water, and
PET200, but they afforded products in lower yields
(Table 1, entries 14–18). As a control experiment, the
same reaction mixture was heated at 140 °C for 30 min-
utes in a sealed tube using an oil bath, and the product was
obtained in 10% yield. This observation demonstrates the
Many methodologies exist for the preparation of aryl sul-
fones, such as the oxidation of corresponding sulfides,7
the reaction of organolithium or Grignard reagents with
sulfonate esters,8 and the sulfonylation of arenes,9 which
are attractive methods because of their simplicity. Howev-
er, the incompatibility of various functional groups with
these methods reduces their scope of application. Over the
past decade, there has been a significant improvement in
metal-mediated coupling of sulfinic acid salts with aryl
halides10 or triflates11 as well as arylboronic acids with
sulfonyl chlorides12 as alternatives to these conventional
methods. However, the scope is limited to aryl bromides/
iodides or triflates, and the use of air- or moisture-sensi-
tive reagents is sometimes not avoidable. The need for
clean manufacturing processes demands the development
of new strategies for the preparation of aryl sulfones.
Microwave-assisted organic synthesis has attracted con-
siderable attention in the past decade.13 Microwave irradi-
ation often leads to a remarkable decrease in reaction
time, increased yields, and easier workup consistent with
green-chemistry protocols and may enhance the regio-
and stereoselectivity of reactions.14 Recently, Lei,15
Kwong,16 and Zou17 reported that aryl halides could cou-
ple with nucleophilic reagents to give coupling products
employing microwave techniques in the absence of cata-
lyst, but we found the usage of transition-metal catalysts
or organic base promoted the reactivity dramatically. In
this paper, we present our studies toward the conversion
SYNLETT 2011, No. 18, pp 2750–2756
x
x
.x
x
.2
0
1
1
Advanced online publication: 19.10.2011
DOI: 10.1055/s-0031-1289541; Art ID: W17111ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Aryl Sulfones
2751
Table 1 Optimization of Reaction Conditionsa
O
O
Cl
NaO2S
solvent, base, cat.
MW, 5–30 min
S
+
O2N
CH3
O2N
CH3
Entry
1
Solvent
Catalyst
no
Base
Temp (°C)
140
140
140
140
140
140
140
140
140
140
140
140
140
140
115
120
105
140
Yield (%)b
60
NMP
no
2
NMP
no
K2CO3
65
3
NMP
no
KOH
60
4
NMP
no
DBU
70
5
NMP
no
quinoline
KOH
76
6
NMP
CuI
CuI
CuI
CuCl
PdCl2
no
65
7
NMP
DBU
82
8
NMP
quinoline
quinoline
quinoline
KOH
85
9
NMP
90
10
11
12
13
14
15
16
17
18
NMP
79
DMSO
DMSO
DMSO
DMF
50
no
quinoline
quinoline
quinoline
quinoline
quinoline
quinoline
quinoline
55
CuI
CuI
CuI
CuI
CuI
CuI
80
60
toluene
2-PrOH
H2O
50
40
trace
65
PET200
a Reaction conditions: 1-chloro-4-nitrobenzene (1.0 mmol), base (10 mol%), catalyst (10 mol%), sodium p-toluenesulfinate (1.0 mmol), and
NMP (1.5 mL), MW 250 W, 3 min for the indicated temperature.
b Isolated yields.
advantage of microwave irradiation over the conventional oxybenzene in the presence of copper(I) chloride (10
heating techniques.
mol%) and quinoline (10 mol%) provided only a trace of
product even after one hour microwave heating (Table 2,
entries 40 and 41). In order to extend the present method
to the synthesis of aryl alkyl sulfones, coupling of aryl
halides with sodium cyclopropanesulfinate was investi-
gated. Due to the higher nucleophilicity of cyclopropyl-
sulfinate anion, the yields of cyclopropyl aryl sulfones
were superior to those of their diaryl counterparts.
We further evaluated the microwave-assisted coupling re-
action with respect to substituted aryl chlorides. To test
the scope of this reaction, aryl chloride was treated with
sodium p-toluenesulfinate, sodium benzenesulfinate, and
sodium cyclopropanesulfinate under the above-men-
tioned conditions. In all examples tested, moderate to
good yields could be achieved in less than 30 minutes. As
shown in Table 2, the conditions worked well for a variety On the basis of the above-mentioned results and other re-
of electron-deficient aryl chlorides. It should be pointed ports,18 we believe that the coupling reaction underwent a
out that the coupling reactions with aryl chlorides gener- nucleophilic aromatic substitution pathway. Firstly, the
ally provided better yields than those with the correspond- microwave heating promoted the formation of p complex
ing iodides and bromides. Of special note was that the formed from CuCl and aryl chloride. Secondly, the nu-
yield of the reaction was greatly influenced by the pres- cleophilic reagent sulfinic acid salts attack of the Cl atom
ence of electron-donating or electron-withdrawing groups on the aryl ring to give a p-complex intermediate. Finally,
on the aryl halides. For example, treatment of sodium p- quinoline assisted in removing the CuCl from the p-com-
toluenesulfinate with chlorobenzene or 1-chloro-4-meth- plex to give the products.
Synlett 2011, No. 18, 2750–2756 © Thieme Stuttgart · New York

2752
Y.-q. Yuan, S.-r. Guo
LETTER
Table 2 Synthesis of Diaryl and Cyclopropyl Aryl Sulfones under Microwave Heatinga
O
O
Cl
S
NMP, quinoline, CuCl
MW, 5–30 min
R2
R1
R2
SO2Na
R1
+
X
X = C, N, thiophene
R1 = NO2, CHO, Ac, etc.
R
2 = 4-tolyl, Ph, cyclopropyl
Entry
1
Halides
Product19
Time (min)
3
Yield (%)b
90, 76c
O
O
Cl
Cl
Cl
I
S
O2N
O2N
O2N
O2N
O2N
O2N
CH3
O
O
O
O
O
O
O
O
S
S
S
S
2
3
4
5
3
3
3
6
86
92
50
85
O2N
O2N
O2N
CH3
CH3
Br
O2N
O2N
Cl
O
O
O
O
O
O
S
S
S
6
7
8
4
4
3
81, 56c
CH3
NO2
Cl
Cl
O2N
84
NO2
NO2
O2N
85
O
O
Cl
S
9
10
11
12
10
10
8
75, 45c
NO2
Cl
NO2
CH3
O
O
O
S
72
NO2
Cl
NO2
O
S
80
NO2
NO2
O
O
Cl
S
10
82, 60c
OHC
OHC
CH3
Synlett 2011, No. 18, 2750–2756 © Thieme Stuttgart · New York

LETTER
Synthesis of Aryl Sulfones
2753
Table 2 Synthesis of Diaryl and Cyclopropyl Aryl Sulfones under Microwave Heatinga (continued)
O
O
Cl
S
NMP, quinoline, CuCl
MW, 5–30 min
R2
R1
R2
SO2Na
R1
+
X
X = C, N, thiophene
R1 = NO2, CHO, Ac, etc.
R
2 = 4-tolyl, Ph, cyclopropyl
Entry
13
Halides
Product19
Time (min)
10
Yield (%)b
80
O
O
O
O
O
O
Cl
Cl
Br
Cl
Cl
S
S
OHC
OHC
14
15
16
17
18
19
20
10
10
15
85
OHC
OHC
S
80
OHC
OHC
CH3
O
O
O
S
S
78, 52c
H3COC
H3COC
H3COC
H3COC
CH3
O
15
15
15
30
75
O
O
O
O
Cl
Br
S
S
80
H3COC
H3COC
N
H3COC
75
H3COC
O
CH3
O
S
74, 55c
N
Cl
CH3
O
O
O
O
S
S
S
21
22
30
30
70
75
N
N
Cl
Cl
N
O
N
O
23
24
15
10
75
N
N
Br
CH3
O
O
Cl
S
75, 60c
N
CH3
N
CO2CH3
CO2CH3
Synlett 2011, No. 18, 2750–2756 © Thieme Stuttgart · New York

2754
Y.-q. Yuan, S.-r. Guo
LETTER
Table 2 Synthesis of Diaryl and Cyclopropyl Aryl Sulfones under Microwave Heatinga (continued)
O
O
Cl
S
NMP, quinoline, CuCl
MW, 5–30 min
R2
R1
R2
SO2Na
R1
+
X
X = C, N, thiophene
R1 = NO2, CHO, Ac, etc.
R
2 = 4-tolyl, Ph, cyclopropyl
Entry
25
Halides
Product19
Time (min)
10
Yield (%)b
70
O
O
O
Cl
S
N
N
N
N
N
N
CO2CH3
CO2CH3
CO2H
CO2CH3
O
S
Cl
26
27
28
10
10
10
82
70
65
N
CO2CH3
O
S
O
O
O
Cl
CH3
N
CO2H
O
S
Cl
N
CO2H
CO2H
O
S
Cl
29
30
10
15
75
N
S
CO2H
CO2H
O
O
S
S
S
65, 36c
Cl
CH3
O
O
S
31
32
15
15
60
70
S
S
Cl
Cl
O
O
O
O
S
S
S
S
33
15
50
S
I
CH3
O
O
O
H3COC
H3COC
S
S
S
S
34
35
6
6
85, 70c
H3COC
H3COC
S
S
Cl
Cl
CH3
O
86
Synlett 2011, No. 18, 2750–2756 © Thieme Stuttgart · New York

LETTER
Synthesis of Aryl Sulfones
2755
Table 2 Synthesis of Diaryl and Cyclopropyl Aryl Sulfones under Microwave Heatinga (continued)
O
O
Cl
S
NMP, quinoline, CuCl
MW, 5–30 min
R2
R1
R2
SO2Na
R1
+
X
X = C, N, thiophene
R1 = NO2, CHO, Ac, etc.
R
2 = 4-tolyl, Ph, cyclopropyl
Entry
36
Halides
Product19
Time (min)
6
Yield (%)b
87
O
O
H3COC
S
S
H3COC
PhOC
S
Cl
O
O
PhOC
PhOC
S
S
37
6
82, 67c
S
Cl
CH3
O
O
O
O
S
S
S
S
38
39
6
5
85
88
PhOC
PhOC
S
S
Cl
Cl
PhOC
O
O
Cl
S
40
41
60
60
trace
trace
CH3
O
O
Cl
S
H3CO
H3CO
CH3
a Reaction conditions: aryl halides (1.0 mmol), CuCl (10 mol%), quinoline (10 mol%), and sulfinic acid salts added to NMP (1.5 mL), MW 250
W at 140 °C for the indicated time.
b Isolated yield.
c Isolated yield without CuCl catalyst.
It is worth mentioning that all the sulfones formed are sta- Acknowledgment
ble at high temperatures and therefore the dielectric heat-
This work was supported by the Natural Science Foundation of
ing did not create any decomposition problem. Rather, the
Zhejiang Province, P. R. of China (Project Y407240) and the Key
reaction under microwave irradiation was very clean, and
no byproducts were detected.
Science Foundation of Lishui university (project KY07002).
To summarize, this CuCl-catalyzed transformation using
microwave heating is a useful route for the synthesis of
unsymmetrical diaryl sulfones and aryl-alkyl sulfones.
Electron-deficient aryl chlorides were shown to be well
tolerated in the coupling process, and the synthesized sul-
fones were usually isolated in moderate to good yields.
The simplicity of this short and clean procedure and gen-
erally satisfactory yields render this method particularly
attractive.
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Synlett 2011, No. 18, 2750–2756 © Thieme Stuttgart · New York

2756
Y.-q. Yuan, S.-r. Guo
LETTER
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(19) Typical Procedure
Aryl halides (1.0 mmol), CuCl (10% mol), quinoline (10%
mol), and sulfinic acid salts added to NMP (1.5 mL) MW
250 W at 140 °C for the indicated time. The reaction was
found not to be sensitive to air and moisture; hence there
was no need for an inert atmosphere. With the use of a
microwave power of 250 W, the reaction mixture was
ramped from r.t. to 140–150 °C over 30 s, and then held
at this temperature for another 3–30 min until complete
consumption of starting material (GC monitoring). After
being cooled to rt, the resulting mixture was mixed with
an ample amount of ice water, extracted with EtOAc. The
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to yield the product, which was purified by silica gel
chromatography to give the 1-methyl-4-(4-nitrophenyl-
sulfonyl)benzene in 90% yield. 1H NMR (300 MHz,
CDCl3): d = 8.27 (d, J = 7.0 Hz, 2 H), 8.05 (d, J = 7.0 Hz, 2
H), 7.78 (d, J = 8.2 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 2 H), 2.35
(s, 3 H). 13C NMR (75 MHz, CDCl3): d = 150.1, 147.8,
145.3, 137.0, 130.3, 128.8, 128.1, 124.4, 21.6. The identity
and purity of other products was confirmed by1H NMR and
13C NMR spectroscopic analysis.
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