Copper-mediated cascade synthesis of diaryl sulfones via the sandmeyer reaction

Article abstract of DOI:10.1055/s-0033-1340736

A convenient and efficient method for the copper-mediated cascade synthesis of diaryl sulfones via the Sandmeyer reaction has been developed. The protocol uses readily available aryl amines and arylsulfinic acids as the starting materials, isoamyl nitrite as the diazotizating reagent of the aryl amines, and the method shows mild reaction conditions and high tolerance towards various functional groups in the substrates. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340736

LETTER
▌847
lCettoerpper-Mediated Cascade Synthesis of Diaryl Sulfones via the Sandmeyer
Reaction
Synthesis of Diaryl Sulfones
Xiaobo Yang,*a Liangliang Shi,b Hua Fu*b,c
a
College of Chemistry and Life Science, Shenyang Normal University, Shenyang, Liaoning 110034, P. R. of China
E-mail: bxy1223@gmail.com
b
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. of China
Fax +86(10)62781695; E-mail: fuhua@mail.tsinghua.edu.cn
c
Key Laboratory of Chemical Biology (Guangdong Province), Graduate School of Shenzhen, Tsinghua University, Shenzhen 518057,
P. R. of China
Received: 09.12.2013; Accepted after revision: 15.01.2014
Abstract: A convenient and efficient method for the copper-medi-
ated cascade synthesis of diaryl sulfones via the Sandmeyer reaction
has been developed. The protocol uses readily available aryl amines
and arylsulfinic acids as the starting materials, isoamyl nitrite as the
diazotizating reagent of the aryl amines, and the method shows mild
reaction conditions and high tolerance towards various functional
groups in the substrates.
the previous methods
O
S
oxidation
(a)
(b)
Ar1
Ar1
Ar1
S
H
Ar2
Ar1
Ar2
O
O
O
S
strong acid
+
HO
MO
S
Ar2
Ar2
Ar1
Ar2
Key words: copper, diaryl sulfones, Sandmeyer reaction, diazoti-
zation, sulfonylation
O
O
O
S
O
S
transition-metal-catalyzed
+
Ar1
Ar2
X
(c)
(d)
O
X = halo, B(OH)2
The synthesis of diaryl sulfones has attracted wide atten-
tion for their various promising biological functions.1 For
example, they exhibit antifungal, antibacterial, and antitu-
mor activities,2–4 and some of them are used as inhibitors
of thymidylate synthase5 or HIV-1 reverse transcriptase.6
In addition, diaryl sulfones are also valuable synthetic in-
termediates in organic synthesis.7 Various approaches for
their preparation have been reported, mainly including the
oxidation of sulfides (Scheme 1, a),8 the sulfonylation of
arenes in the presence of strong acids (Scheme 1, b)7 and
the transition-metal-catalyzed couplings of arylsulfinic
acid salts with aryl halides,9 arylboronic acids10 (Scheme
1, c), or diaryliodonium salts (Scheme 1, d).11
O
O
Ar1 I+ Ar3
+
Ar1
S
Ar2
MO
S
Ar2
X–
O
O
S
O
MO
Ar2
CuX
Ar1
S
Ar2
Ar1 NH2
Ar1
X
(e)
(f)
transition-metal-
catalyzed
Sandmeyer reaction
O
X = halo
O
O
Cu, i-AmONO
this work
Ar1 NH2
+
HO
S
Ar2
Ar1
S
Ar2
O
Scheme 1 Synthesis of diaryl sulfones: (a–e) the previous method;
(f) our strategy via the Sandmeyer reaction
On the other hand, aryl amines are common chemicals and
they are used in transformations of functional groups for
the synthesis of various aromatic derivatives.12 Tradition-
al methods for the synthesis of diaryl sulfones from aro-
matic amines undergo sequential two steps: conversion of
aryl amines into the corresponding aryl halides via the
Sandmeyer reaction and transition-metal-catalyzed cou-
pling of aryl halides with arylsulfinic acids salts (Scheme
1, e).13 Herein, we report a novel, convenient, and effi-
cient copper-mediated synthesis of diaryl sulfones via the
Sandmeyer reaction process (Scheme 1, f).
4-(phenylsulfonyl)benzene (3e). As shown in Table 1,
four copper reagents (3 equiv relative to amount of 1e)
were tested using isoamyl nitrite (i-AmONO) as the diaz-
otizating reagent, MeCN as the solvent at 0–25 °C for 12
hours (see the experimental section for the details; Table
1, entries 1–4), and copper powder provided the highest
yield (Table 1, entry 4). No target product was found in
the absence of copper agent (Table 1, entry 5). The yields
decreased when the amount of copper powder was re-
duced (Table 1, entries 6–8), and four equivalents of copper
power afforded the similar yield to entry 4 (Table 1, entry
9). We examined other diazotizating reagents, t-BuONO
and NaNO2, and they gave poor results (Table 1, entries
10 and 11). The effect of solvents was investigated (Table
At first, 4-methoxyaniline (1e) and benzenesulfinic acid
(2a) were chosen as the model substrates to optimize con-
ditions including copper reagents, diazotizating reagents,
solvents, and temperature for the synthesis of 1-methoxy-
SYNLETT 2014, 25, 0847–0852
Advanced online publication: 05.03.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340736; Art ID: ST-2013-W1121-L
© Georg Thieme Verlag Stuttgart · New York

848
X. Yang et al.
LETTER
1, compare entries 4, 12, and 13), and MeCN was a suit- With the optimized conditions in hand, the scope for the
able solvent (Table 1, entry 4). Only trace amount of prod- synthesis of diaryl sulfones from aromatic amines and
uct was observed when the reaction was carried out in air benzenesulfinic acids was investigated. As shown in Ta-
(Table 1, entry 14) or at room temperature (ca. 25 °C; Ta- ble 2, the examined substrates provided the corresponding
ble 1, entry 15). The yield decreased significantly when diaryl sulfones in moderate to good yields. For aromatic
the amount of benzenesulfinic acid (2a) was reduced (Ta- amines, the substrates containing electron-donating
ble 1, entries 16). According to the investigations above, groups showed higher reactivity than those containing
the optimized conditions are as follows: three equivalents electron-withdrawing groups, and the substrates contain-
of copper powder as the mediated agent, three equivalents ing electron-withdrawing groups gave lower yields some
of i-AmONO as the diazotizating reagent, MeCN as the byproducts appearing.
solvent at 0–25 °C under nitrogen atmosphere.
For example, 4-chloroaniline (1g) gave lower yield (53%)
under the standard conditions (Table 2, entry 7), and a lon-
ger reaction time was needed for 4-tert-butylaniline (1d,
Table 1 Copper-Mediated Reaction of 4-Methoxyaniline (1e) with
Benzenesulfinic Acid (2a) Leading to 1-Methoxy-4-(phenylsulfo-
nyl)benzene (3e): Optimization of Conditionsa
Table 2, entries 4, 9, 13, and 18). o-Toluidine (1c) provid-
ed a lower yield (51%) for steric hindrance of methyl (Ta-
ble 2, entry 3). For arylsulfinic acids, the substrates
containing electron-donating groups afforded higher yield
than those containing electron-withdrawing groups, and a
proper aromatic amine was required to get the desired
product for 4-nitrobenzenesulfinic acid because of the
strong electron-withdrawing effect (Table 2, entry 21).
The reactions could tolerate some functional groups in-
cluding ether (Table 2, entries 5, 10, 14, and 19), C–F
bond (Table 2, entries 6, 11, 15, 20, and 21), C–Cl bond
(Table 2, entries 7, 12–15), CF3 (Table 2, entries 16–20),
nitro (Table 2, entry 21) in the substrates. Unfortunately,
when alkyl sulfinic acids were used as the substrates, the
corresponding diazosulfones were observed without sul-
fones appearing. In addition, we attempted 2-aminopyri-
dine as the substrate, and no desired product was found.
MeO
NH2
O
S
1e
[Cu], RONO, solvent
N2, 0–25 °C, 12 h
+
MeO
O
O
S
3e
HO
2a
Entry [Cu] (equiv)
RONO
Solvent
Yield (%)b
1
2
CuSCN (3)
Cu2O (3)
i-AmONO
i-AmONO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCE
trace
41
3
Cu(OAc)2 (3) i-AmONO
trace
62
4
Cu (3)
–
i-AmONO
i-AmONO
i-AmONO
i-AmONO
i-AmONO
i-AmONO
t-BuONO
NaNO2
In summary, we have developed a convenient and effi-
cient copper-mediated synthesis of diaryl sulfones via the
Sandmeyer reaction. The protocol uses readily available
aryl amines and arylsulfinic acids as the starting materials,
and isoamyl nitrite as the diazotizating reagent of the aryl
amines, the reactions were performed well under mild
conditions, and the corresponding target products were
obtained in moderate to good yields. The method could
tolerate various functional groups in the substrates. We
hope that this new method will be used in industrial and
academic researches for rapid synthesis of diaryl sulfones
because of their wide application in various fields.
5
0
6
Cu (0.5)
Cu (1)
Cu (2)
Cu (4)
Cu (3)
Cu (3)
Cu (3)
Cu (3)
Cu (3)
Cu (3)
Cu (3)
8
7
14
8
21
9
63
10
11
12
13
14
15
16
18
trace
0
i-AmONO
i-AmONO
i-AmONO
i-AmONO
i-AmONO
benzene
MeCN
MeCN
MeCN
0
tracec
traced
29e
General Procedure for the Synthesis of Diaryl Sulfones 3a–u
Aryl amine (1, 0.5 mmol), Cu powder (1.5 mmol, 96 mg), arylsul-
finic acid (2, 1.5 mmol), and MeCN (1 mL) were added to a dry
Schlenk tube equipped with a magnetic stir bar, and then isoamyl
nitrite (1.5 mmol, 175.5 mg) in MeCN (1 mL) was injected slowly
into the tube at 0 °C under nitrogen atmosphere. After a 1 h stirring
at this temperature, the tube was kept at r.t. for 11–23 h under nitro-
gen atmosphere. The resulting solution was concentrated by a rotary
evaporator, and the residue was purified by column chromatogra-
phy on silica gel to provide the desired product 3.
a Reaction conditions: 4-Methoxyaniline (1e, 0.5 mmol), benzenesul-
finic acid (2a, 1.5 mmol), RONO (1.5 mmol), solvent (2 mL), 0–25 °C,
12 h, nitrogen atmosphere.
b Isolated yield.
c In air.
d r.t., ca. 25 °C.
e Benzenesulfinic acid (2a, 1.0 mmol).
Synlett 2014, 25, 847–852
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Diaryl Sulfones
849
Table 2 Copper-Mediated Cascade Synthesis of Diaryl Sulfonesa
NH2
R1
O
S
1
Cu, i-AmONO, MeCN
+
N2, 0–25 °C, 12–24 h
O
O
S
R1
R2
HO
3
R2
2
Entry
1
1
2
Time (h)
12
3
Yield (%)b
69
O
S
O
S
NH2
HO
O
1a
2a
3a
O
S
Me
NH2
Me
2
3
2a
2a
12
24
72
51
O
1b
3b
3c
Me
O
NH2
Me
S
O
1c
O
S
NH2
4
5
6
7
8
9
2a
2a
2a
2a
24
12
12
12
12
24
74
62
61
53
82
68
O
1d
3d
O
S
MeO
NH2
MeO
O
1e
3e
O
S
F
NH2
F
O
1f
3f
O
S
Cl
NH2
Cl
O
1g
3g
O
O
S
Me
S
Me
HO
Me
1b
1d
O
2b
3h
3i
O
S
Me
2b
O
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 847–852

850
X. Yang et al.
LETTER
Table 2 Copper-Mediated Cascade Synthesis of Diaryl Sulfonesa (continued)
NH2
R1
O
S
1
Cu, i-AmONO, MeCN
+
N2, 0–25 °C, 12–24 h
O
O
S
R1
R2
HO
3
R2
2
Entry
10
1
2
Time (h)
12
3
Yield (%)b
81
O
S
MeO
Me
1e
2b
2b
O
3j
O
S
F
Me
11
12
13
14
15
16
17
18
19
1f
12
12
24
12
12
24
24
24
24
49
77
69
65
63
70
49
47
52
O
3k
O
O
S
Me
S
Cl
HO
Cl
1b
1d
1e
1f
O
2c
3l
O
S
Cl
Cl
2c
2c
2c
O
3m
O
S
MeO
O
3n
O
S
F
Cl
O
3o
O
S
O
S
CF3
HO
CF3
1a
1b
1d
1e
O
2d
3p
O
Me
S
CF3
2d
2d
2d
O
3q
O
S
CF3
O
3r
O
S
MeO
CF3
O
3s
Synlett 2014, 25, 847–852
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Diaryl Sulfones
851
Table 2 Copper-Mediated Cascade Synthesis of Diaryl Sulfonesa (continued)
NH2
R1
O
S
1
Cu, i-AmONO, MeCN
+
N2, 0–25 °C, 12–24 h
O
O
S
R1
R2
HO
3
R2
2
Entry
20
1
2
Time (h)
24
3
Yield (%)b
73
O
F
S
CF3
1f
2d
O
3t
O
S
O
S
F
NO2
HO
NO2
21
1f
24
61
O
2e
3u
a Reaction conditions: aryl amine (0.5 mmol), arylsulfinic acid (1.5 mmol), i-AmONO (1.5 mmol), Cu powder (1.5 mmol), MeCN (2.0 mL),
0–25 °C, 12–24 h, nitrogen atmosphere.
b Isolated yield.
(2) Langman, M.-J.; Jensen, D.-M.; Watson, D.-J.; Harper, S.-
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