Asymmetric synthesis of N-aryl sulfinamides: Copper(I)-catalyzed coupling of sulfinamides with aryl iodides via kinetic resolution

Article abstract of DOI:10.1016/j.tetlet.2016.04.049

An asymmetric synthesis of N-aryl sulfinamides was achieved through copper-catalyzed coupling reactions of aryl iodides with sulfinamides. Such a kinetic resolution process provided the desired coupling products in moderate to good yields and with moderate enantioselectivities.

Full text of DOI:10.1016/j.tetlet.2016.04.049

Tetrahedron Letters xxx (2016) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric synthesis of N-aryl sulfinamides: copper(I)-catalyzed
coupling of sulfinamides with aryl iodides via kinetic resolution
b,
Yangyuan Liu a,b, Zesheng Wang b, Bin Guo a, , Qian Cai
⇑
⇑
a National & Local Joint Engineering Laboratory for New Petro-chemical Materials and Fine Utilization of Resources, Hunan Normal University, No. 36 Lushan Road, Changsha
410081, China
b Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou 510530, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An asymmetric synthesis of N-aryl sulfinamides was achieved through copper-catalyzed coupling reac-
tions of aryl iodides with sulfinamides. Such a kinetic resolution process provided the desired coupling
products in moderate to good yields and with moderate enantioselectivities.
Ó 2016 Published by Elsevier Ltd.
Received 1 March 2016
Revised 12 April 2016
Accepted 14 April 2016
Available online xxxx
Keywords:
N-Aryl sulfinamide
Copper
Asymmetric catalysis
Cross-coupling
Kinetic resolution
Sulfinamides have found extensive applications as easily-
removed protection groups or functional groups in synthetic
chemistry.1 Among them, chiral sulfinamides such as chiral t-
butanesulfinamide and analogues are especially important, which
have been widely used as chiral auxiliaries or chiral ligands in
asymmetric reactions.2
Many methods have been developed for the synthesis of race-
mic sulfinamides.3 However, the enantioselective synthesis of chi-
ral sulfinamides is relatively rare, especially for the synthesis of N-
aryl sulfinamides.4
ple, Du and coworkers9 used a Pd catalytic system for the coupling
reactions of chiral 2-(20-bromophenyl)oxazolines and (s)-tert-
butanesulfinamides, while Selvakumar and coworkers10 developed
a Pd-catalyzed C–N coupling reaction of racemic tert-butanesulfi-
namide and aryl bromides and chlorides. In these cases, chiral sul-
finamide substrates were used for the formation of chiral products.
No asymmetric coupling reactions were reported with racemic sul-
finamide substrates to date.
As part of our continuous studies11,12 on transition-metal cat-
alyzed asymmetric C–N couplings, we have developed some cop-
per catalytic system for asymmetric aryl C–N coupling
reactions12 through kinetic resolution strategy.13 This promoted
us to envision that the asymmetric synthesis of N-aryl sulfinamides
may be achieved through coupling reactions of racemic sulfi-
namides and aryl halides under the catalysis of copper salts and
chiral ligands through kinetic resolution (Fig. 1). Herein we’d like
to disclose the details.
Our investigation was initiated with the CuI-catalyzed coupling
reaction of 4-chloro-iodobenzene (1a) and recemic tert-butanesul-
finamide (2a) as a model case. A variety of chiral ligands such as
binol (L1),14 amino acid (L2),15 box (L3), were first screened and
only a trace amount of desired coupling product was obtained
(Table 1, entries 1–3). However, when a diamine-derived ligand
L4 was used,16 good yield was obtained albeit in only 30% ee
(Table 1, entry 4). Further exploration of diamine-type ligands
(Table 1, entries 5–9, L5–L9) revealed that L6 was relatively better,
which afforded the product in 82% yield and 56% ee (Table 1, entry
Transition-metals such as Pd5 or Cu-6catalyzed C–N coupling
reactions have been extensively studied in the last few decades
for the formation of aryl carbon–nitrogen and carbon–heteroatom
bonds. The coupling reaction of aryl halides with sulfinamides is an
important method for the formation of N-aryl sulfinamides. In
2010, Touré7 reported a copper-catalyzed coupling reaction of
tert-butanesulfinamide with 2-bromopyridine with >90% conver-
sion. However, the substrate scope was great limited in this work.
In a later study, Zeng and co-workers8 found that only low yields
(<30%) were obtained for most aryl halide substrates under the
copper catalytic system. Thus they resorted to Pd catalytic system,
which could afford the coupling products N-aryl sulfinamides in
high yields. Other groups also developed similar Pd catalysts for
the coupling reactions of aryl halides and sulfonamides. For exam-
⇑
Corresponding authors.
http://dx.doi.org/10.1016/j.tetlet.2016.04.049
0040-4039/Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Liu, Y.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.04.049

2
Y. Liu et al. / Tetrahedron Letters xxx (2016) xxx–xxx
Table 2
O
S
H
N
O
S
[Cu]/chiral ligands
kinetic resolution
Substrate scopea
R
+
Ar-X
+
Ar
S
O
R
NH2
NH2
R
O
S
racemic
H
N
enantioenriched
CuI/L6*
R
+
ArX
R
NH2
Ar
S
O
K3PO4, toluene
75 o
C
Figure 1. Design of asymmetric C–N coupling reactions for the synthesis of N-aryl
sulfonamides via kinetic resolution strategy.
1
(rac)-2
3
Entry ArI
R
Product Yield
(%)b
ee
(%)c
6). Similar results were achieved by switching the base from K3PO4
to K2CO3 or Cs2CO3 (Table 1, entries 10 and 11). Further screening
of other solvents revealed that a higher yield and better enantios-
electivity were obtained in toluene (Table 1, entry 12, 86% yield
and 60% ee). It is noticeable that in this study, 3 equiv of racemic
2a was used, and when only 2 equiv of 2a was used, an inferior
yield and enantioselectivity were observed (Table 1, entry 16),
while little influence was observed for the yield and enantioselec-
tivity when more than 3 equiv of racemic 2a was used.
With the optimized conditions in hand, we further explored the
substrate scope for the reactions. As shown in Table 2, a variety of
aryl iodides were explored and all delivered the corresponding
coupling products in moderate to good yields and moderate ee val-
1
2
3
4
5
6
7
4-ClC6H4I
PhI
4-FC6H4I
4-MeC6H4I
2-MeC6H4I
2-iPrC6H4I
t-Butyl
t-Butyl
t-Butyl
t-Butyl
t-Butyl
t-Butyl
t-Butyl
3a
3b
3c
3d
3e
3f
86
86
87
85
54
34
74
60
55
52
53
36
31
57
3,5-dimethyl
C6H3I
3g
8
9
3-MeOC6H4I
3,5-difluoro C6H3I
3-CNC6H4I
3-CF3C6H4I
4-CF3C6H4I
4-CO2MeC6H4I
1-
t-Butyl
t-Butyl
t-Butyl
t-Butyl
t-Butyl
t-Butyl
t-Butyl
3h
3i
3j
3k
3l
3m
3n
93
90
95
92
95
85
57
53
49
48
51
49
55
26
10
11
12
13
14
iodonaphthalene
2-iodopyridine
4-ClC6H4I
4-ClC6H4I
4-ClC6H4I
15
16
17
18
19
t-Butyl
i-Pr
n-Butyl
ph
2-t-Butyl-
phenyl
3o
3p
3q
3r
3s
72
60
45
40
37
45
51
45
5
Table 1
Screening of the ligands and reaction conditionsa
H
N
I
O
S
t-Bu
4-ClC6H4I
40
CuI/L*
S
O
NH2
t-Bu
base, solvent
Cl
Cl
a
Reagents and reaction conditions: 1 (0.2 mmol), 2 (0.6 mmol, 3.0 equiv), CuI
(0.02 mmol, 10 mol %), ligand (0.03 mmol, 15 mol %), K3PO4 (0.4 mmol), 75 °C, 24 h.
1a
(rac)-2a
3a
b
Isolated yields.
Determined by HPLC analysis.
O
N
O
N
c
OH
OH
CO2H
N
H
Ph
Ph
ues. Both electron-donating and withdrawing substituents on the
aryl rings were well tolerated. However, the substituents at the
ortho-position were disfavored for conversion and only low yields
were obtained (Table 2, entries 5 and 6). Several other sulfinamides
such as i-Pr, n-Bu-, and 2-butylphenyl sulfinamides, were also
explored and all delivered the corresponding products in moderate
yields and moderate enantioselectivities. While the reaction of
phenylsulfinamide and 4-chloro-iodo-benzene afforded the
desired product 3r in only 5% ee (Table 2, entry 19). Aryl bromides
were also tested in these reactions, however, they were not suit-
able substrates for this reaction since a much higher reaction tem-
perature was needed for the conversion and only a small amount of
the desired products (<10%) were obtained (data not shown). In all
these cases, the selective factors are relatively low.17 For example,
in the case of 3l, the selective factor is only about 4 by calculation,
which indicated that more efforts should be put to improve the
enantioselectivity for practical use. A simple recrystallization
worked well for the improvement of the enantiopurity in this case.
The product 3l was obtained in 50% yield and 92% ee after recrys-
tallization. The absolute configuration of coupling product 3a was
determined as S by comparing with the literature reported data.8b
The absolute configurations of other products were designed by
analogue to that of 3a.
L3
L2
L1
L4
H
N
HN
NH
HN
HN
NH
N
H
L5
L6
HN
NH
NH
HN
NH
L9
L8
Base/solvent
L7
L⁄
Me
Me
Entry
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L9
L6
L6
L6
L6
L6
L6
L6
K3PO4/1,4-dioxane
K3PO4/1,4-dioxane
K3PO4/1,4-dioxane
K3PO4/1,4-dioxane
K3PO4/1,4-dioxane
K3PO4/1,4-dioxane
K3PO4/1,4-dioxane
K3PO4/1,4-dioxane
K3PO4/1,4-dioxane
K2CO3/1,4-dioxane
Cs2CO3/1,4-dioxane
K3PO4/acetone
<10
<10
<10
79
70
82
72
<10
15
43
82
10
rac
16
30
24
56
25
9
13
50
52
40
34
48
60
45d
9
10
11
12
13
14
15
16
In summary, a copper-catalyzed coupling reaction for the asym-
metric synthesis of chiral N-aryl sulfinamides was developed
through kinetic resolution. The desired coupling products were
obtained in high yields and with moderate enantioselectivity. Fur-
ther endeavors were needed in this field.
76
82
80
86
K3PO4/MeCN
K3PO4/THF
K3PO4/toluene
K3PO4/toluene
60
a
Reagents and reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol, 3.0 equiv), CuI
Acknowledgments
(0.02 mmol, 10 mol %), ligand (0.03 mmol, 15 mol%), base (0.4 mmol), 75 °C, 24 h.
b
Isolated yields.
Determined by HPLC analysis.
2a (0.4 mmol, 2.0 equiv) was used.
The authors are grateful to the National Natural Science Foun-
dation (Grant 21272234, & 21572229) for their financial support.
c
d
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Y. Liu et al. / Tetrahedron Letters xxx (2016) xxx–xxx
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