Mechanistic aspects of copper (II)-catalyzed synthesis of sulfones from sulfinate salts and aryl halides under C-S coupling

Article abstract of DOI:10.1016/j.mcat.2017.12.016

Copper(II)-catalyzed synthesis of sulfones from sulfinate salts and aryl halides was investigated by means of a combination of experiment and DFT calculation. Experimental results demonstrated the wide applicability of the title approach. The reaction mechanisms are revealed by in-situ IR and theoretical study. It reveals remarkable ligand effect the bidentate amine plays in the reaction, that is, it initially activats the C-I bond of iodobenzene so as to enhance the whole catalytic process.

Full text of DOI:10.1016/j.mcat.2017.12.016

Molecular Catalysis 449 (2018) 72–78
Contents lists available at ScienceDirect
Molecular Catalysis
journal homepage: www.elsevier.com/locate/mcat
Mechanistic aspects of copper (II)-catalyzed synthesis of sulfones
from sulfinate salts and aryl halides under C-S coupling
Xin Gea,b, Fengli Sun , Xuemin Liu , Xinzhi Chen , Chao Qian , Shaodong Zhou
a
a
b
b,∗
b,∗
a
School of Chemical and Material Engineering, Jiangnan University, Wuxi, PR China
Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou,
PR China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 June 2017
Received in revised form
Copper(II)-catalyzed synthesis of sulfones from sulfinate salts and aryl halides was investigated by means
of a combination of experiment and DFT calculation. Experimental results demonstrated the wide appli-
cability of the title approach. The reaction mechanisms are revealed by in-situ IR and theoretical study. It
reveals remarkable ligand effect the bidentate amine plays in the reaction, that is, it initially activats the
C-I bond of iodobenzene so as to enhance the whole catalytic process.
1
2 December 2017
Accepted 12 December 2017
©
2017 Elsevier B.V. All rights reserved.
Keywords:
Copper
C-S coupling reaction
in-situ IR
Mechanism
DFT
1
. Introduction
diamine and proline ligands. Up till now, various ligands such as
anion-functionalized ionic liquid [12], 1,10-phenanthroline [13],
D-Glucosamine [14] and chitosan [15] have been developed for pro-
moting the coupling of sulfinate salts with aryl halides. In contrast
to the vast number of reports on Ullmann C N and C O coupling
reaction, there are only a few reports on C-S coupling of sulfinate
salts with aryl halides, and detailed mechanism study is still lacking.
Recently, considerable effort has been made to elucidate the
mechanism of Ullmann C N coupling reaction. The oxidation addi-
tion/reductive elimination mechanisms are widely accepted [16],
Aryl sulfone is an important class of compounds which play a
major role in pharmaceuticals and agrochemicals [1]. Especially,
their versatile bioactivities e.g. anti-HIV [2], anti-tumor [3] and
anti-inflammatory [4] continue to attract much attention in med-
ical industry. Sulfones can be prepared via quite a few routes,
among which the oxidation of sulfides [5] and the sulfonylation
of arenes [6] are classic. However, these two routes suffer from
some disadvantages, e.g. low yield and fastidiousness about the
substrate. Further, for the oxidation route, the harsh condition
required and limited applicability of organometallic catalyst con-
cerning various functional groups are also annoying. Recently,
metal-catalyzed coupling reaction is becoming the most power-
ful tool for functionalization of arylated compound [7]. Compared
with other metal-catalyst, copper-complex is more promising for
coupling of sulfinate salts with aryl halides due to the benign con-
dition needed and the wide applicability for various functional
groups including olefin, amine etc [8]. In 1995, Suzuki et.al. [9]
first reported the sulfones were synthesized by using 1.5 equiv
I
in which the ligand-Cu -nucleophile intermediates were identi-
fied as the active species for the C N coupling process [17].
I
Moreover, the oxidative addition of ligand-Cu -nucleophile inter-
mediates with aryl halides was identified as the rate-determining
step [16][16d]. By contrast, analogous mechanistic studies on Ull-
mann C-S [18] coupling reaction received less attention. Shyu et.
al. [18][18a] reported that several Cu-thiolate intermediates in
the C-S coupling of thiophenol with aryl halide were observed by
in situ ESI–MS study. Weng and Hartwig et. al. [18][18b] prepared
I
ligand-Cu -thiophenolato complexes and examined their reactiv-
◦
of CuI as catalyst in DMF at 110 C; the afterward work done by
Wang [10] and Ma [11] improved this strategy by introducing
ity in the copper-catalyzed thioetherification of aryl halides. Upon
comparing several proposed mechanisms for Ullman reaction,
e.g. oxidative addition/reductive elimination, ␴-bond metathesis,
single-electron transfer (SET) and halogen-atom transfer (HAT)
mechanisms, Zhang et. al. [18][18c] found that HAT is the most
favorable mechanism for Ullmann C-S coupling of thiophenol with
∗ Corresponding authors.
E-mail addresses: qianchao@zju.edu.cn (C. Qian), szhou@zju.edu.cn (S. Zhou).
https://doi.org/10.1016/j.mcat.2017.12.016
2
468-8231/© 2017 Elsevier B.V. All rights reserved.

X. Ge et al. / Molecular Catalysis 449 (2018) 72–78
73
Table 1
Ullmann C-S coupling of iodobenzene with sodium benzenesulfinate a
.
Entry
Copper Salt
Solvent
Yield (%)b
1
2
3
4
5
CuCl
CuBr
CuI
CuSO4·5H2O
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
85
83
74
71
95
0
c
6
7
d
0
8
9
84
31
0
Methanol
DMSO:H2O (1:1)
1
0
a
reaction conditions: iodobenzene 1a (1.0 mmol), sodium benzenesulfinate 2a (1.2 mmol), copper salt (0.01 mmol), DMEDA (0.02 mmol), K2CO3 (2.0 mmol), solvent (5 mL),
◦
1
10 C, under air, 2 h.
b
Isolated yield.
No ligand.
No K2CO3.
c
d
aryl halide. However, the mechanism of C-S coupling of sulfinate
salts with aryl halides remains a mystery. The previously reported
mechanisms for Ullmann reactions imply that different nucle-
ophiles may react via different mechanisms. In this work, we reveal
the mechanistic aspects for Ullmann C-S coupling of sulfinate salts
with aryl halides catalyzed by Cu(II)-complexes. Several conceiv-
able pathways were considered and the influence of diamine-type
ligand on the synthesis of aryl sulfones will be discussed.
2
. Result and discussion
Initial experimental investigations focused on the influence of
diamine-type ligand structure on the catalytic activity. The cou-
pling of iodobenzene (1.0 equiv.) and sodium benzenesulfinate (1.2
equiv.) was adopted as the model reaction, and detailed ligand
screening are shown in Fig. 1. By using 10 mol% of cyclohexane-1,2-
diamine (L1) and ethylenediamine (L2), the sulfone was obtained
in good yields. When N,N’-dimethylehylenediamine (DMEDA, L3)
was used as ligand, the yield increased to 95%. Ligand contain-
ing secondary amine serves as more active catalysts as compared
to those with primary amine group. We speculated that ligands
possessing primary amine is less electron-donating such that the
so formed complex is less active. Accordingly, secondary-amine-
ligand L5 possessing two electron-withdrawing benzene groups
is also less active. Moreover, due to steric hindrance, L4 is diffi-
cult to bound with copper for forming stable chelate, resulting in
less reactivity of associated system. The other bidentate N-ligand
Fig. 1. Ligand screening in copper-catalyzed synthesis of sulfones from sulfinate
a
salts and aryl halides
reaction conditions: iodobenzene 1a (1.0 mmol), sodium benzenesulfinate 2a
1.2 mmol), Cu(OAc)2 (0.01 mmol), ligand (0.02 mmol), K2CO3 (2.0 mmol), DMSO
.
a
(
1
,10-phenanthroline (L6) gave good result with 88% yield.
(5 mL), 110 oC, under air, 2 h. The yield of product is isolated yield.
For Ullmann C-S coupling of iodobenzene with sodium ben-
zenesulfinate, various copper sources and solvent were studied
in presence of DMEDA. The detained results were summarized in
Table 1. Comparison of different copper sources, i.e. CuI, CuBr, CuCl,
CuSO ·5H O and Cu(OAc) , showed that Cu(OAc) was the best
IR. As shown in Fig. 2, all these three copper-catalyzed reactions
exhibit zero-order character, and the initial rates of Cu(OAc) , CuCl
2
and CuI were 0.019 mM/min, 0.012 mM/min and 0.0094 mM/min,
respectively. Clearly, Cu(OAc)2 outperforms the other two copper
salts.
4
2
2
2
copper source (Table 1, Entry 1–5). This suggested that the oxi-
dation state of copper may have no influence on the formation of
catalyst precursor, which have also been observed previously [19].
However, copper source without the ligand was completely inac-
tive (Table 1, Entry 6). In addition, base is found to be essential
in this protocol for the formation of C-S bond (Table 1, Entry 7).
Next, a serious of solvents were tested and it was found that polar
aprotic solvents were favorable for this C-S coupling (Table 1, Entry
Further study focused on testing the scope of Cu(OAc) /DMEDA
2
catalyzed C-S coupling reaction. As showed in Table 2, to our
delight, both aryl sulfonate and alkyl sulfonate react efficiently with
iodobenzene and targeted product was obtained with excellent
yields (Table 2, Entry 1–4). Moreover, it is notable that the sul-
fonates with electron-donating groups are more reactive than the
ones with electron-withdrawing groups. For aryl iodide, neither
5
,8–10). The detailed kinetic profiles were obtained using in-situ

7
4
X. Ge et al. / Molecular Catalysis 449 (2018) 72–78
Scheme 1. Proposed mechanism.
Table 2
Cu(OAc)2/DMEDA catalyzed C-S coupling reaction a.
Entry
Ar
X
R
Yield (%)b
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
I
I
I
I
I
I
I
I
I
I
I
I
I
I
Br
Ph
95 (3a)
96 (3b)
82 (3c)
97 (3d)
93 (3e)
92 (3b)
88 (3f)
87 (3c)
90 (3 g)
94 (3 h)
81 (3i)
85 (3j)
71 (3k)
64 (3l)
47 (3a)
4-MeC6H4
4-ClC6H4
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeOC6H4
4-MeC6H4
4-HOC6H4
4-ClC6H4
4-NO2C6H4
4-CF3C6H4
4-CH3COC6H4
3-NO2C6H4
2-MeC6H4
2-MeOOCC6H4
Ph
10
11
12
13
14
15
a
◦
reaction conditions: 1 (1.0 mmol), 2 (1.2 mmol), Cu(OAc)2 (0.01 mmol), DMEDA (0.02 mmol), K2CO3 (2.0 mmol), DMSO (5 mL), 110 C, under air, 2 h.
Isolated yield.
b
electron donating nor withdrawing groups substituted on the ring
have obvious influence on the yields (Table 2, Entry 5–11), while the
steric hindrance by ortho-substituents decreases the reaction effi-
ciency (Table 2, Entry 12–14). In line with the previous study [9,10],
the reactivity of aryl bromide is lower than iodobenzene (Table 2,
Entry 15).
To elucidate the reaction mechanisms, we used in-situ IR to
monitor the stoichiometric reaction of DMEDA-ligated copper A
with iodobenzene or sodium benzenesulfinate. Initially, DMEDA-
ligated copper A formed in situ by the stoichiometric reaction of
◦
DMEDA and Cu(OAc)2 in DMSO at 110 C. As shown in Fig. 3a,
−1
after the addition of iodobenzene, the peak at 731 cm concern-
ing Ar-I stretch vibration migrated to 742 cm−1. Then, the addition
of sodium benzenesulfinate to the mixture resulted in the ConcIRT
−
1
−1
migration of S O stretching from 1130 cm to 1158 cm . Finally,
when the K CO3 was added into the reaction system, the new
2
−
1
peak at 1119 cm
regarding S O stretching was formed. How-
ever, when sodium benzenesulfinate was first added to mixture,
the in-situ IR had no obvious change. Thus, a prototypical reaction
mechanism for C-S coupling of iodobenzene with sodium benzene-
Fig. 2. Kinetic profiles of C-S coupling catalyzed by Cu species.

X. Ge et al. / Molecular Catalysis 449 (2018) 72–78
75
Fig. 3. (a) ConcIRT spectra of in-situ 1a. (b) Overall three-dimensional Fourier transform IR (3D-FTIR) profile of the reaction between complex B and 2a. (c) 3D-FTIR profile
of the reaction between complex C and K2CO3.

7
6
X. Ge et al. / Molecular Catalysis 449 (2018) 72–78
Fig. 4. PES and selected structural information for route 1; A is for bare Cu2+ catalyzed reaction, while B is for the Cu(II)-catalyzed one.

X. Ge et al. / Molecular Catalysis 449 (2018) 72–78
77
Fig. 5. PES and selected structural information for route 2; A is for bare Cu2+ catalyzed reaction, while B is for the Cu(II)-catalyzed one.
sulfinate catalyzed by copper is proposed, as shown in Scheme 1.
Initially, complex B is formed via oxidative addition of complex
A with iodobenzene, which activates Ar-I bond. The nucleophilic
reaction of complex B with sodium benzenesulfinate generates
complex C. This results in the cleavage of Ar-I bond, which is proved
ing to the experimental results, was thus used for modeling the
Cu(II)-catalyzed reaction; the latter will be compared with the bare
2+
Cu catalyzed system. In order to obtain common information
about the reaction mechanism, the production of diphenylsulfone
was selected as the model. Two possible routes, e.g. oxidative
addition/reductive elimination and ␴-bond metathesis, were con-
sidered, and the potential energy surfaces (PESs) as well as some
structural information of relevant species are shown in Figs. 2 and 3,
respectively.
−1
by consumption of the peak at 731 cm (see Fig.S2 in the SI). With
the addition of base to mixture, the final product was obtained by
reductive elimination and DMEDA-ligated copper was regenerated.
Next, the reaction mechanisms were interrogated by density
functional theory (DFT) calculation. For the Ullmann reaction,
the oxidative addition/reductive elimination mechanism is widely
For route 1 (␴-bond metathesis mechanism), the C-S coupling
concerts with activation of the C H5-I bond. As shown in Fig. 4A,
6
[
16d,e]
2+
accepted
. However, the mechanism of C-S coupling of sul-
for bare Cu catalyzed reaction, the transformation starts from
finate salts with aryl halides remains unknown. Thus, we first
studied the influence of diamine-type ligand on the synthesis of
aryl sulfones. Ligand L2, which gives the best performance accord-
an encounter complex 1a, in which the copper atom interacts
with the iodine atom of iodobenzene and one oxygen atom of
benzenesulfinate. By surmounting TS1a/2a, the C H5-I bond is
6

7
8
X. Ge et al. / Molecular Catalysis 449 (2018) 72–78
activated under formation of the Cu-I and C H5 O bonds, form-
(2016YFB0301800), China Postdoctoral Science Foundation funded
project (2016M590536) and the Fundamental Research Funds for
the Central Universities (JUSRP115A05).
6
ing 2a. Subsequently, the phenyl group of original iodobenzene
migrates from the oxygen atom to the sulfur atom, producing the
product complex 3a, the dissociation of which releases neutral
+
diphenylsulfone and CuI . The Cu(II)-catalyzed reaction, Fig. 4B,
Appendix A. Supplementary data
2+
structurally resemble the bare Cu catalyzed reaction one, i.e.
1
b → TS1b/2b → 2b → TS2b/3b → 3b. However, both reaction path-
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.mcat.2017.12.
016.
ways are too energetically demanding to be available.
For route 2 (oxidative addition/reductive elimination mecha-
nism), the C-S coupling is achieved in a stepwise manner, that is, the
C H5-I bond activation takes place first which is followed by cou-
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8
Acknowledgements
The authors are grateful for the financial support from the
Natural Science Foundation of China (21476194, 21606104),
the National Key Research and Development Program of China