Copper-mediated S-N formation via an oxygen-activated radical process: A new synthesis method for sulfonamides

Article abstract of DOI:10.1039/c4cc01353k

Copper-mediated direct S-N formation using readily available starting materials via an oxygen-activated radical process has been developed. This method provides a novel and direct approach for synthesis of sulfonamides under air conditions. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01353k

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Copper-mediated S–N formation via an
oxygen-activated radical process: a new
synthesis method for sulfonamides†
Cite this: Chem. Commun., 2014,
50, 4582
Received 21st February 2014,
Accepted 16th March 2014
Xin Huang, Jichao Wang, Zhangqin Ni, Sichang Wang and Yuanjiang Pan*
DOI: 10.1039/c4cc01353k
www.rsc.org/chemcomm
Copper-mediated direct S–N formation using readily available
starting materials via an oxygen-activated radical process has been
developed. This method provides a novel and direct approach for
synthesis of sulfonamides under air conditions.
Scheme 1 Strategy for the synthesis of sulfonamides.
Sulfonamides that possess a wide range of biological activities
have been widely used in the pharmaceutical industry.1 The
traditional methods for the synthesis of sulfonamides principally
involve (1) reaction of amines with sulfonyl chlorides or sulfonic
esters;2a (2) coupling of N-unsubstituted/N-monosubstituted sulfona-
mides with amines or organohalides;2b and (3) oxidation of sulfena-
mides.2c Although these methods are available and can be used to
easily build the S–N bond, they are limited by their not readily
available reactants, multistep reactions, strong oxidants and toxic
derivatives. Transition metal-catalyzed reaction is a new strategy for
the synthesis of sulfonamides.3 In 2010, Taniguchi et al.4 developed a
method for copper-catalyzed synthesis of sulfonamides from thiols
and amines under an oxygen atmosphere. Recently, Jiang et al.5
reported on copper-catalyzed sulfonamide formation using
sodium sulfinates and amines under an oxygen balloon. Using
oxygen as an oxidant is favorable for green chemistry. However,
limited substrate scope and restricted reaction conditions hinder
the widespread application of oxygen as an oxidant. Thus,
developing an efficient and versatile strategy for the synthesis
of sulfonamides is necessary.
Based on increasing interest in thiols,10 we report copper-
mediated direct sulfonamide formation from thiols and for-
mamides under air conditions (Scheme 1). To the best of our
knowledge, this study is the first to use formamides as the N
sources in the synthesis of sulfonamides.
4-Chlorothiophenol 1a and DMF 2a were used as the model
substrates to optimize the reaction conditions. The results are
summarized in Table 1.
The reaction was performed at 110 1C in the presence of CuCl
(1 equiv.), Cu(OAc)2 (1 equiv.) and benzoic acid (1 equiv.) (as an additive)
Table 1 Optimization of the reaction conditionsa
Copper salts
(equiv.)
Oxidant
(equiv.)
Additive
(equiv.)
Yieldb
(%)
Entry
Dimethyl formamide (DMF) is a polar solvent that has been used
as a precursor for –NMe2, –CONMe2, and –Me groups.6 Among these
reaction units, the decarbonylation of DMF as a source of –NMe2 has
elicited the attention of chemists.7 In 2009, Chang et al.8 developed a
silver-mediated amination of benzoxazoles with DMF. Meanwhile,
Wan et al.9 introduced DMF as the source of the aminyl radical
in the synthesis of amides.
1
2
3
4
5
6
7
8
CuCl (1)
CuI (1)
CuBr (1)
CuCl2 (1)
—
CuCl (2)
CuCl (0.1)
CuCl (1)
CuCl (1)
CuCl (1)
CuCl (1)
CuCl (1)
CuCl (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Benzoic acid (1)
Benzoic acid (1)
Benzoic acid (1)
Benzoic acid (1)
Benzoic acid (1)
Benzoic acid (1)
Benzoic acid (1)
Cinnamic acid (1)
L-Proline (1)
81
15
28
37
0
78
Trace
83
57
44
48
37
38
9
10
11
12
13
L-Phenylalanine (1)
CH3COOH (2)
H2SO4 (2)
Department of Chemistry, Zhejiang University, Hangzhou 310027, Zhejiang,
P. R. China. E-mail: panyuanjiang@zju.edu.cn; Fax: +86 571 87951629;
Tel: +86 571 87951629
—
a
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc01353k
Reaction conditions: 1a (0.5 mmol), 2a (1.5 ml), copper salts, oxidant,
b
additive under air conditions at 110 1C for 24 h. Isolated yield.
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Table 3 Substrate scope of formamides with 4-chlorothiophenola
under air conditions for 24 h. The desired product 3aa was isolated in a
yield of 81% (Table 1, entry 1). Then, different copper salts were
introduced, among which CuCl showed the best activity (Table 1,
entries 1–4). However, no desired product was obtained when no
copper salt was added, implying that the CuI was necessary for the
transformation (Table 1, entry 5). The amount of copper salt was also
investigated, when 2 equiv. of CuCl was used, the yield slightly
decreased to 78% (Table 1, entry 6). By contrast, only a trace amount
of the product was obtained when 0.1 equiv. of CuCl was used (Table 1,
entry 7). This result indicated that the stoichiometric amount of copper
salt was essential for the fluent conversion. A series of additives was also
examined (Table 1, entries 8 to 13). Only 38% yield of the product was
obtained in the absence of acid (Table 1, entry 13), suggesting the
importance of acid in the reaction. Cinnamic acid and benzoic acid
proved to be better than other acids.11 Moreover, Cu(OAc)2 produced
the best result among different oxidants.12 The reaction time, tempera-
ture and solvent were also tested (see ESI,† Table S1). Thus, the optimal
reaction conditions involved CuCl (1 equiv.)/Cu(OAc)2 (1 equiv.)/
cinnamic acid (1 equiv.) under air conditions.
With the optimal reaction conditions in hand, we then investi-
gated the substrate scope of thiols. As shown in Table 2, the reaction
proceeded smoothly with substrates containing electron-withdrawing
groups and electron-donating groups in moderate to good yield
(3aa–3la). In general, thiophenols bearing electron-donating groups
produced lower yields. For example, when 4-methylthiophenol
a
Conditions: 1a (0.5 mmol), 2 (1.5 ml), Cu(OAc)2 (1 equiv.), cinnamic
acid (1 equiv.), CuCl (1 equiv.) under air conditions at 110 1C for 24 h.
Isolated yield. 2f (1 mmol), DMA (1.5 ml), 6 h.
b
c
reacted with DMF under the optimal conditions, the isolated yield was
46% (3fa), whereas strong electron-withdrawing groups such as 4-CF3
(3ga) and 4-NO2 (3da) could produce products with yields of 62% and
76%, respectively. Halide groups (3aa–3ca, 3ka) were all well tolerated
and the corresponding products could be applied in further reactions.
When 3,4-dichlorothiophenol was used, the desired product (3ka) was
isolated in good yield. The steric effects had minimal influence on the
transformation as confirmed by the higher yield facilitated by the 2-Cl
substrate (3ja) than the 3-Cl substrate (3ha) (58% to 51%). However,
neither the aliphatic thiol (3ma) nor the heterocyclic thiol (3na) was
suitable for the smooth conversion. These results indicated that the
aromatic groups were essential for the reaction.
Table 2 Copper-mediated S–N formation by DMF and various thiolsa
A series of formamides was also examined to expand the
synthetic utility of the protocol (Table 3). For N,N-disubstituted
formamides, lower yields of products (3aa vs. 3ab and 3ac) were
obtained as the carbon chain on the N atom increased. These
results could be attributed to the larger steric hindrance on the N
atom of formamides. Meanwhile, the formamides derived from
cyclic amines produced higher yields (3ad and 3ae) compared with
those derived from linear amines. However, no desired product was
obtained for the N-monosubstituted formamides. In addition, 3af
was isolated when N-methyl formamide reacted with 1a through
a dehydrogenation process. Besides, N-methylformanilide (3ag)
and formanilide (3ah) did not provide good results. This finding
could be attributed to the strong conjugation between the amide
group and the phenyl ring that inhibited the decarbonylation of
formamides.9
To gain further insights into the mechanism, a series of control
experiments was carried out. The results are shown in Table 4. Only
a trace amount of 3aa was detected when 4-chlorobenzenesulfonic
acid and 4-chlorobenzenesulfonyl chloride reacted with DMF under
a
Conditions: 1 (0.5 mmol), DMF (1.5 ml), CuCl (1 equiv.), Cu(OAc)2
(1 equiv.), cinnamic acid (1 equiv.) under air conditions at 110 1C for
24 h. Isolated yield.
b
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Table 4 Investigation into the mechanism of reaction
Scheme 2 Proposed reaction mechanism.
(V) coupled with the sulfonyl radical (III) to generate the desired
product 3aa with the release of CuI.
In summary, we developed copper-mediated direct S–N
bond formation from thiols and formamides. This protocol
provides a novel and direct synthesis of sulfonamides from
readily available starting materials via an oxygen-activated
radical process. Further studies on the mechanism and related
work are ongoing in our group.
a
Conditions: 1 (0.5 mmol), 2a (1.5 ml), Cu(OAc)2 (1 equiv.), cinnamic
The authors gratefully acknowledge financial support from
the National Science Foundation of China (21025207).
acid (1 equiv.), CuCl (1 equiv.) under air conditions in 110 1C for 24 h.
b
c
Condition: under a N2 atmosphere. Conditions: 1a (0.5 mmol), 2i
(1 mmol), DMA (1.5 ml), Cu(OAc)2 (1 equiv.), cinnamic acid (1 equiv.),
d
CuCl (1 equiv.) under air conditions in 110 1C for 12 h. Conditions: 1a
Notes and references
(0.5 mmol), 2d (1.5 ml), Cu(OAc)2 (1 equiv.), cinnamic acid (1 equiv.),
CuCl (1 equiv.), TEMPO (1.5 equiv.) under air conditions in 110 1C for
1 For selected papers, see: (a) C. T. Supuran, A. Casini and A. Scozzafava,
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24 h. Conditions: 1q (0.5 mmol), 2i (1 mmol), DMA (1.5 ml), Cu(OAc)2
(1 equiv.), cinnamic acid (1 equiv.), CuCl (1 equiv.), TEMPO (1.5 equiv.)
under air conditions at 110 1C for 24 h. Isolated yield.
the optimal conditions (Table 4, eqn (1) and (2)). However, the
desired product produced a yield of 52% when 4-chlorobenzene-
sulfinic acid was used as the reactant (Table 4, eqn (3)). No desired
product was detected when we changed the reaction atmosphere
from air to nitrogen (Table 4, eqn (4)). These results suggested that
benzenesulfinic acid may act as the intermediate formed by the
oxidation of thiol under air conditions. Then, 56% yield of 3ad was
obtained when formamide was changed to amine (Table 4, eqn (5)).
This result indicated that amine may be another intermediate
obtained by the decarbonylation of formamide.
Furthermore, only a trace amount of the product was detected in
the presence of the radical scavenger 2,2,6,6-tetramethylpiperidine-
N-oxyl (Table 4, eqn (6) and (7)). This result implied that a radical
step was involved in the reaction.
A plausible mechanism deduced according to the results above
and recent publications5,13 is presented in Scheme 2. First, thiol
(1a) was oxidized to sulfinic acid with copper salts under air
´
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11 We thank the reviewers for pointing out that the aromatic acid could
(I). The sulfinyl anion (I) was activated by oxygen via single electron
transfer, providing an oxygen-centered radical (II) that could reso-
also act as a ligand to promote the reaction.
nate with the sulfonyl radical (III). Meanwhile, CuI was oxidized to 12 Cu(OAc)2 is regarded as a co-oxidant according to the results in ESI†.
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CuII species to form intermediate (V). Finally, the copper complex
4584 | Chem. Commun., 2014, 50, 4582--4584
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