Cu-catalyzed aerobic oxidative synthesis of sulfonamides from sulfonyl hydrazides and amines

Article abstract of DOI:10.1016/j.tetlet.2019.02.016

An environmentally friendly route for sulfonamides has been developed. The oxidative coupling of sulfonyl hydrazides and amines was catalyzed by CuBr₂ to produce various sulfonamides with the water and nitrogen gas as byproducts. Preliminary experiments revealed that the sulfonyl radical is likely to be involved in the reaction mechanism.

Full text of DOI:10.1016/j.tetlet.2019.02.016

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cu-catalyzed aerobic oxidative synthesis of sulfonamides from sulfonyl
hydrazides and amines
⇑
Sohyun Chung, Jinho Kim
Department of Chemistry, and Research Institute of Basic Sciences, Incheon National University, 119 Academy-ro, Yeonsu-gu, Incheon 22012, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
An environmentally friendly route for sulfonamides has been developed. The oxidative coupling of sul-
Received 20 December 2018
Revised 31 January 2019
Accepted 8 February 2019
Available online xxxx
2
fonyl hydrazides and amines was catalyzed by CuBr to produce various sulfonamides with the water
and nitrogen gas as byproducts. Preliminary experiments revealed that the sulfonyl radical is likely to
be involved in the reaction mechanism.
Ó 2019 Published by Elsevier Ltd.
Keywords:
Aerobic oxidation
Copper catalysis
Sulfonyl hydrazides
Sulfonamides
Organic synthesis
The synthesis of sulfonamide functional group is important in
medicinal and synthetic chemistry, because the sulfonamide moi-
ety is not only a key structural motif of many natural products,
pharmaceuticals, and bioactive compounds [1] but also a versatile
amine protecting group [2]. In order to introduce the sulfonamide
moiety in organic compounds, a construction of SAN bond has
been regarded as a crucial process. Traditionally, the SAN bond for-
mation could be achieved by nucleophilic substitutions of sulfonyl
chlorides with amines in the presence of a base [3,4].
An alternative SAN bond formation for the synthesis of sulfon-
amides has been reported by Jiang and co-workers in 2013 [5].
They revealed that an oxidative coupling of sodium sulfinates
and amines facilitated SAN bond formation to generate sulfon-
radicals, have been independently developed by Yotphan [10], Yu
[11], and Peddinti [12] (Scheme 1A). The conditions of these proto-
cols are quite similar and commonly required iodine catalyst such
2 4
as I or NH I and tert-butyl hydroperoxide (TBHP) oxidant to gen-
erate sulfonyl radicals from sulfonyl hydrazides. Although these
reactions exhibited interesting utilizations of sulfonyl hydrazides
for sulfonamides through the generation of sulfonyl radicals, the
substrate scope of sulfonyl hydrazides was limited to aromatic sul-
fonyl hydrazides and the use of superstoichiometric amounts of
TBHP was less attractive.
Aerobic oxidative transformations using oxygen as an oxidant
have emerged as environmentally friendly protocols because these
reactions utilize the readily accessible and inexpensive molecular
oxygen, and produce only water as a byproduct [13]. However,
no aerobic methods for sulfonamides synthesis from sulfonyl
hydrazides have been reported. Recently, our group revealed that
the use of copper efficiently catalyzed the aerobic oxidation of sev-
eral hydrazines such as di-tert-butyl hydrazodicarboxylates and
alkyl 2-phenylhydrazinecarboxylates [14]. On the basis of these
results and our continued interest in aerobic oxidations [15], we
tried to apply copper and oxygen system to the oxidative coupling
of sulfonyl hydrazides and amines. Herein, we describe a Cu-cat-
alyzed aerobic oxidative synthesis of sulfonamides from sulfonyl
hydrazides and amines (Scheme 1B) [16]. The developed sulfon-
amide synthesis fulfills the requirement for green and sustainable
chemistry because only Cu catalyst is required without any addi-
tive or base, and water and nitrogen gas are produced as
byproducts.
2
amides in the presence of CuBr and DMSO as a catalyst and an oxi-
dant, respectively. In their proposed mechanism, the used sodium
sulfinates underwent one electron oxidation by Cu(II) and a sul-
fonyl radical intermediate was generated. Finally, the generated
sulfonyl radical combined with copper amine complex to cause
the SAN bond formation for the desired sulfonamide products.
After Jiang’s pioneering work, various oxidative coupling methods
of sodium sulfinates using stoichiometric amounts of iodine [6] or
catalytic amounts of iodine with an external oxidant [7] have been
reported [8].
In 2016, elegant SAN bond formations for sulfonamides, which
employed sulfonyl hydrazides [9] as precursors for sulfonyl
⇑
Corresponding author.
E-mail address: jinho@inu.ac.kr (J. Kim).
https://doi.org/10.1016/j.tetlet.2019.02.016
040-4039/Ó 2019 Published by Elsevier Ltd.
0
Please cite this article as: S. Chung and J. Kim, Cu-catalyzed aerobic oxidative synthesis of sulfonamides from sulfonyl hydrazides and amines, Tetrahedron
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S. Chung, J. Kim / Tetrahedron Letters xxx (xxxx) xxx
Table 2
Substrate scope of amines for Cu-catalyzed aerobic oxidative coupling.a
Scheme 1. (A) Previously reported sulfonamides synthesis (B) Aerobic oxidative
sulfonamides synthesis.
With benzenesulfonyl hydrazide 1a and morpholine 2a as
model substrates, the reactivity of various copper sources was
screened in acetonitrile solvent under air (Table 1) [17]. Gratify-
ingly, the used copper sources catalyzed oxidative coupling of 1a
2
and 2a, and CuBr exhibited a superior result to other copper
sources (entries 1–6). The use of other solvents such as DMF,
DMSO, and toluene gave the desired sulfonamide 3a in moderate
yields (entries 7–9). The Cu-catalyzed aerobic oxidative coupling
was effective even using reduced amounts of 2a (3.0 equiv) (entry
1
0). The use of reduced amounts of CuBr
and no significant increase of the yield was observed even in the
high loading of CuBr (entry 11). Although the present reaction
took place at 25 °C, we found that increasing the temperature to
0 °C generally showed better results for the broader range of sul-
2
showed a moderate yield
2
5
fonyl hydrazides (entry 12). However, the present reaction showed
a decreased yield at 70 °C in spite of full conversion of 1a (entry
1
2
3). When the present reaction was carried out under O balloon,
instead of under air, 3a was produced in 50% yield (entry 14).
a
2
Reaction conditions: 1a (0.5 mmol), 2 (1.5 mmol), and CuBr (10 mol %) in
CN (4.0 mL) under air at 50 °C for 12 h, isolated yield. n.r.: no reaction.
b
Table 1
CH
3
Optimization of Cu-catalyzed aerobic oxidative coupling of benzenesulfonyl hydra-
zide and morpholine.a
The optimized reaction conditions were then tested in the aer-
obic oxidative couplings of 1a and a number of different amines
Table 2). The employment of cyclic amines such as pyrrolidine
(
and piperidine efficiently produced the corresponding sulfon-
amides in good yields (3b and 3c). Piperazines having a methyl
or phenyl group at nitrogen showed moderate yields (3d and 3e).
While the oxidative coupling of 1a and 1,2,3,4-tetrahydroquinoline
was sluggish, a successful transformation was observed in the
oxidative coupling of 1a and 1,2,3,4-tetrahydroisoquinoline (3f).
A variety of secondary acyclic amines including diethylamine, N-
ethylbutylamine, dibutylamine, and N-methylbenzylamine under-
went the developed oxidative coupling in moderate to good yields
(3g–3j). The reactivity of primary amines was also investigated in
the present oxidative coupling, and it was revealed that the desired
secondary sulfonamides were efficiently synthesized in moderate
yields (3k–3n). No signification influence of the para-substitutions
was observed in the used benzylamines (3o–3q). The present aer-
o
Yield (%)b
Entry
Cu source
Solvent
Temp. ( C)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
CuCl
CuBr
CuI
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CN
CN
CN
CN
CN
CN
50
50
50
50
50
50
50
50
50
50
50
25
70
50
68
64
50
29
78
20
52
40
63
80
Cu(CH
CuBr
Cu(OAc)
3 4 6
CN) PF
2
2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
2
2
2
2
2
2
2
2
DMF
DMSO
toluene
0c
CH
3
CH
3
CH
3
CH
3
CH
3
CN
CN
CN
CN
CN
c
d
e
1
2
3
4
57 , 81
c
79
61
50
c
c,f
obic oxidative coupling of 1a and
a-methylbenzylamine 2r pro-
a
duced the corresponding sulfonamide 3r in 62% yield.
Unfortunately, aniline, 2-pyrrolidinone, pyrrole, imidazole, and
pyrazole did not produce any sulfonamides presumably due to
the poor basicity. The present aerobic oxidative sulfonamide syn-
thesis was effective on a larger scale [17]. The use of 7 mmol of
1a in the present reaction conditions with 2a provide 3a in 72%
yield (1.15 g). Although the optimized conditions were not
Reaction conditions: 1a (0.5 mmol), 2a (2.0 mmol, 4.0 equiv), and Cu source
10 mol %) in solvent (4.0 mL) under air for 12 h.
(
b
1
Yield determined by
tetrachloroethane).
H NMR spectroscopy (internal standard: 1,1,2,2-
c
3
.0 equiv of 2a was used.
The use of 5 mol % of CuBr
The use of 20 mol % of CuBr
Under O balloon.
d
e
f
2
.
2
.
2
Please cite this article as: S. Chung and J. Kim, Cu-catalyzed aerobic oxidative synthesis of sulfonamides from sulfonyl hydrazides and amines, Tetrahedron
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S. Chung, J. Kim / Tetrahedron Letters xxx (xxxx) xxx
3
effective in the oxidative couplings of 1a and amine hydrochloride
salts, comparable results to the reactions of simple amine substrate
were observed in the presence of a stoichiometric amount of base
2 3
such as Na CO (Scheme 2).
Next, the substrate scope of sulfonyl hydrazides was investi-
gated, and the results were illustrated in Table 3. A variety of
para-substituted sulfonyl hydrazides produced the corresponding
sulfonamides in good yields regardless of their electronic environ-
ments (4a-4f). Not only ortho-substituted benzene sulfonyl hydra-
zides but also 1-naphthalene sulfonyl hydrazide efficiently
underwent the present oxidative coupling to produce correspond-
ing sulfonamides (4g-4i). It is noteworthy that aliphatic sulfonyl
hydrazides could be employed in the developed Cu-catalyzed aer-
obic oxidative coupling, while the previously reported iodine sys-
tems were not effective in aliphatic substrates (4j and 4k) [10–
1
2]. Notably, the medicinally relevant sulfonamide 4l, an interme-
diate for probenecid, was able to be synthesized by the developed
coupling reaction in 42% yield [18].
In order to understand the mechanism of the present protocol,
several experiments were carried out. When the aerobic oxidative
coupling of 1a and 2a was carried out without copper or under N
2
balloon, 3a was not produced, and 78% or 14% of 1a were recov-
ered, respectively (Scheme 3A and B). These results indicate that
the copper catalyst and oxygen are essential for the synthesis of
sulfonamides, and the decomposition of sulfonyl hydrazides was
facilitated by copper rather than oxygen [19]. It was observed that
the addition of TEMPO (2.0 equiv) to the model reaction inhibited
the production of sulfonamides in spite of the full conversion of 1a
Scheme 3. Control experiments for mechanistic investigation.
(Scheme 3C). In addition, the use of sodium benzenesulfinate,
instead of 1a, in the model reaction produced 3a in 27% yield
Scheme 3D). These observations imply that the developed oxida-
tive coupling proceeds through the benzenesulfonyl radical
5,16c,20]. When 4-(benzoyloxy)morpholine was employed
(
[
instead of morpholine, the corresponding sulfonamide 3a was effi-
ciently produced, suggesting the copper amine complex might be
involved in the reaction pathway (Scheme 3E) [21].
On the basis of our observations and related Ref. [22], a plausi-
ble mechanism was proposed in Scheme 4. Initially, the sulfonyl
radical A is generated by the Cu-catalyzed aerobic oxidation of sul-
fonyl hydrazides [10–12,22a]. The generated sulfonyl radical A
reacts with Cu(II) to give Cu(III) complex B. Then, ligand substitu-
tion takes place to form Cu(III) intermediate C. The desired sulfon-
amide and Cu(I) species D are produced by reductive elimination of
Scheme 2. Sulfonylation of amine hydrochloride salts.
Table 3
a
Substrate scope of sulfonyl hydrazides.
2
intermediate C. Finally, the regeneration of Cu(II)Br by the aerobic
oxidation of D in the presence of HBr finishes the catalytic cycle of
the developed reaction.
a
2 3
Reaction conditions: 1 (0.5 mmol), 2 (1.5 mmol), and CuBr (10 mol %) in CH CN
(
4.0 mL) under air at 50 °C for 12 h, isolated yield.
Scheme 4. Proposed mechanism.
Please cite this article as: S. Chung and J. Kim, Cu-catalyzed aerobic oxidative synthesis of sulfonamides from sulfonyl hydrazides and amines, Tetrahedron
Letters, https://doi.org/10.1016/j.tetlet.2019.02.016

4
S. Chung, J. Kim / Tetrahedron Letters xxx (xxxx) xxx
In conclusion, we have developed an environmentally friendly
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of sulfonyl hydrazides and amines produced the desired sulfon-
amides with water and nitrogen gas as byproducts. The developed
coupling showed broad substrate scope in amines including sec-
ondary amines, primary amines, and amine hydrochloride salts.
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unreactive in the previously reported anaerobic systems, could
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mechanism was proposed, and further studies are underway to
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Please cite this article as: S. Chung and J. Kim, Cu-catalyzed aerobic oxidative synthesis of sulfonamides from sulfonyl hydrazides and amines, Tetrahedron
Letters, https://doi.org/10.1016/j.tetlet.2019.02.016