NaHSO3-Mediated Direct Synthesis of Sulfinic Esters from Sulfonyl Hydrazides under Transition-Metal-Free Conditions

Article abstract of DOI:10.1002/adsc.202001202

We have developed a protocol for the NaHSO₃-promoted esterification of sulfonyl hydrazides with alcohols for the synthesis of sulfinic esters. Various sulfonyl hydrazides could be converted to the corresponding sulfinic esters in good to high yields. The merits of this protocol include mild transition-metal-free reaction conditions, an inexpensive and available reagent, and operational simplicity. Controlled experiments reveal that this transformation probably undergoes via a radical pathway. (Figure presented.).

Full text of DOI:10.1002/adsc.202001202

Title: NaHSO3-Mediated Direct Synthesis of Sulfinic Esters from
Sulfonyl Hydrazides under Transition-Metal-Free Conditions
Authors: guofu Zhang, Qiankun Fan, Huimin Wang, Yiyong Zhao, and
Chengrong Ding
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202001202
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10.1002/adsc.202001202
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
NaHSO3-Mediated Direct Synthesis of Sulfinic Esters from
Sulfonyl Hydrazides under Transition-Metal-Free Conditions
Guofu Zhang,a Qiankun Fan,a Huimin Wang,a Yiyong Zhao,b and Chengrong Ding a,*
a
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, People’s Republic of China
Fax: (+86)-571-88320147; e-mail: dingcr@zjut.edu.cn
Zhejiang Ecological Environment Low Carbon Development Center，Hangzhou 310012, P. R. China
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
sulfonylhydrazones (Scheme 1).[8] Despite the
significant utility, many of these methods
encounter several blemishes, such as to require
Abstract: We have developed a protocol for the NaHSO3-
promoted esterification of sulfonyl hydrazides with
alcohols for the synthesis of sulfinic esters. Various
sulfonyl hydrazides could be converted to the
stoichiometric amounts of oxidants or the use of
transition metals, odorous reagent, harsh reaction
conditions, or limited substrate scope, etc.
Sulfonyl hydrazides, readily accessible, stable
and odor-free solids, were diffusly used as
convenient sulfur source in organic synthesis.[9]
In 2016, Pan and co-workers first reported the
cross coupling reaction of sulfonyl hydrazides
with alcohols in the presence of Cu(OTf)2 to
access diverse sulfinic ester in moderate to good
yield.[10] Subsequently, Liu group obtained
sulfinic ester derivatives through esterification of
sulfonyl hydrazides in alcohols under the
mediation of Cu(OTf)2.[11] Both of the two
strategies undergo the generation of arylsulfuric
acid intermediates, which are confirmed by
controlled experiments. To the best of our
knowledge, synthesis of sulfinic ester using
corresponding sulfinic esters in good to high yields. The
merits of this protocol include mild transition-metal-free
reaction conditions, an inexpensive and available reagent,
and operational simplicity. Controlled experiments reveal
that this transformation probably undergoes via a radical
pathway.
Keywords: sulfonyl hydrazides; alcohols; sulfinic esters;
transition-metal-free; radical pathway
The synthesis of sulfinic esters has attracted
much attention due to their promising biological
and therapeutic activities, such as stimulating the
glucose uptake in muscle cells,[1] regulating the
mitochondrial function of the Parkinsonism
protein DJ-1,[2] and employing as chemical
probes in living cells.[3] Besides, sulfinic esters
have shown widespread applications in the
synthesis of various sulfur-containing organic
compounds because of their behave as both sulfonyl hydrazides with the assistance of
nucleophilic and electrophilic reagents.[4] In the reductant has not been explored. Herein, we
light of the aforementioned applications, report an efficient and practical transformation of
preparation of the sulfinic ester derivatives has structurally diverse sulfonyl hydrazides with
been pursued for a long time by researchers.
alcohols into sulfinic ester in the presence of
At present, various synthetic routes have been NaHSO3 as reductant (Scheme 1f).
developed to synthesize sulfinic ester, mainly
Based on our previous work on reductant-
including: (a) the oxidation of diaryl disulfides mediated reactions of sulfonyl hydrazides,[12]
via various oxidants,[5] (b) the cross- optimization of the reaction was performed with
dehydrogenative coupling reaction of thiols with 4-methylbenzenesulfonohydrazide 1a (0.2 mmol),
alcohols,[6] (c) the nucleophilic substitution NaHSO3 (0.2 mmol) in CH3OH (2.0 mL) was
reactions of sulfinic acids or sulfinyl chlorides or stirred at 80 °C under air for 5 h, 78% yield of
sodium sulfinates with alcohols,[7] (d) the direct the desired methyl 4-methylbenzenesulfinate 3a
synthesis
of
sulfinic
ester
from
N-
1
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10.1002/adsc.202001202
Advanced Synthesis & Catalysis
product was isolated (Table 1, entry 1). entries 15-16). Therefore, the optimal reaction
Encouraged by this result, further screening of
conditions were found to include 4-
methylbenzenesulfonohydrazide 1a (0.2 mmol),
NaHSO3 (1.0 equiv.) in CH3OH (1.5 mL) at
80 °C under air for 6 h.
Table 1. Reaction conditions optimization for sulfinic
esters synthesis [a]
Entry
1
2
3
4
Reductants
NaHSO3
Na2SO3
NaHSO2·CH2O
Na2S2O3·5H2O
Na2S2O4
Na2S2O5
NaHSO3
NaHSO3
-
Time/h
Yields/%k
78
5
5
5
5
5
5
5
5
5
5
5
5
5
6
6
6
N.D
44
N.D
6
<5
37
9
N.D
23
77
81
5
6
7b
8c
9
10d
11e
12f
13g
14h
15i
16j
NaHSO3
NaHSO3
NaHSO3
NaHSO3
NaHSO3
NaHSO3
NaHSO3
75
85
Trace
76
a
Reaction conditions: 1a (0.2 mmol), reductant (0.2
mmol), in CH3OH (2.0 mL) at 80 °C under air for 5 h. b
NaHSO3 (0.2 equiv.). NaHSO3 (1.2 equiv.). 60 C.
100 C. CH3OH (1.5 mL). CH3OH (3.0 mL). 6 h.
Under: N2. Under: O2. Isolated yield. N.D: Not
Detected.
Scheme 1. Methods for the synthesis of sulfinic esters
c
d
e
i
o
f
g
h
o
j
k
reductants such as Na2SO3, NaHSO2·CH2O,
Na2S2O3·5H2O, Na2S2O4 and Na2S2O5 suggested
that NaHSO3 exhibited the optimal efficiency
(Table 1, entries 2-6). The attempt to increase or
decrease the amount of NaHSO3 just resulted in
lower yields (Table 1, entries 7-8). From the
controlled experiments, it was revealed that the
use of reductant was essential for the reaction of
1a and no reaction was observed without
NaHSO3 (Table 1, entry 9). The adverse impact
on the yield of product 3a was showed whether
the reaction was taken place at a higher or lower
temperature (Table 1, entries 10-11). With the
increase of solvent volume, poor yields of 3a
were observed, but decrease solvent volume
could give target product with 81% yields (Table
1, entries 12-13). To our delight, the isolated
yield was further improved to 85% by prolonging
the reaction time to 6 h (Table 1, entry 14). At
last, a decreased yield was obtained when the
reaction was carried out under N2 or O2 (Table 1,
Once the optimization studies were concluded,
we focused our attention on investigating the
substrate scope of the present protocol (Table 2).
At the outset, the reaction of a series of sulfonyl
hydrazides with methanol was tested. Various
sulfonyl hydrazides derived from sulfonyl
chlorides could be used as substrates (1a-1w),
and the corresponding products (3a-3w) were
obtained in moderate to excellent yield (31-91%).
The sulfonyl hydrazides vary from electron-
withdrawing to electron-donating and also
including hetereoaromatic ones. In general,
substrates
1
bearing electron-withdrawing
substituents in aryl groups such as fluoro, chloro,
and trifluoromethyl, trifluoromethoxy, and nitro
aryl groups were badly reduced to the
corresponding sulfinic ester (3e-3j, 3l-3n, 3p-3r).
The substrates with electron-donating aryl
substituents gave moderate to excellent yields (3a,
2
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10.1002/adsc.202001202
Advanced Synthesis & Catalysis
3c-3d, 3k, 3s). We speculated that electron- It was interesting that other primary aliphatic
donating aryl sulfonyl hydrazides are propitious alcohol can also be subjected to the
to form stable radical intermediates, thus transformation, thus generating the desired
preferring the radical coupling process. Moreover, products in acceptable yields (3aa-3ad).
polycyclic aromatic sulfonyl hydrazides proved Moreover, the reactions were also conducted
to be a suitable reactant, affording 3t and 3u in a efficiently with secondly aliphatic alcohol,
moderate yield. The less reactive hetereoaromatic delivering the sulfinic ester derivatives 3ae in
substrate (1v) reacted slowly under the reaction 56% yield. To our surprise, aromatic alcohols
conditions and provided the corresponding also reacted with sulfonyl hydrazide to form the
esterification product 3v in 31% yield. It was desired product 3af in 32% yield.
worth noting that trisubstituted aromatic sulfonyl To probe the possible reaction pathway, some
hydrazides was also suitable substrates to attain controlled experiments were carried out (Scheme
methyl 2,4,6-trimethylbenzenesulfinate (3w) in 2). Initially, we conducted the radical trapping
86% yield.
experiments by adding 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) into the model reaction
under the standard conditions. As expected, the
reaction is completely suppressed (Scheme 2A),
while the capture of sulfonyl radical by TEMPO
can be detected by LC−MS (See supporting
information). Thus, this case indicates that a
radical pathway should be involved in this
process with the existence of sulfonyl radical
intermediates. Subsequently, a series of GC-MS
spectroscopic analysis experiment were carried
out on the reaction process. Delightfully, the p-
tolyl disulfoxide was detected by EI+ mode, and
this result indicated that the reaction may
undergo a p-tolyl disulfoxide intermediate. (See
supporting information). Due to multitudinous
sulfur-containing compounds being present in the
reaction system, the exact source of the sulfur
moiety was investigated by reacted the various
sulfur sources with CH3OH (Scheme 2B-2G).
Table 2. Substrate scope in the synthesis of sulfinic esters
[a][b]
[a] Reaction conditions: substrate (0.2 mmol), NaHSO3 (0.2
mmol) in CH3OH (1.5 mL) at 80 oC under air for 6 h. [b]
Isolated yields.
To extend the synthetic utility of this reaction,
various alcohols were successfully investigated
by our method. Notably, when using ethanol as
substrates, sulfonyl hydrazides with different
substituents gave almost the same yields (3x-3z).
Scheme 2. Mechanistic studies
3
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10.1002/adsc.202001202
Advanced Synthesis & Catalysis
Various sulfur sources, such as sodium 4- In summary, we have developed an efficient,
methylbenzenesulfinate, 4-methylbenzenesulfinic environmentally friendly and economic synthetic
acid, S-(p-tolyl)-4-methylbenzenesulfonothioate, method for the preparation of sulfinic ester. This
p-tolyl disulfide, were react with methanol under synthetic method proceeds with the merits of
standard conditions, products 3a were not mild transition-metal-free reaction conditions, an
obtained (Scheme 2B-2E). The reaction of S-(p- inexpensive and available reagent, operational
tolyl)-4-methylbenzenesulfinothioate
with simplicity, good functional group tolerance and
CH3OH, was performed under the same moreover without any toxic by-products. In
reactions conditions, and afforded the target addition, mechanistic studies suggested that the
product 3a in 75% yield, which demonstrated reaction proceeds via a radical pathway involving
that
S-(p-tolyl)-4-methylbenzenesulfinothioate the sulfonyl radical intermediates. Further studies
might be an intermediate for this reaction on this original approach are ongoing in our
(Scheme 2F). It was noteworthy that 4- laboratory.
methylbenzenethiol as the sulfur sources,
affording the p-tolyl disulfide product in 97%
yield (Scheme 2G).
Experimental Section
General procedure A for the synthesis of 1. Eighty
Based on the above results and previous
reports,[6,11,13-14] a possible reaction pathway was
proposed in Scheme 3. Initially, a sulfonyl radical
A was generated through the oxidation of 4-
methylbenzenesulfonohydrazide 1a by air upon
heating.[15] Subsequently, some of the sulfonyl
radicals were reduced to thiyl radical B by
NaHSO3. In the meantime, self-coupling of the
radical A generated the disulfone C, which may
be also reduced by NaHSO3 to give the
corresponding disulfoxide D.[16-17] Next, the
homolytic cleavage of unstable intermediate D
takes place under heating, and the generated
sulfinyl radical E may easily coupling with p-
tolyl disulfide G, which was formed by the
homo-coupling of thiyl radical B, to attain S-(p-
tolyl)-4-methylbenzenesulfinothioate F. Finally,
nucleophilic substitution reaction of methanol
with intermediate F occurred to attain target
product 3a.
percent hydrazine hydrate (50 mmol) was added dropwise
to a solution of arenesulfonyl chlorides (20 mmol) in
tetrahydrofuran (20 mL) surrounded by an ice-water bath.
The mixture was stirred for 0.5-1h under a nitrogen
atmosphere (detected by TLC). After the mixture was
diluted with ethyl acetate, the solution was washed with
saturated brine and the organic layer was dried with
anhydrous magnesium sulfate. Then filtering the inorganic
salt, and added slowly to stirred petroleum ether (25 mL)
over 6 min. After being stirred for 15 min, the mixture was
filtered, and the collected solid was dried in vacuum. The
yields for the formation of arylsulfonyl hydrazides range
from 70% to 97%.
General procedure for the synthesis of compounds 3. A
mixture of 1 (0.2 mmol), alcohol 2 (1.5mL), NaHSO3 (0.2
mmol, 20.8 mg) in a 15 mL Schlenk tube was heated at 80
oC under air for 6 hours. Then the resulting mixture was
filtered and washed with ethyl acetate, and then
concentrated by removing the solvent under vacuum. The
crude product was purified by column chromatography on
silica gel (petroleum ether /EtOAc=1:1 to 30:1) to yield 3
as a colorless oil.
Acknowledgements
We acknowledge financial support from the National Natural
Science Foundation of China (No. 20702051), the Natural
Science Foundation of Zhejiang Province (LY13B020017).
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10.1002/adsc.202001202
Advanced Synthesis & Catalysis
UPDATE
NaHSO3-Mediated Direct Synthesis of Sulfinic
Esters from Sulfonyl Hydrazides under Transition-
Metal-Free Conditions
Adv. Synth. Catal. Year, Volume, Page – Page
Guofu Zhang,a Qiankun Fan,a Huimin Wang,a
Yiyong Zhao,b and Chengrong Ding a,*
6
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