Conversion of thiols into sulfonyl halogenides under aerobic and metal-free conditions

Article abstract of DOI:10.1039/c7gc00556c

An environmentally benign, metal-free synthesis of sulfonyl chlorides and bromides from thiols in the presence of ammonium nitrate, an aqueous solution of HCl and HBr and oxygen as a terminal oxidant was developed. The reactivity of various substituted thiophenols, benzylic-, aliphatic- and heteroaromatic thiols was examined. Ammonium nitrate served as a source of nitrogen oxides (NO/NO₂), which are the crucial players in a redox-catalytic cycle. Sulfonyl chlorides and bromides were isolated without extraction and "filtered" over a short pad of silica gel; the use of solvents was greatly reduced in comparison with traditional isolation and purification. A "one-pot" protocol for the conversion of thiol into sulfonamide is also demonstrated. Scale-up experiments on the preparation of sulfonyl chloride and bromide are shown. A possible reaction pathway is discussed.

Full text of DOI:10.1039/c7gc00556c

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Page 1 of 22
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Conversion of thiols into sulfonyl halogenides under aerobic and metal-free conditions
Marjan Jereb* and Luka Hribernik
Faculty of Chemistry and Chemical Technology, Večna pot 113, 1001 Ljubljana, Slovenia
Eꢀmail: marjan.jereb@fkkt.uniꢀlj.si; Fax: +386 1 241 9144; Tel: + 386 1 479 8577
† Electronic supplementary information (ESI) available.
An environmentally benign, metalꢀfree synthesis of sulfonyl chlorides and bromides from thiols in the presence of
ammonium nitrate, an aqueous solution of HCl and HBr and oxygen as a terminal oxidant was developed. The reactivity of
variously substituted thiophenols, benzylicꢀ, aliphaticꢀ and heteroaromatic thiols was examined. Ammonium nitrate served as
a source of nitrogen oxides (NO/NO2), which are the crucial players in a redoxꢀcatalytic cycle. Sulfonyl chlorides and
bromides were isolated without extraction and ‘’filtered’’ over a short pad of silica gel; the use of solvents was greatly
reduced in comparison with traditional isolation and purification. A ‘‘oneꢀpot’’ protocol for the conversion of thiol into
sulfonamide is also demonstrated. Scaleꢀup experiments on the preparation of sulfonyl chloride and bromide are shown. A
possible reaction pathway is discussed.
Key words: aerobic conditions, oxygen, metalꢀfree, thiols, sulfonyl halogenides
Introduction
Green chemistry has become an increasingly important subject in organic chemistry.1 In an
era of serious climate changes, humanity will be forced to strengthen endeavors in the
direction of sustainable development. Reducing the use of hazardous reagents and solvents,
minimizing the production of harmful waste, and enhancing safety, costꢀ and atom efficiency,
with renewable resources in operationally simple processes are the prime targets in this
regard.2
Oxidation reactions are common chemical transformations employing a vast number of
oxidizing agents. Several metalꢀ and halogenꢀbased oxidants are toxic and hazardous;
moreover, they produce considerable amounts of hazardous waste. Although often efficient,
such reagents need safer and nonꢀtoxic replacements. Environmentally benign oxidants, such
as an aqueous solution of hydrogen peroxide3 and air or oxygen, are ’’green’’ alternatives that
produce no dangerous waste, and are welcome from an economic point of view.4 Hence,
aerobic transformation is a current hot topic in chemistry.5
Organic sulfonyl halogenides are versatile intermediates in chemical, agrochemical, and
medicinal chemistry. They can be converted into numerous different sulfonyl derivatives i.e.
amides, hydrazides, azides, cyanides, sulfonates, sulfinates, sulfones, and others. One unique
and interesting feature of SO2 moietyꢀcontaining molecules is the extrusion of sulfur dioxide,
generating reactive and hardꢀtoꢀprepare intermediates.6 The extrusion of sulfur dioxide from
cyclic sulfones leads to ringꢀcontracted products that may not be readily obtained by other
methods.7 Sulfonyl chlorides may undergo diverse desulfitative crossꢀcouplings;8,9 they could
serve as arylating agents.10,11,12 Sulfones are a noteworthy type of compounds in
organocatalysis due to their stereoelectronic properties and the possibility of subsequent
1

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transformations;13 in addition, they are essential in the Juliaꢀtype olefination reactions.14 3ꢀ
[18F]fluoropropanesulfonyl chloride was utilized for the preparation of radiolabeled
sulfonamides that can be used as imaging agents for positron emission tomography.15
[35S]aryl sulfonyl chlorides could be transformed into the corresponding sulfonamides,
important radioligands to study biological functions, and have certain advantages over
tritiated and iodinated markers.16,17 Sulfonamide moiety is extremely important because it is
present in sulfa drugs,18 a broad family of antimicrobial and antibacterial agents. Sulfonyl
azides are particularly important in cycloaddition reactions,19 while sulfonyl hydrazides,20
sulfonyl chlorides,21 and sulfinates22 could serve as odorless surrogates for thiophenols as well
as for sulfonylations.23
Sulfonyl chlorides could be prepared in several different ways. Oxidative chlorination of
thiols was frequently applied synthetic pathway using several combinations of oxidants and
chloride sources, i.e. NCS/Bu4NCl,24 TCCA/BnMe3NCl,25,26,27 chloramineꢀT/Bu4NCl,28
DCH/BnMe3NCl,29 H2O2/ZrCl4,30 H2O2/TiCl4,31 POCl3/H2O2 in SDS micelles,32
H2O2/SOCl2,33 NaOCl/HCl,34 PCBS or TCBDA/BnMe3NCl,35 nitrate salt with TMSCl36 or
sulfuryl chloride,37 and Oxone/KX.38 In addition, the sole oxidants may play a dual role also
42
as a source of chloride i.e. NaOCl·5H2O,39 NCS,40 DCDMH,41 and ClO2. There are several
methods for the synthesis of sulfonyl chlorides from miscellaneous reactants. These include
43
chlorination of sodium sulfonates with Ph3P · Cl2 or cyanuric chloride,44 chlorination of
sulfonic acids with cyanuric chloride,39 1,3,5ꢀtriazoꢀ2,4,6ꢀtriphosphorine 2,2,4,4,6,6ꢀ
hexachloride (TAPC),45 and Cl3CCN/PPh3.46 It can be achieved by reaction of disulfides with
NCS,47 oxidation of the biologically relevant sulfides48 with chlorine on an industrial scale,49
transformation of Sꢀalkylisothiourea salts with NaClO2,50 NaClO51 and NCS.52 In addition,
sulfonyl chlorides can be prepared from other different sulfur functionalities,53,54,55 by
56
oxidation of triisopropylsilanylsulfanyls with KNO3/SO2Cl2, oxidation/chlorination of
thioacetates,57 reaction of the Grignard reagents with SO258 and DABSO,59 and transformation
of the lithiated aromatics with SO2 and NCS,60 and others. Meerwein’s batch approach61 was
successfully modified by chlorosulfonation with SO2/CuCl2 of an in situ generated diazonium
salts by using a continuous flow reactor.62
Chlorosulfonation of arenes can also be performed directly by reacting with ClSO3H, SO2Cl2,
or a mixture of SO2 and Cl2; however, these reagents are extremely hazardous, irritable, and
highly reactive. Reagents like ClSO3H, PCl5 or SOCl2 can convert sulfonic acid into sulfonyl
chlorides; however, these agents are noxious and their use may be dangerous due to the
possible internal pressure.63 Phenyl chlorosulfate was found to be an excellent source of
2

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[SO2Cl]+ species in a Pdꢀcatalyzed Suzuki–Miyura crossꢀcoupling reaction.64 Several other
halogenating agents and oxidants, i.e. NCS, 1,3ꢀdichloroꢀ5,5ꢀdimethylhydantoin (DCDMH),
cyanuric chloride, trichloroisocyanuric acid (TCCA), 1,3,5ꢀtriazoꢀ2,4,6ꢀtriphosphorine
2,2,4,4,6,6ꢀhexachloride (TAPC), Oxone and Ph3P · Cl2 are efficient reagents; however, they
are associated with a generation of considerable amount of waste. A sustainable synthetic
method for the preparation of sulfonyl halogenides embracing an environmentally benign
oxidant and natural form of halogen is therefore highly desired. Here, we report on a metalꢀ
free synthesis of sulfonyl halogenides from thiols in the presence of ammonium nitrate, an
aqueous solution of HCl or HBr and oxygen as a terminal oxidizer.
Results and discussion
4ꢀMethylthiophenol 1a was selected as a model substrate to optimize the reaction conditions.
It was let to react in a selected in the presence of HBr (48% aqueous solution, 1.1 equiv.) and
NH4NO3 (0.2 equiv.) at 60°C for 1.25 h. Results of the solvent screening experiments are
summarized in Table 1 and briefly discussed as follows. Whereas compound 1a remained
completely unreacted in water (entry 1), a 7% conversion into disulfide 3a was observed in
methanol (entry 2). Aprotic and rather nonꢀpolar DCM was also found to be ineffective (entry
3). The full conversion of 1a and encouraging selectivity was noted in acetic acid, affording
33% of disulfide 3a and 67% of sulfonyl bromide 2a (entry 4). Finally, the reaction in
acetonitrile took place with quantitative conversion of 1a, yielding exclusively and in
excellent isolated yield the desired sulfonyl bromide 2a (entry 5).
Table 1 The effect of solvent on the product distributiona
Entry
Solvent
H2O
T (°C) 2ab
3ab
0
Conv. (%)b
1
2
3
4
5
60
60
40
60
60
0
0
MeOH
DCM
0
7
7
0
6
6
AcOH
67
100
33
0
100
100 (93)c
MeCN
a Reaction conditions: 1a (124 mg, 1 mmol), solvent (5 mL),
NH4NO3 (16 mg, 0.2 mmol), HBr (48 % aqueous solution,
b
186 mg, 1.1 mmol), 1.25 h, balloon of O2.
Relative
c
distribution of products determined by 1H NMR. Isolated
yield.
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With acetonitrile as the solvent of choice, we examined the effect of the reaction temperature.
The experiments were conducted at three different temperatures under otherwise identical
reaction conditions, and the results are summarized in Table 2. At room temperature and 40
°C, a modest 6% and 24% conversion of thiophenol 1a into disulfide 3a was noted (entries 1
and 2). Interestingly, raising the temperature to 60 °C resulted in a full conversion into the
target sulfonyl bromide 2a, which could be isolated in 93% yield, setting 60 °C as the
temperature of choice (entry 3) for further experiments.
Table 2 Effect of the reaction temperature on the oxidation of thiophenol 1aa
Entry T (°C)
2ab
0
3ab
6
Conv. (%)b
1
2
rt
6
40
60
0
24
0
24
100
3
100
a
Reaction conditions: 1a (124 mg, 1 mmol),
MeCN (5 mL), NH4NO3 (16 mg, 0.2 mmol),
HBr (48
%
aqueous solution, 186 mg, 1.1
b
mmol), 1.25 h, balloon of O2.
Relative
distribution of products determined by 1H NMR.
Next, we examined the effect of concentration of thiophenol 1a in the reaction mixture, and
the results are collected in Table 3. The transformation of one mmol of 1a in various amounts
of MeCN was examined. Whereas the reaction in 1 mL of the solvent proved to be inefficient
(entry 1), the use of considerably larger amount of MeCN (20 mL) resulted in 100%
conversion into 2a (entry 2). Some additional screening indicated that the amount of MeCN
could be reduced to as low as 5 mL with no loss in the outcome (entry 3). This concentration
(0.2 M) of 1a in MeCN was thus selected for further experiments.
Table 3 The effect of the concentration of 1a on the selectivity of the brominationa
4

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Entry V (mL)
2ab
0
3ab
26
0
Conv. (%)b
1
2
1
26
20
5
100
100
100
100
3
0
a
Reaction conditions: 1a (124 mg, 1 mmol), MeCN (1–20
mL), NH4NO3 (16 mg, 0.2 mmol), HBr (48 % aqueous
solution, 186 mg, 1.1 mmol), 1.25 h, balloon of O2. b Relative
distribution of products determined by 1H NMR.
In the next step, the effect of various atmospheres on the transformation of 1a was examined
(Table 4). Reaction in the atmosphere of pure oxygen proceeded with complete selectivity
towards the desired sulfonyl bromide 2a (entry 1). Air atmosphere contains approximately
20% oxygen; however, it was considerably less efficient, affording disulfide 3a as the only
product (entry 2). The transformation of 1a under nitrogen atmosphere took place with 23%
conversion into disulfide 3a as the sole product (entry 3).
Table 4 The role of reaction atmosphere on functionalization of 1aa
Entry Atmosphere
2ab
100
0
3ab
0
Conv. (%)b
1
2
3
O2
Air
N2
100
46
46
0
23
23
a Reaction conditions: 1a (124 mg, 1 mmol), MeCN (5
mL), NH4NO3 (16 mg, 0.2 mmol), HBr (48 % aqueous
solution, 186 mg, 1.1 mmol), 1.25 h, balloon of gas. b
Relative distribution of products determined by 1H
NMR.
The role of ammonium nitrate (AN) was also examined, and the results are summarized in
Table 5. To demonstrate its role, the functionalization of 1a was performed under the
optimized reaction conditions as indicated above in the presence of different amounts of AN.
Increasing amount of AN, ranging between 0–0.1 equiv. relative to 1a, increased the
conversion into disulfide 3a (entries 1–3). Surprisingly, a complete turn in selectivity was
observed when using 0.2 equiv. of AN, affording full conversion of thiophenol 1a into
sulfonyl bromide 2a (entry 4).
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Table 5 The role of AN on the transformation of 1a with HBr under aerobic conditions
Entry
AN (equiv.) 2ab
3ab
4
Conv. (%)b
1
2
3
0
0
4
0.05
0.1
0.2
0
27
57
0
27
57
100
0
4
100
a
Reaction conditions: 1a (124 mg, 1 mmol), MeCN (5
mL), NH4NO3 (16 mg, 0.2 mmol), HBr (48 % aqueous
b
solution, 186 mg, 1.1 mmol), 1.25 h, balloon of O2.
Relative distribution of products determined by 1H NMR.
In principle, one equiv. of HBr should be a sufficient amount for the complete conversion of
1a into 2a. The experimental work, however, demonstrated that a small excess of acid is
beneficial and that 1.1 equiv. of 48% aqueous solution of HBr provided an optimal
performance. The above screening through the reaction conditions revealed the optimal
concentration and solvent (0.2 M of 1a in MeCN), temperature (60 °C), atmosphere (O2
balloon) and additives (0.2 equiv. of AN and 1.1 equiv. of 48% HBr), which were used in the
subsequent experiments.
Having optimized parameters for aerobic bromination of thiophenol 1a, the experiments were
directed towards aerobic chlorination with HCl. For this reaction, the amounts of AN and HCl
were reoptimized, and the results are summarized in Table 6. An optimal (100%) conversion
into the desired sulfonyl chloride 5a was achieved by using 1.0 equiv. of AN and 1.8 equiv. of
37% aqueous solution of HCl. Here again, in the absence of AN only trace amounts of 1a
reacted to form disulfide 3a, confirming the importance of AN (entry 1).
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Table 6 Optimization of amounts of AN and HCl in aerobic transformation of 1aa
Entry AN (equiv.)
HCl (equiv.)
5ab
0
3ab
4
4ab
0
Conv. (%)b
4
1
2
3
4
0
1.8
2.0
1.5
1.8
0.5
1.0
1.0
64
89
100
10
0
26
11
0
100
100
100 (84)c
0
a Reaction conditions: 1a (124 mg, 1 mmol), MeCN (5 mL), NH4NO3 (up to 80
mg, 1.0 mmol), HCl (37 % aqueous solution, up to 197 mg, 2.0 mmol), 1 h,
b
c
balloon of O2. Relative distribution of products determined by 1H NMR.
Isolated yield.
Due to the higher oxidation potential, the chloride ion is expected to be less reactive as
compared to the bromide ion; explaining higher amounts of HCl and AN required for the
transformation (compare Tables 5 and 6). However, although by employing 0.5 equiv. of AN
and 2.0 equiv. of HCl full conversion of 1a could be achieved, the selectivity was
disappointing with sulfonyl chloride 5a, disulfide 3a and thiosulfonate 4a in the ratio
64:10:26 (entry 2). It appeared that a larger excess of HCl could not compensate the lower
amount of AN. An additional optimization finally returned the optimal reaction conditions for
the selective formation of sulfonyl chloride 5a (entries 3 and 4).
In the next step, we explored the substrate scope. Several aromatic and aliphatic thiols were
subjected to the reaction conditions, optimized for the preparation of sulfonyl bromides, and
the results are summarized in Table 7. Thiophenols 1aꢀ1d bearing electronꢀdonating groups
yielded the corresponding sulfonyl bromides 2aꢀ2d in moderate to high yield (entries 1–4).
Transformation proceeded well with electronꢀdeficient thiophenols also (entries 5–13)
furnishing the related sulfonyl bromides in good to high yields. No significant substituent
effect could be observed.
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Table 7 Bromination of thiols 1 into sulfonyl bromides 2a
Entry
1
R
1
t (h)
1.25
1.5
1.5
1.5
1.5
1.0
1.5
1.25
2.5
2.0
3.0
1.5
1.5
3.5
1.5
4.0
4.0
2
Yield (%)b
93
4ꢀMeꢀC6H4ꢀ
4ꢀiꢀPrꢀC6H4ꢀ
2,4ꢀdiꢀMeꢀC6H3ꢀ
4ꢀMeOꢀC6H4ꢀ
3ꢀMeOꢀC6H4ꢀ
C6H5ꢀ
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
2
89
3
49
4
75
5
78
6
74
7
4ꢀClꢀC6H4ꢀ
2,5ꢀdiꢀClꢀC6H3ꢀ
3,4ꢀdiꢀClꢀC6H3ꢀ
2ꢀFꢀC6H4ꢀ
1g
1h
1i
2g
2h
2i
73
8
97
9
73
10
11
12
13
14
15
16
17
1j
2j
67
4ꢀFꢀC6H4ꢀ
1k
1l
2k
2l
73
2,4ꢀdiꢀFꢀC6H3ꢀ
3ꢀCF3ꢀC6H4ꢀ
C6F5ꢀ
64
1m
1n
1o
1p
1q
2m
2n
2o
2p
2q
81
67
2ꢀNapthylꢀ
1ꢀOctyl
70
71
Cyclohexylꢀ
84
a Reaction conditions: 1 (1 mmol), MeCN (5 mL), NH4NO3 (16 mg,
0.2 mmol), HBr (48 % aqueous solution, 186 mg, 1.1 mmol), balloon
of O2. b Isolated yield.
Difluoroꢀ and dichlorothiophenols (entries 8, 9 and 12) exhibited good reactivity, and we
decided to test pentafluorothiophenol 1n (entry 14). The corresponding sulfonyl bromide 2n
was isolated in a good yield under considerably milder conditions than known in the
literature.65,66 2ꢀNaphthalenethiol 1o yielded the related sulfonyl bromide 2o in 70% yield
(entry 15). In addition, the reactivity of aliphatic thiols 1p and 1q was examined. Both thiols
produced the desired sulfonyl bromides 2p and 2q in good yields (entries 16 and 17). The
reaction was exemplified on a heterocyclic coumarine derivative 1r. The related sulfonyl
bromide 2r was isolated in 49% yield, Scheme 1. The acidicꢀlabile lactone functionality did
not interfere in spite of the acidic reaction conditions and the elevated temperature.
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Scheme 1 Aerobic functionalization of coumarine derivative 1r
Reaction times for aliphatic thiols are longer as compared to the aromatic thiols, indicating
that nucleophilicity is not the most important parameter determining the reactivity in this
transformation. By taking into account the relative insensitivity of the reaction rate on the
substituents in the case of aryl thiols, acidity can also be ruled out. This suggests that radical
species may play a role in the reaction mechanism. It is based on the fact that the thiophenoxy
radicals are more stabilized than the thioalkoxy counterparts, tentatively explaining an
increased reactivity of arylꢀ over alkyl thiols.
The substrate scope was explored for the transformation of thiols 1 into the corresponding
sulfonyl chlorides 5; the results are presented in Table 8.
Table 8 Chlorination of thiols 1 into sulfonyl chlorides 5a
Entry
1
R
1
t (h)
1.0
1.5
3.0
2.0
3.25
2.5
3.0
2.25
5.0
3.5
2.0
3.25
3.5
2.5
2.0
4.5
3.5
5
Yield (%)b
84
4ꢀMeꢀC6H4ꢀ
4ꢀiꢀPrꢀC6H4ꢀ
2,4ꢀdiꢀMeꢀC6H3ꢀ
3,5ꢀdiꢀMeꢀC6H3ꢀ
2ꢀMeOꢀC6H4ꢀ
3ꢀMeOꢀC6H4ꢀ
C6H5ꢀ
1a
1b
1c
1cc
1dd
1e
1f
5a
5b
5c
5cc
5dd
5e
5f
2
63
3
89
4
75
5
79
6
84
7
87
8
4ꢀClꢀC6H4ꢀ
2,5ꢀdiꢀClꢀC6H3ꢀ
3,4ꢀdiꢀClꢀC6H3ꢀ
2ꢀFꢀC6H4ꢀ
1g
1h
1i
5g
5h
5i
74
9
55
10
11
12
13
14
15
16
17
55
1j
5j
75
4ꢀFꢀC6H4ꢀ
1k
1l
5k
5l
77
2,4ꢀdiꢀFꢀC6H3ꢀ
3ꢀCF3ꢀC6H4ꢀ
2ꢀNapthylꢀ
1ꢀOctyl
73
1m
1o
1p
1q
5m
5o
5p
5q
66
73
67
Cyclohexylꢀ
83
a Reaction conditions: 1 (1 mmol), MeCN (5 mL), NH4NO3 (80 mg,
1.0 mmol), HCl (37 % aqueous solution, 178 mg, 1.8 mmol),
balloon of O2. b Isolated yield.
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As evident from Table 8, chlorination of thiols 1 is more sluggish than bromination and there
is no apparent substituent effect. This is consistent with the aboveꢀmentioned chlorination and
bromination results. Both electron deficient and electron rich as well as aromatic and aliphatic
substrates afforded the desired sulfonyl chlorides 5 in good yields. The results suggest that
chlorination and bromination reaction pathways are similar.
Unlike aromatic and aliphatic thiols, benzylic thiols turned out to be somehow more specific
substrates in the transformation with HBr/AN, exhibiting considerably higher reactivity.
Scheme 2 Aerobic functionalization of benzylic thiols 6a–c with HBr/AN
For this reason, the reactions were performed under slightly modified conditions, at 40 °C
with 0.4 equiv. of AN and 2.2 equiv. of HBr. Higher temperatures and lower amounts of
reagents returned complex reaction mixtures. Nevertheless, 4ꢀmethoxybenzyl thiol 6a
transformed into two unexpected products, 7a and 8a. Apparently, oxidation into aldehyde 8a
and ipsoꢀsubstitution into 7a is accompanied by an electrophilic aromatic substitution ortho to
the activating methoxy group. In contrast, 4ꢀchlorobenzyl thiol 6b yielded the corresponding
disulfide 7b, and only 3ꢀ(trifluoromethyl)benzyl thiol 6c furnished the expected sulfonyl
bromide 7c in a moderate 22% yield.
As discussed above, under certain conditions, oxidative halogenation of thiol 1a gave rise to
disulfide 3a and thiosulfonate 4a (Tables 1–6). To shed light into the reaction mechanism, the
aboveꢀmentioned presence of disulfide 3a and thiosulfonate 4a prompted us to prepare and
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react three disulfides 3a–g and thiosulfonate 4g. As shown in Schemes 3 and 4, upon reaction
with HCl or HBr in the presence of AN both types of the substrates afforded the
corresponding sulfonyl halogenides, with no other products being detected. This suggested
that disulfides 3 and/or thiosulfonates 4 are potential intermediates in the reaction pathway
from 1 to 2 or 5.
Scheme 3 Aerobic oxidative transformation of disulfides 3a, f, g with HX/AN
Scheme 4 Aerobic transformation of thiosulfonate 4g with HX/AN
The transformation of 1a under the optimized reaction conditions was then carried out with
HBr/AN in the presence of various inhibitors and traps, including 2,2,6,6ꢀ
tetramethylpiperidine oxil (TEMPO), 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylphenol (BHT) and oꢀ
dinitrobenzene (oꢀDNB) in equimolar amounts. The results are presented in Table 9.
Table 9 The role of inhibitors on the aerobic transformation of 1aa
SH
SO2Br
HBr, NH4NO3
S
S
S
S
+
+
MeCN, 60 °C, O2
inhibitor
O2
4a
1a
2a
3a
Entry Inhibitor
2ab
100
36
3ab
0
4ab
0
Conv. (%)b
100
100c
1
2
3
/
TEMPO
BHT
0
0
71
17
12
100
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4
oꢀDNB
94
0
6
100
a Reaction conditions: 1a (37 mg, 0.3 mmol), MeCN (2.5
mL), inhibitor (0.3 mmol), NH4NO3 (5 mg, 0.06 mmol),
HBr (48 % aqueous solution, 56 mg, 0.33 mmol), 1.25 h,
balloon of O2. b Relative distribution of products determined
1
c
by H NMR. 64% of an unknown product was observed,
and it transformed into 4a during column chromatography
on silica gel.
The reaction course in the presence of TEMPO (entry 2) was noticeably different from a
reaction without TEMPO (entry 1). Full conversion of 1a was noted, and only 36% of the
targeted product 2a was formed, signifying that radical intermediates play one of the key roles
in this transformation. In addition, 64% of unknown product was observed, which
transformed into thiosulfonate 4a during the attempt of isolation. A potential explanation is
presented in Scheme 5. Although the effect of BHT was less pronounced, it significantly
modified the distribution of the products (Table 9, entry 3). oꢀDNB as an electron scavenger
made little impact, but its influence on the course of the reaction was in favor of the
involvement of singleꢀelectron transfer and radical intermediates (Table 9, entry 4).
Scheme 5 Transformation of vicꢀdisulfoxide (A) into thiosulfonate (F)
As established earlier,67 it is reasonable to expect that vicꢀdisulfoxide (A) decomposes to
sulfinyl radical (B), and the latter recombines into OSꢀsulfenyl sulfinate (C). The unstable
species (C) fragments into sulfenylꢀ (D) and sulfonyl radical (E) that recombine into
thiosulfonate (F), Scheme 5.
One of the potential pathways for the formation of disulfide 3a from 1a could be via sulfenyl
halogenide (RSX), a source of RS+. As compounds RSX are highly reactive and difficult to
isolate, experiments were performed to test their presence in the reaction mixture. Thus, thiol
1a was treated with HBr/AN under the optimized reaction conditions in the presence of 1
equiv. of 1,1ꢀdiphenylethene (DPE), a potential scavenger of electrophilic species.
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Scheme 6 Trapping of electrophilic intermediates with DPE
When TLC noted complete consumption of 1a, the reaction was quenched and the crude
1
reaction mixture was analyzed by H NMR spectroscopy. It revealed the full conversion of
DPE, and the presence of three compounds. One of those, exhibiting singlet resonance in the
aliphatic region at approximately δ 4.5 ppm (minor component in the spectrum), was
tentatively assigned to the addition product (G). The other two compounds, having singlet
resonances in the olefinic region at δ 6.8 ppm were assigned to the additionꢀelimination
products (H) (major component) and (I). Sulfonyl bromide 2a could only be detected in trace
amounts. To reduce the complexity of the above crude reaction mixture, it was let to react
1
with potassium carbonate in refluxing DCM for 6 h. Subsequent H NMR analysis showed
disappearance of the resonance belonging to (G), whereas those to (H) and (I) remained
present. GCꢀMS analysis revealed the presence of the main product (H) with m/z 302, and
two minor products, 1ꢀbromoꢀ2,2ꢀdiphenylethene (I) (m/z 258) and disulfide 3a (m/z 246).
Detection of product (H) gives a strong indication for the presence of electrophilic sulfenyl
bromide. Product (I) confirmed the formation of electrophilic bromine species. Another
positive indication of the electrophilic bromonium species is the above mentioned aromatic
ring bromination of 6a into 7a and 8a (Scheme 2).
In bromination of thiol 1a into sulfenyl bromide 2a, pꢀtolylsulfenyl bromide is likely an
intermediate. To confirm this hypothesis, in independent experiments, 1a was upon treatment
with NBS and NCS transformed into pꢀtolysulfenyl bromide and chloride, respectively, which
were then further treated with oxygen in the presence of ammonium nitrate at 60 °C. pꢀ
Tolylsulfenyl bromide was completely converted into sulfonyl bromide 2a, whereas the
oxidation of pꢀtolylsulfenyl chloride into sulfonyl chloride 5a proceeded with lower
conversion and selectivity. It could be concluded that RSX may play a role as intermediate in
this transformation.
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A potential reaction cycle, proposed in Scheme 7 is similar to the one proposed by
Madabhushi.38 Ammonium nitrate decomposition in the acidic medium yielded NO/NO2,
which are the key players in the catalytic cycle. Indeed, during the experiments it was possible
to observe several consecutive appearances and disappearances of brown gas.
O2
NO2
HX
NO
HOX
RSH
RSO2X
HX
RSO2
RSX
RSH
HX
RSSR
HOX
HX
SR
[RS(O)
S(O)R]
HX
[RS(O)
SR]
O2
HOX
O2
Scheme 7 Proposed reaction pathways for the transformation of thiols into sulfonyl
halogenides
NO2 served as an oxidizer for halogenide ion into the electrophilic halogen species, and the
latter might be involved in oxidation processes on the way to the final sulfonyl halogenides.
Oxidation of NO into NO2 took place with oxygen as the terminal oxidizer. Thiol probably
reacted first with the electrophilic halogenic species that it is formed from HX, thus giving
RSX. Thiol could react with RSX, yielding disulfide and HX. A direct formation of disulfide
from thiols and without RSX could not be completely ruled out;68 however, the reaction could
in part take place directly and partly over RSX formation. Disulfide is further likely oxidized
into thiosulfonate with the involvement of the potential intermediates on Scheme 5. An
experiment in favor of these intermediates may possibly be in Table 9, entry 2, where an
unknown product transformed into thiosulfonate 4a during the column chromatography.
Thiosulfonate is finally transformed into the target sulfonyl halogenide by attack of
halogenide ion, while concomitantly formed RSH enters a new cycle.
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Sulfonyl halogenides are versatile synthons for the preparation of sulfonyl amides, which are
very useful in pharmacy and human and veterinary medicine. One of our goals was a ‘‘oneꢀ
pot’’ transformation of thiols into sulfonamides, Scheme 8.
Scheme 8 ‘‘Oneꢀpot’’ conversion of thiols to sulfonamides
4ꢀMethylthiophenol 1a and 4ꢀchlorothiophenol 1g were transformed into the corresponding
sulfonyl bromides 2a and 2g and sulfonyl chlorides 5a and 5g, and were treated further
without isolation with the aqueous solution of ammonia. Sulfonamides 9a and 9g were
successfully isolated; however, the yields of sulfonamides from sulfonyl bromides were
appreciably higher (Scheme 8).
Finally, we explored the reaction scaleꢀup with HBr and HCl systems. Thiol 1a (20 mmol)
was solubilized in 20 mL of MeCN and stirred at 60 °C in the presence of 0.2 equiv. of AN (4
mmol) and 1.1 equiv. of 48% aqueous solution of HBr. The reaction was completed in 3 h as
judged by TLC. Reactions on one mmol scale were conducted in higher amount of MeCN (5
mL) in order to assure relatively short reaction times. In the case of scaleꢀup, we decided to
reduce the amount of solvent at cost of a reasonably longer reaction time. We were pleased to
see that reaction was completed in 3 h in comparison with the 1.25 h on a one mmol scale.
Several cycles of NOx were observed with appearances and disappearances of brown gas. The
balloon was replaced with the new balloon of oxygen when the cycling ceased. Two
replacements of balloons with oxygen were made. The solvent was removed under reduced
pressure, and 40 mL of water was added and solid filtered. The airꢀdried solid was ‘‘filtered’’
over a short pad of silica gel, and 56% of 2a was isolated.
Scaleꢀup in the case with HCl/AN was also carried out on 20 mmol of 1a in 20 mL of MeCN
with 1.8 equiv. of 36% aqueous solution of HCl and 1.5 equiv. of AN. Similarly as in the case
of HBr, the lower amount of solvent was used, and the reaction was completed in 4.5 h. On a
one mmol scale, the reaction was completed in 1 h. The reaction course was similar to the
previous example. Two replacements of balloons with oxygen were made. The solvent was
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evaporated, and 20 mL of methylꢀtꢀbutyl ether (MTBE) and a few drops of water were added.
The resulting mixture was cooled in an iceꢀbath, carefully neutralized with the solid NaHCO3,
dried with the anhydrous sodium sulfate and filtered. The filtrate was concentrated, and
‘’filtered’’ over a short pad of silica gel. Sulfonyl chloride 5a was isolated in 52% yield.
Conclusion. Environmentally benign, metalꢀfree aerobic oxidation of thiols into sulfonyl
bromides and chlorides with the aqueous solutions of HBr and HCl in the presence of AN was
developed. Inorganic reactants were used in their natural form – bromide, chloride, nitrate and
oxygen. Halogenated solvents were not used. The reacting system consisted of NOx gases, a
crucial actor, while oxygen was the terminal oxidizer. The HBr/AN system exhibited higher
reactivity than the HCl/AN system due to the more favorable oxidation potential of the
bromide ion. Consequently, transformations in the case of HBr/AN required lower amounts of
reactants: 0.2 equivalents of AN and 1.1 equivalents of HBr, thus contributing noticeably to
the atom economy. The transformations produced low amounts of nonꢀhazardous inorganic
waste, while there was practically no organic waste in contrast to the numerous known
methods for the preparation of sulfonyl halogenides. Acetonitrile was removed by distillation
and could be reused. Arylꢀ and alkylꢀsubstituted thiols furnished the corresponding sulfonyl
halogenides as sole products, whereas benzyl thiols exhibited higher reactivity and products
with different selectivity. An important contribution to green chemistry principles was made
by isolation and purification. Sulfonyl halogenides were isolated without extraction and
column chromatography. Owing to excellent reaction selectivity and the purity of the crude
products, ‘‘filtration’’ over a short pad of silica gel was done. Avoidance of both classic
operations saved considerable amounts of solvents. The reaction pathways were examined
and a catalytic cycle was proposed. Disulfides and thiosulfonates as potential intermediates
could yield the sulfonyl halogenides under the studied reaction conditions. Electrophilic sulfur
species RS+ and HOX were also the likely intermediates according to the isolated products.
Radicals are likely to be important intermediates in this transformation, and the substituents
have a rather low influence on the reactivity of the arylꢀsubstituted thiols. Comparison of the
reactivity of alkylꢀ and aryl thiols may be an indication that nucleophilicity was not the main
factor governing the reactivity. Little differences in reactivity of aryl thiols indicated that
neither acidity was the decisive factor determining the reactivity. It appears that stabilization
of thiophenoxy radical is the more important parameter. ‘‘Oneꢀpot’’ transformation of thiol
into sulfonamide via sulfonyl bromide and chloride was demonstrated. Scaleꢀup preparation
of sulfonyl bromide and chloride was also carried out.
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Acknowledgements
We would like to express our gratitude to Prof. A. Togni, Dr. J. Charpentier, E. Pietrasiak and
Mass Spectrometry Laboratory at ETH Zurich, Switzerland for their kind, swift and generous
response with HRMS analyses. Prof. J. Cerkovnik for GCꢀMS, Mrs. T. Stipanovič and Prof. J.
Svete for the elemental combustion analyses and the Slovenian Research Agency (P1ꢀ0134
and P1ꢀ0230) for financial support are gratefully acknowledged. Dedicated to Professor
Emeritus Marko Zupan on the occasion of his 70th anniversary.
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DOI: 10.1039/C7GC00556C
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Graphical abstract
O2 as terminal oxidizer
NH4NO3, HX(aq)
MeCN, 60 °C, O2
metal-free
RSH
RSO2X
natural form of reactants
low amount of waste
no extraction
no chromatography
scale-up
up to 98%
yield
X = Br, Cl
Highly efficient, aerobic and metalꢀfree conversion of thiols into sulfonyl halogenides was
developed.
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