Preparation and Reactions of Perfluoroalkanesulfenyl Chlorides

Article abstract of DOI:10.1002/cjoc.201600933

Several perfluoroalkanesulfenyl chlorides were prepared from the corresponding perfluoroalkanesulfenic acids in high yields, and their reactions with thiol, amine, arene and alkene were studied. A series of perfluoroalkyl-containing disulfides, sulfonamides, aryl sulfides and α-chlorosulfides were synthesized under mild conditions.

Full text of DOI:10.1002/cjoc.201600933

FULL PAPER
DOI: 10.1002/cjoc.201600933
Preparation and Reactions of Perfluoroalkanesulfenyl
Chlorides
Ze-Feng Xu,a,b Min Jiang,a Jin-Tao Liu*,a
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
b Department of Chemistry, Zhejiang Sci-Tech University, Xiasha West Higher Education District,
Hangzhou, Zhejiang 310018, China
Several perfluoroalkanesulfenyl chlorides were prepared from the corresponding perfluoroalkanesulfenic acids
in high yields, and their reactions with thiol, amine, arene and alkene were studied. A series of perfluoroal-
kyl-containing disulfides, sulfonamides, aryl sulfides and α-chlorosulfides were synthesized under mild conditions.
Keywords perfluoroalkanesulfenyl chloride, perfluoroalkanesulfenyl acid, substitution, disulfide, addition
Introduction
Therefore, we further investigated the reaction of per-
fluoroalkanesulfenyl chlorides with different reagents.
The results are reported in this paper.
Sulfenic acids and their derivatives have been known
as key intermediates in many biological activities and
the related researches are still very attractive.[1] Gener-
ally, sulfur containing substrates in organisms, such as
thiol, sulfide and disulfide, are firstly oxidized to sul-
fenic acids and then the sulfur could be involved in bio-
logical activities.[1,2] It is well known that sulfenic acid
is highly reactive and generally the self-condense reac-
tion is very easy to occur.[3] Therefore, great efforts have
been made to obtain stable sulfenic acids.[4] As one of
important derivatives of sulfenic acids, sulfenyl halides
are more stable and regarded as key intermediates for
further transformation of sulfenic acids in organisms.
Because of the R－S－Cl (R＝alkyl or aryl) connectiv-
ity, sulfenyl chlorides are also very reactive and behave
as sources of RS＋. For these reasons, the chemistry of
sulfenyl chloride was studied much more than the ac-
id.[1,5]
Recently, a series of perfluoroalkanesulfenic acids
was successfully synthesized in our laboratory.[6] Due to
the high electron-withdrawing effect of perfluoroalkyl
groups, these fluorinated sulfenic acids were quite stable
and could exist in solution for months. In further studies
on their properties and synthetic applications, it was
found that perfluoroalkanesulfenyl chlorides could be
obtained from them under mild conditions. Although
there are some reports about the reaction of trifluoro-
methanesulfenyl chloride,[7] in consideration of the
unique properties of perfluoroalkyl group, the reactivity
of perfluoroalkanesulfenyl chloride is worth exploring.
Experimental
General procedure for the synthesis of perfluoroal-
kanesulfenyl chlorides (2)
To a solution of perfluoroalkanesulfenic acids 1 (0.4
mmol) in toluene (5 mL) was added saturated Et2O•HCl
(5.0 equiv.) in darkness under nitrogen. The reaction
mixture was stirred at room temperature for 30 min. The
corresponding sulfenyl chlorides 2 were obtained in
more than 95% yields as determined by 19F NMR using
C6F6 as internal standard.
General procedure for the reaction of 2 and thiol
In darkness, to a solution of 2b (0.4 mmol) in tolu-
ene (5 mL) was added the solution of phenyl thiol (0.4
mmol in 5 mL of toluene) slowly at room temperature.
Then the mixture was stirred at room temperature for 3
h. After the reaction was completed (monitored by 19F
NMR), the solvent was evaporated and the residue was
purified by column chromatography on silica gel (hex-
ane) to give product 3b in 77% yield.
General procedure for the reaction of 2 and amine
In darkness, to a solution of 2b (0.4 mmol) in tolu-
ene (5 mL) was slowly added the solution of aniline
(10.0 equiv. in 5 mL of DCM) at 0－5 ℃. After addi-
tion, the mixture was stirred for 1 h. Then saturated
NaHCO3 was dropwisely added to reach the pH＝7－8.
*
E-mail: jtliu@sioc.ac.cn
Received December 29, 2016; accepted February 14, 2017; published online XXXX, 2017.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201600933 or from the author.
Dedicated to Professor Xikui Jiang on the occasion of his 90th birthday.
Chin. J. Chem. 2017, XX, 1—5
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The aqueous phase was extracted with ethyl acetate
(10.0 mL×3), and the combined organic phase was
dried over anhydrous Na2SO4. After being concentrated,
the residue was purified by flash column chromatog-
raphy on silica gel (hexane/ethyl acetate) to give sul-
fenamide 5a in 86% yield.
gave the corresponding disulfides 3d－3e in good iso-
lated yields (Entries 4－5, 75%－77%). However, the
strong electron withdrawing NO2 group in thiol made
the yield decrease to 45%, and disulfide ClC2F4-S-S-
C2F4Cl was formed as the major byproduct (Entry 6). It
is worthy to mention that benzylthiol could also react
with 2 to give the corresponding disulfide in good yield
(Entry 7).
General procedure for the reaction of 2 and arene
In darkness, to a solution of 2b (0.4 mmol) in tolu-
ene (5 mL) was slowly added the solution of indol (10.0
equiv. in 5 mL of DCM) at room temperature. After the
reaction was completed (monitored by 19F NMR), the
mixture was concentrated and the residue was purified
by column chromatography on silica gel (hexane) to
give product 6d in 94% yield.
Table 1 The reactions of perfluoroalkanesulfenyl chlorides with
thiols
Entrya
2/Rf
R
3, Yieldb/%
3a, 76
3b, 77
3c, 73
General procedure for the reaction of 2 and alkene
1
2
3
4
5
6
7
2a/CF2CF2Cl
2b/n-C4F9
C6H5
C6H5
C6H5
In darkness, to a solution of 2b (0.4 mmol) in tolu-
ene (5 mL) was slowly added the solution of 1-octene
(10.0 equiv. in 5 mL of DCM). The mixture was stirred
at 55 ℃ for 7.5 h (monitored by 19F NMR). After reac-
tion, the mixture was concentrated and the residue was
purified by column chromatography on silica gel (hex-
ane) to give product 7a and 7a' in 88% total yield with a
ratio of 1.0∶0.3.
2c/n-C6F13
2a/CF2CF2Cl
2a/CF2CF2Cl
2a/CF2CF2Cl
2a/CF2CF2Cl
p-MeO-C6H4
o-MeO-C6H4
p-O2N-C6H4
C6H5CH2
3d, 77
3e, 75
3f, 45
3g, 75
a Reaction conditions: 2 (0.4 mmol), thiol (0.4 mmol), toluene (10
mL), r.t., in darkness. b Isolated yield.
Results and Discussion
As shown in Scheme 1, perfluoroalkanesulfenyl
chlorides 2a－2c were easily prepared from the reaction
of perfluoroalkanesulfenic acids 1a－1c with Et2O•HCl
(5.0 equiv.) at room temperature. More than 95% yields
could be obtained as determined by 19F NMR with C6F6
as internal standard.
Under similar conditions, the reaction of sodium
p-toluenesulfinate with sulfenyl chloride 2b was also
tested, and product 4 was obtained in 65% yield. When
p-toluenesulfinic acid, which is more soluble, was used
instead of the salt, the yield could be improved to 85%
(Scheme 2).
Scheme 2 The reaction of 2b and p-toluenesulfinic acid (salt)
Scheme 1 The synthesis of perfluoroalkanesulfenyl chlorides
Disulfides are very important functional groups in
organism and the formation of S－S bond in organism
always involves the reactions of sulfenic acid deriva-
tives and thiols.[1,2] In our initial experiments, we stud-
ied the reaction of 2 with various thiols. It was found
that perfluoroalkanesulfenyl chlorides were pho-
to-sensitive and converted completely to perfluoroalkyl
disulfides within 30 min under visible light. Therefore,
all reactions were carried out in darkness. As shown in
Table 1, perfluoroalkanesulfenyl chlorides 2a－2c could
react with phenyl thiol readily at room temperature.
There was no obvious difference in yields of perfluoro-
alkyl phenyl disulfides (3a－3c) (Table 1, Entries 1－3,
73%－77%). Further investigation found that thiols
with electron donating groups in the phenyl ring also
Sulfenamides have been proposed for many practical
applications.[1,8] For example, they are very important
rubber additives, and of great technical interest as fun-
gecides and microbicides. Furthermore, they are also
very useful in the protection of functional groups.[1a]
Thus, we further explored the reactions of sulfenyl
chloride 2b with a series of amines. As shown in Table 2,
both primary amines and secondary amines could react
with 2b under mild conditions to give the corresponding
sulfenamides in moderate to high yields. Arylamines
bearing methoxyl or nitro substituent at p-position af-
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Preparation and Reactions of Perfluoroalkanesulfenyl Chlorides
forded sulfenamides 5b and 5c in 96% and 60% yield,
respectively. 1-Naphthylamine, 2-benzothiazolamine
and benzylamine also reacted well to give sulfenamides
5d－5f in good yields. Similarly, secondary amines
such as N-methylaniline, diphenylamine and 1-benzyl-
piperazine reacted readily with 2b to afford the desired
sulfenamides in moderate to good yields.
Some other activated aromatic derivates were also tried,
such as furane, 1,3-dimethoxybenzene and toluene, but
no desired substitution product was obtained, and disul-
fide n-C4F9-S-S-C4F9-n was the only product. It was
reported that trifluoromethylsulfenyl chloride could re-
act with these substrates easily.[9] The above results
demonstrated that the reactivity of perfluoroalkanesul-
fenyl chlorides with longer chain has lower reactivity
compared with CF3SCl.
Table 2 The reactions of sulfenyl chloride 2b with amines
Table 3 The reactions of perfluorobutanesulfenyl chloride 2b
with arenes
Reaction conditions: 2b (0.4 mmol), arene (4.0 mmol), toluene (5
mL), DCM (5 mL), r.t., in darkness, isolated yield.
The addition to carbon-carbon double bond is a typ-
ical property of sulfenyl chloride, differing from other
chlorides such as acyl chloride, sulfonyl chloride and
sulfinyl chloride, which rarely undergo this kind of ad-
dition reaction.[10] There have been several reports on
the addition reactions of nonfluorine-containing sulfenyl
chlorides.[10] Therefore, taking 2b as a model substrate,
we further studied the addition reactions of 2 and al-
kenes. Condition screening showed that the addition
reaction of 2b and 1-octene occurred at a higher tem-
perature (55 ℃) and the amount of alkene had an im-
portant influence on the reaction. When 2.0 equivalent
of 1-octene was used, perfluorobutyl disulfide
(n-C4F9-S-S-C4F9-n) was formed as the major product.
Full conversion and high selectivity for the desired ad-
dition products were reached using 10 equiv. of
1-octene (88% isolated yield). As shown in Table 4, the
addition reaction was very sensitive to the structure of
alkenes. While acyclic alkenes such as 1-octene, 1,
7-octa-diene and allylbenzene reacted with 2b at 55 ℃
(Table 4, Entries 1－3), the reaction of cyclohexene
took place at room temperature to give the correspond-
ing adducts in good yield (Entry 4), and even lower
temperature was needed for the reaction of cyclopentene
(0－5 ℃, Entry 5). In the case of acyclic alkenes, both
Markovnikov adducts (7) and anti-Markovnikov ad-
ducts (7′) were obtained with a ratio ranging from 1∶
0.1 to 1∶0.4. It is worth mentioning that only one dou-
ble bond participated the addition when non-conjugated
Reaction conditions: 2b (0.4 mmol), amine (4.0 mmol), toluene
(5 mL), DCM (5 mL), 0－5 ℃, in darkness, isolated yield.
Having achieved the reaction of 2 with amines, We
continued to test the reactions of 2b with (hetero)arenes
(Table 3). It was found that only some electron-rich
arenes could react with 2b. For example, the reaction of
N,N-diethylaniline with 2b occurred at room tempera-
ture to give sulfide 6a in 39% yield, and a large amount
of disulfide n-C4F9-S-S-C4F9-n was formed as major
product. In the case of N-phenylaniline, the correspond-
ing sulfide 6b was obtained in 30% yield and sulfena-
mide 5f was the major product. Pyrrole performed better
and sulfide 6c was formed in 53% yield as indicated by
19F NMR. Unfortunately, 6c was not stable enough to
isolate. Among all arenes tested, indol is the most effi-
cient substrate, giving 3-indolyl sulfide 6d in 94% yield.
Chin. J. Chem. 2017, 35, 1—6
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Xu, Jiang & Liu
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diene was used. Contrary to common nonfluorinated
sulfenyl chlorides which easily reacted with conjugated
dienes and electron-deficient alkenes,[10] 2b could not
react with those alkenes such as dimethylbutadiene and
2-cyclopentenone even at 70 ℃ for prolonged reaction
time.
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Entrya
1
Alkene
Temp./℃
t/h
55
7.5
88 (1∶0.3)
2
3
4
5
55
55
7.5
6.5
12
5
87 (1∶0.4)
81 (1∶0.1)
84
r.t.
0－5
85
a Reaction conditions: 2b (0.4 mmol), alkene (4.0 mmol), toluene
(5 mL), DCM (5 mL), in darkness. Total isolated yield of 7 and
7'; the ratio of 7 and 7' in parenthesis was determined by 19F
b
NMR spectroscopy.
Conclusions
In summary, perfluoroalkanesulfenyl chlorides could
be easily prepared from the corresponding sulfenyl ac-
ids. Compared with nonfluorine-containing sulfenyl
chlorides and trifluoromethanesulfenyl chloride, these
perfluoroalkylated sulfenyl chlorides showed similar
properties in some substitution and addition reactions,
but their reactivity was relatively lower in certain reac-
tions. Under mild conditions, they could react readily
with many sulfur and nitrogen nucleophiles, aniline and
pyrrole derivatives, and common alkenes, providing
useful methods for the preparation of a series of per-
fluoroalkyl-containing disulfides, sulfenamides, aryl
sulfides and α-chlorosulfides.
Acknowledgement
We thank the National Natural Science Foundation
of China (No. 21572257 and 21502213) and Shanghai
Sailing Program (No. 15YF1414800) for financial sup-
port.
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Preparation and Reactions of Perfluoroalkanesulfenyl Chlorides
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