Direct Phosphorus-Induced Fluoroalkylthiolation with Fluoroalkylsulfonyl Chlorides

Article abstract of DOI:10.1002/adsc.201600651

A simple and practical method of fluoroalkylthiolation using fluoroalkylsulfonyl chlorides (R_fSO₂Cl, R_f=CF₃, C₄F₉, C₈F₁₇, CF₂H and CH₂CF₃

Full text of DOI:10.1002/adsc.201600651

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DOI: 10.1002/adsc.201600651
Direct Phosphorus-Induced Fluoroalkylthiolation with
Fluoroalkylsulfonyl Chlorides
Lvqi Jiang,+a Wenbin Yi,+a,* and Qiran Liua
a
Chemical Enginering College, Nanjing University of Science and Technology, 200 Xiao Ling Wei Street, Nanjing, Jiangsu,
Peopleꢀs Republic of China
E-mail: yiwenbin@njust.edu.cn
+
These authors contributed equally to this paper.
Received: June 21, 2016; Revised: August 22, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600651.
Abstract: A simple and practical method of fluo-
roalkylthiolation using fluoroalkylsulfonyl chlorides
(RfSO2Cl, Rf =CF3, C4F9, C8F17, CF2H and CH2CF3)
has been developed. These easy-to-handle reagents
are powerful and can be used for electrophilic fluo-
roalkylthiolation of electron-rich arenes and thiols
using diethyl phosphite as reducing agent.
other fluoroalkyl groups in many pharmacological
studies,[7] which makes the SCH2CF3 moiety an inter-
esting group with respect to the design of bioactive
molecules. Examples of fluoroalkylthiolated drugs
and agrochemicals including Toltrazuril,[8] Cefaza-
flur,[9] Flomoxef sodium,[10] Pyriprole,[11] Losartan ana-
logues[12] and Polythyazid[13] are shown in Figure 1.
Various approaches for the direct installment of
a SCF3 moiety have been reported and represented
more attractive approaches to RSCF3 products.[14]
One attractive strategy for the construction of C–
SCF3 bonds is to use an electrophilic trifluorome-
thylthiolating reagent. The original electrophilic tri-
Keywords: electron-rich arenes and thiols; fluoroal-
kylsulfonyl chlorides; fluoroalkylthiolation; phos-
phorus-induced reaction
Organofluorine chemistry has experienced a resur-
gence of interest and consequently a very fast expan-
sion.[1] Due to the unique ability of the fluorine atom
and fluorinated groups to modify the biological and
physical properties of a molecule, their presence is
often crucial for the discovery and design of new
pharmaceuticals and agrochemicals.[2] Already today,
around 25% of all pharmaceuticals and 30% of the
applied agrochemicals contain at least one or even
more trifluoromethyl substituents, or
a fluorine
atom.[3]
In the organofluorine family, the trifluoromethyl-
ACHTUNGTRENNUNG
Figure 1. Examples of the RfS-containing biologically active
group (SCH2CF3) can confer greater activity than compounds.
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fluoromethylthiolating reagent is CF3SCl, which was
Although there are continuing elegant synthetic
used to react with some nucleophiles but with high works on SCF3 moieties, methods for the straightfor-
toxicity.[15] When it comes to the 20th century, Muna- ward introduction of SCF2H, SCH2CF3 and SRf
valli utilized N-(trifluoromethylthio)-phthalimide groups are very limited. Recently, Shen and co-work-
(Figure 2, 1a) as the trifluoromethylthiolating reagent ers demonstrated the Sandmeyer-type difluorome-
for the preparation of a-SCF3 carbonyl compounds in thylthiolation of diazonium salts for the formation of
2000.[16] PhNHSCF3 and PhN(Me)SCF3, initially de- electrophilic difluoromethylthiolated arenes and het-
veloped by Billard and Langlois, were effective for eroarenes using the N-heterocyclic carbene (NHC) li-
the trifluoromethylthiolation of alkenes, alkynes, in- gated difluoromethylthiolated silver complex [(SI-
doles, and Grignard and lithium reagents, but a strong Pr)Ag(SCF2H)] (Figure 2, 1i).[21] They subsequently
Lewis acid or Brønsted acid was required to activate reported a new electrophilic reagent N-difluorome-
these reagents.[17] Then in 2013, Lv and Shen reported thylthiophthalimide (1j) for the direct difluorome-
the trifluoromethylthiolation of b-keto esters using thylthiolation of hydrocarbon derivatives and hetero-
a novel hypervalent iodine reagent 1b[18a] which was arenes.[22] The Shibata group reported difluorometha-
later revised by Buchwald to have the structure of nesulfonyl (SO2CF2H) hypervalent iodonium ylides
a trifluoromethanesulfenate (1b’).[18b] In the same (1k) as electrophilic difluoromethylthiolating reagents
year, the group of Shibata used the hypervalent tri- for a wide range of nucleophiles.[23] As to perfluoroal-
fluoromethanesulfonyl iodonium ylide 1c (R=IPh)[19a] kylthiolation, our group recently reported a method
as a CF3SO2-based trifluoromethylthiolating reagent for the perfluoroalkylthiolation of indoles using
and recently they reported another similar reagent NaSO2Rf.[24]
(1c, R=N2).[19b,c] In 2014, Shen and his co-workers de-
It is worth mentioning that although great progress
scribed a new shelf-stable electrophilic reagent N-tri- in direct fluoroalkylthiolation methods was reported
fluoromethylthiosaccharin 1d which was easy to pre- in recent years, there are still serious practical limita-
pare and has a broad scope.[20a] After that Billard re- tions in the field, especially in the application for
ported a trifluoromethanesulfenamide 1e which could large-scale fluoroalkylthiolation reactions. Most previ-
be used for the a-trifluoromethylthiolation of the ously reported fluoroalkylthiolating reagents suffer
enolate of acetophenone.[20b] Very recently, Shen and from a common drawback which is that multiple steps
co-workers demonstrated another electrophilic re- are required and the generation of stoichiometric
agent N-trifluoromethylthiodibenzenesulfonimide 1f amounts of metal salts decrease the overall synthetic
which was more powerful than 1b’, 1d and 1e.[20c]
efficiency. Recently, our group reported the reduction
of Langloisꢀ reagent (CF3SO2Na, 1g) to CF3SSCF3 by
using (EtO)2P(O)H, and its application in the electro-
philic trifluoromethylthiolation of indoles, pyrroles
and enamines. This reagent is cheap and stable com-
pared with the reported reagents and the method has
been successfully extended for perfluoroalkylthiola-
tion using RfSO2Na.[24a] In the same year, Vivic also
reported a method using CF3SO2Na to generate
CuSCF3 and then reacted it with (hetero)aryl iodi-
des.[24b] Our system was similar to Dengꢀs work, who
reported an iodine-catalyzed sulfenylation of indoles
with sodium sulfonates (Figure 3).[25] In 2011,You and
his co-workers reported the synthesis of di(hetero)ar-
yl sulfides by using arylsulfonyl chlorides, triphenyl-
Figure 2. Some user-friendly electrophilic trifluoromethyl-
thiolating and difluoromethylthiolating reagents.
Figure 3. Some related previous work and this work.
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phosphine was used as the reductant.[26] As a deduc-
tion, we speculated that trifluoromethanesulfonyl
chloride (CF3SO2Cl) could also conceivably generate
reactive SCF3 species without any additional sulfur
sources (Figure 3).[27] Trifluoromethanesulfonyl chlo-
ride is an inexpensive and readily available com-
pound. It has been used for more than a century in
materials science and medicinal chemistry.[28]
Table 2. Scope of the trifluoromethylthiolation of indole de-
rivatives and other electron-rich heterocycles.[a]
Initial studies were focused on searching for suita-
ble reductants. We first examined the reaction of
CF3SO2Cl and indole with some phosphine com-
pounds (Table 1, entries 1–3). Reaction of 2 equiva-
Table 1. Optimization of trifluoromethylthiolation with
CF3SO2Cl.[a]
Entry
Reductant
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
9
PPh3
PPh2Me
PPhMe2
(MeO)2P(O)H
(EtO)2P(O)H
(EtO)2P(O)H
(EtO)2P(O)H
(EtO)2P(O)H
(EtO)2P(O)H
PhMe
PhMe
PhMe
PhMe
PhMe
DCM
MeCN
MeCN
MeCN
35
23
18
66
85
81
91
trace[c]
21[d]
[a]
Conditions: indole, pyrrole or activated benzene
(0.2 mmol), 1h (0.3 mmol), (EtO)2P(O)H (0.4 mmol), in
MeCN (1 mL) at 908C for 10 h; isolated yields.
[a]
Conditions: 2a (0.2 mmol), solvent (1 mL), 908C.
Yields were determined by 19F NMR using PhCF3 as an
internal standard.
[b]
[b]
3 equiv. FeCl3 were used.
[c]
[d]
At room temperature.
At 508C.
methyl (3i) and 1,2-dimethyl (3j) groups were also
lents of PPh3 and CF3SO2Cl at 908C gave the submitted to our trifluoromethylthiolation protocol.
trifluoromethylthiolation product 3a in 35% yield Indoles with an electron-donating group gave better
ACHTUNGTRENNUNG
(Table 1, entry 3). Inspired by this result, we screened results than those with an electron-withdrawing group
other reductants. After testing some phosphite esters such as for 3b and 3f. Similarly, reaction of pyrroles
(Table 1, entries 4 and 5) we were excited to find that with different substituted groups occurred to give the
the reaction with (EtO)2P(O)H (2 equiv.) afforded corresponding trifluoromethylthiolated pyrroles in
a high yield of 3a. Optimization of the solvents good yield (4a, 4b). Besides indoles and pyrroles, acti-
(Table 1, entries 6 and 7) and temperature (Table 1, vated benzenes such as 1,3,5-trimethoxybenzene (5a),
entries 8 and 9) revealed that using (EtO)2P(O)H 1,3-dimethoxybenzene (5b) and 3,5-dimethoxyphenol
(2.0 equiv.) in acetonitrile at 908C for 10 h could in- (5c) reacted with CF3SO2Cl in the presence of
crease the product yield to 91% (Table 1, entry 7).
iron(III) chloride (3 equiv.) occurred to give the cor-
Reactions of a variety of indoles with electron-do- responding trifluoromethylthiolated heteroarenes in
nating or electron-withdrawing groups were conduct- moderate yields (55–74%, 5a–5c), less active than in-
ed under the optimized condition and proceeded in doles and pyrroles.
good to excellent yields (Table 2). 5-Substituted in-
Due to the importance of the SCF2H group, our ex-
doles with functional groups such as fluoride (3c), amination of the scope of substrates used in reactions
chloride (3d), iodide (3e), and cyano (3f) groups re- with CF2HSO2Cl was more extensive. It was found
acted to generate the corresponding trifluorome- that under the conditions that were optimal for
thylthiolated indoles in high yields. Other indole de- CF3SO2Cl, CF2HSO2Cl also yielded the desired prod-
rivatives including 4-methoxy (3g), 6-chloro (3h), 2- uct (Table 3). Substituents such as ester (6c), and
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Table 3. Fluoroalkylthiolation with RfSO2Cl of indole and
Table 4. Trifluoromethylthiolation of thiols with CF3SO2Cl.[a]
pyrrole derivatives.[a]
[a]
Conditions:
thiols
(0.2 mmol),
1h
(0.3 mmol),
(EtO)2P(O)H (0.4 mmol) in MeCN (1 mL) at 908C for
7 h; isolated yields.
tional groups such as chloride (10d) and fluoride
(10e) were well tolerated. Thiols with 4-substituted
groups gave better results than those with 3-substitut-
ed groups such as for 10a and 10g. Naphthalene-1-
thiol also reacted with 1h to provide the desired prod-
uct in 70% yield (8a). Although other methods for
the syhtnesis of trifluoromethyl-substituted disulfides
have been already describred,[20c,30] this method pro-
vided a alternative route with easy-to-handle reagents
under simple conditions.
[a]
Conditions: indole or pyrrole (0.2 mmol), RfSO2Cl
(0.3 mmol), (EtO)2P(O)H (0.4 mmol) in MeCN (1 mL)
at 908C for 10 h; isolated yields.
[b]
Yields were determined by 19F NMR using PhCF3 as an
internal standard.
To understand the mechanism of this phosphorus-
reduced reaction, a reaction of indole under the opti-
chloride (6d) on indoles were well-tolerated in these mized condition was monitored by 19F-NMR. There
reactions. Reactions with 2,4-dimethyl- and 2-phenyl- was only a new peak at d=À78.83 ppm appeared
pyrroles were identified to solely afford 2-SCF2H except for the starting material CF3SO2Cl (d=
products in good yields (7a, 7b). Other fluoroalkylsul- À75.31) and the trifluoromethylthiolated product 3a
fonyl chlorides such as CF3CH2SO2Cl, C4F9SO2Cl and (d=À44.60). A similar peak of CF3S(O)H (d=
C8F17SO2Cl were also tested with indole derivatives, À78.58) in our previous work was observed,[24] which
the results with CF3CH2SO2Cl were similar to those demonstrated that trifluoromethanesulfinyl chloride
with CF3SO2Cl and CF2HSO2Cl (8a–8d). However, (CF3SOCl, the peak at d=À78.83) could be firstly
results with C4F9SO2Cl and C8F17SO2Cl were more formed. A similar reduction of CF3SOCl afforded tri-
negative than those with CF3SO2Cl, CF2HSO2Cl and fluoromethanesulfenyl chloride CF3SCl, which was
CF3CH2SO2Cl, even when the iodole was activated by the real reactive electrophilic species as in Shibataꢀs
a methoxy group (9b, 9d), the yields were obviously observation.[27] 31P NMR was also used to monitor the
lower.
reaction and showed that most of the diethyl phos-
Trifluoromethyl disulfides are important as precur- phite (d=À7.25) was converted to diethyl phosphate
sors of biologically active trifluoromethyl thiosulfo- (d=À0.31). A large amount of diethyl phosphate was
nates,[29] thus we futher studied the reaction of thiols also observed from GC-MS. On the basis of these ob-
with reagent 1h. To our delight, reactions of 1h with servations, a plausible mechanism consisting of reduc-
a variety of aryl thiols under similar conditions oc- tion of CF3SO2Cl with (EtO)2P(O)H to CF3SCl and
curred in excellent yields (Table 4). Common func- electrophilic attack of CF3SCl on indole to give the
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column chromatography to give the corresponding trifluoro-
methylthiolation product.
General Procedure for Fluoroalkylthiolation of
Indoles and Pyrroles (6a–6f, 7a, 7b, 8a–8d, 9a–9d)
A 10-mL oven-dried reaction vessel was charged with the
indole or pyrrole (0.2 mmol), fluoroalkylsulfonyl chlorides
(0.3 mmol), and diethyl phosphite (51.2 mL, 0.4 mmol). Ace-
tonitrile (1 mL) was added to the sealed reaction vessel by
syringe. The resulting solution was stirred at 908C for 10 h.
After cooling to room temperature the volatiles were re-
moved under vacuum and the residue was purified by
column chromatography to give the corresponding fluoroal-
kylthiolation product.
Scheme 1. Proposed mechanism for trifluoromethylthiola-
tion with CF3SO2Cl.
General Procedure for Trifluoromethylthiolation of
Thiols (10a–10h)
trifluoromethylthiolated product 3a is proposed in
Scheme 1.
A 10-mL oven-dried reaction vessel was charged with the
thiol (0.2 mmol), trifluoromethansulfonyl chloride (1h,
50.6 mg, 0.3 mmol), diethyl phosphite (51.2 mL, 0.4 mmol).
Acetonitrile (1 mL) was added to the sealed reaction vessel
by syringe. The resulting solution was stirred at 908C for
7 h. After cooling to room temperature the volatiles were
removed under vacuum and the residue was purified by
column chromatography to give the corresponding trifluoro-
methylthiolation products.
In summary, we have developed a cheap and stable
electrophilic
trifluoromethylthiolating
reagent,
CF3SO2Cl. This reagent was able to efficiently tri-
fluoromethylthiolate indoles, pyrroles, activated ben-
zenes and thiols. The reaction system is very
simple and the method has been successfully extend-
ed for other fluoroalkylthiolation reactions using
CF2HSO2Cl, CF3CH2SO2Cl and RfSO2Cl. This user-
friendly reagent has a potential for the preparation of
more complicated, densely functionalized drug-like
molecules. It also has a potential for use on a larger
scale, or even in industrial applications.
Acknowledgements
We gratefully acknowledge Fundamental Research Funds for
the Central Universities (30916011102, 30916014103), the Na-
tional Natural Science Foundation of China (21476116), Nat-
ural Science Foundation of Jiangsu (BK20141394), Qing Lan
Project, Priority Academic Program Development of Jiangsu
Higher Education Institutions, and the Center for Advanced
Materials and Technology in Nanjing University of Science
and Technology for financial support.
Experimental Section
General Procedure for Trifluoromethylthiolation of
Indoles and Pyrroles (3a–3j, 4a, 4b)
A 10-mL oven-dried reaction vessel was charged with an
indole or pyrrole (0.2 mmol), trifluoromethanesulfonyl chlo-
ride (1h, 50.6 mg, 0.3 mmol) and diethyl phosphite (51.2 mL,
0.4 mmol). Acetonitrile (1 mL) was added to the sealed re-
action vessel by syringe. The resulting solution was stirred at
908C for 10 h. After cooling to room temperature the vola-
tiles were removed under vacuum and the residue was puri-
fied by column chromatography to give the corresponding
trifluoromethylthiolation product.
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Adv. Synth. Catal. 0000, 000, 0 – 0
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ÞÞ
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COMMUNICATIONS
Direct Phosphorus-Induced Fluoroalkylthiolation with
Fluoroalkylsulfonyl Chlorides
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Adv. Synth. Catal. 2016, 358, 1 – 7
Lvqi Jiang, Wenbin Yi,* Qiran Liu
Adv. Synth. Catal. 0000, 000, 0 – 0
7
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!