Oxidative decarboxylative radical trifluoromethylthiolation of alkyl carboxylic acids with silver(i) trifluoromethanethiolate and selectfluor

Article abstract of DOI:10.1039/c6ra26133g

A straightforward silver-mediated oxidative decarboxylative radical trifluoromethylthiolation reaction of aliphatic carboxylic acid is described. This reaction operates under mild conditions and allows the synthesis of various valuable alkyltrifluoromethylthioethers from abundant alkyl carboxylic acids and convenient nucleophilic AgSCF₃ reagent. It provides a practical and efficient approach for the preparation of alkyltrifluoromethylthioethers.

Full text of DOI:10.1039/c6ra26133g

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Oxidative decarboxylative radical
trifluoromethylthiolation of alkyl carboxylic acids
with silver(I) trifluoromethanethiolate and
selectfluor†
Cite this: RSC Adv., 2017, 7, 880
*
*
Bin He, Zhiwei Xiao, Hao Wu, Yong Guo, Qing-Yun Chen and Chao Liu
A straightforward silver-mediated oxidative decarboxylative radical trifluoromethylthiolation reaction of
aliphatic carboxylic acid is described. This reaction operates under mild conditions and allows the
synthesis of various valuable alkyltrifluoromethylthioethers from abundant alkyl carboxylic acids and
Received 1st November 2016
Accepted 16th November 2016
DOI: 10.1039/c6ra26133g
convenient nucleophilic AgSCF3 reagent. It provides
a practical and efficient approach for the
www.rsc.org/advances
preparation of alkyltrifluoromethylthioethers.
triuoromethylthiolation reagents have been reported for effec-
tive triuoromethylthiolation of organometallic nucleophilic or
direct a-SCF3 of carbonyl compounds.6 Recently, the direct tri-
uoromethylthiolation of unactivated C(sp3)–H by AgSCF3/
K2S2O8 was described via a radical pathway.7
Introduction
The selective introduction of uorine and uorine-containing
groups into organic molecules can dramatically alter their phys-
ical, chemical and biological properties.1 As a star group in or-
ganouorine chemistry in recent years, the triuoromethylthio
group (CF3S) has attracted much attention because of its
electron-withdrawing nature, unique high lipophilicity and
metabolic stability. Compounds containing CF3S are frequently
found in pharmaceuticals and agrochemicals.2 Many methods
are now available to efficiently synthesize various organic
substrates containing CF3S on the basis of electrophilic, nucle-
ophilic, radical, and oxidative direct triuoromethylthiolation.3
Among them, more popular strategy of choice for the introduc-
tion of the CF3S group into organic substrates is the direct
formation of the C–SCF3 bond. Compared with numerous
methods for the efficient formation of C(sp2)–SCF3 and C(sp)–
SCF3 bonds, relatively limited methods are currently available for
the general and site-specic formation of various C(sp3)–SCF3
bonds. The resulting alkyltriuoromethylthioethers are mainly
accessible by the nucleophilic, electrophilic, or radical tri-
uoromethylthiolation of the corresponding alkanes or olens.
For examples, a direct dehydroxytriuoromethylthiolation of
alkyl alcohols using AgSCF3 and n-Bu4NI has been reported to
efficiently form C(sp3)–SCF3 bonds.4 A direct nucleophilic tri-
uoromethylthiolation of various alkyl chlorides, bromides and
tosylates with AgSCF3 was described in the presence of nBu4NI or
Aliphatic carboxylic acids are cheap and abundant raw
materials, and have been widely used as desirable starting
materials for the preparation of many important and valuable
compounds with different functional groups. The fundamental
transformation process involves decarboxylation with the
release of traceless by-product CO2 to generate alkyl radicals,
and their subsequent reactions with a variety of reagents lead to
efficient formation of many functionalized compounds. This
important transformation process has been applied in several
elegant decarboxylative uorinations.8 Shen and co-workers
described the silver-catalyzed oxidative decarboxylative tri-
uoromethylthiolation of alkyl carboxylic acids with electro-
philic triuoromethylthiolating reagent I in an aqueous emulsion
(Scheme 1a).8b Very recently, Glorius group reported the visible-
light-promoted decarboxylative triuoromethylthiolation of alkyl
carboxylic acids with electrophilic triuoromethylthiolating
reagent II under mild conditions (Scheme 1b).8f Although these
methods are effective for the site-selective formation of C(sp3)–
SCF3, they utilize relatively expensive electrophilic tri-
uoromethylthiolating reagents as the CF3S source, which are
commonly prepared from readily available AgSCF3.
Recently, we developed a practical and efficient method for
the direct triuoromethylthiolation of unactivated C(sp3)–H
bonds by AgSCF3/K2S2O8 under mild conditions.7b However, the
regioselectivity of the reaction generally depends on the alkyl
radical stability in situ formed, and several regioselective
isomers are oen generated in many cases. With the aim of
overcoming the issue and further expanding the scope of the
oxidative radical triuoromethylthiolation methodologies,
a
combination of nBu4NI/nBu4NBr.5 Several electrophilic
Key Laboratory of Organouorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China. E-mail:
chaoliu@sioc.ac.cn
† Electronic supplementary information (ESI) available. CCDC 1484006. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c6ra26133g
880 | RSC Adv., 2017, 7, 880–883
This journal is © The Royal Society of Chemistry 2017

View Article Online
Paper
RSC Advances
Table 1 Optimization of reaction conditionsa
Entry AgSCF3 (equiv.) Oxidant (equiv.) Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
2.0
K2S2O8 (2.0)
Na2S2O8 (2.0)
(NH4)2S2O8
CH3CN
CH3CN
CH3CN
0
37c
28c
31
1
Selectuor (2.0) Acetone
Selectuor (2.0) CH3CN
Selectuor (2.0) DMF
3
Selectuor (2.0) Acetone/CH3CN 3d
Selectuor (2.0) Acetone/H2O
NFSI (2.0)
FP (2.0)
Selectuor (2.0) Acetone
Selectuor (4.0) Acetone
Selectuor (4.0) Acetone
Selectuor (4.0) Acetone
0e
25
5
54
65
82f
0g
Scheme 1 Trifluoromethylthiolation of aliphatic carboxylic acids.
9
Acetone
Acetone
10
11
12
13
14
herein we report an efficient and general site-selective prepa-
ration of alkyltriuoromethylthioethers by means of oxidative
decarboxylative radical triuoromethylthiolation of various
aliphatic carboxylic acids by AgSCF3/selectuor (Scheme 1c).
a
Reaction conditions: decanoic acid (0.2 mmol, 1.0 equiv.), AgSCF3
(1.0–2.0 equiv.), oxidant (2.0–4.0 equiv.), and solvent (2.0 mL) at 60 ꢀC
for 4 hours under Ar atmosphere. Yields were determined by 19F
b
c
NMR spectroscopy with benzotriuoride as the internal standard.
di-triuoromethylthiolation isomer mixture was obtained. Acetone/
CH3CN (1 : 1 v/v) was used. Acetone/H2O (4 : 1 v/v) was used. 2,6-
Lutidine (2.0 equiv.) was used as ligand. CuSCF3 was used instead of
A
d
Results and discussion
e
f
g
Our study commenced by examing the oxidative decarboxylative
triuoromethylthiolation reaction of decanoic acid 1a with
AgSCF3 (ref. 9) (1.0 equiv.) at 60 ꢀC for 4 hours in the presence of
different oxidants and solvents (Table 1). Unfortunately, no
desired triuoromethylthiolation product was observed with
K2S2O8 as oxidant in CH3CN (Table 1, entry 1). To our surprise,
under similar conditions, Na2S2O8 resulted in the formation of
oxidative decarboxylative triuoromethylthiolation products
(Table 1, entry 2). However, aer careful analysis and spectro-
scopic characterization, it was found that the products are not the
desired product 2a, but a various di-triuoromethylthiolation
isomer mixture, which is presumably due to concurrent occur-
rence of both direct triuoromethylthiolation of C(sp3)–H and
the desired oxidative decarboxylative triuoromethylthiolation of
1a (Scheme 2). In order to suppress the undesired direct tri-
uoromethylthiolation of C(sp3)–H, different solvents including
DMSO, DMF, acetone, and ClCH2CH2Cl/CH3CN/H2O were
screened. However, the reactions led to no formation of the
desired products.10 When AgSCF3 was used as the limiting
reagent with 5 equiv. of 1a in CH3CN in the presence of Na2S2O8,
a complex di-triuoromethylthiolation isomer mixture was still
obtained (Table 1, entry 3).
Next, we were delighted to nd that when selectuor was
used as oxidant, the desired oxidative decarboxylative mono-
triuoromethylthiolation product 2a was obtained and no
undesired di-triuoromethylthiolation products were observed,
demonstrating the successful suppression of the undesired
direct triuoromethylthiolation of C(sp3)–H (Table 1, entry 4).
Notably, neither competitive oxidative decarboxylative uori-
nation reaction was observed, which was considered to
presumably occur under the reaction conditions according to
literature.8a These results demonstrate that oxidative decar-
AgSCF3.
conditions is the predominant process presumably because
selectuor would not activate the C(sp3)–H to give the corre-
sponding key C(sp3)-centered radical intermediate. Among
several common reaction solvents we screened, acetone was the
best one and provided 31% yield of the desired product 2a
(Table 1, entries 4–7). It is worth noting that water was harmful
for the reaction and resulted in no formation of the desired
product (Table 1, entry 8). Then various oxidants such as N-
uorobenzenesulfonimide (NFSI), and 1-uoropyridium tetra-
uoroborate (PF) were further tested, it turned out that worse
results were observed (Table 1, entries 9 and 10). By changing
the amount of AgSCF3/selectuor, the yield of the desired
product 2a was further improved to 65% (Table 1, entries 11 and
12). The inuence of several ligands were also estimated, 2,6-
lutidine gave the best yield of 82% (Table 1, entry 13), which
might coordinate with active Ag species to enhance their
stability during the reaction.10 Furthermore, the replacement of
AgSCF3 with CuSCF3 led to no formation of the desired product,
demonstrating the key role of the free silver cation for the
reaction (Table 1, entry 14). All these experimental results
indicate that a combination of AgSCF3 (2.0 equiv.)/selectuor
(4.0 equiv.)/2,6-lutidine (2.0 equiv.) in acetone at 60 ꢀC for 4
Scheme 2 Competitive oxidative trifluoromethylthiolation reactions
boxylative triuoromethylthiolation under the reaction of 1a.
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 880–883 | 881

View Article Online
RSC Advances
Paper
hours is established as the optimal conditions for oxidative
decarboxylative triuoromethylthiolation reactions of various
aliphatic carboxylic acids.
With the optimal conditions in hand, we then explored the
generality of the oxidative decarboxylative triuoromethyl
thiolation reactions with a variety of aliphatic carboxylic acids
(Scheme 3). It was found that various aliphatic carboxylic acids
including primary, secondary and tertiary carboxylic acids are
all suitable substrates for the oxidative decarboxylative tri-
uoromethylthiolation reactions. For example, a number of
primary alkyl carboxylic acids underwent smooth oxidative decar-
boxylative triuoromethylthiolation to give the desired alkylthi-
uormethylthioethers in isolated yields of 48–84% (2a–k).
Secondary aliphatic carboxylic acids could also be subjected to the
reactions to provide the corresponding products in modest to good
yields (2l–q). When tertiary alkyl carboxylic acids were employed
as the substrates, the desired oxidative decarboxylative tri-
uoromethylthiolation products were generated in acceptable
yields (2r, s). It should be mentioned that reduced reaction time
should be applied to the aliphatic carboxylic acids 1j and 1l since
signicant decrease in the yields of the corresponding desired
triuoromethylthiolation products was observed under the
optimal reaction conditions,10 which might be due to the insta-
bility of the corresponding products 2j and 2l under the reaction
Scheme 4 Proposed mechanism.
conditions. With regard to the potential of the reaction in late-
stage functionalization of valuable synthetic intermediates,
a structurally complicated biologically active steroid derivative was
applied to the oxidative decarboxylative triuoromethylthiolation
reaction and the desired product 2k was produced smoothly in
good isolated yield. Its structure was unambiguously assigned by
various spectral analysis, including X-ray single-crystal analysis.
To gain some understanding on the reaction pathway,
a radical inhibitor (hydroquinone) or a radical scavenger
(2,2,6,6-tetramethyl-1-piperidinyloxy, TEMPO) were added to
the reaction of 1a, and a sharp decrease in the yield was
observed for both cases.10 These preliminary results combined
with previous reports on silver-mediated oxidative decarbox-
ylative functionalization7,8a,b indicate that the reaction proceeds
through a radical pathway.10 First, AgSCF3 is oxidized by
selectuor to generated Ag(II)SCF3 intermediate, CF3S radical or
CF3SSCF3. Ag(II) combines with alkyl carboxylic acids to
generate the corresponding alkyl radical via decarboxylation
pathway. Then, the produced alkyl radical attacks a CF3S
radical, CF3SSCF3, or abstracts the CF3S ligand of Ag(II)SCF3
intermediate to provide the desired oxidative decarboxylative
triuoromethylthiolation product (Scheme 4).
Conclusions
In conclusion, we developed a practical and effective silver-
meditated oxidative decarboxylative triuoromethylthiolation
reaction of aliphatic carboxylic acids using nucleophilic AgSCF3
as CF3S source and selectuor as the oxidant. The reaction can
be applied to primary, secondary and tertiary alkyl carboxylic
acids under mild conditions and is tolerant of many functional
groups. It represents an alternative approach for site-selective
construction of C(sp3)–SCF3 bonds.
Acknowledgements
The authors gratefully acknowledge the nancial support from
the National Basic Research Program of China (2012CB821600),
the National Natural Science Foundation of China (21032006,
21302207, 21421002).
Scheme
3
Scope
of
oxidative
decarboxylative
tri-
fluoromethylthiolation reactions of various aliphatic carboxylic acid-
Notes and references
a
s.a,b
Reaction conditions: 1 (0.5 mmol), AgSCF3 (1.0 mmol),
selectfluor (2.0 mmol), and 2,6-lutidine (1.0 mmol) in acetone (1 mL) at
´
´
1 (a) J.-P. Begue and D. Bonnet-Delpon, Bioorganic and
Medicinal Chemistry of Fluorine, John Wiley & Sons, New
Jersey, 2008; (b) I. Ojima, Fluorine in Medicinal Chemistry
and Chemical Biology, Wiley-Blackwell, Hong Kong, 2009;
(c) W. K. Hagmann, J. Med. Chem., 2008, 51, 4359; (d)
b
60 ꢀC for 4 h under Ar atmosphere. Yields were determined by 19F
NMR spectroscopy with trifluorotoluene as internal standard. Yields of
c
isolated products are given in parentheses. Reaction time: 2 h.
d Reaction time: 15 min. e 1 (1.5 mmol), AgSCF3 (0.5 mmol), selectfluor
(1.0 mmol), and 2,6-lutidine (0.5 mmol) were used.
882 | RSC Adv., 2017, 7, 880–883
This journal is © The Royal Society of Chemistry 2017

View Article Online
Paper
S. Purser, P. R. Moore, S. Swallow and V. Gouverneur, Chem.
RSC Advances
J. Colomb and T. Billard, Angew. Chem., Int. Ed., 2012, 51,
10382; (g) T. Bootwicha, X. Liu, R. Pluta, I. Atodiresei and
M. Rueping, Angew. Chem., Int. Ed., 2013, 52, 12856; (h)
Y. D. Yang, A. Azuma, E. Tokunaga, M. Y. Amasaki,
M. Shiro and N. Shibata, J. Am. Chem. Soc., 2013, 135,
8782; (i) X. L. Zhu, J. H. Xu, D. J. Cheng, L. J. Zhao,
X. Y. Liu and B. Tan, Org. Lett., 2014, 16, 2192; (j) S. Alazet,
L. Zimmer and T. Billard, J. Fluorine Chem., 2015, 171, 78.
7 (a) S. Guo, X. Zhang and P. Tang, Angew. Chem., Int. Ed., 2015,
54, 4065; (b) H. Wu, Z. Xiao, J. Wu, Y. Guo, J.-C. Xiao, C. Liu
and Q.-Y. Chen, Angew. Chem., Int. Ed., 2015, 54, 4070.
8 For recent reports, see: (a) F. Yin, Z. Wang, Z. Li and C. Li, J.
Am. Chem. Soc., 2012, 134, 10401; (b) F. Hu, X. Shao, D. Zhu,
L. Lu and Q. Shen, Angew. Chem., Int. Ed., 2014, 53, 6105; (c)
M. Rueda-Becerril, O. Mahe, M. Drouin, M. B. Majewski,
J. G. West, M. O. Wolf, G. M. Sammis and J. F. Paquin, J.
Am. Chem. Soc., 2014, 136, 2637; (d) S. Ventre,
F. R. Petronijevic and D. W. C. MacMillan, J. Am. Chem.
Soc., 2015, 137, 5654; (e) H. Huang, K. Jia and Y. Chen,
Angew. Chem., Int. Ed., 2015, 54, 1881; (f) L. Candish,
¨
Soc. Rev., 2008, 37, 320; (e) K. Muller, F. Faeh and
F. Diederich, Science, 2007, 317, 1881.
´
´
˜
2 J. Wang, M. Sanchez-Rosello, J. L. Acena, C. D. Pozo,
A. E. Sorochinsky, S. Fustero, V. A. Soloshonok and H. Liu,
Chem. Rev., 2014, 114, 2432.
3 For selected reviews, see: (a) X.-H. Xu, K. Matsuzaki and
N. Shibata, Chem. Rev., 2015, 115, 731; (b) F. Toulgoat,
S. Alazet and T. Billard, Eur. J. Org. Chem., 2014, 2415; (c)
X. Shao, C. Xu, L. Lu and Q. Shen, Acc. Chem. Res., 2015,
48, 1227; (d) L. Chu and F.-L. Qing, Acc. Chem. Res., 2014,
47, 1513; (e) G. Landelle, A. Panossian, S. Pazenok,
J.-P. Vors and F. Leroux, Beilstein J. Org. Chem., 2013, 9,
2476; (f) T. Liang, C. Neumann and T. Ritter, Angew. Chem.,
Int. Ed., 2013, 52, 8214; (g) V. Boiko, Beilstein J. Org. Chem.,
2010, 6, 880; (h) K. Zhang, X. Xu and F. Qing, Chin. J. Org.
Chem., 2015, 35, 556; (i) H. Zheng, Y. Huang and Z. Weng,
Tetrahedron Lett., 2016, 57, 1397; (j) H. Chachignon and
D. Cahard, Chin. J. Chem., 2016, 34, 445.
4 J.-B. Liu, X.-H. Xu, Z.-H. Chen and F.-L. Qing, Angew. Chem.,
Int. Ed., 2015, 54, 897.
´
´
L. Pitzer, A. Gomez-Suarez and F. Glorius, Chem.–Eur. J.,
5 C. Xu, Q. Chen and Q. Shen, Chin. J. Chem., 2016, 34, 495.
6 For representative examples, see: (a) X. Shao, X. Wang,
T. Yang, L. Lu and Q. Shen, Angew. Chem., Int. Ed., 2013,
2016, 22, 4753.
9 The
exact
molecular
formula
of
silver(I)
triuoromethanethiolate prepared according to the
¨
52, 3457; (b) E.
V. Vinogradova, P. Muller and
literature (G. Teverovskiy, D. S. Surry and S. L. Buchwald,
S. L. Buchwald, Angew. Chem., Int. Ed., 2014, 53, 3125; (c)
X. Wang, T. Tang, X. Cheng and Q. Shen, Angew. Chem.,
Int. Ed., 2013, 52, 12860; (d) C. Xu, B. Ma and Q. Shen,
Angew.
Chem.,
Int.
Ed.,
2011,
50,
7312)
is
3AgSCF3$CH3CN.7b For simplicity, we used AgSCF3 instead
of 3AgSCF3$CH3CN in the text.
Angew. Chem., Int. Ed., 2014, 53, 9316; (e) X. Shao, T. Liu, 10 See the ESI for details.†
L. Lu and Q. Shen, Org. Lett., 2014, 16, 4738; (f) F. Baert,
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 880–883 | 883