Metal-Free Direct Dehydroxytrifluoromethylthiolation of Alcohols via the Umpolung Reactivity of Trifluoromethanesulfenamides

Article abstract of DOI:10.1002/ejoc.201600197

A direct dehydroxytrifluoromethylthiolation of alcohols with trifluoromethanesulfenamide has been described. This method, based on the original umpolung reactivity of trifluoromethanesulfenamides, proposes a direct "OH-SCF₃ exchange" under mild and, more especially, metal-free conditions.

Full text of DOI:10.1002/ejoc.201600197

DOI: 10.1002/ejoc.201600197
Communication
Trifluoromethylthiolation
Metal-Free Direct Dehydroxytrifluoromethylthiolation of
Alcohols via the Umpolung Reactivity of
Trifluoromethanesulfenamides
Quentin Glenadel,[a] Anis Tlili,[a] and Thierry Billard*[a,b]
Abstract: A direct dehydroxytrifluoromethylthiolation of alco- fluoromethanesulfenamides, proposes a direct “OH-SCF3 ex-
hols with trifluoromethanesulfenamide has been described. change” under mild and, more especially, metal-free conditions.
This method, based on the original umpolung reactivity of tri-
Introduction
nucleophilic substitution. The scope of this reaction appears the
most extended. However, if these two approaches are efficient,
the use of an excess amount of metal, inherent to the structure
of the used trifluoromethylthiolating reagents, constitutes a
major drawback (Scheme 1).
Because fluorinated compounds are more and more used in
various fields of applications,[1] new methods to introduce fluor-
inated groups into organic molecules are highly desirable.[2]
The trifluoromethylthio group has attracted particular attention,
notably due to its specific electronic properties (Hammett con-
stants σp = 0.50, σm = 0.40; Swain–Lupton constants F = 0.36,
R = 0.14)[3] and its high lipophilicity (Hansch parameter πR
=
1.44).[4] In the last years, growing efforts have been made to
develop efficient reagents and strategies to synthesize trifluoro-
methylthiolated molecules, with a particular focus on direct ap-
proaches using “CF3S-donor reagents”.[2f,5] Many of these meth-
ods are based on the nucleophilic substitution of various leav-
ing groups.[5f] However, due to the wide availability of alcohols,
a direct “OH-SCF3 exchange”, without prefunctionalization,
could constitute a pertinent strategy. Nevertheless, despite such
an interest, only two methods have dealt with this direct trans-
formation of a hydroxyl group to a CF3S moiety, that is, de-
hydroxytrifluoromethylthiolation reactions. A Lewis acid medi-
ated strategy has been recently developed, it uses an excess
amount of CF3SCu as trifluoromethylthiolating reagent.[6] How-
ever, this approach is limited to allylic and benzylic substrates
and requires an excess amount of Lewis acid, which could limit
the functional-group tolerance. In the same time, an elegant
approach using CF3SAg has been proposed.[7] In this strategy,
the trifluoromethylthiolating reagent, in excess, acts both as ac-
tivating reagent for the alcohol, through the functionalization
of the OH group with difluorothiophosgene arising from the
decomposition of CF3SAg, and as CF3S– donor to perform the
Scheme 1. Different strategies for direct “OH-SCF3 exchange”.
Results and Discussion
We have recently demonstrated the Janus faces of trifluoro-
methanesulfenamide (BB23), which can release the CF3S– anion
under simple iodide activation.[8] Consequently, this reagent
could constitute a valuable metal-free alternative to the CF3S–
metal reagents generally used. Hence, a direct dehydroxytri-
fluoromethylthiolation, based on Qing's strategy,[7] was envis-
aged.
Inspired by our previously described results,[8] the reaction
conditions were optimized with benzyl alcohol (1a) (Table 1).
Good yields were already obtained with 2 equiv. of BB23
and 2.2 equiv. of Bu4NI (entry 1). An excess amount of Bu4NI
(3.3 equiv.) slightly improved yield (entry 2). Furthermore, in-
creasing the reaction temperature to 60 °C led to excellent re-
sults (entry 3). Afterwards, solvents other than acetone were
evaluated under the optimal conditions without success, re-
gardless of their polarity (entries 4–11).
[a] Institute of Chemistry and Biochemistry (ICBMS – UMR CNRS 5246),
Université Lyon 1, CNRS
43 Bd du 11 novembre 1918, 69622 Villeurbanne, France
E-mail: Thierry.billard@univ-lyon1.fr
www.FMI-Lyon.fr
[b] CERMEP - in vivo imaging, Groupement Hospitalier Est,
59 Bd Pinel, 69003 Lyon, France
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600197.
Eur. J. Org. Chem. 2016, 1955–1957
1955
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Table 1. Reaction between BB23 and benzyl alcohol.
donors or acceptors led to similar results. The position of the
substituents also does not seem to have significant effects. All-
ylic and propargylic alcohols provided the corresponding tri-
fluoromethyl sulfides but with lower yields than benzylic alco-
hols. Less reactive primary aliphatic alcohols also reacted, but
only medium yields were then observed.
However, the reaction appears to be sensitive to steric hin-
drance, because only medium yield was observed with 1-
phenylethan-1-ol (1k). By doubling the amount of trifluoro-
methylthiolating reagent, good results were then obtained. We
can suppose that steric hindrance disfavors the nucleophilic at-
tack compared to the collapse of the intermediate CF3S– species
into difluorothiophosgene (4). The excess amount of reagent
used contributes to increase the amount of CF3S– anion in the
solution and, thus, favors substitution against the degradation.
This deleterious steric effect is more crucial with very hindered
secondary cyclic alcohol 1l, with which only modest yields were
obtained, even with an excess amount of reagent BB23.
From a mechanistic point of view, in the presence of Bu4NI,
the BB23 reagent forms the CF3SI species presenting a reverse
Entry
Bu4NI [equiv.]
Solvent
T [°C]
2a [%][a]
1
2
3
4
5
6
7
8
2.2
3.3
3.3
3.3
3.3
3.3
3.3
3.3
3.3
3.3
3.3
acetone
acetone
acetone
CH3CN
CH3CN
THF
Diglyme
Toluene
DMF
40
40
60
60
80
60
60
60
60
60
60
80
85
96
64
60
58
53
48
56
50
36
9
10
11
DMSO
H2O
[a] Yields as determined by 19F NMR spectroscopy by using PhOCF3 as an
internal standard.
With optimal conditions in hand (entry 3), various alcohols sulfur polarity,[9] as described previously.[8] This transient spe-
were engaged (Scheme 2). In general, the reaction gave satis- cies can, then, be activated by iodide or fluoride anions to gen-
factory to excellent yields. In the benzylic series, good yields erate the CF3S– anion. This last intermediate partly collapses
were obtained, regardless of the substituents. Indeed, electron into difluorothiophosgene (4) which can, then, form carbono-
fluoridothioate 3, as described previously by Qing et al.[7] The
non-degraded CF3S– anion can substitute compound 3 to pro-
vide the expected trifluoromethylthiolated products
2
(Scheme 3). This intermediate formation of 3 from alcohols has
been confirmed by the identification of the compound 3l in
the reaction medium.
Scheme 3. Mechanistic proposal.
In this mechanism proposal (Scheme 3), only 2.2 equiv. of
Bu4NI should be sufficient, as confirmed by the good results
already obtained under these conditions (Table 1 – entry 1).
However, the better yield observed with 3.3 equiv. of Bu4NI can
be rationalized by the better activation of CF3SI by iodide than
by fluoride, due to a more favorable soft–soft (iodine–iodine)
interaction with iodide than the soft–hard (iodine–fluorine) in-
Scheme 2. Dehydroxytrifluoromethylthiolations of alcohols. Yields shown are
those of isolated products; values in parentheses are yields as determined by
19F NMR spectroscopy by using PhOCF3 as an internal standard.
Eur. J. Org. Chem. 2016, 1955–1957
www.eurjoc.org
1956
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
teraction with fluoride. It is noteworthy that no monofluorin-
ated side-products (R–F) have been detected.
Keywords: Fluorine · Trifluoromethylthiolation · Alcohols ·
Nucleophilic substitution · Dehydroxytrifluoromethylthiolation
Conclusions
[1] a) B. E. Smart, J. Fluorine Chem. 2001, 109, 3–11; b) A. Becker, Inventory
of Industrial Fluoro-biochemicals, Eyrolles, Paris, 1996; c) M. Pagliaro, R.
Ciriminna, J. Mater. Chem. 2005, 15, 4981–4991; d) M. Hird, Chem. Soc.
Rev. 2007, 36, 2070–2095; e) G. Theodoridis in Advances in Fluorine Sci-
ence Vol. 2 (Ed.: A. Tressaud), Elsevier, Amsterdam, 2006, pp. 121–175; f)
T. Fujiwara, D. O'Hagan, J. Fluorine Chem. 2014, 167, 16–29; g) E. P. Gillis,
K. J. Eastman, M. D. Hill, D. J. Donnelly, N. A. Meanwell, J. Med. Chem.
2015, 58, 8315–8359; h) J. Wang, M. Sánchez-Roselló, J. L. Aceña, C.
Del Pozo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok, H. Liu, Chem.
Rev. 2014, 114, 2432–2506; i) Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu,
J. L. Aceña, V. A. Soloshonok, K. Izawa, H. Liu, Chem. Rev. 2016, 116, 422–
518.
[2] a) P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis Reactivity, Applica-
tions, Wiley-VCH, Weinheim, 2013; b) M. G. Campbell, T. Ritter, Chem.
Rev. 2015, 115, 612–633; c) J. Charpentier, N. Früh, A. Togni, Chem. Rev.
2015, 115, 650–682; d) X. Liu, C. Xu, M. Wang, Q. Liu, Chem. Rev. 2015,
115, 683–730; e) C. Ni, M. Hu, J. Hu, Chem. Rev. 2015, 115, 765–825; f)
X.-H. Xu, K. Matsuzaki, N. Shibata, Chem. Rev. 2015, 115, 731–764.
[3] C. Hansch, A. Leo, R. W. Taft, Chem. Rev. 1991, 91, 165–195.
[4] a) A. Leo, C. Hansch, D. Elkins, Chem. Rev. 1971, 71, 525–616; b) C.
Hansch, A. Leo, Substituent constants for correlation analysis in chemistry
and biology, Wiley, New York, 1979; c) C. Hansch, A. Leo, D. H. Hoekman,
Exploring QSAR.: Hydrophobic, Electronic, and Steric Constants, American
Chemical Society, Washington DC, 1995.
Direct dehydroxytrifluoromethylthiolation is a valuable strategy
to obtain, rapidly, various trifluoromethylthiolated compounds,
avoiding the preliminary transformation of the OH group into
a leaving group. The described strategy proposes mild and
metal-free conditions, which offer an advantage over the few
previously reported methods. Furthermore, this work has con-
firmed that trifluoromethanesulfenamide reagents constitute a
very valuable alternative to generate the CF3S– anion and effi-
ciently perform nucleophilic trifluoromethylthiolation without
use of any metals. These results reaffirm the “universal reagent”
status of trifluoromethanesulfenamides and reinforce their posi-
tion in the fluorine chemistry toolbox.
Experimental Section
To a flask equipped with a magnetic stirrer were added alcohol 1
(0.3 mmol), trifluoromethanesulfenamide BB23 (0.60 mmol,
2 equiv.), Bu4NI (1 mmol, 3.3 equiv.), and acetone (1 mL). The reac-
tion mixture was stirred for 20 h at 60 °C. Conversion was checked
by 19F NMR spectroscopy by using PhOCF3 as internal standard. The
reaction mixture was partitioned between pentane and water. The
aqueous layer was extracted with pentane, and the combined or-
ganic layers were washed with brine, dried with Na2SO4, filtered,
and concentrated to dryness (under moderate vacuum, 800 mbar,
at 40 °C). The crude residue was purified by flash chromatography
to afford the desired product.
[5] a) V. N. Boiko, Beilstein J. Org. Chem. 2010, 6, 880–921; b) A. Tlili, T. Billard,
Angew. Chem. Int. Ed. 2013, 52, 6818–6819; Angew. Chem. 2013, 125,
6952–6954; c) F. Toulgoat, S. Alazet, T. Billard, Eur. J. Org. Chem. 2014,
2415–2428; d) J.-H. Lin, Y.-L. Ji, J.-C. Xiao, Curr. Org. Chem. 2015, 19, 1541–
1553; e) K. Zhang, X. Xu, F. Qing, Chin. J. Org. Chem. 2015, 35, 556–569;
f) H. Zheng, Y. Huang, Z. Weng, Tetrahedron Lett. 2016, 57, 1397–1409.
[6] P. Nikolaienko, R. Pluta, M. Rueping, Chem. Eur. J. 2014, 20, 9867–9870.
[7] J.-B. Liu, X.-H. Xu, Z.-H. Chen, F.-L. Qing, Angew. Chem. Int. Ed. 2015, 54,
897–900; Angew. Chem. 2015, 127, 911.
[8] Q. Glenadel, M. Bordy, S. Alazet, A. Tlili, T. Billard, Asian J. Org. Chem.
2016, 5, 428–433.
[9] R. Minkwitz, R. Lekies, Z. Anorg. Allg. Chem. 1985, 527, 161–168.
Acknowledgments
We thank the Centre National de la Recherche Scientifique
(CNRS) and the French Ministry of Research for their financial
support. We also thank the French Fluorine Network for its sup-
port.
Received: February 22, 2016
Published Online: April 5, 2016
Eur. J. Org. Chem. 2016, 1955–1957
www.eurjoc.org
1957
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim