Synthesis of trifluoromethanesulfinamidines and -sulfanylamides

Article abstract of DOI:10.1021/jo8018544

(Chemical Equation Presented) Fluorinated moieties constitute important substituents used in many applications to modify the properties of molecules. The action of DAST onto Ruppert's reagent yields to a not isolable intermediate that can then react with various primary amines to give trifluoromethanesulfinamidines and trifluoromethane-sulfanylamides. Such compounds were unknown until now and constitute interesting new families of fluorinated molecules.

Full text of DOI:10.1021/jo8018544

Synthesis of Trifluoromethanesulfinamidines and -sulfanylamides
Aure´lien Ferry,† Thierry Billard,*,† Bernard R. Langlois,*,† and Eric Bacque´‡
ICBMS, UniVersite de Lyon, UniVersite Lyon 1, CNRS, Laboratoire SERCOF,
43 bouleVard du 11 noVembre 1918, Villeurbanne, F-69622 France, and Sanofi-AVentis S.A.,
136 Quai Jules Guesde, BP 14, 94403 Vitry-Sur-Seine Cedex, France
billard@uniV-lyon1.fr
ReceiVed August 27, 2008
Fluorinated moieties constitute important substituents used in many applications to modify the properties
of molecules. The action of DAST onto Ruppert’s reagent yields to a not isolable intermediate that can
then react with various primary amines to give trifluoromethanesulfinamidines and trifluoromethane-
sulfanylamides. Such compounds were unknown until now and constitute interesting new families of
fluorinated molecules.
Introduction
These past years, heteroatomic fluorinated groups have
attracted a growing interest. The most popular representative
of such moieties is the perfluoroalkylsulfonylimidyl group,
which has found applications as electrolytes for lithium batteries,
as ionic liquids,5 as Lewis acid catalysts,6 and as intermediates
for bioactive molecules.7
Surprisingly, among these nitrogen- and sulfur-containing
groups, trifluoromethanesulfinamidines 1 have never been
described and studied until now.
In our quest for new fluorinated groups exhibiting specific
physicochemical properties for biological applications or materi-
als, we focused our interest on the synthesis of such trifluo-
romethanesulfinamidines.
Fluorine occupies a specific place among all elements of the
periodic classification because of its high electronegativity and
its specific properties. This singular nature of the fluorine atom,
combined with the unique physical and chemical properties that
fluorine imparts to compounds that contain it, explains the
importance of organofluorine chemistry.1 Indeed, the specific
physicochemical properties of fluorinated organic compounds
are of huge interest in a wide range of applications.1,2
Consequently, organofluorine chemistry has been steadily grow-
ing to become, today, a field of great importance with a
distinctive role in highly diverse technological developments
(fluoropolymers, pharmaceutical and agrochemical products,
materials science, etc.).3,4
Results and Discussion
† ICBMS.
In our retrosynthetic strategy, the use of commercially
available, easy to handle reagents was the sine qua non
condition.
Such considerations led us to envisage the preparation of 1a
starting from Ruppert’s reagent (4a) and DAST derivatives (3),
via a trifluoromethyl difluorosulfur intermediate (2a) (Scheme
1). To our knowledge, preparation of the later type of com-
pounds has only been reported once:8 compound 2 (R1 ) R2 )
‡ Sanofi-Aventis S.A.
(1) (a) Groꢀ, U. ; Ru¨diger, S. In Organo-Fluorine Compounds; Baasner, B.,
Hagemann, H., Tatlow, J. C., Eds.; Thieme: Stuttgart, 1999; Vol. E10a, Houben-
Weyl: Methods of Organic Chemistry; pp 18-26. (b) Smart, B. E. J. Fluorine
Chem. 2001, 109, 3–11. (c) Hiyama, T. Organofluorine Compounds: Chemistry
and Properties; Springer-Verlag: Berlin, 2000. (d) Dunitz, J. D. ChemBioChem
2004, 5, 614–621. (e) Biffinger, J. C.; Kim, H. W.; DiMagno, S. G. ChemBio-
Chem 2004, 5, 622–627.
(2) (a) Filler, R.; Kobayashi, Y.; Yagulpolskii, L. M. Organofluorine
Compounds in Medicinal Chemistry and Biomedical Applications; Elsevier:
Amsterdam, 1993. (b) Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine
Chemistry: Principles and Commercial Applications; Plenum Press: New York,
1994. (c) Hiyama, T. Organofluorine Compounds: Chemistry and Properties;
Springer-Verlag: Berlin, 2000; Chapter 5, pp 137-182. (d) Becker, A. InVentory
of Industrial Fluoro-Biochemicals; Eyrolles: Paris, 1996.
(5) Bonhote, P.; Dias, A.-P.; Papageorgiou, N.; Kalyanasundaram, K.; Gratzel,
M. Inorg. Chem. 1996, 35, 1168–1178.
(6) Mikami, K.; Kotera, O.; Motoyama, Y.; Sakaguchi, H.; Maruta, M. Synlett
1996, 171–172.
(3) Dolbier, W. R., Jr. J. Fluorine Chem. 2005, 126, 157–163.
(4) Schofield, H. J. Fluorine Chem. 1999, 100, 7–11.
(7) Vij, A.; Kirschmeier, R. L.; Schreeve, J. M.; Verma, R. D. Coord. Chem.
ReV. 1997, 158, 413–432.
9362 J. Org. Chem. 2008, 73, 9362–9365
10.1021/jo8018544 CCC: $40.75 2008 American Chemical Society
Published on Web 11/07/2008

Trifluoromethanesulfinamidines and -sulfanylamides
SCHEME 1. Retrosynthetic Scheme of Trifluoromethane-
sulfinamidines
SCHEME 3. Synthesis of 1 and 5a
SCHEME 2. Expected Formation of 2a
a Crude yield determined by 19F NMR with internal standard.
SCHEME 4. Mechanism of Formation of 1 and 5
Me) was prepared very inconveniently by reaction of CF3SF3
and TMS-NMe2 between -196 and -78 °C.
Our rationale came from a work previously reported by one
of us and featuring the easy transformation of a naturally
occurring alcohol ROH (R ) pristinamycin II) into R-Nu upon
reaction with DAST and Bu4N+Nu- (Nu ) Hal, SCN, ONO,
etc.).9 In these reactions, involvement of the new species
Et2NSF2-Nu was strongly suspected. On the basis of these
results, we envisioned that 2a (R1 ) R2 ) Et) would be readily
formed by mixing 4a with DAST (3a). We supposed that an
equilibrium between the covalent and the ionic forms of DAST
could take place and generate a fluoride anion, able to activate
4a (Scheme 2).
SCHEME 5. Transformation of 1 into 5 in Acidic
Conditions
However, the first attempts to obtain 2a led us to an
unchanged mixture of 3a and 4a. Examination of the 19F NMR
spectra of the corresponding DAST solutions did not show any
trace of fluoride, which precluded the existence of the expected
equilibrium. In order to activate DAST and favor this equilib-
rium, various additives were tried. Surprisingly, when DAST
was mixed with tertiary amines (Et3N, DIEA, pyridine), the
formation of a fluoride anion was observed by 19F NMR, thus
suggesting the occurrence of the expected equilibrium. This was
further confirmed by the quantitative formation of 2a when
adding 4a to this mixture. Such activation of DAST by a tertiary
amine could be rationalized by the nucleophilic displacement
onto the sulfur atom of fluoride by amine.
Nevertheless, 2a was not stable enough to be isolated. It was
very sensitive to hydrolysis and readily led to the corresponding
trifluoromethanesulfinamide (CF3S(O)NEt2). Its utilization in situ
was therefore envisaged, by adding a primary amine following
its formation.
This reaction was initially tested with aniline and 4-nitro-
aniline (Scheme 3). In both cases, after 4 h of reaction, 19F NMR
monitoring showed the formation of two compounds. In the case
of aniline, the ratio between these two products was inverted,
after 24 h. The formed compounds were identified as the
expected trifluoromethanesulfinamidines (1) and the trifluo-
romethanesulfanylamides (5). Product 1aaa turned out to be
too unstable under the aqueous conditions of the workup to be
isolated. Its identity was only ascertained on the basis of the
19F NMR spectrum of the crude reaction mixture by analogy
between its NMR shift and that of its congeners.
Considering these results, we reasonably supposed that
sulfanylamides (5) stemmed from the in situ transformation of
sulfinamidines (1). Since product 1aab, arising from p-NO2
aniline, underwent far more slowly the same transformation and
because of the acidity of the reaction mixture, the hypothesis
of the protonation of 1 was postulated as the starting point of
the subsequent transformation into 5. Such hypothesis was in
accordance with the previously described transformation of
sulfimides into sulfanylamides under acidic conditions.10 Con-
sequently, a mechanism is proposed in Scheme 4.
In our mechanism (Scheme 4), the intermediate resulting from
the reaction of primary amine onto 2a could eliminate HF, which
is neutralized by the DIEA, to generate the second intermediate
A. This one would then eliminate a second equivalent of HF to
yield trifluoromethanesulfanylamide 5. This second equivalent
of HF could react with 5 to regenerate the intermediate A.
(8) Sprenger, G. H.; Cowley, A. H. J. Fluorine Chem. 1976, 7, 333–346.
(9) (a) Achard, D.; Bacque´, E.; Barrie`re, J. C.; Bouquerel, J.; Desmazeau,
P.; Grisoni, S.; Leconte, J. P.; Ribeill, Y.; Ronan, B. WO 2001002427. (b)
Bacque´, E.; Barrie`re, J. C.; Berthaud, N. Curr. Med. Chem.: Anti-Infect. Agents
2005, 4, 185–217.
(10) Claus, P. K.; Silbernagel, W.; Franek, W.; Rieder, W. Monatsh. Chem.
1985, 116, 841–850.
J. Org. Chem. Vol. 73, No. 23, 2008 9363

Ferry et al.
SCHEME 7. Other Fluorinated Sulfinamidines (1)a
SCHEME 6. Trifluoromethanesulfinamidines (1)a
a Isolated yield. In parentheses: crude yield determined by 19F NMR with
internal standard.
SCHEME 8. One-Pot Synthesis of 5a
a Isolated yield. In parentheses: crude yield determined by 19F NMR with
internal standard.
Because of the high electron-withdrawing character of NO2
moiety, the protonation of the imino nitrogen in 1aab should
be disfavored by inductive effect, explaining the greater stability
of 1aab compared to that of 1aaa. The intermediate A could
also undergo an intramolecular rearrangement, which would
yield trifluoromethanesulfinamidine 1 with elimination of HF
and imine 6.
In order to substantiate this mechanism, we first checked the
effective possibility to transform isolated 5 into 1 under acidic
conditions.
With 1.2 equiv of trifluoroacetic acid, 1aab has been rapidly
and quantitatively transformed into 5ab, at room temperature,
confirming the role of an acidic catalysis in this transformation.
To confirm that, within the reaction mixture, released HF was
sufficient to cause the formation of 5, the same reaction was
conducted with 2 equiv of DIEA in order to neutralize all acidic
species. After 4 h of reaction, starting from aniline, 1aaa was
the only formed product and no trace of 5aa could be detected.
To assert unambiguously the proposed mechanism, the acidic
transformation of isolated 1aab was conducted in CD2Cl2 and
a Isolated yield. In parentheses: crude yield determined by 19F NMR with
internal standard.
that selected sulfonamides and carbamates afforded in good
yields isolable trifluoromethanesulfinamidines (see 1aaf, 1aag,
and 1aah).
Similar products were also synthesized following reaction of
morpholino-DAST with 4a or that of DAST with pentafluoro-
ethylsilane (Scheme 7).
Since our methodology afforded very easily trifluoromethane-
sulfinamides (5), we next focused our interest onto these
products. Only a few representatives of this family have been
previously described in the literature and reported to have
agrochemical applications.11 However, their preparations from
1
monitored by H NMR. Formation of imine 6 was detected,
and after hydrolysis with D2O, disappearance of the character-
istic signals of 6 and apparition of acetaldehyde confirmed this
observation. A similar monitoring of the complete reaction, from
the point where aniline is added to 2a, was also realized, and
the same observations (in particular the formation of acetalde-
hyde) were noted.
13
very volatile and toxic CF3SCl12 or CF3SSCF3 have limited
their production. On the other hand, nonfluorinated analogues
are well documented and display various interesting biological
With such a methodology in hand, various trifluoromethane-
sulfinamidines (1) were then synthesized (Scheme 6). Only those
trifluoromethanesulfinamidines arising from amines bearing
electron-withdrawing groups could be isolated. In the other
cases, even if the trifluoromethanesulfinamidines could be
detected in the NMR spectra of the crude mixtures, they were
too unstable to be isolated. Also noteworthy was the observation
(11) For example: (a) Schallner, O.; Schwarz, H.-G.; Hoischen, D.; Linker,
K.-H.; Drewes, M. W.; Dahmen, P.; Feucht, D.; Pontzen, R. (Bayer AG) WO
2002006277, 2002; Chem. Abstr. 2002, 136, 118455. (b) Maurer, F.; Gayer, H.;
Gerdes, P.; Heinemann, U.; Krueger, B.-W.; Markert, R.; Stenzel, K.; Haenssler,
G.; Mauler-Machnik, A. (Bayer AG) DE 19925780, 2000; Chem. Abstr. 2000,
132, 166019.
(12) Kolasa, A.; Lieb, M. J. Fluorine Chem. 1995, 70, 45–47.
(13) Peach, M. E. Can. J. Chem. 1967, 45, 429–432.
9364 J. Org. Chem. Vol. 73, No. 23, 2008

Trifluoromethanesulfinamidines and -sulfanylamides
SCHEME 9. Synthesis of 5 from 1 under Acidic
Conditionsa
Conclusion
In conclusion, we have described a method to prepare, very
easily, two new families of fluorinated compounds, namely, the
trifluoromethanesulfinamidines (1) and the trifluoromethane-
sulfanylamides (5). The interest of our methodology lies in its
easy implementation that does not require any expertise in
fluorine chemistry. These two families of compounds should
be of great interest in various fields of applications, from
conception of materials to drug design. Exploration of the
reactivity and of the potential applications of compounds 1 and
5 are under studies in our laboratory and will be published in
due course.
Experimental Section
Typical Procedure. Synthesis of N,N-Diethyl-1,1,1-trifluoro-N′-
(4-nitrophenyl)methane Sulfinimidamide 1aab. A flame-dried
double-necked vessel was successively charged, under nitrogen,
with diisopropylethylamine (14 mL, 80 mmol) and anhydrous
dichloromethane (80 mL). The resulting mixture was cooled to -20
°C before addition of diethylaminosulfurtrifluoride (5.5 mL, 44
mmol), followed by the addition of trimethylsilyltrifluoromethane
(5.9 mL, 40 mmol) or trimethylsilylpentafluoroethane (7.7 mL, 40
mmol) in 20 min intervals. After 1 h under stirring at -20 °C,
aniline (1equiv) was added at 0 °C. The reaction medium was then
warmed to room temperature and kept under stirring for a further
4 h. The reaction medium was then washed with 6% aqueous
NaHCO3. The organic phase was dried over Na2SO4 and evaporated
in vacuo. The crude residue was simply washed with pentane or
purified by chromatography over silica gel (eluent ) pentane/
acetone 30/1) in the presence of 0.5% of Et3N to afford the
corresponding 1aab: orange solid, mp 40-41 °C. 1H NMR: δ 7.97
(m, 2H), 6.78 (m, 2H), 3.31 (q, 3J(H,H) ) 7.3, 4H), 1.11 (t, 3J(H,H)
a Isolated yields.
SCHEME 10. Other Fluorinated Sulfanylamides 5 with
Various Fluorinated Moieties
4
) 7.2, 6H). 13C NMR: δ 123.8 (q, J(C,F) ) 1.1), 140.9, 125.7,
1
123.8 (q, J(C,F) ) 329), 119.7, 41.0, 13.8. 19F NMR: δ -70.85.
Anal. Calcd for C11H14F3N3O2S: C 42.71, H 4.56, N 13.59, S 10.37.
Found: C 42.82, H 4.63, N 13.87, S 10.14.
Typical procedure: Synthesis of N-[(Trifluoromethyl)thio]-
aniline 5aa. A flame-dried double-necked vessel was successively
charged, under nitrogen, with diisopropylethylamine (7 mL, 40
mmol) and anhydrous dichloromethane (80 mL). The resulting
mixture was cooled to -20 °C before addition of diethylamino-
sulfurtrifluoride (5.5 mL, 44 mmol), followed by the addition of
trimethylsilyltrifluoromethane (5.9 mL, 40 mmol) or trimethylsi-
lylpentafluoroethane (7.7 mL, 40 mmol) in 20 min intervals. After
1 h under stirring at -20 °C, aniline (1equiv) was added at 0 °C.
The reaction medium was then cooled to room temperature and
kept under stirring overnight. After this period, the reaction medium
was washed with distilled water. The organic phase was dried over
Na2SO4 and evaporated in vacuo. The crude residue was purified
by chromatography over silica gel to afford the corresponding
properties,14 suggesting that our compounds 5 might also find
interesting applications, in particular, in the field of life science.
Trifluoromethanesulfanylamides (5) were obtained following
two procedures. When the intermediary sulfinamidines 1 were
unstable, products 5 were directly isolated following reaction
of 2 with primary amines (Scheme 8).
In the case of the stable sulfinamidines, compounds 5,
including the N-sulfonyl and N-benzyloxycarbonyl analogues,
were synthesized by acidic transformation of the corresponding
purified 1 (Scheme 9).
Whereas the formation of 5ab, 5aj, and 5ao required only
1.2 equiv of TFA and 1 h at room temperature, more drastic
conditions were needed for 5af and 5ah (3.5 equiv TFA/50 °C/
24 h), certainly because of the higher deactivation of the nitrogen
atom. Moreover, 1aag could never be transformed probably
because of the incapacity of its imino nitrogen to be protonated.
Related sulfanylamides, bearing different fluorinated moieties
RF, such as CF2CF3, CF2SPh, and CF2-2-benzoxazolyl, were
also synthesized by the same methodology, starting from RF-
TMS and DAST (Scheme 10).
1
sulfanylamides 5aa: yellow oil. H NMR: δ 7.35 (m, 2H), 7.15
(m, 2H), 7.06 (m, 1H), 5.09 (NH). 13C NMR: δ 145.5, 129.8 (q,
1J(C,F) ) 315), 129.7, 122.3, 115.6. 19F NMR: δ -53.33. Anal.
Calcd for C7H6F3NS: C 43.52, H 3.13, N 7.25 S 16.60. Found: C
43.55, H 3.08, N 7.36, S 16.24
Acknowledgment. We thank the CNRS and the Sanofi-
Aventis Co. for financial support.
Supporting Information Available: Experimental proce-
dures, full spectral data for all new compounds, and copies of
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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(b) Turos, E.; Coates, C.; Shim, J.-Y.; Wang, Y.; Leslie, J. M.; Long, T. E.;
Reddy, G. S. K.; Ortiz, A.; Culbreath, M.; Dickey, S.; Lim, D. V.; Alonso, E.;
Gonzalez, J. Bioorg. Med. Chem. 2005, 13, 6289–6308. (c) Dou, Q. P.; Turos,
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