Trifluoromethanesulfinamide from ephedrine: A more efficient trifluoromethylating reagent

Article abstract of DOI:10.1055/s-2004-831322

Nucleophilic trifluoromethylation of non-enolizable and enolizable carbonyl compounds was achieved with the trifluoromethanesulfinamide derived from O-silylated ephedrine. In contrast to the trifluoroacetamide analog, previously described, this reagent is able to trifluoromethylate more acidic enolizable compounds.

Full text of DOI:10.1055/s-2004-831322

LETTER
2119
Trifluoromethanesulfinamide from Ephedrine: A More Efficient Trifluoro-
methylating Reagent
T
rifluorometh
o
l
de as
T
v
rifluorometh
e
ylating
R
ea
i
gent g Roussel,a Thierry Billard,*a Bernard R. Langlois,*a Laurent Saint-Jalmesb
a
Laboratoire SERCOF (UMR CNRS 5181), Université Claude Bernard-Lyon 1, Bât Chevreul, 43 Bd du 11 novembre 1918, 69622
Villeurbanne, France
b
Rhodia Co., Centre de Recherche de Lyon, 85 Av. des Frères Perret, 69192 Saint-Fons Cedex, France
Fax +33(4)72431323; E-mail: billard@univ-lyon1.fr; E-mail: Bernard.langlois@univ-lyon1.fr
Received 7 July 2004
CF3SiMe3,6a–6c CF3I,6e HCF3,6d CF3CHO,6d etc.; see
Scheme 1).
Abstract: Nucleophilic trifluoromethylation of non-enolizable and
enolizable carbonyl compounds was achieved with the trifluo-
romethanesulfinamide derived from O-silylated ephedrine. In con-
trast to the trifluoroacetamide analog, previously described, this
reagent is able to trifluoromethylate more acidic enolizable com-
pounds.
Nevertheless, if the reaction works well with non-enoliz-
able carbonyl compounds and enolizable ketones, 1 is not
able to trifluoromethylate enolizable aldehydes. This dis-
appointing result can be rationalized by considering the
pKa of the substrates. As aldehydes (pKa = 17)8 are more
acidic than ketones (pKa = 19),8 the alcoholate, generated
during the reaction, should be basic enough to deprotonate
aldehydes instead of adding to the trifluoroacetamide
moiety to form the reactive tetrahedral intermediate
(Scheme 2).
Key words: amino alcohols, nucleophilic additions, fluorine, nu-
cleophilic trifluoromethylation, trifluoromethanesulfinamides
The last years have shown a tremendous increase of new
organofluorine compounds1 due to the unique properties
exhibited by such substrates.2 Among them, trifluoro-
methyl-substituted molecules constitute a particular class
because of the specific properties, such as the high
lipophilicity, brought by the CF3 moiety. Recently, such
molecules found outstanding applications in the pharma-
ceutical field (i.e. Efavirenz3 and Celecoxib4). However,
in spite of this growing interest for trifluoromethylated
compounds, methods and reagents for the introduction of
a CF3 group are not still very numerous and always
require new developments.1b,c,2a,5 In recent years, nucleo-
philic trifluoromethylation has emerged as one of the most
powerful strategies. However, this method suffers from
the limited availability of efficient reagents that are able to
overcome the high instability of the CF3 anion.6
Ph
O
Ph
F– cat.
NMe
CF3
1
O
NMe
CF3
O
O
O
O
R1
R1
H
R2
Ph
OH
R2
F3C
HO
NMe
R1
O
CF3
In our quest for new trifluoromethylating reagents, we re-
cently described the synthesis of a new reagent arising
from (1R,2S)-ephedrine and its efficiency for nucleophilic
trifluoromethylation.7 This trifluoroacetamide from O-si-
lylated ephedrine (1) is able to trifluoromethylate carbon-
yl compounds at room temperature and seems to be a
promising alternative to known reagents (e.g.
Scheme 2 Reaction of 1 with enolizable substrates
Such a hypothesis has been confirmed by using diben-
zylketone, which bears very acidic a-hydrogen.8b Indeed,
not any trifluoromethylation of this substrate has been ob-
served.
In previous works,9 we have shown that trifluoromethane-
sulfinamides, easily synthesized from alkaline triflinates
O
Ph
OSiMe3
–
R1
R2
(CF3SO2 M+),10 also constitute efficient reagents for tri-
R2
Me3SiO
NMe
CF3
F3C
fluoromethylation and that the sulfur atom is more elec-
trophilic towards alcoholates than the carbon atom in cor-
responding trifluoroacetamides. Thus, we anticipated that
the alcoholate, generated by desilylation, should react
faster as nucleophile towards the sulfur atom than as base
towards the enolizable substrates.
R1
F– cat.
O
1
Scheme 1 Trifluoromethylation with O-trimethylsilyl-N-trifluoroa-
cetylephedrine
To verify this assertion, the trifluoromethanesulfinamide
2 deriving from ephedrine has been synthesized
(Scheme 3).
SYNLETT 2004, No. 12, pp 2119–2122
Advanced online publication: 26.08.2004
DOI: 10.1055/s-2004-831322; Art ID: G26004ST
© Georg Thieme Verlag Stuttgart · New York
0
1
.1
0
.2
0
0
4

2120
S. Roussel et al.
LETTER
Ph
obtained as a mixture of two diastereomers but with a low
diastereoselectivity (de = 20%).11
Ph
ImSiMe3
NHMe
HO
Me3SiO
NHMe
This new reagent in hands, its reactivity has been com-
pared to that of 1. With benzophenone, benzaldehyde and
acetophenone, similar results were obtained under the
same conditions. To validate the previous hypothesis con-
cerning the higher electrophilicity of the trifluo-
romethanesulfinamide moiety which should avoid the
deprotonation side reaction, 2 was tested with two differ-
ent fluoride catalysts, towards valeraldehyde and dibenzyl
ketone which were not trifluoromethylated by 1 (Table 1).
CF3SO+
DIEA
(2 equiv)
–
2 CF3SO2 + POCl3
Ph
Me3SiO
NMe
O
S
CF3
Table 1 Reactivity of 2
2 (70% / de = 20%)
Entry
Carbonyl compounds Fluoride (10 mol%)/ Yield (%)
Solventa
Scheme 3 Synthesis of trifluoromethanesulfinamide 2
1
2
3
4
Valeraldehyde
Valeraldehyde
Dibenzyl ketone
Dibenzyl ketone
CsF/DME
TBAT/THF
CsF/DME
TBAT/THF
30
0
Because of the acidity of the preformed mixture equiva-
lent to CF3SO+ and the high sensitivity of the O-silylated
ephedrine to acids, the conditions previously described10
have been modified. The preformed CF3SO+ equivalent
was dropped into a solution of the O-silylated ephedrine
(preformed in situ) and two equivalents of Hünig’s base.
Because of the chiral character of the sulfur(IV) atom, 2 is
20
45
a DME: 1,2-dimethoxyethane, TBAT: tetrabutylammonium triphe-
nyldifluorosilicate (Ph3SiF2– +NBu4).
Scheme 4 Reactivity of 2 [Method A: CsF (10 mol%) in DME; Method B: TBAT (10 mol%) in THF]
Synlett 2004, No. 12, 2119–2122 © Thieme Stuttgart · New York

LETTER
Trifluoromethanesulfinamide as Trifluoromethylating Reagent
2121
These results confirm the previous supposition: the com-
petition between the basicity and the nucleophilicity of the
alcoholate generated during the reaction can be modulated
by increasing the electophilicity of the trifluoromethylat-
ed moiety of the reagent. The best results obtained with
ketones in the presence of TBAT are in accordance with
our previous observations.7 Nevertheless, with valeralde-
hyde, the inverted results are more surprising and not yet
very easy to rationalize. However, 2 seems to be more ef-
ficient than 1 for the nucleophilic trifluoromethylation of
acidic compounds. Consequently, its reactivity towards
diverse carbonyl compounds was examined (Scheme 4).
References
(1) (a) Schofield, H. J. Fluorine Chem. 1999, 100, 7.
(b) Hiyama, T. Organofluorine Compounds: Chemistry and
Properties; Springer-Verlag: Berlin, 2000. (c) Chambers,
D. R. Fluorine in Organic Chemistry; Blackwell Publishing:
Abingdon, 2004.
(2) (a) Gross, U.; Rüdiger, S. Organo-Fluorine Compounds, In
Houben-Weyl: Methods of Organic Chemistry, Vol. E10a,
Baasner, B.; Hagemann, H.; Tatlow, J. C., Eds.; Thieme:
Stuttgart, 1999, 18–26. (b) Smart, B. E. J. Fluorine Chem.
2001, 109, 3.
(3) (a) Ren, J.; Milton, J.; Weaver, K. L.; Short, S. A.; Stuart, D.
I.; Stammers, D. K. Structure 2000, 8, 1089. (b) Pedersen,
O. S.; Pedersen, E. B. Synthesis 2000, 479.
Thus, a wide range of non-enolizable and enolizable car-
bonyl compounds (aldehydes, ketones, a,b-unsaturated
substrates) were trifluoromethylated with 2 in the range of
30–90%.12 It can be noticed that dibenzylideneacetone
(delivering 3n) has been trifluoromethylated in good yield
with 2 whereas 1 led only to 36% yield. This compound,
synthesized for the first time with a good isolated yield,13
as well as the bipyridine derivative 3o can constitute inter-
esting fluorinated ligands for organometallic catalysis,
even in the FBS (fluorous biphase system) strategy, and
are under study in our laboratory.
(4) (a) Jackson, L. M.; Hawkey, C. J. Drugs 2000, 59, 1207.
(b) Price, M. L. P.; Jorgensen, W. J. J. Am. Chem. Soc. 2000,
122, 9455.
(5) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48,
6555.
(6) (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97,
757. (b) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56,
7613. (c) Prakash, G. K. S.; Mandal, M. J. Fluorine Chem.
2001, 112, 123. (d) Langlois, B. R.; Billard, T. Synthesis
2003, 185. (e) Aït-Mohand, S.; Takechi, N.; Médebielle, M.;
Dolbier, W. R. Jr. Org. Lett. 2001, 3, 4271.
(7) Joubert J., Roussel S., Christophe C., Billard T., Langlois B.
R., Vidal T.; Angew. Chem. Int. Ed.; 2003, 42, 3133.
(8) (a) Carey, F. A.; Sundberg, R. J. Advanced Organic
Chemistry, 3rd ed.; Plenum Press: New York, 1990.
(b) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(9) (a) Jablonski, L.; Joubert, J.; Billard, T.; Langlois, B. R.
Synlett 2003, 230. (b) Inschauspe, D.; Sortais, J.-B.; Billard,
T.; Langlois, B. R. Synlett 2003, 233.
Although 2 is a chiral reagent wherein the chiral sulfoxide
bears a CF3 group, it did not induce any chirality in the tri-
fluoromethylation of prochiral carbonyl substrates. In the
aim to improve this disappointing result, a diastereomeri-
cally and enantiomerically pure form of 2 has been isolat-
ed by flash chromatography and tested for the
trifluoromethylation of benzaldehyde. Nevertheless, no
enantiomeric excess was observed. The tentative to in-
duce stereoselectivity with this chiral reagent at lower
temperatures (0 °C and –78 °C) or by using chiral fluoride
(N-benzylcinchonium fluoride)14 failed, the reaction ki-
netic becoming very slow (less than 5% of conversion in
2 weeks).
(10) Billard, T.; Greiner, A.; Langlois, B. R. Tetrahedron 1999,
55, 7243.
(11) Synthesis of 2:
[CF3SO+] Solution : A flame-dried three-necked vessel was
successively charged, under nitrogen, with potassium
triflinate (3.5g, 20.0 mmol), CH2Cl2 (60 mL) and POCl3
(935 mL, 10.0 mmol). The reaction medium was stirred at r.t.
for 40 min. In another flame-dried three-necked vessel was
successively charged, under nitrogen, ephedrine (1.65 g,
10.0 mmol) and CH2Cl2 (47 mL). The resulting mixture was
cooled to 0 °C before addition of N-
In conclusion, if the trifluoroacetamide derived from O-si-
lylated ephedrine (1), previously described, constitutes an
efficient and easily available new reagent for nucleophilic
trifluoromethylation, the trifluoromethanesulfinamide de-
rivative (2) seems to be a valuable alternative for certain
substrates which do not give satisfactory yields with 1.
The association of these two ephedrine-based reagents
constitutes an especially promising alternative to other
nucleophilic trifluoromethylating reagents towards carbo-
nyl compounds (enolizable and non-enolizable aldehydes
and ketones) under mild conditions. However, the chiral
character of the reagent 2 does not induce any enantiose-
lectivity in the trifluoromethylation of prochiral carbonyl
substrates. This disappointing result leads to give up the
idea of chiral trifluoromethylation by employing 2.
(trimethylsilyl)imidazole (1.5 mL, 10.2 mmol). The reaction
medium was stirred at 0 °C for 20 min then warmed to r.t.
and kept under stirring for 2 h. After this period,
diisopropylethylamine (3.5 mL, 20.0 mmol) was added and
the mixture was cooled again to 0 °C. Then, the [CF3SO+]
solution was dropped within 1 h. After addition, the
temperature was kept at 0 °C for 10 min then raised to r.t.
After stirring for 24 h, the reaction medium was washed with
6% aq NaHCO3. The organic phase was dried over Na2SO4
and evaporated in vacuo. The crude residue was purified by
chromatography over silica gel.
Compound 2: 1H NMR (300 MHz, CDCl3): d = 7.23–7.35
(massif, 5 H), 4.85 (d, 0.6 H, J = 3.9 Hz), 4.68 (d, 0.4 H,
J = 5.7 Hz), 3.70 (dq, 0.4 H, J = 5.7 Hz, J = 7.0 Hz), 3.58
(dq, 0.6 H, J = 3.9 Hz, J = 7.0 Hz), 2.84 (q, 1.8 H, J = 1.4
Hz), 2.70 (q, 1.2 H, J = 1.8 Hz), 1.32 (d, 1.2 H, J = 7.0 Hz),
1.22 (d, 1.8 H, J = 7.0 Hz), 0.06 (s, 5.4 H), 0.04 (s, 3.6 H).
13C NMR (75 MHz, CDCl3): d = 141.8, 141.4, 128.7, 128.6,
128.4, 128.1, 127.0, 126.8, 124.5 (q, J = 343.1 Hz), 124.5 (q,
J = 341.6 Hz), 77.9, 77.0, 64.5 (br s), 62.8, 29.1, 26.6, 13.9,
13.2, 0.34, 0.32. 19F NMR (282 MHz, CDCl3): d = –75.03 (s,
0.6 F), –75.27 (s, 0.4 H). Anal. Calcd for C14H22F3NO2SSi:
Acknowledgment
We thank the CNRS and the Rhodia Co. for financial support and
the Rhodia Co. for a generous gift of potassium triflinate.
Synlett 2004, No. 12, 2119–2122 © Thieme Stuttgart · New York

2122
S. Roussel et al.
LETTER
C, 47.57; H, 6.27; N, 3.96; S, 9.07; Si, 7.95. Found: C, 47.69;
H, 6.56; N, 3.91; S, 9.40; Si, 8.20.
(12) Trifluoromethylation with 2 and CsF:
(TBAT, 54 mg, 0.1 equiv) in THF (0.5 mL) was dropped (in
15 min) to a stirred solution of 2 (1 mmol) and the
electrophile (1 mmol) in THF (1 mL). After 6 h, the crude
mixture was desilylated with 1 M TBAF in THF (1 mL) for
1 h, then extracted with pentane and brine. The organic
phase was dried over Na2SO4 and the solvent evaporated in
vacuo. The crude products were purified by flash
chromatography over silica gel.
To a solution of 2 (1 mmol) and the electrophile (1 mmol) in
DME (1 mL) was added 15 mg of dried CsF (0.1 equiv).
After 24 h, the crude product was desilylated with 1 M
TBAF in THF (1 mL) for 1 h and extracted with pentane and
brine. The organic phase was dried over Na2SO4 and the
solvent evaporated in vacuo. The crude products were
purified by chromatography over silica gel.
(13) For other syntheses see: (a) Ref.7 (b) Large, S.; Roques, N.;
Langlois, B. R. J. Org. Chem. 2000, 65, 8848.
Trifluoromethylation with 2 and TBAT:
A solution of tetrabutylammonium triphenyldifluorosilicate
(14) Iseki, K.; Nagai, T.; Kobayashi, V. Tetrahedron Lett. 1994,
35, 3137.
Synlett 2004, No. 12, 2119–2122 © Thieme Stuttgart · New York