Trifluoroacetamides from amino alcohols as nucleophilic trifluoromethylating reagents

Article abstract of DOI:10.1002/anie.200351301

Both non-enolizable and enolizable carbonyl compounds underwent nucleophilic trifluoromethylation by a new family of cheap and efficient trifluoroacetamide reagents derived from vic-amino alcohols (see picture). From an ecological and an economic viewpoint these represent a promising alternative to other known trifluoromethylation reagents.

Full text of DOI:10.1002/anie.200351301

Angewandte
Chemie
Trifluoromethylation
Trifluoroacetamides from Amino Alcohols as
Nucleophilic Trifluoromethylating Reagents**
JØrôme Joubert, Solveig Roussel, Carole Christophe,
Thierry Billard,* Bernard R. Langlois,* and
Thierry Vidal
In memory of Odile Miani
Fluorinated compounds exhibit unique properties,[1] which
are of huge interest in a wide range of applications.[2]
Consequently, the number of new organofluorine products
that appear each year is growing steadily.[3] Trifluoromethyl-
substituted compounds constitute a particular class with
specific properties, such as the high lipophilicity provided by
this group. Thus, such molecules find pharmaceutical appli-
cations,[2] as illustrated by two drugs recently introduced for
[*] Dr. T. Billard, Dr. B. R. Langlois, J. Joubert, S. Roussel, C. Christophe
Laboratoire SERCOF, UniversitØ Claude Bernard Lyon 1
Bât. Chevreul – 43 Bd du 11 Novembre 1918
69622 Villeurbanne (France)
Fax: (+33)472431323
E-mail: billard@univ-lyon1.fr
bernard.langlois@univ-lyon1.fr
Dr. T. Vidal
Rhodia Co., Centre de Recherche de Lyon
85, Av. des Fr›res Perret, 69192 Saint-Fons Cedex (France)
[**] We thank the CNRS and Rhodia Co. for financial support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2003, 42, 3133 – 3136
DOI: 10.1002/anie.200351301
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3133

Communications
the treatment of human diseases, efavirenz[4] (anti-HIV) and
celecoxib[5] (antiarthritic).
In the last two decades, many reliable methods have been
reported for the introduction of a CF3 group into organic
compounds,[6] and in recent years, anionic trifluoromethyla-
tion has emerged as one of the most powerful strategies.
However, these anionic methods suffer from the limited
availability of efficient reagents that are able to overcome the
high instability of the CF3 anion, which is known to decom-
pose rapidly and almost irreversibly into a fluoride anion and
difluorocarbene.
Scheme 3. N-trifluoroacetyl O-trimethylsilyl vic-amino alcohols.
The most popular reagent for these anionic methods is
currently (trifluoromethyl)trimethylsilane (CF3SiMe3, Rup-
pert–Prakash reagent), which is both very powerful for
synthetic applications and commercially available.[7] How-
ever, its preparation from CF3Br, the industrial production of
which is now restricted for ecological reasons,[8] constitutes a
drawback for large-scale applications.
studies.[9a–b] As models for different types of carbonyl electro-
philes, we chose benzophenone (for non-enolizable sub-
strates), benzaldehyde (for aldehyde substrates), and aceto-
phenone (for enolizable substrates). The results are summar-
ized in Table 1.
In our quest for new trifluoromethylating reagents, we
have recently shown that some hemiaminals of trifluoroacet-
aldehyde are useful tools for the nucleophilic trifluorome-
thylation of non-enolizable carbonyl compounds.[9] More
recently, we demonstrated that trifluoroacetamides,[10a] tri-
fluoromethanesulfinamides,[10b] and a,a,a-trifluoroacetophe-
none[10c] also behave as efficient trifluoromethylating reagents
under the action of potassium tert-butoxide (Scheme 1).
Table 1: Trifluoromethylation of benzophenone, benzaldehyde, and
acetophenone with trifluoroacetamides 1.
Entry
1
T [8C]
Yield [%] (t [h])
R=Ph, R’=H
(2b)
R=R’=Ph
(2a)
R=Ph, R’=CH3
(2c)
1
2
3
4
5
6
7
8
9
a
a
a
b
b
c
c
f
[a]
50
80
50
80
50
80
50
80
[a]
no transfer[b]
59 (24)
60 (5)
50 (30)
50 (24)
44 (24)
54 (24)
71 (6)
no transfer[c]
43 (24)
21 (108)
41 (24)
52 (24)
28 (24)
26 (24)
Scheme 1. Trifluoromethylation with trifluoroacetic acid derivatives.
56 (24)
85 (6)
Although trifluoroacetic acid derivatives are economi-
cally and ecologically friendly trifluoromethylating agents,
the presence of a strong base in these reactions precludes the
use of enolizable substrates. To circumvent this drawback, we
envisaged a strategy in which slow delivery of the alcoholate
would favor nucleophilic attack over deprotonation by this
species. This led us to study the reactivity of trifluoroaceta-
mides derived from O-silylated vic-amino alcohols. These
compounds were easily prepared from commercially avail-
able amino alcohols (Scheme 2).
f
f
74 (2)
76 (24)
10
89 (24)
58 (120)
[a] Room temperature. [b] 3 days. [c] 24 h.
Table 1 shows that the substitution at the nitrogen atom
did not greatly influence the ability of these new reagents to
transfer their CF3 group (entries 1–5). In contrast, the
influence of substituents R1 and R2 was more important.
Indeed, when no substituent was present (R1 = R2 = H), or
when only one substituent was present, and in the a position
A variety of reagents were synthesized by this procedure,
as shown in Scheme 3 (overall yields are given for the purified
compounds). To access their potential as trifluoromethylating relative to the oxygen atom, trifluoromethylation occurred
reagents, 1a–f were desilylated with CsF in 1,2-dimethoxy-
ethane (DME), according to the method used in our previous
under heating at 808C (Table 1, entries 3, 5, and 7). However,
when a substituent was present in the a position relative to
the nitrogen atom (and R1 = H), no CF3 transfer was
observed, and instead migration of the trifluoroacetyl group
from the nitrogen atom to the oxygen atom occurred
(Scheme 4). On the other hand, when both adjacent carbon
centers were substituted, as in the case of 1 f, trifluoromethyl-
ation proceeded even at room temperature (Table 1,
entries 8–10).
Thus, this new family of reagents allowed the trifluoro-
methylation of both non-enolizable and enolizable carbonyl
Scheme 2. Synthesis of N-trifluoroacetyl O-trimethylsilyl vic-amino alcohols.
ImSiMe3 =N-(trimethylsilyl)imidazole.
3134
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 3133 – 3136

Angewandte
Chemie
Scheme 4. Trifluoroacetyl migration with 1d and 1e.
compounds. Compound 1 f, derived from cheap and commer-
cially available ephedrine, was the best candidate, as it
promoted the formation of the desired products in good yields
even at room temperature. Furthermore, 1 f is a stable white
solid that can be stored for long periods of time, whereas 1a–c
have a shelf life of less than 48 h. The long reaction time of 1 f
with acetophenone led us to use soluble tetrabutylammonium
triphenyldifluorosilicate (TBAT)[11] in THF instead of CsF in
DME as the desilylating agent. With this reagent a 60% yield
of 2c was observed after 6 h, in contrast to the 5 days required
with CsF/DME (Table 1, entry 10).
The mechanism shown in Scheme 5 could be proposed, by
analogy with previous work.[7a,9a] This proposal was supported
by the isolation and characterization of oxazolidinones 4 from
Scheme 6. Reactivity of 1 f.
Thus, a wide range of non-enolizable and enolizable
carbonyl compounds (aldehydes, ketones, a,b-unsaturated
ketones) were trifluoromethylated with 1 f in satisfactory
yields. Although 1 f is a chiral reagent, it did not induce any
chirality in the trifluoromethylation of prochiral carbonyl
substrates. No enantiomeric excess was observed for any of
the products.
In conclusion, we have demonstrated that trifluoroaceta-
mides derived from O-silylated vic-amino alcohols constitute
a new class of nucleophilic trifluoromethylating reagents. The
trifluoroacetamide derived from ephedrine is especially
promising, as it trifluoromethylates both enolizable and
non-enolizable carbonyl compounds in satisfying yields
under mild conditions. To our knowledge, this is the first
reagent that is likely to provide competition for the Ruppert–
Prakash reagent. Our new challenge is to design similar
reagents for enantioselective trifluoromethylation. These
studies are in progress in our laboratory.
Scheme 5. Mechanism of the trifluoromethylation with 1.
the reaction. Nevertheless, studies to better understand the
role of the various substituents are in progress in our
laboratory.
From these preliminary results with simple substrates,
compound 1 f appeared to be the most powerful trifluorome-
thylating reagent of those studied. Consequently, its reactivity
toward diverse carbonyl compounds was examined
(Scheme 6).
Experimental Section
Typical procedure: 1 f: A flame-dried three-necked vessel was
successively charged with ephedrine (6.6 g, 40 mmol) and dichloro-
methane (40 mL) under nitrogen. The resulting mixture was cooled to
08C, then N-(trimethylsilyl)imidazole (6 mL, 41 mmol) was added.
The reaction mixture was stirred at 08C for 40 min, then warmed to
Angew. Chem. Int. Ed. 2003, 42, 3133 – 3136
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3135

Communications
room temperature and stirred for a further 2 h. After this period,
Langlois, Synlett 2003, 2, 233 – 235; c) L. Jablonski, T. Billard,
B. R. Langlois, Tetrahedron Lett. 2003, 44, 1055 – 1057.
[11] C. J. Handy, Y.-F. Lam, P. DeShong, J. Org. Chem. 2000, 65,
3542 – 3543.
diisopropylethylamine (7.2 mL, 41.4 mmol) was added and the
mixture was cooled again to 08C. A solution of trifluoroacetic
anhydride (5.6 mL, 40 mmol) in CH2Cl2 (16 mL) was then added
dropwise over 1.5 h, after which the mixture was stirred at 08C for
10 min, then at room temperature for 4 h. The reaction mixture was
then washed with 6% aqueous NaHCO3 and the organic phase was
dried over Na2SO4 and concentrated in vacuo. The crude residue was
purified by chromatography over silica gel.
Typical trifluoromethylation procedure: A solution of tetrabutyl-
ammonium triphenyldifluorosilicate (TBAT; 54 mg, 0.1 equiv) in
THF (0.5 mL) was added dropwise over 15 min to a stirred solution of
1 f (1 mmol) and the electrophile (1 mmol) in THF (1 mL). After 6 h,
the crude product was desilylated by treatment with TBAF (1m in
THF, 1 mL) for 1 h, then the mixture was extracted with pentane and
brine. The organic phase was dried over Na2SO4 and the solvent was
evaporated in vacuo. The crude product was purified by flash
chromatography over silica gel.
Received: February 28, 2003 [Z51301]
Keywords: alcohols · amino alcohols · fluorine · nucleophilic
.
addition · trifluoromethylation
[1] a) “Organo-Fluorine Compounds”: U. Groß, S. Rüdiger, Meth-
ods Org. Chem. (Houben-Weyl) 4th ed. 1952–, Vol. E10a, pp. 18–
26; b) B. E. Smart, J. Fluorine Chem. 2001, 109, 3 – 11.
[2] a) R. Filler, Y. Kobayashi, L. M. Yagulpolskii, Organofluorine
Compounds in Medicinal Chemistry and Biomedical Applica-
tions, Elsevier, Amsterdam, 1993; b) R. E. Banks, B. E. Smart,
J. C. Tatlow, Organofluorine Chemistry: Principles and Com-
mercial Applications, Plenum, New York, 1994; c) J. T. Welch, S.
Eswarakrishnan, Fluorine in Bioorganic Chemistry, Wiley, New
York, 1991; d) Fluorine-containing Amino Acids. Synthesis and
Properties (Eds.: V. P. Kukhar, V. A. Soloshonok), Wiley, Chi-
chester, 1995; e) T. Hiyama, Organofluorine Compounds:
Chemistry and Properties, Springer, Berlin, 2000, chap. 5,
pp. 137–182; f) A. Becker, Inventory of Industrial Fluoro-Bio-
chemicals, Eyrolles, Paris, 1996.
[3] H. Schofield, J. Fluorine Chem. 1999, 100, 7 – 11.
[4] a) J. Ren, J. Milton, K. L. Weaver, S. A. Short, D. I. Stuart, D. K.
Stammers, Structure 2000, 8, 1089 – 1094; b) O. S. Pedersen, E. B.
Pedersen, Synthesis 2000, 479 – 495.
[5] a) L. M. Jackson, C. J. Hawkey, Drugs 2000, 59, 1207 – 1216;
b) M. L. P. Price, W. J. Jorgensen, J. Am. Chem. Soc. 2000, 122,
9455 – 9466.
[6] M. A. McClinton, D. A. McClinton, Tetrahedron 1992, 48, 6555 –
6666.
[7] a) G. K. S. Prakash, A. K. Yudin, Chem. Rev. 1997, 97, 757 – 786;
b) R. P. Singh, J. M. Shreeve, Tetrahedron 2000, 56, 7613 – 7632;
c) G. K. S. Prakash, M. Mandal, J. Fluorine Chem. 2001, 112,
123 – 131; d) T. Billard, B. R. Langlois, Tetrahedron Lett. 1996,
37, 6865 – 6868; e) T. Billard, S. Large, B. R. Langlois, Tetrahe-
dron Lett. 1997, 38, 65 – 68.
[8] a) M. Hudlicky, A. E. Pavlath, Chemistry of Organic Fluorine
Compounds II. A Critical Review, ACS Monograph 187,
American Chemical Society, Washington, DC, 1995, pp. 1092 –
1100; b) B. D. Key, R. D. Howell, C. S. Criddle, Environ. Sci.
Technol. 1997, 31, 2445 – 2454.
[9] a) T. Billard, S. Bruns, B. R. Langlois, Org. Lett. 2000, 2, 2101 –
2103; b) T. Billard, B. R. Langlois, G. Blond, Tetrahedron Lett.
2000, 41, 8777 – 8780; c) T. Billard, B. R. Langlois, G. Blond,Eur.
J. Org. Chem. 2001, 1467 – 1471; d) B. R. Langlois, T. Billard,
Synthesis 2003, 185 – 194.
[10] a) L. Jablonski, J. Joubert, T. Billard, B. R. Langlois,Synlett 2003,
2, 230 – 232; b) D. Inschauspe, J.-B. Sortais, T. Billard, B. R.
3136
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 3133 – 3136