A direct approach to α-trifluoromethylamines

Article abstract of DOI:10.1021/ol034812m

(Matrix presented) S-[1-(N-Acetylamino)-2,2,2-trifluoroethyl]-O-ethyl dithiocarbonate (6), a readily available xanthate, adds efficiently to various functionalized olefins to give the corresponding adducts 8 via a radical chain reaction initiated by a small amount of lauroyl peroxide.

Full text of DOI:10.1021/ol034812m

ORGANIC
LETTERS
2
003
Vol. 5, No. 15
655-2657
A Direct Approach to
r-Trifluoromethylamines
2
Fabien Gagosz and Samir Z. Zard*
Laboratoire de Synth e` se Organique associ e´ au CNRS, Ecole Polytechnique,
91128 Palaiseau, France
zard@poly.polytechnique.fr
Received May 12, 2003
ABSTRACT
S-[1-(N-Acetylamino)-2,2,2-trifluoroethyl]-O-ethyl dithiocarbonate (6), a readily available xanthate, adds efficiently to various functionalized olefins
to give the corresponding adducts 8 via a radical chain reaction initiated by a small amount of lauroyl peroxide.
The introduction of fluorine atoms in a given molecule often
dramatically alters its chemical properties and its pharma-
cological profile in the case of a biologically active com-
addition of nucleophiles to trifluoromethyl iminium species,7
the ring opening of trifluoromethylated aziridines, and the
8
addition of the trifluoromethyl anion to functionalized
1
9
pound. As a consequence, much ongoing effort has been
imines.
devoted to the development of practical synthetic routes to
(
1) (a) Organofluorine in Medicinal Chemistry and Biochemical Ap-
2
the various classes of fluorinated compounds. As part of
plications; Filler, R., Kobayashi, Y., Yagupolski, L. M., Eds.; Elsevier:
Amsterdam, The Netherlands, 1993. (b) Fluorine-Containing Amino Acids;
Kukhar, V. P., Soloshonok, V. A., Eds.; Wiley: Chichester, UK, 1994. (c)
Biomedical Frontiers of Fluorine Chemistry; Ojima, I., McCarthy, J. R.,
Welch, J. T., Eds.; American Chemical Society: Washington, DC, 1996.
3
our continuing work in this area, we have devised a direct,
highly flexible, and efficient approach to R-trifluoromethyl-
amines.
(
d) Ismail, F. M. D. J. Fluorine Chem. 2002, 118, 27.
Several trifluoromethylated amines such as compounds
(2) (a) Fluoroorganic Chemistry: Synthetic Challenges and Biomedical
4
1
-5 exhibit interesting biological activity (Figure 1).
Rewards; Resnati, G., Soloshonok, V. A., Eds.; Tetrahedron Symposium-
in-Print No. 58. Tetrahedron 1996, 52, 1-330. (b) Topics in Current
ChemistrysOrganofluorine Chemistry: Techniques and Synthons; Cham-
bers, R. D., Ed.; Springer: Berlin, Germany, 1997; Vol. 193.
(
3) (a) Boivin, J.; Elkaim, L.; Zard, S. Z. Tetrahedron 1995, 51, 2573.
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Denieul, M. P.; Quiclet-Sire, B.; Zard, S. Z. J. Chem. Soc., Chem. Commun.
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(
1
Lett. 1996, 37, 9057. (e) Bertrand, F.; Pevere, V.; Quiclet-Sire, B.; Zard, S.
Z. Org. Lett. 2001, 3, 1069.
(4) (a) Grunewald, G. L.; Caldwell, T. M.; Li, Q.; Criscione, K. R. J.
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Blank, M.; Peters, K.; Peters, E. M.; Reichman, H.; Janetzky, B.; Grote,
C.; Clement, H. W.; Wesemann, W. Bioorg. Med. Chem. 2000, 6, 1467.
(5) For recent contributions, see: (a) Ohkura, H.; Handa, M.; Katagiri,
T.; Uneyama, K. J. Org. Chem. 2002, 67, 2692. (b) Fustero, S.; Navarro,
A.; Pina, B.; Soler, J. G.; Bartolome, A.; Asensio, A.; Simon, A.; Bravo,
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Figure 1. Some biologically active trifluoromethylamino deriva-
tives.
5
a,b
Their preparation mostly hinges on the reductive
or
5c
alkylating amination of the corresponding trifluoro methyl
ketones, the reduction of trifluoromethylated enamines, the
(6) Begue, J. P.; Bonnet-Delpon, D.; Mesureur, D.; N e´ e, G.; Wu, S. W.
6
J. Org. Chem. 1992, 57, 3807.
1
0.1021/ol034812m CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/01/2003

Table 1. Results of Radical Addition of Xanthate 6 to Olefin 7
Our synthetic design, depicted in Scheme 1, relies on the
R-trifluoromethylamine motif, as demonstrated by the ex-
amples compiled in Table 1. Many of the common functional
groups are tolerated in the olefinic partner, allowing the
synthesis of a wide variety of fluorinated derivatives in
generally good yield.
The adducts lead themselves to a number of useful
transformations (Scheme 2). For example, heating the
addition product 8a in methanol with catalytic amounts of
camphorsulfonic acid resulted in the formation of dimethyl
acetal 9 in good yield (72%). With a conveniently masked
aldehyde function, this compound represents a useful spring-
board for accessing more complex trifluoromethylated
10
rich chemistry of xanthates. Thus, radical addition of
xanthate 6 to olefin 7 leads directly to a variety of
R-trifluoromethyl amides 8. The large-scale preparation of
reagent 6, a nicely crystalline solid, was straightforward
starting from the readily available hemiacetal of trifluoro-
acetaldehyde via the known N-(2,2,2-trifluoro-1-chloroethyl)-
1
1
acetamide.
Indeed, when a solution of 6 and vinyl acetate 7a (1.1
equiv) in 1,2-dichloroethane (1 M) was heated to reflux in
the presence of 2 mol % of lauroyl peroxide, a 95% yield of
the expected adduct 8a was obtained. Xanthate 6 turned out
to be quite an effective reagent for the introduction of the
Scheme 2. Transformation of Adducts 8a and 8i
Scheme 1. Synthetic Route to R-Trifluoromethylamines
2656
Org. Lett., Vol. 5, No. 15, 2003

structures. In the case of 8i, derived from N-vinyl pyrroli-
done, refluxing in chlorobenzene caused the elimination of
the xanthate group to give olefin 10 in quantitative yield.
Alternatively, the xanthate group in the adduct may be
used to implement another radical addition (Scheme 3). This
In the case of adduct 8k, refluxing in the same solvent
with a gradual addition of a stoichiometric amount of
peroxide induced ring-closure onto the aromatic ring to give
the corresponding indoline 12 in 90% yield as a 6/4 mixture
1
2
of diastereoisomers. The xanthate group may simply be
reductively cleaved by using a tin-free procedure we
13
developed a few years ago, as shown by the transformation
of 8j into compound 13. Interestingly, this substance contains
two differently protected amino groups.
Scheme 3. Radical Transformations of Adducts 8h, 8j, and 8k
Finally, we found that exposure of reagent 6 alone to a
stoichiometric amount of lauroyl peroxide furnished a
surprisingly good yield of dimer 14 as a 1/1 mixture of the
meso and dl isomers (Scheme 4). The hitherto undescribed
Scheme 4 Dimerization of Xanthate 6
free diamine corresponding to 14 would be an interesting
building block for novel ligands for transition metals.
In summary, we have presented very promising prelimi-
nary results concerning the use of reagent 6 for the expedient
synthesis of R-trifluoromethylamines. The reaction is quite
general, proceeds under mild conditions, is easily scaled up,
and tolerates a wide variety of functional groups. A large
diversity of hitherto inaccessible trifluoromethylated com-
pounds can now be readily prepared.
is illustrated by the conversion of one the isomers of 8h into
the densely functionalized 11 in 72% yield by heating it with
allyl trimethylsilane (2 equiv) in 1,2-dichloroethane in the
presence of a small amount of lauroyl peroxide (5 mol %).
As expected, the addition of the olefin occurred from the
least hindered face of the carbonate ring to give the trans-
adduct.
Acknowledgment. This paper is dedicated with respect
and admiration to Professor Heinz Viehe. We thank Rhodia
Chimie Fine for generous financial support to one of us
(F.G.) and Drs Jean-Marc Paris and Fran c¸ ois Metz of Rhodia
for friendly discussions.
(
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Supporting Information Available: Detailed experi-
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adducts 8a-k, and compounds 9-14. This material is
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(
OL034812M
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