Nucleophilic trifluoromethylation of N-tosyl aldimines

Article abstract of DOI:10.1055/s-2001-9724

TMSCF₃ and tetrabutylammonium (triphenylsilyl) difluorosilicate (TBAT) were used for efficient nucleophilic trifluoromethylation to N-tosyl aldimines. Aromatic, aliphatic and α,β-unsaturated sulfonaldimines were efficiently trifluoromethylated to obtain the corresponding sulfonamide adducts in good to excellent yields.

Full text of DOI:10.1055/s-2001-9724

LETTER
77
Nucleophilic Trifluoromethylation of N-Tosyl Aldimines
G. K. Surya Prakash,* Mihirbaran Mandal, George A. Olah*
Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, CA 90089-1661,
USA
Fax 213 740 6270; E-mail: gprakash@.usc.edu
Received 9 June 2000
ylation reaction.4 Thus reaction of sulfonaldimines with
Abstract: TMSCF3 and tetrabutylammonium (triphenylsilyl) diflu-
TMSCF3 in the presence of TBAT afforded the trifluo-
orosilicate (TBAT) were used for efficient nucleophilic trifluorom-
romethylated product in good to excellent isolated yields
(see Table). The reaction temperatures have been opti-
ethylation to N-tosyl aldimines. Aromatic, aliphatic and a,b-
unsaturated sulfonaldimines were efficiently trifluoromethylated to
obtain the corresponding sulfonamide adducts in good to excellent mized and the best results were achieved between 0-5 °C.
yields.
Key words: amines, drugs, imines, nucleophilic addition, sul-
fonamides
Table Nucleophilic Trifluoromethylation of N-Tosyl Aldimines.
Although, many of synthetic drugs contain nitrogen,1 in-
troduction of fluorine often results in very special benefi-
cial properties2 due to fluorine’s high electronegativity
and lipophilicity of the C-F bond. There have been, how-
ever, only few literature reports3 regarding the preparation
of trifluoromethylated amines. As their preparation from
imines is advantageous, we were interested in their direct
nucleophilic trifluoromethylation. We have recently re-
ported efficient stereoselective trifluoromethylation of
N-tert-butanesulfinimines4 using TMSCF3 and CsF or
TBAT (tetrabutylammonium (triphenylsilyl) difluorosili-
cate). In that study4 with CsF we encountered two prob-
lems: a) conversion of imines was incomplete even in
presence of excess TMSCF3 and CsF and b) imines with
an a-hydrogen failed to undergo reaction with TMSCF3
due to the basic nature of CsF. We surmised that the low
electrophilicity of sulfinimines together with instability of
pentavalent silicate species (Scheme 1) resulted in the low
yields. We have now overcome these problems by the use
of following two approaches: a) increasing the electrophi-
licity of imines by using N-tosyl aldimines,5,6 and b) em-
ploying
a
nonmetallic fluoride source. When
sulfonaldimines were reacted with TMSCF3 in the pres-
ence of TBAF (tetrabutylammonium fluoride) the desired
products were obtained in only low yields with concomi-
tant formation of trifluoromethane (the hydrolysis product
of TMSCF3) because of the strong hygroscopic nature of
TBAF. We have found that tetrabutylammonium (triphe-
nylsilyl) difluorosilicate (TBAT),7 a soluble fluoride
source, is very effective for our nucleophilic trifluometh-
In a typical reaction, 0.36 mmol TBAT was dissolved in
4 mL of dry THF and cooled to 0 °C under inert condi-
tions. In a separate flask, 0.3 mmol of the imine and 0.39
mmol TMSCF3 were mixed in 3 mL THF. The mixture of
imine and TMSCF3 was slowly added via a syringe to the
Scheme 1
Synlett 2001, No. 1, 77–78 ISSN 0936-5214 © Thieme Stuttgart · New York

78
G. K. S. Prakash et al.
LETTER
solution of TBAT. The reaction mixture was stirred for 45
min to 1 h while maintaining the reaction temperature at
0-5 °C. Saturated NH4Cl (2 mL) was added at 0 °C and
the reaction mixture was slowly warmed to ambient tem-
perature. The quenched reaction mixture was extracted
three times with ethyl acetate and the combined organic
layer was dried over anhydrous Na2SO4. Evaporation of
the solvent under vacuum followed by column chroma-
tography (silica gel, hexanes\ethyl acetate 10\1) gave the
sulfonamides as white solids. In one case, the p-toluene-
sulfonyl group of 2a was removed by treatment with phe-
nol and 48% HBr to obtain 3a8 as a hydrobromide salt in
90% isolated yield (Scheme 2).
Acknowledgement
Support of our work by the Loker Hydrocarbon Research Institute
is gratefully acknowledged.
References and Notes
(1) MDL Drug Data Report, MDL Information Systems, Inc., San
Leandro, CA.
(2) Fluorine-containing Molecules. Structure, Reactivity,
Synthesis, and Applications; Liebman, J. F., Greenberg, A.,
Dolbier, W. R., Jr., Eds.; VCH: New York, 1988. Synthetic
Fluorine Chemistry, G. A. Olah., R. Chambers and G. K. S.
Prakash, Wiley Interscience, 1992, 227-245. Prakash,
G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc.
1989, 111, 393-395. Krishnamurti, R.; Bellew, A. D. R.;
Prakash, G. K. S. J. Org. Chem. 1991, 56, 984-989. Prakash,
G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757-786.
Prakash, G. K. S.; Ramaiah, R. Synlett 1991, 643-644.
Wiedemann, J.; Heiner, T.; Mloston, G.; Prakash, G. K. S.;
Olah, G. A. Angew. Chem. Int. Ed. Engl. 1998, 37, 820-821.
(3) Pirkle, W. H.; Hauske, J. R. J. Org. Chem.1977, 42, 2436.
Pirkle, W. H.; Simmons, K. A. J. Org. Chem. 1981, 46, 3239.
Wang, Y.; Mosher, H. S. Tetrahedron Lett. 1991, 32, 987.
Soloshonok, V. A.; Ono, T. J. Org. Chem. 1997, 62, 3030-
3031. Blazejewski, J-C.; Anselmi, E.; Wilmshurst, M. P.
Tetrahedro Lett. 1999, 40, 5475-5478.
(4) Prakash, G, K, S.; Mandal, M.; Olah, G. A. Angew. Chem. Int.
Ed. Engl., in press.
(5) Addition of organometallic reagents to N-sulfonaldimines is
known: Sisko, J.; Weinreb, S. M. J. Org. Chem. 1990, 55, 393-
395. Reetz, M. T.; Jaeger, R.; Drewlies, R.; Huebel, M.
Angew. Chem. 1991, 103, 76-78. Burgess, K.; Ohlmeyer, M.
J. J. Org. Chem. 1991, 56, 1027-1036. Davis, F. A.; Wei, J.;
Sheppard, A. C.; Gubernick, S. Tetrahedron Lett. 1987, 28,
5115-5118. (e) Mckay, W. R.; Proctor, G. R. J. Chem. Soc.
Perkin. Trans. 1. 1981, 2443-2450.
(6) N-Tosyl aldimines were prepared according to reported
procedures. Jennings, W. B.; Lovely, C. J. Tetrahedron 1991,
47, 5561-5568. Chemla, F.; Hebbe, V.; Normant, J-F.
Synthesis 2000, 75-77.
Scheme 2
Trifluoromethylation of benzaldimine 1a, which contains
no a hydrogen adjacent to the imine group, proceeded
smoothly to give adduct 2a in excellent yield. Aromatic
imines with electron withdrawing as well as electron do-
nating group underwent similar trifluoromethylation.
Even sterically bulky naphthyl sulfonaldimine 1d reacted
smoothly to give 2d9 in 95% isolated yield. Most interest-
ingly, a,b-unsaturated imine 1e, gave exclusively the 1,2
-addition product in good yield. Even sulfonaldimines
containing an enolizable a hydrogen reacted smoothly, for
example, 1f giving the trifluoromethylated adduct in 80%
yield. Aliphatic sulfonaldimines, 1g and 1h, however,
gave lower yield of the product because of their inherent
instability. N-Tosyl ketimines, on the other hand, under
the similar reaction conditions gave very poor yield of the
trifluoromethylated adduct.
(7) Pilcher, A. S.; Ammon, H. L.; DeShong, P. J. Am. Chem. Soc.
1995, 117, 5166-5167.
(8) Spectral data for 3a: 1H NMR (500 MHz, CD3OD) d 5.37 (q,
1H, J = 7.9 Hz), 7.55 (m, 5H), the NH3+ protons could not be
observed due to rapid proton-deuteron exchange with the
methanol solvent; 13C NMR (125 MHz, CD3OD) d 56.6 (q,
2JC-F = 32.8 Hz), 124.8 (q, 1JC-F = 278 Hz), 129.5, 129.6, 130.6,
132.1; 19F (500 MHz, CD3OD) d -73.2 (d, JF-H = 5.6 Hz).
(9) Spectral data for 2d: 1H NMR (360 MHz, CDCl3) d 2.15 (s,
3H), 5.07 (m, 1H), 6.18 (d, 1H, J = 8.9 Hz), 6.96 (d, 2H,
J = 8.2 Hz), 7.24-7.75 (m, 9H); 13C NMR (125 MHz, CDCl3)
d 21.1, 60.7 (q, 2JC-F = 31.8 Hz), 125.8 (q, 1JC-F = 281 Hz),
125.9, 127.5, 127.8, 127.9, 128.5, 129.0, 129.3, 129.5, 130.1,
130.6, 131.2, 134.1, 134.5, 136.3, 139.2, 144.5; 19F (360 MHz,
CDCl3) d -73.9 (d, JF-H = 7.14 Hz); HRMS (DEI) m/z calc for
C19H16F3NO2S (M+) 379.0853, found 379.0863.
In summary, we have developed a very efficient method
for the preparation of trifluoromethylated amine deriva-
tives by trifluoromethylation of corresponding N-tosyl al-
dimines.
Article Identifier:
1437-2096,E;2001,0,01,0077,0078,ftx,en;S03100ST.pdf
Synlett 2001, No. 1, 77–78 ISSN 0936-5214 © Thieme Stuttgart · New York