J.-G. Kim, D. O. Jang / Tetrahedron Letters 51 (2010) 683–685
685
NH2
method has a number of advantages including low cost and avail-
ability of the reagents, easy handling and stability of the reagents,
and ease of operation and workup. This novel trifluoroacetylation
process has the potential to be applied widely for the protection
and activation of amines in organic synthesis.
NHCOCF3
CF3CO2H, CCl3CN/PPh3
Et3N, CH3CN, rt, 2 h
92%
[α]D25 = +137 (c = 1, CHCl3)17
Typical procedure for trifluoroacetylation of amines: To a solution
of triphenylphosphine (525 mg, 2 mmol), amine (1 mmol), and tri-
ethylamine (420
added trifluoroacetic acid (77
(200 L, 2 mmol). The mixture was stirred at room temperature for
l
L, 3 mmol) in CH3CN (2 mL) under argon were
lL, 1 mmol) and trichloroacetonitrile
NHCOCF3
OH
NH2
l
CF3CO2H, CCl3CN/PPh3
OH
several hours. After evaporation of the solvents, the residue was
purified with column chromatography on silica gel to give a pure
product.
Et3N, CH3CN, rt, 2 h
90 %
[α]D25 = -80.6 (c = 1, MeOH)18
Acknowledgment
Scheme 2.
This work was supported by the Center for Bioactive Molecular
Hybrids.
The results of these experiments are presented in Table 2. The reac-
tion showed generality across a wide range of amines, including
amines with low nucleophilicity. Compared to anilines with elec-
tron-withdrawing groups, anilines with electron-releasing groups
were processed more efficiently under these conditions, affording
higher yields of the corresponding products (entries 1–9). Triflu-
oroacetylation with anilines with very low nucleophilicity such
as nitro anilines and N-phenyl aniline proceeded smoothly, result-
ing in high product yields (entries 7 and 10). Secondary amines
were also shown to be good substrates for the reaction (entries
10 and 11). In a substrate with both primary amino and secondary
amino groups, only the primary amino group was trifluoroacetylat-
ed (entry 12). Trifluoroacetylation with aliphatic amines resulted
in high product yields (entries 13–16). Even very sterically hin-
dered tertiary amines underwent trifluoroacetylation under these
conditions (entry 17).
We applied our new method to the trifluoroacetylation of
amines with stereogenic centers (Scheme 2). When (R)-1-phenyle-
thanamine was subjected to our reaction conditions, the corre-
sponding amides were obtained at a 92% yield.17 In the case of
(R)-2-amino-2-phenylethanol, which has both amino and hydroxyl
groups, only the amino group was trifluoroacetylated selectively,
demonstrating the good chemoselectivity of our novel reaction.18
We did not detect any signs of racemization of the stereogenic cen-
ters through the analysis of reaction mixtures by HPLC using a chi-
ral stationary phase.19
References and notes
1. Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 4th ed.;
Wiley-Interscience: New York, 2007.
2. Friestad, G. K.; Banerjee, K. Org. Lett. 2009, 11, 1095.
3. Schallenberg, E. E.; Calvin, M. J. Am. Chem. Soc. 1955, 77, 2779.
4. Forbus, T. R., Jr.; Taylor, J. C.; Martin, J. C. J. Org. Chem. 1987, 52, 4156.
5. Bergeron, R. J.; McMains, J. S. J. Org. Chem. 1988, 53, 3108.
6. Katritzky, A. R.; Yang, B.; Qiu, G.; Zhang, Z. Synthesis 1999, 55.
7. Staab, H. A.; Walter, G. Angew. Chem. 1960, 72, 35.
8. Katritzky, A. R.; Yang, B.; Semenzin, D. J. Org. Chem. 1997, 62, 726.
9. Keumi, T.; Shimada, M.; Morita, T.; Kitajima, H. Bull. Chem. Soc. Jpn. 1990, 63,
252.
10. (a) Katja Heinze, K.; Hempel, K. Chem. Eur. J. 2009, 15, 1346; (b) Beyermann, M.;
Bienert, M.; Niedrich, H.; Carpino, L. A.; Sadat-Aalaee, D. J. Org. Chem. 1990, 55,
721; (c) Yu, S. K. T.; Green, J. B. Anal. Chem. 1989, 61, 1260.
11. (a) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; John Wiley & Sons:
New York, 1967. p 1221; (b) Narang, A. S.; Vince, R. J. Med. Chem. 1977, 20,
1684.
12. Salazar, J.; López, S. E.; Rebollo, O. J. Fluorine Chem. 2003, 124, 111.
13. Ohtaka, J. O.; Sakamoto, T.; Kikugawa, Y. Tetrahedron Lett. 2009, 50, 1681.
14. López, S. E.; Pérez, Y.; Restrepo, J.; Salazar, J.; Charris, J. J. Fluorine Chem. 2007,
128, 566.
15. Jang, D. O.; Park, D. J.; Kim, J. Tetrahedron Lett. 1999, 40, 5323.
16. Jang, D. O.; Cho, D. H.; Kim, J.-G. Synth. Commun. 2003, 33, 2885.
17. The enantiomer (Aldrich catalogue # 399779) has ½a D20
= ꢀ135 (c 1 in CHCl3).
ꢁ
18. Mp 128 °C (lit.8 128–130 °C),1H NMR (300 MHz, DMSO-d6) d 4.19 (m, 2H), 5.41
(m, 1H), 5.55 (s, 1H), 7.77 (m, 5H), 10.26 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d
56.1, 63.5, 115.8, 126.7, 127.3, 127.9, 138.9, 156.2.
19. Chiral
HPLC
analysis
for
(R)-2,2,2-trifluoro-N-(2-hydroxy-1-
phenylethyl)acetamide: Diacel Chiralcel OC; n-hexane/IPA (70/30 v/v); flow
In conclusion, we have developed a mild and selective method
for the trifluoroacetylation of a wide variety of amines. The present
rate = 1.0 mL/min; UV (k = 254 nm); retention time for
retention time for S form = 23.5 min.
R form = 15.2 min;