LETTER
Odorless Trifluoroacetylation of Amino Acids under Aqueous Conditions
257
Overall, the results of these reactions are improved rela-
assays revealed an 82% yield, so the mixture was acidified
using a NaCl–HCl solution to pH 1. The acidic mixture was
8
tive to those observed using S-ethyltrifluorothioacetate.6
extracted with isopropylacetate 3 times. The organic phases
were combined and dried over Na SO and concentrated to
This is believed to be a result of the higher stability of the
S-dodecyltrifluorothioacetate under the reaction condi-
tions. Reactions involving S-ethyltrifluorothioacetate typ-
ically required recharging of the thioester during the
course of the reaction to obtain good yields. The dode-
cylthioester, on the other hand, did not require recharging
during the reaction under the same conditions.
2
4
give TFA-ACC (2) as a white solid (347 mg, 72%).
8) NaCl–HCl workup solution was prepared by dissolving 22 g
of NaCl in 1 L 3 N HCl.
(9) Svirskaya, P. I.; Leznoff, C. C.; Steinman, M. J. Org. Chem.
1987, 52, 1362.
10) For a study of chain length vs the odor of thiols please see:
Node, M.; Kumar, K.; Nishide, K.; Ohsugi, S.; Miyamoto, T.
Tetrahedron Lett. 2001, 42, 9207.
(
(
Under the optimized conditions using 1.5 equivalents S-
dodecyltrifluorothioacetate as the trifluoroacetylating re-
agent, 89% isolated yield of 2 was obtained. This reactiv-
ity was shared among a variety of amino acids as
illustrated in Table 2. Most substrates gave isolated yields
between 71% and 92%. The lower yield of glycine is like-
ly explained by higher water solubility of N-trifluoro-
acetylglycine.
(11) Nishide, K.; Ohsugi, S.; Miyamoto, T.; Kumar, K.; Node, M.
Monatsh. Chem. 2004, 135, 189.
12) Miyazaki, T.; Han-ya, Y.; Tokuyama, H.; Fukuyama, T.
(
Synlett 2004, 477.
1
1
(
13) See ref. and: (a) Ohsugi, S.; Nishide, K.; Fudesaka, M.;
Kodama, S.; Node, M. Tetrahedron Lett. 2002, 43, 5177.
(
b) Nishide, K.; Ohsugi, S.; Oone, K.; Okuyama, K.;
Fudesaka, M.; Kodama, S.; Node, M. Tetrahedron 2003, 59,
393.
14) Patra, P. K.; Nishide, K.; Fuji, K.; Node, M. Synthesis 2004,
003.
8
In conclusion, we have reported a process to cleanly af-
ford N-trifluoroacetyl derivatives of amino acids under
aqueous conditions using S-dodecyltrifluorothioacetate.
This reagent is easily prepared in high yield from inexpen-
sive and readily available materials.
(
(
1
15) For the synthesis of S-octyltrifluorothioacetate see: Billard,
T.; Roques, N.; Langlois, B. R. J. Org. Chem. 1999, 64,
3813.
(
16) A solution of 1-dodecanethiol (61.5 mL, 51.3 g, 0.253 mol)
in CH Cl (250 mL) was cooled to 0 °C. Pyridine (20.5 mL,
2
2
References
20.0 g, 0.253 mol) followed by 100 mg of DMAP were
added and the temperature of the mixture was allowed to
return to 0 °C. A solution of trifluoroacetic anhydride (53.0
mL, 80.0 g, 0.380 mol) in CH Cl (250 mL) was added to the
reaction mixture at 0 °C over 0.5 h (maintaining internal
temperature <5 °C). The mixture was then heated to 40 °C.
After stirring at 40 °C for 5 h, the reaction mixture was
(
(
1) Salaün, J. Top. Curr. Chem. 2000, 207, 1.
2) (a) Stammer, C. H. Tetrahedron 1990, 46, 2231. (b) Rich,
2
2
D. H.; Tam, J. P. Synthesis 1978, 46. (c) Fadel, A.
Tetrahedron 1991, 47, 6265. (d) Zhu, X.; Gan, P. Synth.
Commun. 1998, 28, 3159. (e) Strazewski, P.; Tamm, C.
Synthesis 1987, 298. (f) O’Donnell, M. J.; Bruder, W. A.;
Eckrich, T. M.; Shullenberger, D. F.; Staten, G. S. Synthesis
cooled to r.t., then poured into 500 mL H O and the phases
2
separated. The aqueous phase was extracted 2 times with
CH Cl and the combined organic phases were dried over
1
1
984, 127. (g) Kleemiss, W.; Feld, M. US Pat. 5569781,
996. (h) Seebach, D.; Häner, R. Chimia 1985, 39, 356.
2
2
Na SO . Concentration of the organics gave S-dodecyltri-
2
4
(
(
i) Wheeler, T.; Ray, J. Synth. Commun. 1988, 18, 141.
j) Schubert, H.; Rack, M.; Mühlstädt, M. J. Prakt. Chem./
1
fluorothioacetate 3d as a clear colorless oil (74.4 g). H
NMR (CDCl ): d = 3.06 (t, J = 7.39 Hz, 2 H), 1.65 (m, 2 H),
3
Chem.-Ztg. 1990, 332, 812. (k) Allwein, S. P.; Secord, E.;
Martins, A.; Mitten, J. V.; Nelson, T. D.; Kress, M.; Dolling,
U. H. Synlett 2004, 2489.
1
3
1
(
(
.15–1.50 (m, 18 H), 0.87 (t, J = 0.22 Hz, 3 H). C NMR
CDCl ): d = 14.1, 22.7–29.7, 32.0, 115.7, 185.0. F NMR
CDCl ): d = –76.0.
1
9
3
3
(
3) General procedures for trifluoroacetylation: (a) Greene, T.;
Wuts, P. Protective Groups in Organic Synthesis, 3rd ed.;
Wiley: New York, 1999, 556–558. (b) Kocienski, P.
Protecting Groups, corrected ed.; Georg Thieme Verlag:
Stuttgart, 2000, 189–190.
(
(
(
17) Yield determined by HPLC assay of peak area vs the area of
an analytical sample of TFA-ACC.
18) Borax–NaOH buffer proved ineffective in buffer capacity,
often allowing the pH to drop below 8 within 2–3 h.
19) Typical Procedure:
(
(
4) Wegand, F.; Leising, E. Chem. Ber. 1954, 87, 248.
5) (a) Curphey, T. J. J. Org. Chem. 1979, 44, 2805.
D,L-Phenylalanine (519 mg, 3.14 mmol) was dissolved in 5
2
1
mL sat. aq NaHCO and 5 mL MeCN. Tetrabutylammo-
3
(
b) Steglich, W.; Hinze, S. Synthesis 1976, 399.
6) (a) Schallenberg, E. E.; Calvin, M. J. Am. Chem. Soc. 1955,
7, 2779. (b) The bistrifluoroacetylation of 2,4-diamino-
nium bromide (101 mg, 0.31 mmol) and S-dodecyltrifluoro-
thioacetate (1.415 g, 4.74 mmol) were added, respectively,
and the vigorously stirred heterogeneous system was heated
in a 50 °C oil bath for 6.5 h. The mixture was cooled to r.t.
and the phases were separated. The aqueous layer was
washed with 3 mL EtOAc and the aqueous phase acidified
(
7
glutaric acid using S-phenyltrifluorothioacetate with
aqueous sodium bicarbonate has been reported: Weygand,
F.; Spiess, B. Chem. Ber. 1964, 97, 3456.
7) Typical Procedure:
(
8
,22
to pH 1 by addition of 3 mL NaCl–HCl solution. Then,
the aqueous phase was extracted with EtOAc (3 × 10 mL).
These EtOAc extracts were combined and washed with brine
and dried over Na SO . Concentration of the organic product
ACC (1, 249 mg, 2.46 mmol) was dissolved in 2.5 mL H O
2
and the pH adjusted to 10 using 1 N NaOH (2.8 mL). The S-
ethyltrifluorothioacetate (0.5 mL, 0.63 g, 3.96 mmol) was
added and the biphasic mixture vigorously stirred at r.t. After
ca. 1 h, the pH was readjusted to 10 by dropwise addition of
2
4
stream gave N-trifluoroacetylphenylalanine as a white solid
(747 mg, 91%).
1
N NaOH. After additional 2 h more S-ethyltrifluorothio-
acetate (0.1 mL, 0.12 g, 0.76 mmol) was added. HPLC
Synlett 2005, No. 2, 255–258 © Thieme Stuttgart · New York