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Synlett 2005(2): 255-258  
DOI: 10.1055/s-2004-837209
LETTER
© Georg Thieme Verlag Stuttgart · New York

Trifluoroacetylation of Amino Acids under Aqueous Conditions Using a Readily Prepared Non-Odoriferous Reagent

Matthew R. Hickey*, Todd D. Nelson, Elizabeth A. Secord, Shawn P. Allwein, Michael H. Kress
Merck Research Laboratories, Department of Process Research, 466 Devon Park Drive, Wayne PA 19087, USA
Fax: +1(215)9932100; e-Mail: matthew_hickey@merck.com;
Further Information

Publication History

Received 21 September 2004
Publication Date:
17 December 2004 (online)

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Abstract

The synthesis of S-dodecyltrifluorothioacetate and its application to trifluoroacetylation of amino acids under aqueous conditions are described. This reagent afforded good isolated yields (71-92%) of the N-trifluoroacetyl derivatives via an operationally simple and odor free procedure.

Key words

amino acids - thioester - Schotten-Baumann - trifluoro­acetylation - green chemistry

7

Typical Procedure:
ACC (1, 249 mg, 2.46 mmol) was dissolved in 2.5 mL H2O 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 1 N NaOH. After additional 2 h more S-ethyltrifluorothio-acetate (0.1 mL, 0.12 g, 0.76 mmol) was added. HPLC assays revealed an 82% yield, so the mixture was acidified using a NaCl-HCl solution [8] to pH 1. The acidic mixture was extracted with isopropylacetate 3 times. The organic phases were combined and dried over Na2SO4 and concentrated to 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.

16

A solution of 1-dodecanethiol (61.5 mL, 51.3 g, 0.253 mol) in CH2Cl2 (250 mL) was cooled to 0 °C. Pyridine (20.5 mL, 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 CH2Cl2 (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 cooled to r.t., then poured into 500 mL H2O and the phases separated. The aqueous phase was extracted 2 times with CH2Cl2 and the combined organic phases were dried over Na2SO4. Concentration of the organics gave S-dodecyltri-fluorothioacetate 3d as a clear colorless oil (74.4 g). 1H NMR (CDCl3): δ = 3.06 (t, J = 7.39 Hz, 2 H), 1.65 (m, 2 H), 1.15-1.50 (m, 18 H), 0.87 (t, J = 0.22 Hz, 3 H). 13C NMR (CDCl3): δ = 14.1, 22.7-29.7, 32.0, 115.7, 185.0. 19F NMR (CDCl3): δ = -76.0.

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:
d,l-Phenylalanine (519 mg, 3.14 mmol) was dissolved in 5 mL sat. aq NaHCO3 and 5 mL MeCN. [21] Tetrabutylammo-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 to pH 1 by addition of 3 mL NaCl-HCl solution. [8] [22] Then, the aqueous phase was extracted with EtOAc (3 × 10 mL). These EtOAc extracts were combined and washed with brine and dried over Na2SO4. Concentration of the organic product stream gave N-trifluoroacetylphenylalanine as a white solid (747 mg, 91%).

21

Precipitate formed with some amino acids when MeCN was added.

22

Acidification of the reaction mixture formed a biphasic mixture with some amino acids. The top MeCN phase contained the product and was separated before the EtOAc extraction of the aqueous phase. This MeCN phase was combined with the EtOAc extracts before brine wash and drying of the combined organic extracts.