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

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.

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

References

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General procedures for trifluoroacetylation:

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<A NAME="RS09004ST-6B">6b</A> The bistrifluoroacetylation of 2,4-diamino-glutaric acid using S-phenyltrifluorothioacetate with aqueous sodium bicarbonate has been reported: Weygand F. Spiess B. Chem. Ber.  1964,  97:  3456 

<A NAME="RS09004ST-7">7</A>

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%).

<A NAME="RS09004ST-8">8</A>

NaCl-HCl workup solution was prepared by dissolving 22 g of NaCl in 1 L 3 N HCl.

<A NAME="RS09004ST-9">9</A> Svirskaya PI. Leznoff CC. Steinman M. J. Org. Chem.  1987,  52:  1362 

<A NAME="RS09004ST-10">10</A> 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 

<A NAME="RS09004ST-11">11</A> Nishide K. Ohsugi S. Miyamoto T. Kumar K. Node M. Monatsh. Chem.  2004,  135:  189 

<A NAME="RS09004ST-12">12</A> Miyazaki T. Han-ya Y. Tokuyama H. Fukuyama T. Synlett  2004,  477 

See ref.¹¹ and:

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<A NAME="RS09004ST-14">14</A> Patra PK. Nishide K. Fuji K. Node M. Synthesis  2004,  1003 

<A NAME="RS09004ST-15">15</A> For the synthesis of S-octyltrifluorothioacetate see: Billard T. Roques N. Langlois BR. J. Org. Chem.  1999,  64:  3813 

<A NAME="RS09004ST-16">16</A>

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.

<A NAME="RS09004ST-17">17</A>

Yield determined by HPLC assay of peak area vs the area of an analytical sample of TFA-ACC.

<A NAME="RS09004ST-18">18</A>

Borax-NaOH buffer proved ineffective in buffer capacity, often allowing the pH to drop below 8 within 2-3 h.

<A NAME="RS09004ST-19">19</A>

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%).

<A NAME="RS09004ST-20A">20a</A> Gani D. Young DW. J. Chem. Soc., Perkin Trans. 1  1985,  1355 

<A NAME="RS09004ST-20B">20b</A>

¹H NMR (DMSO-d ₆): δ = 13.22 (br s, 1 H), 10.18 (d, J = 7.22 Hz, 1 H), 7.35 (m, 5 H), 5.42 (d, J = 7.29 Hz, 1 H). ¹³C NMR (DMSO-d ₆): δ = 57.2, 116.3, 128.9, 135.9, 156.7, 170.9. ¹⁹F NMR (DMSO-d ₆): δ = -74.3.

<A NAME="RS09004ST-20C">20c</A> Jass PA. Rosso VW. Racha S. Soundararajan N. Venit JJ. Rusowicz A. Swaminathan S. Livshitz J. Delaney EJ. Tetrahedron  2003,  59:  9019 

<A NAME="RS09004ST-20D">20d</A> Krasnov VP. Levit GL. Bukrina IM. Demin AM. Chupakhrin ON. Yoo JU. Tetrahedron: Asymmetry  2002,  13:  1911 

<A NAME="RS09004ST-21">21</A>

Precipitate formed with some amino acids when MeCN was added.

<A NAME="RS09004ST-22">22</A>

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.