CHIRALITY 27:571–575 (2015)
Special Issue Article New Synthesis of Trifluoromethyl Aldimines Containing L-α-Amino Ester Moieties and Their Use in Mannich-Type Reactions LUCA PARISE, ALESSIA PELAGALLI, LAURA TRULLI, MARIA CECILIA VERGARI, STEFANIA FIORAVANTI,* Dipartimento di Chimica, Università degli Studi di Roma “La Sapienza”, Roma, Italy
AND
LUCIO PELLACANI*
ABSTRACT L-α-Amino esters were considered valuable chiral starting materials in the condensation reaction with trifluoroacetaldehyde (fluoral) ethyl hemiacetal to obtain new functionalized trifluoromethyl aldimines. Starting from these latter compounds, isovaleraldehyde was used in proline-catalyzed Mannich-type addition reactions to give trifluoromethyl syn- or anti-γ-amino alcohols bearing the L-α-amino ester function, simply by changing the reaction temperature. Chirality 27:571–575, 2015. © 2015 Wiley Periodicals, Inc. KEY WORDS: asymmetric synthesis; amino acids; fluorinated compounds; chiral molecules; absolute configuration; stereoselectivity Fluorinated or trifluoromethylated nitrogen compounds have shown important biological effects and special electronic properties in bioactive natural products as well as in pharmaceutically important compounds. So, in these last years, asymmetric synthesis has turned its attention towards fluorinated molecules, in particular carrying the trifluoromethyl group, which improves chemical, physical, and biological properties of drug candidates, such as shown by the number of CF3-containing drugs that are clinically used or are in development.1–6 Fluorine-containing compounds7 can be obtained either through trifluoromethylation techniques or by starting from available fluorinated materials,8 the latter strategy being considered among the most direct and easy methods to obtain structurally elaborated molecules. Even more important is to plan strategies for the synthesis of nitrogencontaining molecules. In this field, we reported a new solvent-free synthesis of (E)trifluoromethyl imines9 starting from trifluoroacetaldehyde (fluoral) ethyl hemiacetal.10 The obtained compounds can be regarded as powerful building blocks for the construction of more complex trifluoromethylated nitrogen compounds.11–20 Recently, (E)-trifluoromethyl aldimines were successfully considered by us in the ZrCl4-catalyzed aza-Henry addition with different nitro alkanes,21 and the obtained nitro amines were converted by simple chemical transformations into interesting N,N’-diprotected CF3-modified dipeptides.22 Continuing our study, we here report an efficient methodology for the synthesis of trifluoromethyl aldimines, derived from α-amino esters, that subsequently were considered in a proline-catalyzed Mannich-type reaction,23 key steps for the synthesis of fluorinated γ-amino alcohols. MATERIALS AND METHODS The synthesis of trifluoromethyl aldimines was carried out in flamedried glassware under an argon atmosphere. The crude reaction mixtures and all purified products were concentrated by using a rotary evaporator. Flash chromatography was performed on 230–400 mesh silica gel. Analytical thin-layer chromatography (TLC) was carried out on precoated (0.25 mm) silica gel plates. High-performance liquid © 2015 Wiley Periodicals, Inc.
chromatography (HPLC) analyses were performed with a Varian (Walnut Creek, CA) 9001 instrument using an analytical column (3.9 × 300 mm, flow rate 1.3 mL/min) equipped with a Varian RI-4 differential refractometer or a Varian 9050 UV/VIS detector. Eluents were HPLC-grade. IR spectra were recorded on a Perkin-Elmer (Norwalk, CT) 1600 Series -1 FT/IR spectrophotometer in CHCl3 as the solvent, and reported in cm . 1 13 19 H, C, and F nuclear magnetic resonance (NMR) spectra were recorded at 300 MHz on a Varian-Mercury 300 instrument and reported in δ values. CDCl3 was used as the solvent and CHCl3 (δ = 7.26 ppm for 1 13 H NMR), CDCl3 (δ = 77.0 ppm for C NMR), and C6F6 (δ = 164.9 for 19 F NMR) were used as internal standards. The NOESY experiments were performed on a Bruker (Billerica, MA) Avance III instrument at 400 MHz using CDCl3 as the solvent and used to assist in structure elucidation.24 Electrospray ionization, mass spectrometry (ESIMS) analyses were performed using a quadrupole-time of flight (Q-TOF) mass spectrometer equipped with an ESI source and a syringe pump. The experiments were carried out in the positive ion mode.
General Procedure for the Synthesis of Trifluoromethyl Aldimines 2a–d A solution of 1 mmol of L-α-amino ester and 1.5 mmol of fluoral ethyl hemiacetal in anhydrous toluene (5 mL) was added under an Ar atmosphere into a round-bottom flask containing previously activated 4Å molecular sieves (3 g). The reaction was stirred at reflux for 1 h. The crude mixture was filtered on filter paper. After solvent removal, the obtained trifluoromethyl aldimines (E)-2a–d (Figure 1) were used without further purification. Methyl (S)-3-methyl-2-{[(1E)-2,2,2-trifluoroethylidene]amino}butanoate (2a). Dark orange oil, 54%. Known compound.25 Methyl (S)-4-methyl-2-{[(1E)-2,2,2-trifluoroethylidene]amino}pentanoate 1 (2b). Dark orange oil, 72%. νmax 1736, 1686. H NMR (CDCl3, 300 MHz, δ): 0.89 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H), 1.44 1.55 (m, 1H), 1.81 (t, J = 7.0 Hz, 2H), 3.76 (s, 3H), 4.16 (t, J = 7.2 Hz, 1H), 13 7.66 7.70 (m, 1H). C NMR (CDCl3, 75.5 MHz, δ): 21.3, 22.7, 24.3, *Correspondence to: Stefania Fioravanti or Lucio Pellacani, Dipartimento di Chimica, Università degli Studi di Roma “La Sapienza”, P.le Aldo Moro 5, I-00185 Roma, Italy. E-mail: stefania.fi[email protected] or E-mail: lucio. [email protected] Received for publication 30 March 2015; Accepted 20 May 2015 DOI: 10.1002/chir.22478 Published online 14 July 2015 in Wiley Online Library (wileyonlinelibrary.com).
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Methyl (S)-3-methyl-2-{[(2R,3R)-1,1,1-trifluoro-3-(hydroxymethyl)1 4-methylpentan-2-yl]amino}butanoate (syn-4’a). Yellow oil, 28%. H NMR (CDCl3, 300 MHz, δ): 1.04 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H), 1,10 (d, J = 6.8 Hz, 3H), 1.13-1.17 (m, 1H), 1.64-1.84 (m, 2H), 2.05-2.15 (m, 1H), 3.05 (d, J = 6.9 Hz, 1H), 3.56-3.79 13 (m, 2H), 3.48 (br, 1H), 3.76 (s, 3H), 5.96-4.10 (m, 1H). C NMR (CDCl3, 75.5 MHz, δ): 19.1, 19.3, 20.9 (2C), 27.3, 42.3, 46.8, 52.1, 60.9, 63.8, 71.3 19 (q, J = 29.3 Hz), 128.5 (q, J = 282.5 Hz), 174.3. F NMR (CDCl3, 282 MHz, + δ): 80.3 (d, J = 7.8 Hz). HRMS (ESI, m/z): [M + H] calcd for C13H25F3NO3: 300.1787, found: 300.1782.
Fig. 1. Trifluoromethyl aldimines derived from L-α-amino esters.
19
41.4, 52.4, 69.5, 118.5 (q, J = 275.1 Hz), 151.4 (q, J = 38.6 Hz), 170.7. F NMR (CDCl3, 282 MHz, δ): 71.46 (d, J = 3.3 Hz). HRMS (ESI, m/z): + [M + Na] calcd for C9H14F3NNaO2 248.0874, found 248.0878. Methyl (2S,3S)-3-methyl-2-{[(1E)-2,2,2-trifluoroethylidene]amino} -1 1 pentanoate (2c). Dark orange oil, 74% . νmax cm 1738, 1686. H NMR (CDCl3, 300 MHz, δ): 0.81 0.91 (m, 6H), 1.02 1.50 (m, 2H), 2.01 2.15 (m, 1H), 3.72 (s, 3H), 3.84 (d, J = 6.5 Hz, 1H), 7.62 (q, J = 3.2 Hz, 1H). 13 C NMR (CDCl3, 75.5 MHz, δ): 10.9, 15.4, 24.8, 37.9, 52.1, 76.7, 118.4 19 (q, J = 275.1 Hz), 151.6 (q, J = 38.5 Hz), 170.3. F NMR (CDCl3, 282 + MHz, δ): 71.5 (d, J = 3.0 Hz). HRMS (ESI, m/z): [M + Na] calcd for C9H14F3NNaO2 248.0874, found 248.0871. Methyl (S)-3-phenyl-2-{[(1E)-2,2,2-trifluoroethylidene]amino}propanoate -1 1 (2d). Dark orange oil, 73%. νmax cm 1737, 1683. H NMR (CDCl3, 300 MHz, δ): 3.03 3.40 (m, 2H), 3.79 (s, 3H), 4.12 4.17 (m, 1H), 7.09 7.33 13 (m, 6H). C NMR (CDCl3, 75.5 MHz) δ: 38.6, 52.3, 72.8, 118.1 (q, J = 275.4 Hz), 127.0, 128.4 (2C), 129.4 (2C), 135.6, 152.0 (q, J = 38.5 Hz), 19 174.2. F NMR (CDCl3, 282 MHz, δ): 71.4 (d, J = 3.0 Hz). HRMS + (ESI, m/z): [M + Na] calcd for C12H12F3NNaO2: 282.0718, found: 282.0725.
General Procedure for the Synthesis of L-α-Amino Ester Functionalized Trifluoromethyl γ-Amino Alcohols syn-4,4’ad or anti-5a–d One mmol of isovaleraldehyde and 5 mol% of L-proline were added to 2 mmol of trifluoromethyl aldimine. The reaction was kept in stirring for 4 h 1 19 at rt, for 2 d at 0°C and for 7 d at –20°C. H and F NMR spectra showed the disappearance of the starting materials and then NaBH4 was added at 0°C (3 h) leading to the formation of the expected trifluoromethyl γ-amino alcohols syn-4,4’a-d or anti-5a-d (Figure 2). Methyl (S)-3-methyl-2-{[(2S,3S)-1,1,1-trifluoro-3-(hydroxymethyl)4-methylpentan-2-yl]amino}butanoate (syn-4a). Yellow oil, 28%. -1 1 νmax cm 3350, 1737. H NMR (CDCl3, 300 MHz, δ): 0.93 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H), 1,10 (d, J = 6.8 Hz, 3H), 1.12-1.18 (m, 1H), 1.64-1.74 (m, 1H), 1.87-1.95 (m, 1H), 1.52-1.62 (m, 2H), 3.68-3.84 (m, 2H), 3.63 (d, J = 6.9 Hz, 1H), 3.76 (s, 3H), 4.0213 4.17 (m 1H). C NMR (CDCl3, 75.5 MHz, δ): 19.0 (2C), 20.3, 21.1, 26.3, 42.1, 46.8, 52.2, 61.6, 64.0, 72.3 (q, J = 29.3 Hz), 128.2 (q, J = 282.1 Hz), 19 174.0. F NMR (CDCl3, 282 MHz, δ): 81.1 (d, J = 7.8 Hz). HRMS + (ESI, m/z): [M + H] calcd for C13H25F3NO3: 300.1787, found: 300.1794.
Fig. 2. L-α-Amino ester functionalized syn-(S,S,S)-, syn-(S,R,R)-4,4’a-d, and anti-(S,S,R)-5a-d trifluoromethyl γ-amino alcohols. Chirality DOI 10.1002/chir
Methyl (S)-4-methyl-2-{[(2S,3S)-1,1,1-trifluoro-3-(hydroxymethyl)4-methylpentan-2-yl]amino}pentanoate (syn-4b). Yellow oil, 24%. -1 1 νmax cm 3345, 1739. H NMR (CDCl3, 300 MHz, δ): 0.98-1.02 (m, 6H), 1.04 (d, J = 6.8 Hz, 3H), 1.06 (d, J = 6.8 Hz, 3H), 1.13-1.17 (m, 1H), 1.521.58 (m, 2H), 1.62-1.65 (m, 1H), 1.76-1.90 (m, 3H), 3.52-3.68 (m, 1H), 13 3.65-3.83 (m, 2H), 3.78 (s, 3H), 4.03-4.20 (m, 1H). C NMR (CDCl3, 75.5 MHz, δ): 19.3, 20.4, 23.0, 23.1, 25.4, 27.3, 40.3, 41.9, 52.2, 58.9, 62.6, 19 72.8 (q, J = 29.3 Hz), 128.6 (q, J = 283.2 Hz), 175.2. F NMR (CDCl3, + 282 MHz, δ): 81.5 (d, J = 7.8 Hz). HRMS (ESI, m/z): [M + H] calcd for C14H27F3NO3: 314.1943, found: 314.1959. Methyl (S)-4-methyl-2-{[(2R,3R)-1,1,1-trifluoro-3-(hydroxymethyl)1 4-methylpentan-2-yl]amino}pentanoate (syn-4’b). Yellow oil, 24%. H NMR (CDCl3, 300 MHz, δ): 0.98 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H), 1.12-1.18 (m, 1H), 1.44-1.52 (m, 2H), 1.96-2.04 (m, 3H), 2.06-2.16 (m, 1H), 3.32-3.40 (m, 2H), 13 3.45-3.63 (m, 1H), 3.77 (s, 3H), 4.00-4.14 (m 1H). C NMR (CDCl3, 75.5 MHz, δ): 20.1, 20.3, 23.2, 23.5, 25.4, 27.3, 40.3, 42.2, 52.3, 58.9, 62.0, 71.2 19 (q, J = 29.3 Hz), 128.9 (q, J = 283.3 Hz), 175.2. F NMR (CDCl3, 282 MHz, + δ): 80.7 (d, J = 7.8 Hz). HRMS (ESI, m/z): [M + H] calcd for C14H27F3NO3: 314.1943, found: 314.1961. Methyl (2S,3S)-3-methyl-2-{[(2S,3S)-1,1,1-trifluoro-3-(hydroxymethyl)4-methylpentan-2-yl]amino}pentanoate (syn-4c). Yellow oil, 20%. -1 1 νmax cm 3355, 1742. H NMR (CDCl3, 300 MHz, δ): 0.98-1.11 (m, 9H), 1.18 (d, J = 6.9 Hz, 3H), 1.21-1.31 (m, 1H), 1.50-1.62 (m, 2H), 1.90-2.06 (m, 4H), 3.30 (d, J = 6.9 Hz, 1H), 3.70-3.89 (m, 2H), 3.80 (s, 3H), 4.0213 4.18 (m, 1H). C NMR (CDCl3, 75.5 MHz, δ): 12.6, 14.2, 20.4 (2C), 27.2, 31.2, 42.0, 46.8, 53.0, 60.0, 61.9, 70.5 (q, J = 29.3 Hz), 128.8 (q, J = 283.6 19 Hz), 174.6. F NMR (CDCl3, 282 MHz, δ): 81.1 (d, J = 7.8 Hz). HRMS + (ESI, m/z): [M + H] calcd for C14H27F3NO3: 314.1943, found: 314.1939. Methyl (2S,3S)-3-methyl-2-{[(2R,3R)-1,1,1-trifluoro-3-(hydroxymethyl)4-methylpentan-2-yl]amino}pentanoate (syn-4’c). Yellow oil, 20%. 1 H NMR (CDCl3, 300 MHz, δ): 1.02 (d, J = 6.9 Hz, 3H), 1.05-1.15 (m, 6H), 1.20 (t, J = 6.9 Hz, 3H), 1.24-1.36 (m, 1H), 1.70-1.90 (m, 3H), 1.96-2.09 (m, 2H), 3.48-3.51 (br, 2H), 3.63-3.84 (m, 2H), 3.76 (s, 3H), 13 4.00-4.18 (m, 1H). C NMR (CDCl3, 75.5 MHz, δ): 11.9, 12.3, 20.2, 22.1, 27.3, 31.0, 42.5, 46.2, 53.1, 61.0, 61.7, 71.3 (q, J = 29.3 Hz), 129.1 (q, J = 19 283.4 Hz), 174.6. F NMR (CDCl3, 282 MHz, δ): 80.9 (d, J = 7.8 Hz). + HRMS (ESI, m/z): [M + H] calcd for C14H27F3NO3: 314.1943, found: 314.1945. Methyl (S)-3-phenyl-2-{[(2S,3S)-1,1,1-trifluoro-3-(hydroxymethyl)4-methylpentan-2-yl]amino}propanoate (syn-4d). Orange oil, 31%. -1 1 νmax cm 3339, 1735. H NMR (CDCl3, 300 MHz, δ): 0.93 (d, J = 6.9 Hz, 3H), 1.02 (d, J = 6.9 Hz, 3H), 1.14-1.31 (m, 1H), 1.95-2.04 (m, 1H), 2.673.04 (m, 2H), 3.08 (br, 2H), 3.50-3.75 (m, 3H), 3.80 (s, 3H), 3.99-4.20 13 (m, 1H), 7.16-7.30 (m, 5H). C NMR (CDCl3, 75.5 MHz, δ): 20.2 (2C), 27.4, 38.2, 46.8, 52.2, 59.3, 61.6, 72.4 (q, J = 29.3 Hz), 127.2, 129.1 (2C), 19 129.6 (2C), 129.9 (q, J = 283.7 Hz), 137.6, 174.2. F NMR (CDCl3, 282 + MHz, δ): 81.2 (d, J = 7.8 Hz). HRMS (ESI, m/z): [M + H] calcd for C17H25F3NO3: 348.1787, found 348.1775. Methyl (S)-3-phenyl-2-{[(2R,3R)-1,1,1-trifluoro-3-(hydroxymethyl)4-methylpentan-2-yl]amino}propanoate (syn-4’d). Orange oil, 31%. 1 H NMR (CDCl3, 300 MHz, δ): 0.98 (d, J = 6.9 Hz, 3H), 1.02 (d, J = 6.9 Hz, 3H), 1.12-1.33 (m, 1H), 1.48-1.57 (m, 1H), 1.80 (br, 2H), 2.81-2.04 (m, 2H), 3.48-3.77 (m, 3H), 3.79 (s, 3H), 3.95-4.16 (m, 1H), 7.15-7.21 (m, 3H), 7.26-
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7.31 (m, 2H). C NMR (CDCl3, 75.5 MHz, δ): 19.5, 20.1, 27.4, 38.0, 47.0, 51.9, 59.3, 60.9, 61.5, 71.6 (q, J = 29.3 Hz), 127.0 (2C), 129.1, 129.3, 129.6 19 (q, J = 281.9 Hz), 137.2, 174.4. F NMR (CDCl3, 282 MHz, δ): 80.7 + (d, J = 7.8 Hz). HRMS (ESI, m/z): [M + H] calcd for C17H25F3NO3: 348.1787, found 348.1773. Methyl (S)-3-methyl-2-{[(2S,3R)-1,1,1-trifluoro-3-(hydroxymethyl)4-methylpentan-2-yl]amino}butanoate (anti-5a). Yellow oil, 42%. νmax -1 1 cm 3351, 1737. H NMR (CDCl3, 300 MHz, δ): 0.96-1.03 (m, 6H), 1.07 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H), 1.13-1.20 (m, 1H), 1.73-1.84 (m, 1H), 1.88-2.16 (m, 3H), 3.60-3.82 (m, 2H), 3.73 (m, 1H), 3.77 (s, 3H), 13 4.06-4.20 (m, 1H). C NMR (CDCl3, 75.5 MHz, δ): 19.0, 19.03, 20.5 (2C), 27.3, 30.0, 47.0, 52.2, 61.7, 63.9, 72.7 (q, J = 29.3 Hz), 128.3 (q, J = 282.7 19 Hz), 174.1. F NMR (CDCl3, 282 MHz, δ): 78.6 (d, J = 7.8 Hz). HRMS + (ESI, m/z): [M + H] calcd for C13H25F3NO3: 300.1787, found: 300.1785. Methyl (S)-4-methyl-2-{[(2S,3R)-1,1,1-trifluoro-3-(hydroxymethyl)4-methylpentan-2-yl]amino}pentanoate (anti-5b). Yellow oil, 38%. -1 1 νmax cm 3343, 1740. H NMR (CDCl3, 300 MHz, δ): 1.00 (d, J = 6.8 Hz, 3H), 1.04-1.06 (m, 6H), 1.08 (d, J = 6.8 Hz, 3H), 1.12-1.18 (m, 1H), 1.39-1.52 (m, 1H), 1.56-1.68 (m, 1H), 1.88-2.05 (m, 3H), 3.49-3.65 (m, 2H), 3.76 13 (s, 3H), 3.82-3.96 (m, 2H), 4.04-4.19 (m, 1H). C NMR (CDCl3, 75.5 MHz, δ): 19.6 (2C), 23.1 (2C), 25.2, 27.3, 40.3, 46.8, 51.9, 59.0, 61.3, 73.1 19 (q, J = 29.3 Hz), 128.7 (q, J = 283.1Hz), 175.6. F NMR (CDCl3, 282 + MHz, δ): 79.1 (d, J = 7.8 Hz). HRMS (ESI, m/z): [M + H] calcd for C14H27F3NO3: 314.1943, found: 314.1957. Methyl (S)-4,5-dimethyl-2-{[(2S,3R)-1,1,1-trifluoro-3-(hydroxymethyl)4-methylpentan-2-yl]amino}hexanoate (anti-5c). Yellow oil, 40%. -1 1 νmax cm 3355, 1739. H NMR (CDCl3, 300 MHz, δ): 1.02 (d, J = 6.9 Hz, 3H), 1.06 (d, J = 6.9 Hz, 3H), 1.08 (d, J = 6.9 Hz, 3H), 1.11 (t, J = 6.9 Hz, 3H), 1.13-1.18 (m, 1H), 1.66-1.78 (m, 1H), 1.96-2.02 (m, 3H), 3.26-3.56 13 (m, 3H), 3.67-3.85 (m, 2H), 3.76 (s, 3H), 4.02-4.20 (m, 1H). C NMR (CDCl3, 75.5 MHz, δ): 15.8, 20.0, 21.5 (2C), 27.3, 31.0, 40.9, 47.0, 53.0, 19 60.2, 62.4, 71.0 (q, J = 29.3 Hz), 129.2 (q, J = 282.4 Hz), 174.3. F NMR + (CDCl3, 282 MHz, δ): 79.2 (d, J = 7.8 Hz). HRMS (ESI, m/z): [M + H] calcd for C14H27F3NO3: 314.1943, found: 314.1932. Methyl (S)-3-phenyl-2-{[(2S,3R)-1,1,1-trifluoro-3-(hydroxymethyl)4-methylpentan-2-yl]amino}propanoate (anti-5d). Yellow orange oil, -1 1 36%. νmax cm 3339, 1735. H NMR (CDCl3, 300 MHz, δ): 0.97-103 (m, 6H), 1.12-1.21 (m, 1H), 2.89-2.93 (m, 1H), 2.97-3.01 (m, 2H), 3.18-3.41 (m, 3H), 3.54-3.65 (m, 2H), 3.78 (s, 3H), 4.01-4.18 (m, 1H), 7.13-7.26 13 (m, 3H), 7.31-7.42 (m, 2H). C NMR (CDCl3, 75.5 MHz, δ): 20.5 (2C), 27.3, 38.0, 46.8, 52.4, 61.0, 62.1, 72.6 (q, J = 29.3 Hz), 127.1, 129.0 (2C), 19 129.4 (q, J = 281.5 Hz), 129.6 (2C), 138.0, 174.2. F NMR (CDCl3, 282 + MHz, δ): 78.9 (d, J = 7.8 Hz). HRMS (ESI, m/z): [M + H] calcd for C17H25F3NO3: 348.1787, found 348.1768.
RESULTS AND DISCUSSION Synthesis of Trifluoromethyl Aldimines Derived From L-α-Amino Esters
To the best of our knowledge, in the literature only one synthesis was reported to obtain trifluoromethyl aldimines derived from α-amino esters starting from two α-amino esters originated from valine and methionine. The condensation reactions were performed with a Dean-Stark trap using PTSA as catalyst and toluene as solvent.25 Following the reported reaction conditions, the condensation between fluoral ethyl hemiacetal and L-valine methyl ester was obtained in 2 h but not in satisfactory yields (
Special Issue Article New Synthesis of Trifluoromethyl Aldimines Containing L-α-Amino Ester Moieties and Their Use in Mannich-Type Reactions LUCA PARISE, ALESSIA PELAGALLI, LAURA TRULLI, MARIA CECILIA VERGARI, STEFANIA FIORAVANTI,* Dipartimento di Chimica, Università degli Studi di Roma “La Sapienza”, Roma, Italy
AND
LUCIO PELLACANI*
ABSTRACT L-α-Amino esters were considered valuable chiral starting materials in the condensation reaction with trifluoroacetaldehyde (fluoral) ethyl hemiacetal to obtain new functionalized trifluoromethyl aldimines. Starting from these latter compounds, isovaleraldehyde was used in proline-catalyzed Mannich-type addition reactions to give trifluoromethyl syn- or anti-γ-amino alcohols bearing the L-α-amino ester function, simply by changing the reaction temperature. Chirality 27:571–575, 2015. © 2015 Wiley Periodicals, Inc. KEY WORDS: asymmetric synthesis; amino acids; fluorinated compounds; chiral molecules; absolute configuration; stereoselectivity Fluorinated or trifluoromethylated nitrogen compounds have shown important biological effects and special electronic properties in bioactive natural products as well as in pharmaceutically important compounds. So, in these last years, asymmetric synthesis has turned its attention towards fluorinated molecules, in particular carrying the trifluoromethyl group, which improves chemical, physical, and biological properties of drug candidates, such as shown by the number of CF3-containing drugs that are clinically used or are in development.1–6 Fluorine-containing compounds7 can be obtained either through trifluoromethylation techniques or by starting from available fluorinated materials,8 the latter strategy being considered among the most direct and easy methods to obtain structurally elaborated molecules. Even more important is to plan strategies for the synthesis of nitrogencontaining molecules. In this field, we reported a new solvent-free synthesis of (E)trifluoromethyl imines9 starting from trifluoroacetaldehyde (fluoral) ethyl hemiacetal.10 The obtained compounds can be regarded as powerful building blocks for the construction of more complex trifluoromethylated nitrogen compounds.11–20 Recently, (E)-trifluoromethyl aldimines were successfully considered by us in the ZrCl4-catalyzed aza-Henry addition with different nitro alkanes,21 and the obtained nitro amines were converted by simple chemical transformations into interesting N,N’-diprotected CF3-modified dipeptides.22 Continuing our study, we here report an efficient methodology for the synthesis of trifluoromethyl aldimines, derived from α-amino esters, that subsequently were considered in a proline-catalyzed Mannich-type reaction,23 key steps for the synthesis of fluorinated γ-amino alcohols. MATERIALS AND METHODS The synthesis of trifluoromethyl aldimines was carried out in flamedried glassware under an argon atmosphere. The crude reaction mixtures and all purified products were concentrated by using a rotary evaporator. Flash chromatography was performed on 230–400 mesh silica gel. Analytical thin-layer chromatography (TLC) was carried out on precoated (0.25 mm) silica gel plates. High-performance liquid © 2015 Wiley Periodicals, Inc.
chromatography (HPLC) analyses were performed with a Varian (Walnut Creek, CA) 9001 instrument using an analytical column (3.9 × 300 mm, flow rate 1.3 mL/min) equipped with a Varian RI-4 differential refractometer or a Varian 9050 UV/VIS detector. Eluents were HPLC-grade. IR spectra were recorded on a Perkin-Elmer (Norwalk, CT) 1600 Series -1 FT/IR spectrophotometer in CHCl3 as the solvent, and reported in cm . 1 13 19 H, C, and F nuclear magnetic resonance (NMR) spectra were recorded at 300 MHz on a Varian-Mercury 300 instrument and reported in δ values. CDCl3 was used as the solvent and CHCl3 (δ = 7.26 ppm for 1 13 H NMR), CDCl3 (δ = 77.0 ppm for C NMR), and C6F6 (δ = 164.9 for 19 F NMR) were used as internal standards. The NOESY experiments were performed on a Bruker (Billerica, MA) Avance III instrument at 400 MHz using CDCl3 as the solvent and used to assist in structure elucidation.24 Electrospray ionization, mass spectrometry (ESIMS) analyses were performed using a quadrupole-time of flight (Q-TOF) mass spectrometer equipped with an ESI source and a syringe pump. The experiments were carried out in the positive ion mode.
General Procedure for the Synthesis of Trifluoromethyl Aldimines 2a–d A solution of 1 mmol of L-α-amino ester and 1.5 mmol of fluoral ethyl hemiacetal in anhydrous toluene (5 mL) was added under an Ar atmosphere into a round-bottom flask containing previously activated 4Å molecular sieves (3 g). The reaction was stirred at reflux for 1 h. The crude mixture was filtered on filter paper. After solvent removal, the obtained trifluoromethyl aldimines (E)-2a–d (Figure 1) were used without further purification. Methyl (S)-3-methyl-2-{[(1E)-2,2,2-trifluoroethylidene]amino}butanoate (2a). Dark orange oil, 54%. Known compound.25 Methyl (S)-4-methyl-2-{[(1E)-2,2,2-trifluoroethylidene]amino}pentanoate 1 (2b). Dark orange oil, 72%. νmax 1736, 1686. H NMR (CDCl3, 300 MHz, δ): 0.89 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H), 1.44 1.55 (m, 1H), 1.81 (t, J = 7.0 Hz, 2H), 3.76 (s, 3H), 4.16 (t, J = 7.2 Hz, 1H), 13 7.66 7.70 (m, 1H). C NMR (CDCl3, 75.5 MHz, δ): 21.3, 22.7, 24.3, *Correspondence to: Stefania Fioravanti or Lucio Pellacani, Dipartimento di Chimica, Università degli Studi di Roma “La Sapienza”, P.le Aldo Moro 5, I-00185 Roma, Italy. E-mail: stefania.fi[email protected] or E-mail: lucio. [email protected] Received for publication 30 March 2015; Accepted 20 May 2015 DOI: 10.1002/chir.22478 Published online 14 July 2015 in Wiley Online Library (wileyonlinelibrary.com).
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Methyl (S)-3-methyl-2-{[(2R,3R)-1,1,1-trifluoro-3-(hydroxymethyl)1 4-methylpentan-2-yl]amino}butanoate (syn-4’a). Yellow oil, 28%. H NMR (CDCl3, 300 MHz, δ): 1.04 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H), 1,10 (d, J = 6.8 Hz, 3H), 1.13-1.17 (m, 1H), 1.64-1.84 (m, 2H), 2.05-2.15 (m, 1H), 3.05 (d, J = 6.9 Hz, 1H), 3.56-3.79 13 (m, 2H), 3.48 (br, 1H), 3.76 (s, 3H), 5.96-4.10 (m, 1H). C NMR (CDCl3, 75.5 MHz, δ): 19.1, 19.3, 20.9 (2C), 27.3, 42.3, 46.8, 52.1, 60.9, 63.8, 71.3 19 (q, J = 29.3 Hz), 128.5 (q, J = 282.5 Hz), 174.3. F NMR (CDCl3, 282 MHz, + δ): 80.3 (d, J = 7.8 Hz). HRMS (ESI, m/z): [M + H] calcd for C13H25F3NO3: 300.1787, found: 300.1782.
Fig. 1. Trifluoromethyl aldimines derived from L-α-amino esters.
19
41.4, 52.4, 69.5, 118.5 (q, J = 275.1 Hz), 151.4 (q, J = 38.6 Hz), 170.7. F NMR (CDCl3, 282 MHz, δ): 71.46 (d, J = 3.3 Hz). HRMS (ESI, m/z): + [M + Na] calcd for C9H14F3NNaO2 248.0874, found 248.0878. Methyl (2S,3S)-3-methyl-2-{[(1E)-2,2,2-trifluoroethylidene]amino} -1 1 pentanoate (2c). Dark orange oil, 74% . νmax cm 1738, 1686. H NMR (CDCl3, 300 MHz, δ): 0.81 0.91 (m, 6H), 1.02 1.50 (m, 2H), 2.01 2.15 (m, 1H), 3.72 (s, 3H), 3.84 (d, J = 6.5 Hz, 1H), 7.62 (q, J = 3.2 Hz, 1H). 13 C NMR (CDCl3, 75.5 MHz, δ): 10.9, 15.4, 24.8, 37.9, 52.1, 76.7, 118.4 19 (q, J = 275.1 Hz), 151.6 (q, J = 38.5 Hz), 170.3. F NMR (CDCl3, 282 + MHz, δ): 71.5 (d, J = 3.0 Hz). HRMS (ESI, m/z): [M + Na] calcd for C9H14F3NNaO2 248.0874, found 248.0871. Methyl (S)-3-phenyl-2-{[(1E)-2,2,2-trifluoroethylidene]amino}propanoate -1 1 (2d). Dark orange oil, 73%. νmax cm 1737, 1683. H NMR (CDCl3, 300 MHz, δ): 3.03 3.40 (m, 2H), 3.79 (s, 3H), 4.12 4.17 (m, 1H), 7.09 7.33 13 (m, 6H). C NMR (CDCl3, 75.5 MHz) δ: 38.6, 52.3, 72.8, 118.1 (q, J = 275.4 Hz), 127.0, 128.4 (2C), 129.4 (2C), 135.6, 152.0 (q, J = 38.5 Hz), 19 174.2. F NMR (CDCl3, 282 MHz, δ): 71.4 (d, J = 3.0 Hz). HRMS + (ESI, m/z): [M + Na] calcd for C12H12F3NNaO2: 282.0718, found: 282.0725.
General Procedure for the Synthesis of L-α-Amino Ester Functionalized Trifluoromethyl γ-Amino Alcohols syn-4,4’ad or anti-5a–d One mmol of isovaleraldehyde and 5 mol% of L-proline were added to 2 mmol of trifluoromethyl aldimine. The reaction was kept in stirring for 4 h 1 19 at rt, for 2 d at 0°C and for 7 d at –20°C. H and F NMR spectra showed the disappearance of the starting materials and then NaBH4 was added at 0°C (3 h) leading to the formation of the expected trifluoromethyl γ-amino alcohols syn-4,4’a-d or anti-5a-d (Figure 2). Methyl (S)-3-methyl-2-{[(2S,3S)-1,1,1-trifluoro-3-(hydroxymethyl)4-methylpentan-2-yl]amino}butanoate (syn-4a). Yellow oil, 28%. -1 1 νmax cm 3350, 1737. H NMR (CDCl3, 300 MHz, δ): 0.93 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H), 1,10 (d, J = 6.8 Hz, 3H), 1.12-1.18 (m, 1H), 1.64-1.74 (m, 1H), 1.87-1.95 (m, 1H), 1.52-1.62 (m, 2H), 3.68-3.84 (m, 2H), 3.63 (d, J = 6.9 Hz, 1H), 3.76 (s, 3H), 4.0213 4.17 (m 1H). C NMR (CDCl3, 75.5 MHz, δ): 19.0 (2C), 20.3, 21.1, 26.3, 42.1, 46.8, 52.2, 61.6, 64.0, 72.3 (q, J = 29.3 Hz), 128.2 (q, J = 282.1 Hz), 19 174.0. F NMR (CDCl3, 282 MHz, δ): 81.1 (d, J = 7.8 Hz). HRMS + (ESI, m/z): [M + H] calcd for C13H25F3NO3: 300.1787, found: 300.1794.
Fig. 2. L-α-Amino ester functionalized syn-(S,S,S)-, syn-(S,R,R)-4,4’a-d, and anti-(S,S,R)-5a-d trifluoromethyl γ-amino alcohols. Chirality DOI 10.1002/chir
Methyl (S)-4-methyl-2-{[(2S,3S)-1,1,1-trifluoro-3-(hydroxymethyl)4-methylpentan-2-yl]amino}pentanoate (syn-4b). Yellow oil, 24%. -1 1 νmax cm 3345, 1739. H NMR (CDCl3, 300 MHz, δ): 0.98-1.02 (m, 6H), 1.04 (d, J = 6.8 Hz, 3H), 1.06 (d, J = 6.8 Hz, 3H), 1.13-1.17 (m, 1H), 1.521.58 (m, 2H), 1.62-1.65 (m, 1H), 1.76-1.90 (m, 3H), 3.52-3.68 (m, 1H), 13 3.65-3.83 (m, 2H), 3.78 (s, 3H), 4.03-4.20 (m, 1H). C NMR (CDCl3, 75.5 MHz, δ): 19.3, 20.4, 23.0, 23.1, 25.4, 27.3, 40.3, 41.9, 52.2, 58.9, 62.6, 19 72.8 (q, J = 29.3 Hz), 128.6 (q, J = 283.2 Hz), 175.2. F NMR (CDCl3, + 282 MHz, δ): 81.5 (d, J = 7.8 Hz). HRMS (ESI, m/z): [M + H] calcd for C14H27F3NO3: 314.1943, found: 314.1959. Methyl (S)-4-methyl-2-{[(2R,3R)-1,1,1-trifluoro-3-(hydroxymethyl)1 4-methylpentan-2-yl]amino}pentanoate (syn-4’b). Yellow oil, 24%. H NMR (CDCl3, 300 MHz, δ): 0.98 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H), 1.12-1.18 (m, 1H), 1.44-1.52 (m, 2H), 1.96-2.04 (m, 3H), 2.06-2.16 (m, 1H), 3.32-3.40 (m, 2H), 13 3.45-3.63 (m, 1H), 3.77 (s, 3H), 4.00-4.14 (m 1H). C NMR (CDCl3, 75.5 MHz, δ): 20.1, 20.3, 23.2, 23.5, 25.4, 27.3, 40.3, 42.2, 52.3, 58.9, 62.0, 71.2 19 (q, J = 29.3 Hz), 128.9 (q, J = 283.3 Hz), 175.2. F NMR (CDCl3, 282 MHz, + δ): 80.7 (d, J = 7.8 Hz). HRMS (ESI, m/z): [M + H] calcd for C14H27F3NO3: 314.1943, found: 314.1961. Methyl (2S,3S)-3-methyl-2-{[(2S,3S)-1,1,1-trifluoro-3-(hydroxymethyl)4-methylpentan-2-yl]amino}pentanoate (syn-4c). Yellow oil, 20%. -1 1 νmax cm 3355, 1742. H NMR (CDCl3, 300 MHz, δ): 0.98-1.11 (m, 9H), 1.18 (d, J = 6.9 Hz, 3H), 1.21-1.31 (m, 1H), 1.50-1.62 (m, 2H), 1.90-2.06 (m, 4H), 3.30 (d, J = 6.9 Hz, 1H), 3.70-3.89 (m, 2H), 3.80 (s, 3H), 4.0213 4.18 (m, 1H). C NMR (CDCl3, 75.5 MHz, δ): 12.6, 14.2, 20.4 (2C), 27.2, 31.2, 42.0, 46.8, 53.0, 60.0, 61.9, 70.5 (q, J = 29.3 Hz), 128.8 (q, J = 283.6 19 Hz), 174.6. F NMR (CDCl3, 282 MHz, δ): 81.1 (d, J = 7.8 Hz). HRMS + (ESI, m/z): [M + H] calcd for C14H27F3NO3: 314.1943, found: 314.1939. Methyl (2S,3S)-3-methyl-2-{[(2R,3R)-1,1,1-trifluoro-3-(hydroxymethyl)4-methylpentan-2-yl]amino}pentanoate (syn-4’c). Yellow oil, 20%. 1 H NMR (CDCl3, 300 MHz, δ): 1.02 (d, J = 6.9 Hz, 3H), 1.05-1.15 (m, 6H), 1.20 (t, J = 6.9 Hz, 3H), 1.24-1.36 (m, 1H), 1.70-1.90 (m, 3H), 1.96-2.09 (m, 2H), 3.48-3.51 (br, 2H), 3.63-3.84 (m, 2H), 3.76 (s, 3H), 13 4.00-4.18 (m, 1H). C NMR (CDCl3, 75.5 MHz, δ): 11.9, 12.3, 20.2, 22.1, 27.3, 31.0, 42.5, 46.2, 53.1, 61.0, 61.7, 71.3 (q, J = 29.3 Hz), 129.1 (q, J = 19 283.4 Hz), 174.6. F NMR (CDCl3, 282 MHz, δ): 80.9 (d, J = 7.8 Hz). + HRMS (ESI, m/z): [M + H] calcd for C14H27F3NO3: 314.1943, found: 314.1945. Methyl (S)-3-phenyl-2-{[(2S,3S)-1,1,1-trifluoro-3-(hydroxymethyl)4-methylpentan-2-yl]amino}propanoate (syn-4d). Orange oil, 31%. -1 1 νmax cm 3339, 1735. H NMR (CDCl3, 300 MHz, δ): 0.93 (d, J = 6.9 Hz, 3H), 1.02 (d, J = 6.9 Hz, 3H), 1.14-1.31 (m, 1H), 1.95-2.04 (m, 1H), 2.673.04 (m, 2H), 3.08 (br, 2H), 3.50-3.75 (m, 3H), 3.80 (s, 3H), 3.99-4.20 13 (m, 1H), 7.16-7.30 (m, 5H). C NMR (CDCl3, 75.5 MHz, δ): 20.2 (2C), 27.4, 38.2, 46.8, 52.2, 59.3, 61.6, 72.4 (q, J = 29.3 Hz), 127.2, 129.1 (2C), 19 129.6 (2C), 129.9 (q, J = 283.7 Hz), 137.6, 174.2. F NMR (CDCl3, 282 + MHz, δ): 81.2 (d, J = 7.8 Hz). HRMS (ESI, m/z): [M + H] calcd for C17H25F3NO3: 348.1787, found 348.1775. Methyl (S)-3-phenyl-2-{[(2R,3R)-1,1,1-trifluoro-3-(hydroxymethyl)4-methylpentan-2-yl]amino}propanoate (syn-4’d). Orange oil, 31%. 1 H NMR (CDCl3, 300 MHz, δ): 0.98 (d, J = 6.9 Hz, 3H), 1.02 (d, J = 6.9 Hz, 3H), 1.12-1.33 (m, 1H), 1.48-1.57 (m, 1H), 1.80 (br, 2H), 2.81-2.04 (m, 2H), 3.48-3.77 (m, 3H), 3.79 (s, 3H), 3.95-4.16 (m, 1H), 7.15-7.21 (m, 3H), 7.26-
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TRIFLUOROMETHYL ALDIMINES IN MANNICH-TYPE REACTIONS 13
7.31 (m, 2H). C NMR (CDCl3, 75.5 MHz, δ): 19.5, 20.1, 27.4, 38.0, 47.0, 51.9, 59.3, 60.9, 61.5, 71.6 (q, J = 29.3 Hz), 127.0 (2C), 129.1, 129.3, 129.6 19 (q, J = 281.9 Hz), 137.2, 174.4. F NMR (CDCl3, 282 MHz, δ): 80.7 + (d, J = 7.8 Hz). HRMS (ESI, m/z): [M + H] calcd for C17H25F3NO3: 348.1787, found 348.1773. Methyl (S)-3-methyl-2-{[(2S,3R)-1,1,1-trifluoro-3-(hydroxymethyl)4-methylpentan-2-yl]amino}butanoate (anti-5a). Yellow oil, 42%. νmax -1 1 cm 3351, 1737. H NMR (CDCl3, 300 MHz, δ): 0.96-1.03 (m, 6H), 1.07 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H), 1.13-1.20 (m, 1H), 1.73-1.84 (m, 1H), 1.88-2.16 (m, 3H), 3.60-3.82 (m, 2H), 3.73 (m, 1H), 3.77 (s, 3H), 13 4.06-4.20 (m, 1H). C NMR (CDCl3, 75.5 MHz, δ): 19.0, 19.03, 20.5 (2C), 27.3, 30.0, 47.0, 52.2, 61.7, 63.9, 72.7 (q, J = 29.3 Hz), 128.3 (q, J = 282.7 19 Hz), 174.1. F NMR (CDCl3, 282 MHz, δ): 78.6 (d, J = 7.8 Hz). HRMS + (ESI, m/z): [M + H] calcd for C13H25F3NO3: 300.1787, found: 300.1785. Methyl (S)-4-methyl-2-{[(2S,3R)-1,1,1-trifluoro-3-(hydroxymethyl)4-methylpentan-2-yl]amino}pentanoate (anti-5b). Yellow oil, 38%. -1 1 νmax cm 3343, 1740. H NMR (CDCl3, 300 MHz, δ): 1.00 (d, J = 6.8 Hz, 3H), 1.04-1.06 (m, 6H), 1.08 (d, J = 6.8 Hz, 3H), 1.12-1.18 (m, 1H), 1.39-1.52 (m, 1H), 1.56-1.68 (m, 1H), 1.88-2.05 (m, 3H), 3.49-3.65 (m, 2H), 3.76 13 (s, 3H), 3.82-3.96 (m, 2H), 4.04-4.19 (m, 1H). C NMR (CDCl3, 75.5 MHz, δ): 19.6 (2C), 23.1 (2C), 25.2, 27.3, 40.3, 46.8, 51.9, 59.0, 61.3, 73.1 19 (q, J = 29.3 Hz), 128.7 (q, J = 283.1Hz), 175.6. F NMR (CDCl3, 282 + MHz, δ): 79.1 (d, J = 7.8 Hz). HRMS (ESI, m/z): [M + H] calcd for C14H27F3NO3: 314.1943, found: 314.1957. Methyl (S)-4,5-dimethyl-2-{[(2S,3R)-1,1,1-trifluoro-3-(hydroxymethyl)4-methylpentan-2-yl]amino}hexanoate (anti-5c). Yellow oil, 40%. -1 1 νmax cm 3355, 1739. H NMR (CDCl3, 300 MHz, δ): 1.02 (d, J = 6.9 Hz, 3H), 1.06 (d, J = 6.9 Hz, 3H), 1.08 (d, J = 6.9 Hz, 3H), 1.11 (t, J = 6.9 Hz, 3H), 1.13-1.18 (m, 1H), 1.66-1.78 (m, 1H), 1.96-2.02 (m, 3H), 3.26-3.56 13 (m, 3H), 3.67-3.85 (m, 2H), 3.76 (s, 3H), 4.02-4.20 (m, 1H). C NMR (CDCl3, 75.5 MHz, δ): 15.8, 20.0, 21.5 (2C), 27.3, 31.0, 40.9, 47.0, 53.0, 19 60.2, 62.4, 71.0 (q, J = 29.3 Hz), 129.2 (q, J = 282.4 Hz), 174.3. F NMR + (CDCl3, 282 MHz, δ): 79.2 (d, J = 7.8 Hz). HRMS (ESI, m/z): [M + H] calcd for C14H27F3NO3: 314.1943, found: 314.1932. Methyl (S)-3-phenyl-2-{[(2S,3R)-1,1,1-trifluoro-3-(hydroxymethyl)4-methylpentan-2-yl]amino}propanoate (anti-5d). Yellow orange oil, -1 1 36%. νmax cm 3339, 1735. H NMR (CDCl3, 300 MHz, δ): 0.97-103 (m, 6H), 1.12-1.21 (m, 1H), 2.89-2.93 (m, 1H), 2.97-3.01 (m, 2H), 3.18-3.41 (m, 3H), 3.54-3.65 (m, 2H), 3.78 (s, 3H), 4.01-4.18 (m, 1H), 7.13-7.26 13 (m, 3H), 7.31-7.42 (m, 2H). C NMR (CDCl3, 75.5 MHz, δ): 20.5 (2C), 27.3, 38.0, 46.8, 52.4, 61.0, 62.1, 72.6 (q, J = 29.3 Hz), 127.1, 129.0 (2C), 19 129.4 (q, J = 281.5 Hz), 129.6 (2C), 138.0, 174.2. F NMR (CDCl3, 282 + MHz, δ): 78.9 (d, J = 7.8 Hz). HRMS (ESI, m/z): [M + H] calcd for C17H25F3NO3: 348.1787, found 348.1768.
RESULTS AND DISCUSSION Synthesis of Trifluoromethyl Aldimines Derived From L-α-Amino Esters
To the best of our knowledge, in the literature only one synthesis was reported to obtain trifluoromethyl aldimines derived from α-amino esters starting from two α-amino esters originated from valine and methionine. The condensation reactions were performed with a Dean-Stark trap using PTSA as catalyst and toluene as solvent.25 Following the reported reaction conditions, the condensation between fluoral ethyl hemiacetal and L-valine methyl ester was obtained in 2 h but not in satisfactory yields (
