Efficient Multicomponent Synthesis
of α-Trifluoromethyl Proline, Homoproline, and
Azepan Carboxylic Acid Dipeptides

Anton V. Gulevich; Nikolay E. Shevchenko; Elisabeth S. Balenkova; Gerd-V. Röschenthaler; Valentine G. Nenajdenko

doi:10.1055/s-0028-1087529

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Synlett 2009(3): 403-406
DOI: 10.1055/s-0028-1087529

LETTER

Efficient Multicomponent Synthesis of α-Trifluoromethyl Proline, Homoproline, and Azepan Carboxylic Acid Dipeptides

Anton V. Gulevich^a, Nikolay E. Shevchenko^a, Elisabeth S. Balenkova^a, Gerd-V. Röschenthaler*^b, Valentine G. Nenajdenko*^a
^a Department of Chemistry, Moscow State University, Leninskije Gory, 119992 Moscow, Russian Federation
Fax: +7(495)9328846; e-Mail: nen@acylium.chem.msu.ru;
^b Institute of Inorganic and Physical Chemistry, University of Bremen, Leobener Str., 28334 Bremen, Germany
Fax: +49(421)2184267; e-Mail: gvr@chemie.uni-bremen.de;

Further Information

Publication History

Received 22 August 2008
Publication Date:
21 January 2009 (online)

Abstract
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Supplementary Material

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Abstract

Cyclic imines bearing CF₃ and C₂F₅ group were successfully used for the first Ugi multicomponent synthesis of polyfluoroalkyl-substituted proline, homoproline, and azepan carboxylic acid derivatives. Based on the suggested reaction the first synthesis of dipeptides containing α-CF₃ cyclic amino acids residue was described. The scope and limitations of the approach are discussed.

Key words

amino acids - peptides - fluorine - multicomponent reactions - imines

Supporting Information

References and Notes

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14

The CF₃-imines 1a,c,e were prepared using a standard Claisen condensation and subsequent decarboxylation, details will be published in due course.
Synthesis of 2- CF₃ Pyrroline (1a)
The stirred suspension of 60% NaH (26.7 g 0.665 mol) in anhyd THF (250 mL) was heated at reflux while a mixture of freshly distilled N-vinylpyrrolidin-2-one (55.0 g, 0.50 mol) and ethyl trifluoroacetate (78.0 g, 0.55 mol) was slowly added. After refluxing for an additional hour the reaction mixture was cooled to r.t. and carefully diluted with solution of AcOH (40 g) in H₂O (100 mL). The organic layer was separated and the solution of crude keto lactam product was slowly added to 6 N HCl (0.5 L) under stirring and heating at reflux. THF was removed during the addition by use of the distilling head. After heating at reflux for 60 h the reaction mixture was cooled to 0 ˚C, made basic to pH 12 by using 50% KOH aq and extracted with Et₂O (4 × 100 mL). The combined organic layers were dried over K₂CO₃ and concentrated under atmospheric pressure to give 73 g of crude cyclic hemi-aminal product as an oil that solidified under cooling. To remove H₂O the cyclic hemi-aminal was distilled at atmospheric pressure to the receiving flask charged with anhyd Na₂SO₄ (20 g). The drying agent was removed by filtration to afford 54.0 g (79% yield) of product as a clear, colorless liquid. ^¹H NMR (200 MHz, CDCl₃): δ = 1.97-2.12 (m, 2 H), 2.70-2.78 (m, 2 H), 3.98-4.08 (m, 2 H). ^¹9F NMR (188 MHz, CDCl₃): δ = -71.4 (s, 3 F). ^¹³C NMR (100 MHz, CDCl₃): δ = 124.9 (q, J = 285.4 Hz, CF₃), 115.9 (q, J = 35.4 Hz), 62.2, 33.7, 22.6. HRMS (EI): m/z calcd for C₅H₆F₃N: 137.0452; found: 137.0462.

15

General Procedure for the Ugi Reaction
The imine (1 mmol) was dissolved in CH₂Cl₂ (10 mL) and TFA (1 mmol), then isocyanide was added at -20 ˚C. The mixture was stirred for 12 h and treated with a mixture of EtOH-HCl aq (10:1, 0.5 mL) to remove any remaining isocyanide. The solvent was evaporated, and the residue was purified by column chromatography (hexane-EtOAc,4:1).

16

Selected Analytical Data
Compound 2a: yield 80%; colorless oil; R _f = 0.8 (hexanes-EtOAc, 3:1). ^¹H NMR (200 MHz, CDCl₃): δ = 1.36 (s, 9 H), 1.97-2.63 (m, 2 H), 2.25-2.60 (m, 2 H), 3.67-3.85 (m, 1 H), 3.90-4.07 (m, 1 H), 6.00 (br s, 1 H) ppm. ^¹9F NMR (188 MHz, CDCl₃): δ = -73.7 (s, 3 F), -69.1 (s, 3 F) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 163.4, 156.1 (m), 124.9 (q, J = 285.4 Hz, CF₃), 115.9 (q, J = 288.4 Hz, CF₃), 52.4, 49.6 (m), 33.8, 28.3, 23.8 ppm. HRMS (EI): m/z calcd for C₁₂H₁₆F₆N₂O₂: 334.1116; found: 334.1112.
Compound 2c: yield 61%; white solid, mp 55-57 ˚C; R _f = 0.8 (hexanes-EtOAc, 3:1). ^¹H NMR (200 MHz, CDCl₃): δ = 1.35 (s, 9 H), 2.00-2.19 (m, 2 H), 2.38-2.55 (m, 2 H), 3.50-3.75 (m, 1 H), 3.90-4.20 (m, 1 H), 6.1 (br s, 1 H) ppm. ^¹9F NMR (188 MHz, CDCl₃): δ = -73.8 (s, 3 F), -80.5 (s, 3 F), -106.2, -107.7, -109.0, -110.5 (AB system, δ_A = -109.3 ppm, δ_B = -107.4 ppm, ^² J _AB = 275.9 Hz, 2 F) ppm. HRMS (EI): m/z calcd for C₁₃H₁₆F₈N₂O₂: 384.1084; found: 384.1080.
Compound 2g: yield 70%; white solid; mp 121-123 ˚C; R _f = 0.8 (hexanes-EtOAc, 3:1). ^¹H NMR (200 MHz, CDCl₃): δ = 1.68-1.87 (m, 3 H), 1.94-2.17 (m, 2 H), 2.31-2.55 (m, 1 H), 3.38 (t, J = 14.7 Hz, 1 H), 3.82-4.11 (m, 1 H), 4.40-4.68 (m, 2 H), 6.0 (br s, 1 H), 6.86 (d, J = 8.6 Hz), 7.19-7.43 (m, 5 H) ppm. ^¹9F NMR (188 MHz, CDCl₃): δ = -71.2 (s, 3 F), -80.6 (s, 3 F), -106.2, -107.7, -109.6, -111.1 (AB system, δ_A =
-110.0 ppm, δ_B = -107.4 ppm, ^² J _AB = 281.1 Hz, 2 F) ppm. HRMS (EI): m/z calcd for C₁₇H₁₆F₈N₂O₂: 432.1084; found: 432.1102.
Compound 2i: yield 59%; colorless oil; R _f = 0.8 (hexanes-EtOAc, 3:1). ^¹H NMR (400 MHz, CDCl₃): δ = 1.25-1.30 (m, 1 H), 1.36 (s, 9 H), 1.66-1.90 (m, 3 H), 1.90-2.00 (m, 1 H), 2.05-2.17 (m, 2 H), 2.23-2.33 (m, 1 H), 3.20-3.30 (m, 1 H), 3.90-4.00 (m, 1 H), 5.40 (br s)ppm. ^¹9F NMR (188 MHz, CDCl₃): δ = -69.8 (s, 3 F), -70.1 (s, 3 F) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 162.1, 157.4 (q, J = 35.9 Hz), 125.9 (q,
J = 289.8 Hz), 116.3 (q, J = 288.3 Hz), 70.2 (q, J = 24.9 Hz), 52.0, 46.2, 33.0, 30.5, 28.6, 22.3, 28.3 ppm. HRMS (EI): m/z calcd for C₁₄H₂₀F₆N₂O₂: 362.1429; found: 362.1433.
Compound 4b (mixture of diastereomers, ca. 1:1): yield 60%; yellow oil; R _f = 0.6 (hexanes-EtOAc, 3:1). ^¹H NMR (200 MHz, CDCl₃): δ = 1.24, 1.25 (dt, J = 6.9 Hz, 3 H), 1.90-2.15 (m, 2 H), 2.26-2.50 (m, 2 H), 3.10-3.22 (m, 2 H), 3.65-3.85 (m, 1 H), 3.89-4.04 (m, 1 H), 4.09-4.30 (m, 2 H), 4.80-4.95 (m, 1 H) 6.6 (br s, 1 H), 7.00-7.35 (m, 5 H) ppm. ^¹9F NMR (188 MHz, CDCl₃): δ = -69.2 (s, 3 F), -73.6, -73.7 (ds, 3 F) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 170.6, 170.5, 164.1, 163.9, 155.4 (q, J = 34.4 Hz), 135.3, 135.2, 129.3, 129.2, 128.4, 127.1, 121.7, 121.6 (dq, J = 286.6 Hz), 118.8 (q, J = 277.6 Hz), 72.7 (m), 61.7, 61.6, 53.7, 53.5, 49.5, 37.5, 37.3, 33.8, 33.7, 23.6, 13.8 ppm. HRMS (EI): m/z calcd for C₁₉H₂₀F₆N₂O₄: 454.1327; found: 454.1333.
Compound 4f (mixture of diastereomers, ca. 1:1): yield 53%; yellow oil; R _f = 0.6 (hexanes-EtOAc, 3:1). ^¹H NMR (200 MHz, CDCl₃): δ = 1.27 (t, J = 7.3 Hz, 3 H), 1.40-1.55 (m, 3 H), 1.97-2.25 (m, 2 H), 2.45-2.70 (m, 2 H), 3.60-3.81 (m, 1 H), 4.00-4.40 (m, 3 H), 4.45-4.70 (m, 1 H), 6.00, 7.50 (br ds, 1 H) ppm. ^¹9F NMR (188 MHz, CDCl₃): δ = -73.2,
-73.3 (ds, 3 F), -79.8, -80.0 (ds, 3 F), -105.5, -107.0, -107.6, -108.7 (AB system, δ_A = -108.3 ppm, δ_B = -106.3 ppm, ^² J _AB = 277.6 Hz), -106.0, -107.4, -109.0, -110.2 (AB system, δ_A = -109.2 ppm, δ_B = -107.2 ppm, ^² J _AB = 277.6 Hz)ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 172.3, 172.1, 163.9, 163.8, 156.8, 115.9 (q, J = 286.9 Hz), 108.0-126.0 (unresolved signals, C₂F₅ group), 72.7 (m), 61.8, 61.7, 49.7 (m), 49.1, 34.1, 23.1, 17.8, 17.7, 14.0 ppm. HRMS (EI): m/z calcd for C₁₄H₁₆F₈N₂O₄: 428.0982; found: 428.0978.
Compound 4i (mixture of diastereomers, ca. 1:1): yield 44%; colorless oil; R _f = 0.6 (hexanes-EtOAc, 3:1). ^¹H NMR (200 MHz, CDCl₃): δ = 1.28 (t, J = 7.3 Hz, 3 H), 1.70-1.95 (m, 4 H), 2.05-2.40 (m, 6 H), 2.40-2.55 (m, 2 H), 3.35-3.60 (m, 1 H), 3.85-4.10 (m, 1 H), 4.21 (q, J = 7.3 Hz, 2 H), 4.53-4.70 (m, 1 H), 6.55-6.80 (m, 1 H) ppm. ^¹9F NMR (188 MHz, CDCl₃): δ = -68.05, -68.41 (ds, 3 F), -70.0, -70.1 (ds, 3 F) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 171.4, 171.3, 164.5, 164.0, 157.0 (m), 125.3, 125.1 (dq, J = 289.8 Hz), 115.9 (q, J = 287.6 Hz), 66.3 (m), 61.8, 52.2, 42.0, 41.7, 30.9, 30.6, 29.7, 29.5, 28.2, 27.7, 21.5, 21.3, 15.2, 15.2, 15.1, 15.0, 13.9 ppm. HRMS (EI): m/z calcd for C₁₆H₂₂F₆N₂O₄S: 452.1205; found: 452.1220.
Compound 4k (mixture of diastereomers, ca. 1:1): yield 50%; colorless oil; R _f = 0.6 (hexanes-EtOAc, 3:1). ^¹H NMR (200 MHz, CDCl₃): δ = 1.20-1.35 9m, 3 H), 1.44 (t, J = 7.3 Hz, 3 H), 1.70-1.87 (m, 3 H), 1.90-1.25 (m, 2 H), 2.30-2.50 (m, 1 H), 3.20-3.50 (m, 1 H), 3.80-4.00 (m, 1 H), 4.10-4.30 (m, 2 H), 4.45-4.68 (m, 1 H), 6.6, 6.2 (br ds, 1 H) ppm. ^¹9F NMR (188 MHz, CDCl₃): δ = -70.6, -70.5 (ds, 3 F), -79.9, -79.8 (ds, 3 F), -106.2, -107.7, -109.7, -111.2 (AB system, δ_A = -110.0 ppm, δ_B = -107.4 ppm, ^² J _AB = 277.6 Hz),
-106.3, -107.8, -109.5, -111.0 (AB system, δ_A = -109.8 ppm, δ_B = -107.5 ppm, ^² J _AB = 277.6 Hz)ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 172.5, 172.3, 162.7, 162.6, 157.5 (q, J = 36.6 Hz), 116.0 (q, J = 287.6 Hz), 111.0-124.0 (unresolved signals, C₂F₅ group), 67.9 (m), 61.8, 61.7, 49.0, 48.9, 48.8 (m), 26.8, 26.3, 20.3, 30.2, 18.0, 17.7, 14.3, 14.2, 13.9, 13.8 ppm. HRMS (EI): m/z calcd for C₁₅H₁₈F₈N₂O₄: 442.1139; found: 442.1133.
Compound 4l˙H₂O: yield 54%; colorless oil; R _f = 0.6 (hexanes-EtOAc, 3:1). ^¹H NMR (200 MHz, CDCl₃): δ = 1.30 (t, J = 7.1 Hz), 1.55-1.65 (m, 1 H), 1.80-2.05 (m, 4 H), 2.50-2.70 (m, 1 H), 3.00-3.15 (m, 1 H), 3.60-3.70 (m, 1 H), 4.02 (d, J = 18.0 Hz, 1 H), 4.25 (q, J = 7.1 Hz, 2 H), 4.54 (q, J = 18.0 Hz, 1 H), 4.9 (br s, 1 H) ppm. ^¹9F NMR (188 MHz, CDCl₃): δ = -77.3 (q, J = 9.7 Hz, 3 F), -80.4 (q, J = 9.7 Hz, 3 F) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 172.0, 169.6, 169.1, 124.6 (q, J = 288.4 Hz), 122.4 (q, J = 291.3 Hz), 96.5 (q, J = 34.4 Hz), 70.2 (m), 60.3, 44.0, 42.7 (m), 32.6, 30.0, 29.9, 22.5, 13.9 ppm. HRMS (EI): m/z calcd for C₁₃H₁₆F₆N₂O₄: 378.1014; found: 378.1000.

Supplementary Material

Supporting Information