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Synlett 2011(2): 211-214  
DOI: 10.1055/s-0030-1259303
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

3-(1-Aminoalkyl)pyrazole- and 4,5-Dihydropyrazole-5-carboxylic Acids as Peptide Bond Replacements

Raymond C. F. Jones*, Laura E. Seager, Mark R. J. Elsegood
Department of Chemistry, Loughborough University, Loughborough, Leics, LE11 3TU, UK
Fax: +44(1509)223925; e-Mail: r.c.f.jones@lboro.ac.uk;
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Publication History

Received 19 August 2010
Publication Date:
05 January 2011 (online)

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Abstract

Orthogonally protected 3-(1-aminoalkyl)pyrazole- and 4,5-dihydropyrazole-5-carboxylic acids are prepared by 1,3-dipolar cycloaddition of α-aminonitrile imines with electron-deficient al­kenes; the pyrazole is incorporated into pseudotri- and tetrapeptides.

Key words

cycloaddition - dipole - heterocycles - amino acids - peptide mimics

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14

Typical Procedure for NCS Chlorination and Method 1
( S )-3-(1- tert -Butoxycarbonylaminoethyl)-2-phenyl-4,5-dihydro-1 H -pyrazole-5-carboxylic Acid Ethyl Ester (7) To (S)-[1-methyl-2-(phenylhydrazono)ethyl]carbamic acid tert-butyl ester (5, 1.24 g, 4.72 mmol) in EtOAc (15 mL) at 60 ˚C was added NCS (0.71 g, 5.35 mmol, 1.1 equiv) and the mixture stirred for 1 h. Ethyl propenoate (0.918 g, 1.0 mL, 9.16 mmol, 1.9 equiv), KHCO3 (2.41 g, 23.97 mmol, 5.1 equiv) and a few drops of H2O were added and the mixture stirred at 70 ˚C for 20 h. The mixture was then filtered and the filtrate concentrated under reduced pressure to give a dark orange oil, purified by column chromatography on silica gel eluting with light PE-EtOAc (7:1, v/v) to yield the title compound 7 (0.72 g, 41%) in an inseparable 1:1 mixture of diastereomers, as an orange solid; mp 93-95 ˚C. IR (CHCl3): νmax = 3354 (NH), 1599 (C=N), 1708 (C=O), 1168 (CO), 750 (PhCH) cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.16 (3 H, t, J = 7.2 Hz, CH2CH 3), 1.35 (3 H, d, J = 7.0 Hz, CH 3CH), 1.38 [9 H, s, C(CH 3)3], 2.99 (1 H, dd, J = 7.2, 17.6 Hz, 4-CHH), 3.24 (1 H, dd, J = 12.4, 17.6 Hz, 4-CHH), 4.14 (2 H, q, J = 7.2 Hz, CH 2CH3), 4.43 (1 H, m, CH3CH), 4.54, 4,57 (each 0.5 H, dd, J = 7.2, 12.4 Hz, CHCO2Et, diastereomers 1 and 2), 5.00 (1 H, br s, NH), 6.78 (1 H, m, ArH), 6.93 (2 H, m, ArH), 7.18 (2 H, m, ArH). ¹³C NMR (100 MHz, CDCl3): δ = 14.2, 21.1 (CH3) 28.2 [(CH3)3C], 40.15 (4-CH2), 46.1 (5-CH), 61.7 (OCH2), 113.0 (PhCH), 113.0, 119.7, 119.8, 129.0 (4 × CH), 129.1 (2 × C), 145.3 (CN), 171.2, 171.5 (2 × CO). MS (EI): m/z = 362 [MH+], 171 (12), 154 (24), 147 (19), 123 (21), 111 (28), 109 (35), 95 (54), 81 (54), 69 (85), 57 (100), 55 (99). HRMS (EI): m/z calcd for C19H27N3O4: 362.2074 [MH+]; found 362.2073 [MH+]. Anal. Calcd (%) for C19H27N3O4: C, 63.1; H, 7.5; N, 11.6. Found: C, 62.6; H, 7.2; N, 11.8.

20

Cf. ref. 16a for a discussion on the reduced rate of nitrile imine cycloadditions with electron-rich dipolarophiles and/or electron-poor dipoles.

21

Crystal Data for 7
C19H27N3O4, M = 361.44, monoclinic, a = 5.14990 (10), b = 11.4316 (4), c = 16.8254 (6) Å, β = 96.320 (2), U = 984.52 (5) ų, T = 120 (2) K, space group P21, graphite monochromated Mo Kα radiation, λ = 0.71073 Å, Z = 2, D c  = 1.219 g cm-³, F(000) = 388, colourless, dimensions 0.36 × 0.09 × 0.04 mm³, µ = 0.086 mm-¹, 3.02 < θ < 28.19˚, 11290 reflections measured, 2363 unique reflections, R int = 0.0376. The structure was solved by direct methods and refined on F ². Friedel pairs were merged due to the lack of any significant anomalous scattering. wR2 = 0.0833 (all data, 244 parameters); R1 = 0.0351 [2223 data with F ² > 2σ(F ² )]. Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. 787832. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 (1223)336033 or e-mail: deposit@ccdc.cam.ac.uk).