Substituted 2-(Cyanomethyl-amino)-acetamides by a Novel Three-Component Reaction

Abstract

A novel three-component, one-pot reaction between ­primary (S)-amino acid amides, aldehydes and isocyanides in the presence of acetic acid yielding substituted 2-(cyanomethyl-amino)-acetamides 4 in good yields, is described. First efforts to ­investigate the mechanism of this reaction were undertaken.

multi-component condensation - MCRs - Ugi reaction - isocyanides - aliphatic nitriles

References

1 Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 

2 Weber L. Curr. Med. Chem.  2002,  9:  1241 

3 Schreiber S.-L. Science  2000,  287:  1964 

4 Dömling A. Curr. Opin. Chem. Biol.  2000,  4:  318 

5 Ugi I. Werner B. Dömling A. Molecules  2003,  8:  53 

6 Weber L. Drug Discovery Today  2002,  7:  143 

7a Ugi I, and Steinbrückner C. inventors; DE-B  1,103,337. 

7b Ugi I. Steinbrückner C. Chem. Ber.  1961,  94:  734 

7c Ugi I. Dömling A. Hörl W. Endeavour  1994,  18:  115 

8 Zhang JD. Jacobson A. Rusche JR. Herlihy W. J. Org. Chem.  1999,  64:  1074 

Reviews:

9a Orru RVA. de Greef M. Synthesis  2003,  1471 

9b Maracaccini S. Torroba T. Org. Prep. Proc. Int.  1993,  25:  141 

9c Armstrong RW. Combs AP. Tempest P. Brown SD. Keating TA. Acc. Chem. Res.  1996,  29:  123 

9d Bienaymé H. Hulme C. Oddon G. Schmitt P. Chem.-Eur. J.  2000,  6:  3321 

10 Janvier P. Bienaymé H. Zhu J. Angew. Chem. Int. Ed.  2002,  41:  4291 

11

General Procedure: To a stirred suspension of the amino acid amide hydrochloride 1 (2 mmol) and aldehyde 2 (2 mmol) in MeOH (4mL) and Et₃N (2 mmol) was added. After 15 min the isocyanide 3 (2 mmol) and glacial acetic acid (2 mmol) were given to the reaction mixture. The solution was stirred overnight, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC (H₂O/MeOH gradient).

12

Spectral data for compound 4a: ¹H NMR (400 MHz, CD₃OD): δ = 2.73 (s, 3 H, CH₃), 3.50 and 3.60 (AB, 2 H, ² J _A,B = 17.6 Hz, CH₂CN), 4.36 (s, 1 H, CH), 7.31-7.44 (m, 5 H, Ar-H’s). ¹³C NMR (100 MHz, CD₃OD, DEPT, HSQC): δ = 26.34 (CH₃), 35.70 (CH₂CN), 66.98 (CH), 118.81 (CN), 128.85 and 129.86 (Ar-C-o,m), 129.54 (Ar-C-p), 139.17 (Ar-C-ipso), 174.25 (CONHCH₃). ESI-MS: C₁₁H₁₃N₃O (203.24) m/z = 204.1 [M + H]⁺, 226.1 [M + Na]⁺.

13

Spectral data for compound 4b: ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.46 and 3.58 (AB, 2 H, ² J = 14.8 Hz, CH₂Ph), 3.43 and 3.67 (AB of ABX, 2 H, ² J _A,B = 15.4 Hz, ³ J _A,X = 6.0 Hz, ³ J _B,X = 6.0 Hz, CH₂CN), 7.12-7.45 (m, 10 H, Ar-H’s), 8.67 (X of ABX, 1 H, ³ J _A,X;B,X = 6.0 Hz, NHCH₂CN). ¹³C NMR (100 MHz, DMSO-d ₆, DEPT, gHSQC): δ = 35.56 (CH₂Ph), 42.77 (CH₂CN), 65.58 (CH), 119.34 (CN), 127.41 and 128.46 (Ar-C-p), 127.74, 128.18, 128.87, 129.01 (Ar-C-o,m), 139.37 and 139.92 (Ar-C-ipso), 171.36 (CO). ESI-MS: C₁₇H₁₇N₃O (279.34) m/z = 280.2 [M + H]⁺, 302.1 [M + Na]⁺.

14

Spectral data for compound 4u′ (minor diastereoisomer, S,S-configuration): [α]_D -44.6 (c 1.0 CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 2.03 (broad s, 1 H, NH), 2.32 (s, 3 H, CH₃), 2.51 (d, 3 H, ³ J = 4.6 Hz, NHCH₃), 2.94 and 3.14 (AB of ABX, 2 H, ² J _A,B = 13.6 Hz, ³ J _A,X = 4.9 Hz, ³ J _B,X = 8.9 Hz, CHCH₂Ph), 3.67 (X of ABX, 1 H, CHCH₂Ph), 4.38 (s, 1 H, CH), 6.17 (broad s, 1 H, NH), 7.12-7.41 (m, 9 H, Ar-H’s). ¹³C NMR (100 MHz, CDCl₃): δ = 21.08 (CH₃), 25.92 (CONHCH₃), 39.89 (CH₂), 50.67 (CHCN), 65.24 (CHCONH), 119.46 (CN), 127.09 (Ar-C), 127.64 (Ar-C), 128.79 (Ar-C), 129.43 (Ar-C), 129.65 (Ar-C), 134.90 (Ar-C), 135.37 and 138.49 (Ar-C-ipso), 170.96 (CO). IR(solid): 2221 (CN) cm^-1. ESI-MS: C₁₉H₂₁N₃O (307.40) m/z = 308.1 [M + H]⁺, 330.0 [M + Na]⁺.

15

Spectral data for compound 4y: ¹H NMR (400 MHz, CD₃OD): δ = 0.93 (d, 3 H, ³ J = 7.2 Hz, CH₃), 0.97 (d, 3 H, ³ J = 6.8 Hz, CH₃), 1.90-1.99 (m, 1 H, CH), 3.02 (d, 1 H, ³ J = 5.2 Hz, CH), 3.43 and 3.67 (AB, 2 H, ² J _A,B = 17.2 Hz, CH₂CN), 4.39 (s, 2 H, CH₂Ph), 7.22-7.32 (m, 5 H, Ar-H’s). ¹³C NMR (100 MHz, CD₃OD, DEPT, HSQC): δ = 17.46 (CH₃), 18.59 (CH₃), 31.62 [CH(CH₃)₂], 35.65 (CH₂CN), 42.84 (CH₂Ph), 67.56 (CH), 118.06 (CN), 127.13 (Ar-C-p), 127.64 and 128.38 (Ar-C-o,m), 138.81 (Ar-C-ipso), 173.97 (CONHCH₃). ESI-MS: C₁₄H₁₉N₃O (245.32) m/z = 246.2 [M + H]⁺, 268.2 [M + Na]⁺.

16a

X-ray single crystal structure determination of compound 4u′. Crystal data: C₁₉H₂₁N₃O, M _r = 307.39, colorless crystal, 0.46 × 0.61 × 0.79 mm³, orthorhombic, space group P2₁2₁2₁ (No. 19), a = 6.1962(1), b = 11.8249(1), c = 22.9857(2) Å, V = 1684.15(3) ų, Z = 4, ρ_calcd = 1.212 g cm^-3, F(000) = 656, µ _{(Mo-K α)} = 0.077 mm^-1, T = 173 K. Data collection: Nonius MACH3 κ-axis CCD-diffractometer, Mo-K_α radiation (λ = 0.71073 Å), unit cell parameters by least-squares for 1827 reflections. A total of 29452 reflections were integrated [16b] and scaled. [16c] After merging (R _int = 0.029) 3076 [2974: I _o>2σ(I _o)] independent reflections remained and all were used to refine 292 parameters. Structure solution and refinement: The structure was solved by a combination of direct methods [16d] and difference-Fourier syntheses. [16e] All non-hydrogen atoms were refined with anisotropic displacement parameters. All hydrogen atoms were found and refined with individual isotropic displacement parameters. Full-matrix least-squares refinements were carried out by minimizing Σw(F _o ²-F _c ²) [2] and converged with R1 = 0.0273 [I _o>2σ(I _o)], wR2 = 0.0686 [all data], GOF = 1.084 and shift/error <0.001. As indicated by Flack’s parameter ε = 0.3(11) the correct enantiomer could not be assigned reliably by diffraction methods. Thermal ellipsoids the ORTEP-style representation of the molecular structures of compound 4u′ in the solid state are drawn are at the 50% probability level. [16f] Crystallographic data (excluding structure factors) for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-223310 (4u′). Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: (internat.) [phone]; e-mail: [e-mail]].

16b

Data Collection Software for Nonius KappaCCD, Delft, The Netherlands, 2001.

16c Otwinowski Z. Minor W. Methods Enzymol.  1997,  276:  307 

16d Altomare A. Cascarano G. Giacovazzo C. Guagliardi A. Burla MC. Polidori G. Camalli M. J. Appl. Crystallogr.  1994,  27:  435 

16e Sheldrick GM. SHELXL-97   University of Göttingen; Göttingen, Germany: 1998. 

16f Spek AL. ‘Platon’: A Multipurpose Crystallographic Tool   Utrecht University; Utrecht, The Netherlands: 2001. 

17a Klingler O. Matter H. Schudok M. Bajaj SP. Czech J. Lorenz M. Nestler HP. Schreuder H. Wildgoose P. Bioorg. Med. Chem. Lett.  2003,  13:  1463 

17b TOTU: O-[(Ethoxycarbonyl)-cyanmethylenamino]-N,N,N′,N′-tetramethyluronium-tetrafluoroborat: König W. Proc. Eur. Pept. Symp. 21st   Leiden; Netherlands: 1991.  p.143