A Versatile Synthesis of 6-Oxo-1,4,5,6-tetrahydro-pyrazine-2-carboxylic Acid Methyl Esters via MCR Chemistry

Abstract

A novel three-component, one-pot condensation yielding 6-oxo-1,4,5,6-tetrahydro-pyrazine-2-carboxylic acid methyl ­esters from aldehydes, amines and 3-dimethylamino-2-isocyano-acrylic acid methyl ester is described. The scope and limitations of the reaction have been investigated.

combinatorial chemistry - multicomponent condensation - Ugi reaction - heterocyclic compounds - tetrahydro-pyrazines

References

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<A NAME="RG19503ST-12B">12b</A> inventors; , CAN 68:49650  CIBA Ltd., US 3503980. 

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For chemistry using 3-dimethylamino-2-isocyano-acrylic acid methyl ester in heterocyclic synthesis, see:

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<A NAME="RG19503ST-15">15</A>

General Procedure: The aldehyde (1 mmol) and the amine (1 mmol) were dissolved or suspended in MeOH (3 mL). The mixture was allowed to stir for 10 min at r.t. After adding 10 mol% Yb(OTf)₃ and isocyanide 4 (1 mmol) the reaction mixture was stirred at r.t. overnight. The solvent was evaporated. The resulting residue was purified by preparative HPLC.

<A NAME="RG19503ST-16">16</A>

Crystal structure analysis of compound 1a: C₁₆H₁₈N₂O₄, M _r = 302.32; colorless fragment (0.18 × 0.30 × 0.56 mm³); triclinic, P-1(No.: 2), a = 7.2017(1), b = 7.8496(1), c = 14.1983(3) Å, α = 75.7470(6)°, β = 86.4000(6)°, γ = 74.6796(9)°, V = 750.28(2) ų, Z = 2, d _calcd = 1.338 gcm^-3; F(000) = 320; µ = 0.097 mm^-1. A total of 17941 reflections were integrated and corrected for Lorentz and polarization effects. After merging (R _int = 0.032), 2735 [2366: I_o > 2σ(I_o)] independent reflections remained and all were used to refine 271 parameters. 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 = 0.0354 [I_o > 2σ(I_o)], wR2 = 0.0967 [all data], GOF = 1.067 and shift/error < 0.001. 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-220501(1a). Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone]; e-mail: [e-mail]]

<A NAME="RG19503ST-17">17</A>

General Procedure for Plate Synthesis: MeOH solution of the amine and aldehyde component (50 mL, 0.1 M) were dispensed on plate. Yb(OTf)₃ (50 mL, 0.1 M) and MeOH solution of the Schöllkopf isocyanide 4 (50 mL, 0.1 M) were added. The plate was shaken overnight at r.t. and the solvent was evaporated. The crude reaction mixtures were prepared for LC-MS analytics (0.1 mM solution in MeOH-H₂O = 1:1).

<A NAME="RG19503ST-18">18</A>

Spectral data for compound 1a: ¹H NMR (400 MHz, DMSO-d ₆): δ = 0.36-0.41 (m, 2 H, CH₂), 0.44-0.52 (m, 2 H, CH₂), 1.10-1.16 (m, 1 H, CH), 3.70 (s, 3 H, CH₃), 3.73 (s, 3 H, CH₃), 4.07 (d, 1 H, J = 7.8 Hz, CH), 6.93 (d, J = 9.14 Hz, 2 H, CH_arom), 7.18 (d, J = 9.48 Hz, 2 H, CH_arom), 7.24 (s, 1 H, CH=), 9.61(s, 1 H, NH). ¹³C NMR (100 MHz, DMSO-d ₆):
δ = 2.24, 4.07, 12.10, 51.25, 55.22, 62.35, 107.18, 114.63, 119.46, 123.48, 136.66, 155.53, 161.49, 161.93. MS (ESI): m/z = 303.3 [M + H]⁺, 325.2 [M + Na]⁺.
Spectral data for compound 1f: ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.20 (t, 2 H, CH₂), 1.43-1.47 (m, 4 H, 2CH₂), 1.61-1.71 (m, 2 H, CH₂), 1.90-1.93 (m, 2 H, CH₂), 3.61 (s, 3 H, CH₃), 6.88 (s, 1 H, CH=), 7.20-7.24 (m, 2 H, 2CH), 7.31-7.35 (m, 2 H, 2CH), 9.32 (s, 1 H, NH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 22.38, 24.62, 30.53, 51.07, 61.09, 105.29, 115.80, 116.03, 129.97, 131.63, 131.72, 138.50, 138.53, 159.80, 161.68, 163.75. MS (ESI): m/z = 319.0 [M + H]⁺, 341.0 [M + Na]⁺.

<A NAME="RG19503ST-19">19</A> Illgen K, Fuchs T, and Nerdinger S. inventors; , CAN 138:401756  Int. Pat. Appl. WO03042187.