New Method for the Combinatorial Search of Multi Component Reactions

Abstract

A novel method for the combinatorial finding of multi component reactions involving replacements of oligomerisation participants is introduced. Using this method the new three-component reaction between isoquinoline, gem-diactivated olefins and isocyanides leading to substituted 2,3-dihydro-10H-pyrrolo[2,1-a]isoquinoline-1-ones is described.

Key words

multi component reaction - isocyanides - isoquinoline - reaction design - combinatorial chemistry

References

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General Procedure. According to the classical experiment, [7a] a mixture of 0.1 mmol of each of the compounds: isoquinoline and two unsaturated starting materials were stirred in 0.13 mL of Et₂O for 48 h at 20 °C. After evaporation of solutions to dryness the residua were analyzed by HPLC. In the case of the products 12, the crude mixtures were purified by crystallisation or flash-chromatography.

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HPLC Analysis of the Reaction Products. The final mixtures were analyzed by reversed-phase HPLC with detection at 230 nm. The chromatography was performed on a Hewlett-Packard HP 1090 apparatus equipped with a diode-array detector. A reverse-phase column was used (Hypersil^® BDS C18, 3µ, 50 × 4.6 mm) under an optimized binary gradient acetonitrile/water, flow 1 mL/min. To validate the analytical method, some products and starting materials were characterized separately. The peaks were assigned to the corresponding products by comparison to the retention time and UV profiles.

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Spectral Data for Compound 12a: ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.47 (s, 5 H, Ph), 7.36 (d, J = 8.9 Hz, 1 H, CH-9), 7.33-7.28 (m, 2 H, CH-7 and CH-8), 7.20 (d, J = 8.8 Hz, 1 H, CH-6), 7.15 (d, J = 7.8 Hz, 1 H, CH-5), 5.90 (d, J = 7.8 Hz, 1 H, CH-4), 5.68 (s, 1 H, CH-3), 5.54 (s, 1 H, CH-10), 1.89 (br s, 3 H, CH-adamantane), 1.58 (br s, 6 H, CH₂-adamantane), 1.47 (br s, 6 H, CH₂-adamantane). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 146.30, 132.49, 132.38, 129.35, 129.26, 129.06, 128.24, 127.30, 125.54, 125.52, 123.54, 123.05, 113.79, 112.74, 106.20, 59.74, 54.10, 52.77, 44.05, 43.50, 35.61, 28.97. MS (70 eV): m/z (%) = 444 (28) [M]⁺, 417 (14) [M - HCN]⁺, 282 (28), 265 (51), 135 (100), [C₁₀H₁₅]⁺.