Solvent- and Catalyst-Free Three-Component Reaction with β-Ketoamides for the Stereoselective One-Pot Access to 1,4-Diazepines

Abstract

The stereoselective one-pot synthesis of polysubstituted 1,4-diazepine derivatives has been achieved via a new solvent- and catalyst-free multicomponent domino reaction from β-ketoamides. This green and experimentally simple sequence is conducted from easily accessible achiral starting materials, does not require any harmful reagents, and results in a high increase in molecular complexity and diversity. Moreover, water is the only byproduct liberated during the reaction.

Key words

multicomponent reaction - 1,4-diazepines - β-keto­amides - solvent-free reaction - green chemistry

References and Notes

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16

Chemical purities were in the range from 80-95% as estimated by NMR. However, flash chromatography purification resulted in a significant lost of pure product, probably due to unrationalized degradation.

17

Stereochemistry of the products has been fully studied by 2D NMR analysis, including a detailed analysis of coupling patterns and constants.

18

A complex mixture of unidentified products was obtained, probably due to degradation of starting materials.

19

Typical Procedure for the Synthesis of Compounds 4
To a 50 mL two-necked round-bottomed flask flushed with Ar, equipped with a magnetic stirring bar and a reflux condenser, were added β-ketoamide 2 (1.28 mmol), aldehyde 3 (1.5 mmol), and diamine 1 (1.28 mmol). The mixture was stirred at 110 °C under Ar for 4 h, diluted with EtOAc (20 mL) after cooling, and filtered through a short pad of Celite. After evaporation, the crude resulting slurry was purified by flash chromatography over SiO₂.
Selected Physical Data for Compounds 4a
Amber oil; R _f = 0.7 (EtOAc). ¹H NMR (300.13 MHz, CDCl₃): δ = 1.10-1.40 (m, 1 H), 1.40-1.60 (m, 1 H), 2.10 (br s, 1 H), 2.30-2.40 (m, 2 H), 2.87 (dd, J = 15.0, 6.0 Hz, 1 H), 3.10 (dd, J = 15.0, 6.0 Hz, 1 H), 3.20-3.30 (m, 2 H), 3.42 (d, J = 12.0 Hz, 1 H), 3.51 (d, J = 12.0 Hz, 1 H), 6.60 (br s, 1 H), 6.95 (t, J = 9.0 Hz, 1 H), 7.10-7.30 (m, 7 H), 7.42 (d, J = 9.0 Hz, 2 H), 8.71 (br s, 1 H). ¹³C NMR (75.47 MHz, CDCl₃): δ = 26.9, 27.4, 47.4, 51.4, 54.1, 68.7, 94.4, 119.6 (2 C), 123.0, 127.6, 127.7 (2 C), 128.5 (2 C), 128.7 (2 C), 138.8, 143.3, 166.4, 167.0. MS (EI): m/z (%) = 225 (6), 241 (43)
[M - Ph⁺], 242 (9), 334 (100) [M + H⁺], 335 (19).

20

Although it is not clear at the moment why we observed this loss of stereoselectivity, the two diastereomers were easily separable by flash chromatography.