Titanium-Mediated Synthesis of Primary Cyclopropylamines from Nitriles and Grignard Reagents

Abstract

This account presents studies on the development of a new method for the preparation of primary cyclopropylamines. The established procedure is simple and the reaction appears to be quite general. A wide range of nitriles and organomagnesium reagents can react to afford diversely substituted cyclopropylamines. Furthermore, bicyclic cyclopropylamines can be obtained via an intramolecular coupling from unsaturated nitriles. The reaction allows an easy preparation of 1-aminocyclopropanecarboxylic acids and 1-azaspirocyclic compounds bearing a cyclopropane ring. The reaction can also be applied to the preparation of polyfunctional and more complex organic molecules as exemplified with the synthesis of carbohydrates bearing aminocyclopropyl moieties and spirocyclopropyl pyrrolidines. During study of the title reaction, an unusual [4+1] cycloaddition reaction to afford cyclopentenylamines or cyclopentenones has been discovered and is described.

• 1 Introduction

• 2 Direct Synthesis of Cyclopropylamines from Nitriles and Grignard Reagents

• 3 Synthesis of Cyclopropylamines via Ligand Exchange

• 4 Attempt to Prepare 2-Alkenyl Cyclopropylamines from 1,3-Dienes and Nitriles: An Unusual [4+1] Assembly Reaction

• 5 Summary and Outlook

Key words

cyclizations - cyclopropanes - Grignard reagents - nitriles - titanium

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13

Bertus, P.; Szymoniak, J., unpublished results.

14

The intermediacy of C was demonstrated by deuterolysis.

16

Attempts to perform the aminocyclopropanation reaction by using Cp₂Zr(ethylene) led to complex reaction mixtures.

30

The introduction of EtMgBr to a mixture of 61 and 0.2 equiv of Ti(Oi-Pr)₄ in Et₂O over a 1, 15, or 30 min period led, respectively, to a 19%, 40%, or 55% yield of 55.

46

The yield of 94 decreased rapidly at temperatures higher than 0 °C, due to the instability of the complex J.