Synthesis of bis-spirocyclic derivatives of 3-azabicyclo[3.1.0]hexane via cyclopropene cycloadditions to the stable azomethine ylide derived from Ruhemann's purple

Abstract

A reliable method for the synthesis of bis-spirocyclic derivatives of 3-azabicyclo[3.1.0]hexanes through the 1,3-dipolar cycloaddition (1,3-DC) reactions of cyclopropenes to the stable azomethine ylide - protonated form of Ruhemann's purple (PRP) has been developed. Both 3-substituted and 3,3-disubstituted cyclopropenes reacted with PRP, affording the corresponding bis-spirocyclic 3-azabicyclo[3.1.0]hexane cycloadducts in moderate to good yields with high diastereofacial selectivity. Moreover, several unstable 1,2-disubstituted cyclopropenes were successfully trapped by the stable 1,3-dipole under mild conditions. The mechanism of the cycloaddition reactions of cyclopropenes with PRP has been thoroughly studied using density functional theory (DFT) methods at the M11/cc-pVDZ level of theory. The cycloaddition reactions have been found to be HOMO_cyclopropene-LUMO_ylide controlled while the transition-state energies for the reaction of 3-methyl-3-phenylcyclopropene with PRP are fully consistent with the experimentally observed stereoselectivity.

Keywords: DFT calculations; azomethine ylides; cycloaddition; cyclopropenes; spiro heterocycles.

Scheme 1

Early studies concerning cyclopropene cycloadditions to azomethine ylides and cycloaddition reactions involving protonated Ruhemann's purple (PRP).

Scheme 2

The pilot experiment aimed at studying the cycloaddition reaction between the protonated form of Ruhemann's purple (1) and 1,2,3-triphenylcyclopropene (2a).

Scheme 3

Synthesis of meso-3'-azadispiro[indene-2,2'-bicyclo[3.1.0]hexane-4',2''-indene] derivatives 3b–g via 1,3-DC reactions of N-protonated Ruhemann's purple (1) with 3-substituted 1,2-diphenylcyclopropenes 2b–g.

Figure 1

ORTEP representation of the molecular structure of 3e.

Scheme 4

The reaction of protonated Ruhemann's purple (1) with 3-methyl-3-phenylcyclopropene (2j).

Scheme 5

Attempts to carry out the cycloaddition reactions between 3,3-disubstituted cyclopropenes 2k,l and azomethine ylide 1.

Scheme 6

The reactions of protonated Ruhemann's purple (1) with unstable cyclopropenes 2m–p.

Scheme 7

The acid–base reaction of Ruhemann's purple with hydrochloric acid and relative Gibbs free energy change (ΔG, kcal/mol) for acid–base reactions resulting in the formation of three protonated forms of Ruhemann's purple.

Scheme 8

Plausible mechanism of the 1,3-DC reaction of protonated Ruhemann's purple (1) with 3-methyl-3-phenylcyclopropene (2j) and corresponding DFT calculations (relative Gibbs free energy change between reagents, transition states and possible products are given in kcal/mol).

Scheme 9

Plausible mechanism of the 1,3-DC reaction of protonated Ruhemann's purple (1) with 1-chloro-2-phenylcyclopropene (2m) and corresponding DFT calculations (relative Gibbs free energy change between reagents, transition states and possible invertomers are given in kcal/mol).