Preparation of Contiguous Bisaziridines for Regioselective Ring-Opening Reactions

Summary

Contiguous bisaziridines containing non-activated and activated aziridines were synthesized by asymmetric organocatalytic aziridinations and then subjected to chemoselective ring-opening reactions under acidic or basic conditions. The non-activated aziridine ring opens with less reactive nucleophiles under acidic conditions, whereas the activated aziridine ring opens with more reactive nucleophiles under basic conditions.

Abstract

Aziridines, a class of reactive organic molecules containing a three-membered ring, are important synthons for the synthesis of a large variety of functionalized nitrogen-containing target compounds through the regiocontrolled ring-opening of C-substituted aziridines. Despite the tremendous progress in aziridine synthesis over the past decade, accessing contiguous bisaziridines efficiently remains difficult. Therefore, we were interested in synthesizing contiguous bisaziridines bearing an electronically diverse set of N-substituents beyond the single aziridine backbone for regioselective ring-opening reactions with diverse nucleophiles. In this study, chiral contiguous bisaziridines were prepared by organocatalytic asymmetric aziridination of chiral (E)-3-((S)-1-((R)-1-phenylethyl)aziridin-2-yl)acrylaldehyde with N-Ts-O-tosyl or N-Boc-O-tosyl hydroxylamine as the nitrogen source in the presence of (2S)-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine as a chiral organocatalyst. Also demonstrated here are representative examples of regioselective ring-opening reactions of contiguous bisaziridines with a variety of nucleophiles such as sulfur, nitrogen, carbon, and oxygen, and the application of contiguous bisaziridines to the synthesis of multi-substituted chiral pyrrolidines by Pd-catalyzed hydrogenation.

Introduction

Rational design of small organic molecules with diverse reactive sites that precisely control product selectivity is a key goal in modern organic synthesis and green chemistry^{1,2,3,4,5,6,7,8}. To achieve this goal, we were interested in the modular synthesis of aziridines. Aziridines are of interest to most organic chemists, owing to their structurally important framework

Protocol

The details of all the synthesized products (1-5), including the structure, full NMR spectra, optical purity, and HRMS-MALDI data, are provided in Supplementary File 1.

1. Synthesis of 3-(aziridin-2-yl)acryl aldehyde (1a)

1. Flame dry a 50 mL round-bottomed flask equipped with a stirrer bar and a septum under vacuum conditions. Cool it to room temperature while filling it with argon gas.
2. Add anhydrous toluene (19 mL) and (

Discussion

The formation of an inseparable mixture of diastereomers has occasionally been observed during the course of organocatalytic aziridination of chiral 3-[1-(1-phenylethyl)aziridin-2-yl)]acrylaldehyde, when N-Boc-O-tosyl or N-Ts-O-tosyl hydroxylamine was used as the nitrogen source. Further, the yield of contiguous bisaziridine product decreased when the amount of diaryl silyl ether prolinol as catalyst was increased from 7 mol% to 20 mol%^47,

Materials

Name	Company	Catalog Number	Comments
(R)-(+)-α,α-Diphenyl-2-pyrrolidinemethanol trimethylsilyl ether	Sigma-Aldrich	677191	reagent
(R)-1-((R)-1-phenylethyl)aziridine-2-carbaldehyde	Imagene Co.,Ltd.		reagent
(S)-(–)-α,α-Diphenyl-2-pyrrolidinemethanol trimethylsilyl ether	Sigma-Aldrich	677183	reagent
(S)-2-(diphenyl((trim ethylsilyl)oxy)methyl)pyrrolidine	Sigma-Aldrich	677183	reagent
(Triphenylphosphoranylidene) acetaldehyde	Sigma-Aldrich	280933	reagent
1,2-Dichloroethane	Sigma-Aldrich	284505	solvent
AB Sciex 4800 Plus MALDI TOFTM (2,5-dihydroxybenzoic acid (DHB) matrix	Sciex		High resolution mass spectra
Acetic acid	Sigma-Aldrich	A6283	reagent
Ammonium chloride	Sigma-Aldrich	254134	reagent
aniline	Sigma-Aldrich	132934	reagent
Autopol III digital polarimeter	Rudolph Research Analytical		polarimeter
AVANCE III HD (400 MHz) spectrometer	Bruker		NMR spectrometer
Bruker Ascend 500 (500 MHz)	Bruker		NMR spectrometer
Celite 535	Sigma-Aldrich	22138	For Celite pad
Dichloromethane	Sigma-Aldrich	270997	solvent
Di-tert-butyl dicarbonate	Sigma-Aldrich	361941	reagent
Ethyl Acetate	Sigma-Aldrich	270989	solvent
Ethyl nitroacetate	Sigma-Aldrich	192333	reagent
Imidazole	Sigma-Aldrich	I2399	reagent
INOVA 400WB (400 MHz)	Varian		NMR spectrometer
JMS-700	JEOL		High resolution mass spectra
Methanol	Sigma-Aldrich	322415	solvent
N-Boc-O-tosylhydroxylamine	Sigma-Aldrich	775037	reagent
P-2000	JASCO		polarimeter
Palladium hydroxide on carbon	Sigma-Aldrich	212911	reagent
Phenyl-1H-tetrazole-5-thiol	TCI	P0640	reagent
Silica gel	Sigma-Aldrich	227196	For flash clromatography
Silica gel on TLC plates	Merck	60768	TLC plate
Sodium acetate	Sigma-Aldrich	S8750	reagent
Sodium azide	Sigma-Aldrich	S2002	reagent
Sodium borohydride	Sigma-Aldrich	452882	reagent
Sodium carbonate	Sigma-Aldrich	S2127	reagent
tert-Butyldimethylsilyl chloride	Sigma-Aldrich	190500	reagent
Tetrahydrofuran	Sigma-Aldrich	401757	solvent
Toluene	Sigma-Aldrich	244511	solvent
Zinc bromide	Sigma-Aldrich	230022	reagent
Zinc chloride	Sigma-Aldrich	429430	reagent