Synthesis and Purification of Iodoaziridines Involving Quantitative Selection of the Optimal Stationary Phase for Chromatography

Summary

A protocol for the diastereoselective one-pot preparation of cis-N-Ts-iodoaziridines is described. The generation of diiodomethyllithium, addition to N-Ts aldimines and cyclization of the amino gem-diiodide intermediate to iodoaziridines is demonstrated. Also included is a protocol to rapidly and quantitatively assess the most appropriate stationary phase for purification by chromatography.

Abstract

The highly diastereoselective preparation of cis-N-Ts-iodoaziridines through reaction of diiodomethyllithium with N-Ts aldimines is described. Diiodomethyllithium is prepared by the deprotonation of diiodomethane with LiHMDS, in a THF/diethyl ether mixture, at -78 °C in the dark. These conditions are essential for the stability of the LiCHI₂ reagent generated. The subsequent dropwise addition of N-Ts aldimines to the preformed diiodomethyllithium solution affords an amino-diiodide intermediate, which is not isolated. Rapid warming of the reaction mixture to 0 °C promotes cyclization to afford iodoaziridines with exclusive cis-diastereoselectivity. The addition and cyclization stages of the reaction are mediated in one reaction flask by careful temperature control.

Due to the sensitivity of the iodoaziridines to purification, assessment of suitable methods of purification is required. A protocol to assess the stability of sensitive compounds to stationary phases for column chromatography is described. This method is suitable to apply to new iodoaziridines, or other potentially sensitive novel compounds. Consequently this method may find application in range of synthetic projects. The procedure involves firstly the assessment of the reaction yield, prior to purification, by ¹H NMR spectroscopy with comparison to an internal standard. Portions of impure product mixture are then exposed to slurries of various stationary phases appropriate for chromatography, in a solvent system suitable as the eluent in flash chromatography. After stirring for 30 min to mimic chromatography, followed by filtering, the samples are analyzed by ¹H NMR spectroscopy. Calculated yields for each stationary phase are then compared to that initially obtained from the crude reaction mixture. The results obtained provide a quantitative assessment of the stability of the compound to the different stationary phases; hence the optimal can be selected. The choice of basic alumina, modified to activity IV, as a suitable stationary phase has allowed isolation of certain iodoaziridines in excellent yield and purity.

Introduction

The aim of this method is to prepare iodoaziridines that offer potential for further functionalization to aziridine derivatives. The method incorporates a protocol for the quantitative selection of the optimal stationary phase for chromatography.

Aziridines, as three-membered rings, posses inherent ring strain that makes them important building blocks in organic chemistry¹. They display a vast array of reactivity often involving aziridine ring opening^2,3, particularly as intermediates in the synthesis of functionalized amines^4,5, or the formation of other nitrogen containing heterocycles^6,7. The s....

Protocol

1. Preparation of Iodoaziridines with Diiodomethyllithium

1. Flame dry a 100 ml round bottom flask containing a stirrer bar and fitted with a septum, under a stream of argon, then allow to cool to room temperature under an argon atmosphere. NOTE: Glassware dried in an oven overnight (125 °C) and cooled to room temperature in an analogous fashion is also appropriate.
2. To the flask, add 5.7 ml anhydrous THF and 2.7 ml anhydrous Et₂O via syringe, and freshly distilled hexamethyldisilazane (1.50 mmol, 315 µl) via a microsyringe.
3. Stir the resulting solution and cool to -78 °C in a dry ice/acetone bath ....

Results

The procedure described affords cis-(±)-2-iodo-3-(4-tolyl)-1-(4-tolylsulfonyl)aziridine as a single diastereoisomer and with excellent purity (Figure 1). Prior to purification, a yield of 59% of the iodoaziridine product was calculated by ¹H NMR spectroscopy. However, this iodoaziridine was particularly challenging to purify and underwent significant decomposition on silica. Purification on basic alumina (activity IV) as determined by the stationary phase screen allowed the product to.......

Discussion

A procedure for the diastereoselective preparation of cis-N-Ts-iodoaziridines is described, along with a stability study protocol to quantitatively indicate the best stationary phase for purification of potentially unstable compounds by flash column chromatography. It is envisaged that access to iodoaziridines through this approach will enable methods to access to a wide range of aziridines to be developed, by derivatization of the intact ring.

An appropriate modification to .......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Hexamethyldisilazane	999-97-3	Alfa Aesar	Distill from KOH under argon prior to use.
n-Butyllithium	109-72-8	Sigma Aldrich	2.5 M in hexanes, titrate prior to use.
Diiodomethane	75-11-6	Alfa Aesar	Contains copper as a stabilizer.
1,3,5-Trimethoxybenzene	621-23-8	Sigma Aldrich
Silica	112945-52-5	Merck
Basic alumina	1344-28-1	Sigma Aldrich
Neutral alumina	1344-28-1	Merck
Florisil	1343-88-0	Sigma Aldrich
THF	All anhydrous solvents were dried through activated alumina purification columns.
Et2O
CH2Cl2
NMR spectrometer	Bruker AV 400	n/a
NMR processing software	MestReNova	7.0.2-8636