Reactivity of 1-alkyl-2-(bromomethyl)aziridines towards n -butyllithium

The reactivity of 1-alkyl-2-(bromomethyl)aziridines with regard to n -butyllithium has been evaluated for the first time, resulting in a variety of reaction products due to competitive reaction pathways. The main components in these mixtures are 1-alkyl-2-( N -alkyl- N - allylaminomethyl)aziridines (11-36%), 1-alkyl-2-pentylaziridines (13-26%), N -alkyl- N -allyl- N - butylamines (1-24%), N -alkyl- N -pentylamines (4-12%) and N -alkyl- N -allylamines (1-7%). A few of these components were isolated by means of preparative gas chromatography. The structural identity of some other constituents has been proven by independent syntheses.


Introduction
Aziridines are versatile building blocks for the synthesis of a large variety of ring opened and ring expanded amines due to the inherent reactivity of these compounds, 1 an effect undoubtedly resulting from the necessary compression of bond angles in the three-membered ring.Although many reports on the utility of substituted aziridines in organic synthesis are available, 1-alkyl-2-(bromomethyl)aziridines comprise a peculiar and rather unknown class of non-activated aziridine derivatives with high synthetic potential due to three different electrophilic carbon atoms in their structure. 2s reported before, 1-alkyl-2-(bromomethyl)aziridines are suitable synthetic equivalents for the aziridinylmethyl cation, providing an easy access to 1,2-dialkylaziridines such as 2-ethyl-, 2pentyl-and 2-(phenylmethyl)aziridines upon treatment with the appropriate lithium dialkylcuprate reagent. 3A similar reactivity of 1-alkyl-2-(bromomethyl)aziridines has been observed in reaction with oxygen-centered nucleophiles such as alkoxides, phenoxides and carboxylates, affording the corresponding 2-substituted aziridines in a clean and straightforward reaction. 4Very recently, the reaction of 2-(bromomethyl)aziridines with methyllithium has been reported to afford 1-alkyl-2-(N-alkyl-N-ethylaminomethyl)aziridines through a highly unusual reaction pathway. 5However, up to now, the reactivity of 1-alkyl-2-(bromomethyl)aziridines with regard to n-butyllithium, a frequently used reagent in organic chemistry, 6 has not been investigated yet, and this will be discussed in the present report.
N Br The formation of 2-(aminomethyl)aziridines 2 can be rationalized considering a halophilic reaction by the butyl anion onto the bromo atom, followed by ring opening of the intermediate aziridinylmethyl anion towards N-allyl lithium amides 7 and liberation of butyl bromide (Scheme 2).These lithium amides 7 can act as nucleophiles in a displacement reaction with unreacted 2-(bromomethyl)aziridine 1, affording 2-(aminomethyl)aziridines 2. If no electrophilic substrate 1 is available anymore, lithium amides 7 will be protonated during workup resulting in allylamines 6 (Scheme 2).

Scheme 4
The formation of 2-pentylaziridines 3 in the reaction mixtures obtained after treatment of aziridines 1 with BuLi is the result of a nucleophilic displacement of the bromo atom of aziridines 1 by a butyl anion, in accordance with the aziridinylmethyl cation equivalency of the latter compounds.Allylamines 4 can arise from a nucleophilic attack of lithium amides 7 onto in situ liberated butyl bromide (Scheme 5).

Scheme 5
A representative example of constituents 3 in the reaction mixtures has been prepared by an independent synthesis in order to prove their presence.2-Pentylaziridine 3b was prepared by treatment of aziridine 1b with 1.5 equivalents of lithium dibutylcuprate in diethyl ether for 4 hours at room temperature (Scheme 6). 3 Comparison of the retention time and mass spectra confirmed the presence of these compounds in the reaction mixtures obtained after treatment of 2-(bromomethyl)aziridines 1 with n-butyllithium.A plausible explanation for the formation of secondary amines 5 upon treatment of aziridines 1 with BuLi is depicted in Scheme 7, in which the substrate 1 undergoes a S N 2'-type substitution, followed by conversion of the resulting enamines 10 into lithium amides 11.The nucleophilic attack of a butyl carbanion at the unsubstituted aziridine carbon atom of aziridines 1 towards Nalkyl-N-pentyl-N-vinylamines 10 via a S N 2'-type reaction is not unlikely, since also cyclopropanes behave in some respects like double-bond compounds due to the so called bent bonds. 9Small vinylamines are known to be unstable, 10 and the thus quite labile enamines 10 can undergo deprotonation by the excess of butyllithium with expulsion of acetylene, resulting in Nethyl lithium amides 11.A similar, although far more selective, reactivity has been reported very recently, in which an analogous transformation was described upon treatment of 2-(bromomethyl)aziridines with methyllithium, resulting in 1-alkyl-2-(N-alkyl-Nethylaminomethyl)aziridines upon liberation of acetylene. 5Finally, neutralization of the lithium amides 11 during workup afforded amines 5.

Experimental Section
General Procedures. 1 H NMR spectra were recorded at 270 MHz (JEOL JNM-EX 270) or at 300 MHz (JEOL ECLIPSE+) with CDCl 3 as solvent and tetramethylsilane as internal standard.13 C NMR spectra were recorded at 68 MHz (JEOL JNM-EX 270) with CDCl 3 as solvent.Mass spectra were obtained with a mass spectrometer (VARIAN MAT 112, 70 eV using a GC-MS coupling (RSL 200, 20 m glass capillary column, i.d.0.53 mm, He carrier gas).IR spectra were measured with a Spectrum One FT-IR spectrophotometer.Preparative gas chromatography was performed using a Delsi Intersmat IGC 120 ML.Diethyl ether and tetrahydrofuran were distilled over sodium benzophenone ketyl, dichloromethane was distilled over calcium hydride.Other solvents were used as received from the supplier.

Treatment of 1-alkyl-2-(bromomethyl)aziridines 1 with n-butyllithium. General procedure.
To an ice-cooled solution of 2-(bromomethyl)aziridine 1 (5 mmol) in THF (10 mL) was added dropwise n-BuLi (3 mL, 1.5 equiv, 2.5M in hexane) via a syringe under nitrogen atmosphere.The resulting solution was further stirred at room temperature for 19-21 hours under nitrogen atmosphere.Workup was carried out by pouring the reaction mixture in an aqueous sodium hydroxide solution (10 mL, 0.5M in H 2 O), followed by extraction with diethyl ether (2×10 mL, 1×5 mL).After drying of the organic phase over K 2 CO 3 and filtration of the drying agent, the solvent was removed in vacuo, and the resulting oil was analyzed by means of GC-MS or preparative gas chromatography.