Dimerization of Lithiated Terminal Aziridines

Abstract

It has been known for a long time that lithiated epoxides 1 (Scheme 1, X = O) can display carbenoid-type reactivity, including dimerization.[1] Such dimerizations have been developed recently by our research group as a synthetic method for the preparation of symmetric 2-ene-1,4-diols 2 (X = O) from terminal epoxides.[2] Although a useful entry to this valuable class of compounds, this method unfortunately displayed only a 2:1 selectivity in favor of the E isomer of the newly formed alkene when using epoxides with primary (R = C 5 H 11 ) or secondary (R = cyclohexyl) alkyl substituents (62 % and 77 % yield of 2-ene-1,4-diol olefin isomer mixtures, respectively).Following on from this, we considered the possibility that lithiated terminal aziridines 1 (X = NPG, PG = protecting group) [3] might undergo similar dimerization, thus leading to synthetically useful (protected) 2-ene-1,4-diamines 2 (X = NPG).[4] At the outset of our studies we were not aware of any examples of such dimerizations in the literature, [5] and it was not known whether the method would yield dimer compounds in useful efficiencies or whether other pathways such as formation of 2H-azirines 3[6] (Scheme 1) would be favored. Although certain lithiated aziridines fused to 5-to 8-membered rings undergo carbenoid transformations, [7] formation of 2H-azirines in these cases would be significantly disfavored because of additional ring strain. There is little precedent for lithiated aziridines having carbenoid reactivity when the aziridine is not fused to a second ring.[7b]One additional variable for aziridines (relative to epoxides) is the choice of the protecting/activating group at the aziridine nitrogen atom. In our initial studies we attempted to dimerize alkyl substituted terminal aziridines bearing the groups Boc (butyloxycarbonyl), tosyl, or Bus (tert-butylsulfonyl), [8] by using lithium 2,2,6,6-tetramethylpiperidide (LTMP) as the base.[3] Upon treatment with this base, the N-Boc-and N-tosyl-protected aziridines gave complex mixtures of products with no dimers observed, but the lithiated NBus-protected aziridine 1 a (X = NBus; R = C 5 H 11 ) formed and underwent dimerization in 90 % yield to give the protected 2-ene-1,4-diamine 2 a (X = NBus; R = C 5 H 11 ) as a mixture of three discernible diastereoisomers.There are only two possible isomers (alkene E and Z isomers) that could arise upon dimerization of an enantiopure terminal aziridine, and so this method seems better suited to enantiopure substrates. With this in mind, we examined the scope of the dimerization reaction with a range of enantiopure (99 % ee) N-Bus-protected terminal aziridines [9] ( Table 1). The enantiopure aziridines (entries 1-5) all dimerized in high efficiency under the same straightforward reaction conditions (aziridine 0.32 mol dm À3 in THF/hexanes (2:3), 3 equiv LTMP, À78 8C to 08C, total reaction time 80 min; see Experimental Section).[10] Crucially, all these reactions proceeded with complete E selectivity for the alkene bond formed, with no traces of the Z alkene ...

Lithiation‐Induced Migrations from Nitrogen to Carbon in Terminal Aziridines

“…Aziridines are receiving increasing research interest, and a variety of methods have been recently developed for the synthesis of terminal aziridines 1 (PG=protecting group) in racemic or enantiopure form 1. 2 We have been studying the chemistry of lithiated N ‐Bus (Bus= tert ‐butylsulfonyl) terminal aziridines 2 3 and recently reported their dimerization to give 2‐ene‐1,4‐diamines,4 their intramolecular cyclopropanation (where R bears an unsaturated functional group),5 and their trapping of an external electrophile to give 2,3‐disubstituted aziridines (e.g. 3 ) 6.…”

“…Given the propensity of related lithiated terminal aziridines to dimerize (likely as a result of aggregated species),4 we sought to establish whether the present migration reaction was inter‐ or intramolecular by a crossover experiment (Scheme 2). A 1:1 mixture of aziridines 5 f and 6 was treated with 3 equivalents of LTMP at −78 °C for 90 min; the resulting product mixture was carefully purified and analyzed for the presence of products arising from crossover of the protecting groups.…”

Regio- and Stereoselective Lithiation of Terminal Oxazolinylaziridines: The Aziridine N-Substituent and the Oxazolinyl Group Effect

“…Regioselectivity of the lithiation reaction of aziridines is dramatically dependent upon the aziridine ring substitution: e.g., 1-alkyl-2-phenyl aziridines are smoothly ortho -lithiated, trans -1-alkyl-2,3-diphenylaziridines are cleanly α-lithiated, and the corresponding cis isomers are not lithiated at all (Figure ) . Moreover, it occurs that with an electron-withdrawing group (EWG) on one of the aziridine ring atoms, lithiation takes place normally α to that group, whereas with alkyl-substituted terminal aziridines (bearing an EWG on the nitrogen), lithiation takes place at the β-position trans to the alkyl group (Figure ) 1 Regioselective lithiation of aziridines: the ring substituents effect. …”

“…Reactions with halides (MeI, Bu 3 SnCl, Me 3 SiCl, AllylMe 2 SiCl, AllylBr, EtI, BnBr) and other electrophiles led to the formation of highly enantiomerically enriched cis -2,3-disubstituted aziridines 5b − j in good yields (Table ): in all cases a S E ret mechanism is likely to occur . It might be useful to point out that while lithiation/trapping of a terminal aziridine such as ( S )- 3a leads to cis -configured oxazolinylaziridines, the reported lithiation/trapping of terminal N - tert -butylsulfonyl-2-alkylaziridines leads to trans -configured aziridines …”