Highly cis-selective synthesis of iodo-aziridines using diiodomethyllithium and in situ generated N-Boc-imines w

Aziridines continue to provide both structural fascination, and important synthetic intermediates for wide ranging applications in chemical synthesis. Consequently, diverse synthetic methods for their preparation have been disclosed. In recent years the functionalisation of intact aziridine rings has become important, allowing access to a variety of aziridine derivatives from single precursors. In particular, anionic functionalisation of aziridines, in the absence of a stabilising group, has been mediated either by functional group exchange, or by direct deprotonation at the most acidic site. Recently, Vedejs and co-workers reported the palladium catalysed cross coupling of aziridine metal species, formed by Bu3Sn–Li exchange, with aryl halides. We envisaged that more efficient routes to suitably functionalised aziridines, that would enable regiocontrolled and diverse derivatisation of the intact ring, could find numerous applications in synthesis. C-Heteroatom substituted aziridines can dramatically influence the reactivity and stability of the 3-membered ring. Chloro-aziridines, in particular dichloroaziridines, often formed by the reaction of dichlorocarbenes and imines, are widely used in the preparation of N-containing heterocycles. Bromoaziridines are more difficult to access, and have been reported on only a few occasions. Ziegler first formed bromoaziridines by a Barton decarboxylation–bromination from aziridine carboxylates, affording amixture of cis/trans-isomers. These were used as radical precursors in the synthesis of mitomycin-like antitumour agents. Yudin has reported bromoaziridines through an N-transfer approach, generating a nitrene under oxidative conditions, as has Huang using TsNBr2. 14 Additionally, Oshima reported the intermediacy of bromoaziridines in the preparation of silyl aziridines, proposing an in situ elimination of bromide. Monoand di-fluoroaziridines have also been recently reported. Iodoaziridines, on the other hand, are unknown in the literature to date. We chose to explore the possibility of forming iodoaziridines, as a potential reactive substrate for cross coupling, which should also provide precursors for anionic or radical functionalisation. Here we report the preparation of this new functional group, in high yields and excellent cisstereoselectivity in one step from simple N-Boc-imine–sulfinic acid adducts. We proposed an addition-cyclisation protocol to access iodoaziridines from imines using diiodomethyllithium, analogous to the aza-Darzens reaction (Scheme 1). Recently Charette and Bull utilised diiodomethane anions at 78 1C to prepare alkyl diiodides by alkylation, and to form styryl halides by alkylation/ elimination, but diiodomethyllithium remains an underutilised reagent. Importantly, whereas in the aza-Darzens reaction itself the diastereochemistry of the aziridine product is determined in the initial addition, here, due to the symmetrical nature of the diiodomethyllithium nucleophile the cyclisation step would be diastereodetermining. The stability of potential iodoaziridines was naturally a significant concern, due to potential loss of iodide amongst other potential decomposition routes. We elected to examine N-Boc imines to provide an electron-withdrawing group on N as well as offering potential for further functionalisation or ring opening. Initial investigations concentrated on the addition of diiodomethyllithium to phenyl N-Boc imine to afford the aminodiiodide. Diiodomethyllithium was preformed by deprotonation of CH2I2 with LiHMDS at 78 1C prior to addition of the imine. Both the imine and imine–HO2STol adduct 1a were examined, with the latter preferred for practical simplicity, generating the imine in situ by deprotonation with excess base. Careful optimisation of the reaction conditions was undertaken, including the equivalents of base and CH2I2, the use of Lewis basic additives, as well as concentration and the solvent ratio (a mixture of THF and ether was essential). The optimal Scheme 1 Proposed route to iodoaziridines.

The first preparation of iodoaziridines is described.The addition of diiodomethyllithium to N-Boc-imines affords these novel aziridines in high yields.The reaction proceeds in one-pot via a highly diastereoselective cyclisation of an amino gem-diiodide intermediate.
Aziridines continue to provide both structural fascination, 1 and important synthetic intermediates for wide ranging applications in chemical synthesis. 2Consequently, diverse synthetic methods for their preparation have been disclosed. 3In recent years the functionalisation of intact aziridine rings has become important, allowing access to a variety of aziridine derivatives from single precursors.In particular, anionic functionalisation of aziridines, 4 in the absence of a stabilising group, has been mediated either by functional group exchange, 5 or by direct deprotonation at the most acidic site. 6Recently, Vedejs and co-workers reported the palladium catalysed cross coupling of aziridine metal species, formed by Bu 3 Sn-Li exchange, with aryl halides. 7We envisaged that more efficient routes to suitably functionalised aziridines, that would enable regiocontrolled and diverse derivatisation of the intact ring, could find numerous applications in synthesis.
C-Heteroatom substituted aziridines can dramatically influence the reactivity and stability of the 3-membered ring. 8hloro-aziridines, in particular dichloroaziridines, often formed by the reaction of dichlorocarbenes and imines, 9,10 are widely used in the preparation of N-containing heterocycles. 8Bromoaziridines are more difficult to access, and have been reported on only a few occasions.Ziegler first formed bromoaziridines by a Barton decarboxylation-bromination from aziridine carboxylates, affording a mixture of cis/trans-isomers. 11These were used as radical precursors in the synthesis of mitomycin-like antitumour agents. 12Yudin has reported bromoaziridines through an N-transfer approach, generating a nitrene under oxidative conditions, 13 as has Huang using TsNBr 2 . 14Additionally, Oshima reported the intermediacy of bromoaziridines in the preparation of silyl aziridines, proposing an in situ elimination of bromide. 15Mono-and di-fluoroaziridines have also been recently reported. 16odoaziridines, on the other hand, are unknown in the literature to date.We chose to explore the possibility of forming iodoaziridines, as a potential reactive substrate for cross coupling, which should also provide precursors for anionic or radical functionalisation.Here we report the preparation of this new functional group, in high yields and excellent cisstereoselectivity in one step from simple N-Boc-imine-sulfinic acid adducts.
We proposed an addition-cyclisation protocol to access iodoaziridines from imines using diiodomethyllithium, analogous to the aza-Darzens reaction (Scheme 1). 17,18Recently Charette and Bull utilised diiodomethane anions at À78 1C to prepare alkyl diiodides by alkylation, 19 and to form styryl halides by alkylation/ elimination, 20 but diiodomethyllithium remains an underutilised reagent. 21Importantly, whereas in the aza-Darzens reaction itself the diastereochemistry of the aziridine product is determined in the initial addition, here, due to the symmetrical nature of the diiodomethyllithium nucleophile the cyclisation step would be diastereodetermining.
The stability of potential iodoaziridines was naturally a significant concern, due to potential loss of iodide amongst other potential decomposition routes.We elected to examine N-Boc imines to provide an electron-withdrawing group on N as well as offering potential for further functionalisation or ring opening.
Initial investigations concentrated on the addition of diiodomethyllithium to phenyl N-Boc imine to afford the aminodiiodide.Diiodomethyllithium was preformed by deprotonation of CH 2 I 2 with LiHMDS at À78 1C prior to addition of the imine. 22Both the imine and imine-HO 2 STol adduct 1a were examined, with the latter preferred for practical simplicity, generating the imine in situ by deprotonation with excess base. 23,24Careful optimisation of the reaction conditions was undertaken, including the equivalents of base and CH 2 I 2 , the use of Lewis basic additives, as well as concentration and the solvent ratio (a mixture of THF and ether was essential).19a The optimal conditions (3.0 equiv.CH 2 I 2 , 2.6 equiv.LiHMDS, THF/Et 2 O, À78 1C) provided amino-diiodide 2a in 80% yield (Scheme 2).
We next assessed the conversion of diiodide 2a to aziridine 3a using a variety of bases and Lewis acids to promote the cyclisation.Under these conditions, multiple pathways could be conceived: the desired cyclisation may occur to form either syn or anti-aziridines, cyclisation to the oxazoline, or alternatively elimination to the vinyl iodide.Pleasingly, the use of Cs 2 CO 3 in DMF produced an effective cyclisation, providing iodoaziridine 3a (54% yield, Scheme 3). 25 Remarkably, aziridine 3a was stable to isolation and could be purified on silica gel without decomposition. 26Furthermore, exclusive formation of the cis-aziridine was observed indicating a highly stereoselective cyclisation step was occurring.
Having proved iodoaziridine 3a was indeed a viable structure, the possibility of a one-pot synthesis investigated.Cyclisation could be promoted by subsequent warming of the reaction mixture, after the initial addition of LiCHI 2 was complete, under otherwise similar reaction conditions.Subtle control of the reaction temperature profile proved to be critical.
The addition of LiCHI 2 to the generated imine occurred very rapidly at À78 1C, 27,28 but the intermediate was stable at this temperature (Table 1, Entry 1).Warming to rt by removing the flask from the dry ice bath led to inseparable mixtures of iodoaziridine 3a with the elimination product 4a.Cyclisation was observed to occur only slowly at À20 1C, with diiodide 2a the major product after 60 min.At 0 1C the diiodide reacted completely to afford a 3 : 1 mixture of iodoaziridine 3a and the elimination product iodide 4a, and rapid warming to rt in a water bath gave an improved ratio (entries 2-4).Ultimately the rate of warming was shown to be crucial in avoiding elimination.Therefore the cyclisation was performed in a water bath at 30 1C, to ensure rapid and reproducible warming.This completely prevented the elimination pathway and iodoaziridine 3a could be isolated cleanly in excellent yield (Table 1, entry 5, Table 2 entry 1). 29Performing the reaction on a 3 mmol scale afforded similarly excellent yield and selectivity (Table 2, Entry 2).
Variation of the aromatic group of the imine with alkyl and napthyl substituents gave the corresponding iodoaziridines in high yields, and exclusively as the cis-isomers (Table 2, entries 3-6).The ortho-tolyl substrate displayed more reluctance to cyclise, requiring a longer time at the elevated temperature (30 min) to achieve complete cyclisation from the amino-diiodide (entry 4), presumably due to unfavourable steric interactions.
Next halogenated aromatics were examined, which were well tolerated by the reaction conditions (entries 7-10).With orthochlorophenyl (Entry 8) cyclisation was more significantly slowed presumably due to coordination of the lone pairs on the orthosubstituent with the lithium cation in the intermediate.Notably in this example the trans-iodoaziridine was observed. 30All other examples were isolated in >95 : 5 cis-selectivity by 1 H NMR.
The 3-methoxyphenyl bearing imine was also tolerant of the reaction conditions but required the short reaction times to prevent decomposition (Entry 11).As electron rich N-Boc aziridines are prone to S N 1-type opening, purification required chromatography on neutral alumina to prevent decomposition.Electron poor aryl-imines were successful (entries 12-13) but with lower yields due to increased amounts of elimination and other side product formation.Alkyl imines were generally not successful, for example with cyclohexyl imine-adduct (1m), only the corresponding diiodide (2m) was isolated in 29% yield.The use of CH 2 Br 2 in the place of CH 2 I 2 under otherwise identical  This journal is c The Royal Society of Chemistry 2012 conditions with 1a led to the formation of the corresponding bromoaziridine (5) with exclusive cis-stereochemistry in an unoptimised yield of 30%.
Our proposal for the cis-selectivity in forming the iodoaziridines is based on steric factors (Scheme 4). 31The aryl and Boc groups are likely to adopt an anti-orientation preferentially, providing two conformations (A and B) with N and I in an anti-periplanar arrangement appropriate for cyclisation.We propose that an unfavourable interaction between the nondisplaced iodide with the Boc group is dominant in the cyclisation transition state where the N-atom becomes sp 3 hybridised.Hence the non-displaced iodine prefers to adopt a position away from the bulk of the Boc group and so gauche to the Ph group, resulting in the cis-aziridine configuration.
In summary, we report the first examples of iodoaziridines.The use of diiodomethyllithium with careful temperature control allows either the isolation of the amino-diiodide or complete cyclisation to the iodoaziridine with very high cis-selectivity, and both with excellent yields.We are currently developing methods for the functionalisation of iodoaziridines to various aziridine derivatives, which will be reported in due course.
For financial support we gratefully acknowledge the EPSRC (Career Acceleration Fellowship to JAB), the Ramsay Memorial Trust (Research Fellowship 2009-2011 to JAB), The Royal Society for a research grant, the Nuffield foundation and Pfizer for UG bursaries (TT, TB), and Imperial College London.Thank you to Prof Alan Armstrong for generous support and advice.
a b d.r. of crude mixture by 1 H NMR.Where >95 : 5 is stated, the minor diastereoisomer could not be observed by 1 H NMR. d.r. of purified compound indicated in parentheses where relevant.c Reaction performed on a