Synthesis of cis-C-Iodo-N-Tosyl-Aziridines using Diiodomethyllithium: Reaction Optimization, Product Scope and Stability, and a Protocol for Selection of Stationary Phase for Chromatography

The preparation of C-iodo-N-Ts-aziridines with excellent cis-diastereoselectivity has been achieved in high yields by the addition of diiodomethyllithium to N-tosylimines and N-tosylimine–HSO2Tol adducts. This addition-cyclization protocol successfully provided a wide range of cis-iodoaziridines, including the first examples of alkyl-substituted iodoaziridines, with the reaction tolerating both aryl imines and alkyl imines. An ortho-chlorophenyl imine afforded a β-amino gem-diiodide under the optimized reaction conditions due to a postulated coordinated intermediate preventing cyclization. An effective protocol to assess the stability of the sensitive iodoaziridine functional group to chromatography was also developed. As a result of the judicious choice of stationary phase, the iodoaziridines could be purified by column chromatography; the use of deactivated basic alumina (activity IV) afforded high yield and purity. Rearrangements of electron-rich aryl-iodoaziridines have been promoted, selectively affording either novel α-iodo-N-Ts-imines or α-iodo-aldehydes in high yield.


■ INTRODUCTION
Aziridines, the smallest saturated aza-heterocycles, are important and common synthetic intermediates in organic chemistry. 1,2 The small bond angles and associated ring strain inherent in aziridines affords high reactivity toward ringopening reactions with carbon and heteroatom nucleophiles, providing functionalized amines with stereocontrol. 3 Aziridines participate in a range of additional transformations that take advantage of the ring strain, including cycloaddition reactions and rearrangements, which have been employed particularly in the synthesis of other nitrogen heterocycles. 4,5 C-Halogensubstituted aziridines introduce additional structural complexity and a further range of reactivity. 6 Halo-aziridines bearing chlorine have been most widely investigated, especially gemdihalogenated aziridines due to their ease of preparation by the addition of dichlorocarbene to imines, 7 and other suitable methods. 6,8,9 These have been used as important building blocks in the synthesis of heterocyclic compounds due to their high reactivity toward both ring-opening and ring expansion reactions.
The preparation and isolation of monohalogenated aziridines is less common and more challenging due to rearrangement chemistry dominating their reactivity. 6 Pioneering work in the formation of monochloroaziridines was reported by Deyrup and co-workers; a monochloroaziridine was generated by the reaction of dichloromethyllithium with N-benzylideneaniline at low temperatures, affording the cis-chloroaziridine ( Figure  1A). 9a Since this seminal investigation, α-chloroaziridines have been accessed via reductive halogenation from gemdihalogented aziridines, 10 addition of acid chlorides across 2Hazirines, 11 nitrene addition to chloroalkenes, 12 and trapping of metalated aziridines with an electrophilic source of chlorine ( Figure 1B). 13 Chlorinated aziridines have been shown to undergo nucleophilic displacement of chloride with a variety of nucleophiles including NaOMe, NaCN and LiAlH 4 , leaving the aziridine intact. 9a The synthesis of bromoaziridines has only relatively recently been reported. Ziegler first disclosed a 4:1 cis/trans mixture of bromoaziridines, formed via a Barton decarboxylation-bromination sequence ( Figure 1C). 14a These bromoaziridine products were used to regenerate the radical from the C−Br bond to promote intramolecular cyclization, toward the synthesis of mitomycin-like antitumor agents. 14 More recently, Yudin adopted a nitrogen-transfer approach, generating nitrenes from N-aminophthalimide with PhI(OAc) 2 in the presence of bromoalkenes ( Figure 1D). 15 Huang has formed bromoaziridines through a multiple electrophilic addition of TsNBr 2 to ene-ynoates. 16 Bromoaziridines have also been reported as intermediates, formed by the reaction of a silyldibromomethyllithium with imines, from which bromide was displaced in situ (RMgX, LiAlH 4 ) leaving the aziridine intact. 17 Dibromoaziridines have been recently reported by Li through addition of bromoform to imines followed by cyclization. 18 Mono and difluoroaziridines have also been reported recently. 19 There has been significant recent interest in the functionalization of intact aziridine rings as a divergent route to aziridine derivatives. To date this has largely been achieved through the formation of aziridine anions followed by reaction with electrophiles. 20 Deprotonation of unstabilized monosubstituted aziridines can occur regio-and stereoselectively: occurring trans to the substituent at the least hindered position for alkyl-aziridines, or at the benzylic position for arylaziridines. 21 Functional group exchange has also been demonstrated to be an effective method for generating aziridinyl anions, which react with electrophiles at the predefined position. 13,22 In addition, the palladium-catalyzed cross-coupling of intact aziridines has recently been achieved; separately Vedejs,23 and ourselves 24 have reported the crosscoupling of aryl halides with aziridine metal species formed by Bu 3 Sn−Li exchange and TolSO−Mg exchange respectively. In both examples, the cross-couplings proceeded via transmetalation to zinc and afforded retention of stereochemistry at the reacting center.
We are interested in methods for the functionalization of intact aziridines. 24 We envisaged that iodo-substituted aziridines would offer potential for functionalization of the intact ring via a variety of methods in a regio-and stereoselective fashion. We proposed that an efficient preparation of iodoaziridines would open possibilities for new complementary reactivity, with nucleophilic or electrophilic reagents, or via cross-coupling. We recently communicated the first examples of the iodoaziridine functional group bearing an N-Boc group through the reaction of diiodomethyllithium with N-Boc-imine−sulfinic acid adducts ( Figure 1E). 25 This was successful with aromatic imine substrates, proceeding via a gemdiiodide intermediate in a highly diastereoselective manner, to afford aziridines bearing the aryl and iodo groups in a cisrelationship.
Here we disclose the full study into the preparation of a new class of alkyl and aromatic substituted iodoaziridines bearing an N-Ts group, isolated with excellent cis-diastereoselectivity, in high yields in one step from N-tosylimines and N-tosylimine− HSO 2 Tol adducts ( Figure 1F). We report in detail the development of the reaction to form N-Ts iodoaziridines, and their differing reactivity and stability to the N-Boc iodoaziridines. The present methodology extends the reaction scope, being successful for alkyl as well as aryl imine substrates, and we also report the diastereoselective reaction with a stereochemically pure N-sulfinyl imine. In addition, we report a protocol for determining the optimal stationary phase to use in chromatography for the purification of potentially unstable compounds, which resulted in increased yields for the iodoaziridines. The selective transformation of an iodoaziridine to novel α-iodo-N-Ts-imine and α-iodo-aldehyde functional groups is also reported.
■ RESULTS AND DISCUSSION Reaction Optimization. We proposed iodoaziridines could be accessed by an addition-cyclization protocol involving the reaction of N-Ts-imines with diiodomethyllithium, analogous to the aza-Darzens reaction. The aza-Darzens reaction involves the addition of a carbon nucleophile bearing a leaving group to an imine to form a β-haloamine intermediate that undergoes cyclization to afford the aziridine (Scheme 1). 2c Commonly the carbene equivalent reagent is stabilized by an electronwithdrawing group, often an ester (e.g., R 3 = CO 2 R in Scheme 1). In these cases, the diastereoselectivity in the aziridine product is determined in the initial addition, which is followed by a stereospecific cyclization. There are examples of unsubstituted, unstabilized MCH 2 X reagents (R 3 = H) being used to afford terminal aziridines. Concelloń has reported the enantioselective preparation of terminal aziridines using iodomethyllithium and enantioenriched imines. 26 Chloromethyllithium has been employed in a similar fashion. 27 Diiodomethylmetal reagents (MCHI 2 ) differ from both above scenarios, being unstabilized and substituted, and importantly as symmetrical nucleophiles, the initial addition step is not diastereodetermining. Consequently the cyclization step  determines the diastereochemistry of the aziridine product through selecting one of two potential iodide leaving groups.
Since MCHI 2 reagents were first described by Seyferth and Lambert in 1973, 28 they have had relatively little use in synthesis, possibly due to the required low temperatures. 29 Charette recently described improved conditions for the formation of diiodomethane anions (LiCHI 2 and NaCHI 2 ) at −78°C generating gem-diiodoalkanes by alkylation with primary alkyl iodides, and (E)-β-aryl vinyl iodides from benzyl bromides by alkylation/elimination. 30−32 Initial investigations were undertaken on the addition of MCHI 2 to phenyl N-Ts imine, chosen due to ready availability and stability. The tosyl group was expected to be an appropriate electron-withdrawing group to stabilize charge in the intermediate (n N −σ* (S−O) ), 33 and prevent elimination of iodide from the iodoaziridine products, while also providing a degree of steric bulk sufficient to engender diastereocontrol in the cyclization step.
In this study, MCHI 2 reagents were preformed by deprotonation of CH 2 I 2 for 20 min at −78°C, prior to addition of the imine, and the reaction quenched after 1 h at −78°C to avoid any potential product decomposition on warming. The initial choice of solvent conditions (a mixture of THF:Et 2 O) was selected due to the stabilizing effect on the carbenoid reagent. 28,30 Early studies varied the base used for deprotonation and workup procedures to ensure stability of the products. 34 The use of LiHMDS as base to afford LiCHI 2 was shown to be productive, affording a mixture of products, of which three components were identified: amino gem-diiodide 3a, the desired iodoaziridine 4a, as the cis-isomer, as well as aminal 2a formed by the direct addition of LiHMDS to the imine (Table 1, entry 1). These products exhibited highly characteristic 1 H NMR signals: amino gem-diiodide 3a characterized by signals at δ 5. 34, 5.27, and 4.51 ppm (NH; CHI 2 ; CHPh); cis-iodoaziridine 4a, characterized by doublets at δ 4.89 and 3.89 ppm (CHI; CHPh); aminal 2a displayed doublets at δ 5.85 and 5.19 ppm (NH; CHPh). Both gemdiiodide 3a and aziridine 4a were observed at −78°C, indicating cyclization was occurring at low temperature. It was notable that elimination to afford the vinyl iodide was not observed, even though this was the major side product in the N-Boc derivatives. 25 The ratio of products was determined by 1 H NMR of the crude reaction mixture in the presence of an internal standard.
We were concerned with minimizing the formation of the undesired aminal product 2a, and aimed to optimize for the combined yield of diiodide 3a and iodoaziridine 4a. The formation of aminal 2a suggested that deprotonation of CH 2 I 2 was incomplete under these conditions, which was also implied by deuteration studies, leaving LiHMDS in solution. Increasing the equivalents of LiHMDS led to increased formation of 2a. Indeed, in the absence of diiodomethane, treatment of imine 1a with LiHMDS at −78°C afforded aminal 2a in almost quantitative yield. 35 The formation of aminal 2a was irreversible under the reaction conditions, 36 and as a result varying the reaction time at −78°C had no effect on the formation of 2a. Increasing the deprotonation time to 40 min and 1 h caused a dramatic drop in the combined yield of 3a and 4a.
Increasing the excess of diiodomethane employed to 10 equiv did afford a significant increase in the formation of 3a and Scheme 1. Comparison of the Stereochemical Outcome in the aza-Darzens Reaction 4a (entry 2), though the formation of aminal 2a remained at similar levels. Reaction concentration and ratio of THF:Et 2 O were found to be important to the product distribution and these were thoroughly explored under these conditions, but with little overall increase in yield. Interestingly, reducing the concentration of the reaction, led to a notable increase in the proportion of the diiodide that underwent cyclization in the time frame of the reaction (compare entries 2 and 3). To reduce the excess diiodomethane employed, we examined the effect of Lewis basic additives (compare entries 1 and 4−7). The use of HMPA was detrimental, whereas TMEDA afforded an increase in the formation of 2a, but promoted cyclization. The addition of 1 equiv DMPU afforded the highest combined yield of 3a and 4a (entry 6). We found that reducing the concentration under these conditions afforded an increase in cyclization product 4a (entry 7). Despite extensive further investigation using DMPU as an additive, we were unable to make further improvements. Instead we examined the effect of increasing the equivalents of diiodomethane and base (up to 4 equiv LiHMDS) at a higher concentration, which gave rise to an increased combined yield of 3a and 4a (entries 8−10), presumably due to an increase in the amount of LiCHI 2 present in solution. Finally, it became apparent that the addition of diiodomethyllithium to the imine was rapid and the iodoaziridine product was decomposing under the reaction conditions. We continued with 3 equiv LiHMDS and it was identified that warming the reaction mixture to 0°C was sufficient to promote rapid and complete cyclization, with minimum decomposition (entry 11). The precise mixture of THF:Et 2 O was optimized, with a mixture of of 2.5:1 THF/ Et 2 O giving the maximum yield. Finally, reducing the time under the reaction conditions to a minimum, that is, warming the reaction as soon as addition of the imine was complete, afforded the highest yield of 4a, with complete cyclization of any diiodide intermediate (entry 12). This provided our standard conditions for further study, affording an 81% 1 H NMR yield, which corresponded to a 76% isolated yield of iodoaziridine 4a, exclusively as the cis-diastereoisomer. Rationale of Diastereoselectivity. Throughout the optimization, only the cis-diastereoisomer of the iodoaziridine was observed, assigned on the basis of the magnitude of the coupling constant between CHAr and CHI protons (J = 6.1 Hz). These assignments are consistent with the coupling constants observed for cis-N-Boc iodoaziridines isolated by ourselves, 25 and for cis-N-Boc bromoaziridines by Ziegler and co-workers. 14 To rationalize the excellent cis-diastereoselectivity for the reaction, we invoke the steric properties of the bulky SO 2 Tol group to discriminate between three possible conformations ( Figure 2). The R and sulfonyl groups will align in an anti conformation to avoid the eclipsing interactions that make conformer C-trans unfavorable. Placing the N-group and iodide in an antiperiplanar fashion appropriate for cyclization therefore provides two possible conformations Acis and B-trans. In the transition state the pyramidalization of N will position the toluenesulfonyl group to one side of the ring, which clashes with other ring substituents. 37 We propose that an unfavorable interaction between the nondisplaced iodide and the toluenesulfonyl group is dominant. In the preferred conformation, A-cis, the iodide is positioned away from the bulk of the tolyl-sulfonyl group leading to the cis-iodoaziridine. 38 In conformation B-trans, the unfavorable interaction between the nondisplaced iodide and the large toluenesulfonyl group results in the conformation being disfavored.
Reaction Scope. To explore the scope of the iodoaziridination reaction a range of of N-Ts imines 1 and N-Ts imine− HSO 2 Tol adducts 5 were prepared by literature procedures, with some minor modifications (Scheme 2 and Scheme 3). 39−41 Certain alkyl substrates with α-protons were retained as their imine−HSO 2 Tol adducts, due to the increased stability to hydrolysis and enamine formation compared to the imines.
With a series of imines in hand we examined the scope of the iodoaziridination reaction under our optimized set of reaction conditions. Initially we examined the addition of diiodomethyllithium to aromatic imines under the reaction conditions optimized for 4a, forming the iodoaziridines in high yields with exclusive cis-diastereoselectivity (Table 2).
Electron-donating groups were tolerated under the reaction conditions, as shown by the 4-Me and 4-tBu-phenyl examples ( Table 2, entries 2 and 3). It is notable that while phenyl iodoaziridine was stable to chromatography on silica, these more electron-rich examples were not; purification on deactivated basic alumina (activity IV) afforded the yields stated. The remainder of the scope was purified by chromatography using basic alumina (activity IV, see below for further discussion). ortho-Substituted aromatic substrates were warmed to rt as they required an increased temperature to induce full cyclization from the intermediate β-amino gemdiiodides (entries 4 and 5, denoted Method B). For 2-tolyl imine 1d, a 9:5 ratio of iodoaziridine (4d)/amino gem-diiodide (3d) was observed under the standard conditions. Warming to rt by removing the reaction flask from the dry ice bath ensured complete cyclization (>19:1) to yield the corresponding cisiodoaziridine in high yield. This was similarly successful with the 1-napthyl substituent affording an excellent yield of iodoaziridine 4e (entry 5). 4-Fluoro-and 4-chloro-substituted aromatics were also well tolerated under the reaction conditions (entries 6 and 7).
ortho-Chlorophenyl imine 1h was subjected to the orthosubstituted reaction conditions (Method B) but no cyclization was observed, and attempts to promote cyclization by additional warming of the reaction mixture led to decomposition. The lack of cyclization was attributed to stabilizing coordinating interactions of the lone pairs of chlorine in the postulated lithiated intermediate (Scheme 4), preventing the required orientation for cyclization being achieved. The corresponding amino gem-diiodide 3h could be isolated in high yield by quenching the reaction at −78°C. Subjecting isolated 3h to cyclization conditions previously developed for β-N-Boc diiodides to their corresponding iodoaziridines (Cs 2 CO 3 , DMF, rt), 25 only afforded degradation of the starting material.
In our previous work on N-Boc iodoaziridines, alkyl imines were unsuccessful. 25 Pleasingly with the N-Ts group, alkyl iodoaziridines could be successfully accessed, constituting a significant increase in reaction scope. Using the cyclohexyl imine 1i, the reaction performed similarly to the aryl examples, that is, the diiodide formed rapidly and complete cyclization occurred to the iodoaziridine on warming the reaction mixture to 0°C. The cyclohexyl substituted iodoaziridine 4i was also obtained from the imine−HSO 2 Tol adduct through the use of identical reaction conditions except for an additional equivalent of base and diiodomethane employed (Method C) to form the imine in situ. The two methods returned cis-iodoaziridine 4i in comparable yields (68% from imine 1i vs 57% from imine− HSO 2 Tol adduct 5i, Table 3 entries 1 and 2). Due to ease of synthesis and handling of the adducts, several of the alkyl imines were used in this form. A range of branched alkyl imine−HSO 2 Tol adducts were examined under the modified reaction conditions (entries 3 to 5), each displaying complete cis-diastereoselectivity upon cyclization with good yields. Using the α-chiral imine generated from 5l afforded excellent cis:trans selectivity in the cyclization step, but only minimal diastereoselectivity in the addition step (facial selectivity = 1.9:1). Alkene containing imine 1m was also successful, but again without significant facial selectivity. The tBu-substituted imine 1n was submitted under the ortho-reaction conditions (Method B), due to concerns with the steric bulk of the tBu group affecting the degree of cyclization. Remarkably, under these conditions, iodoaziridine 4n was isolated in an excellent yield of 70%, and only the cis-iodoaziridine was observed, despite significant eclipsing interactions between the tBu and iodide groups in the product.
Primary alkyl imine−HO 2 STol adducts did not perform well under the reaction conditions with nPr and nHex side chains returning only 6 and 4% yields of the corresponding cisiodoaziridines respectively (Scheme 5). Here aminal formation was the major product from the reaction as the reduced steric demands of these primary alkyl substrates allows the irreversible addition of the bulky LiHMDS, which is prevented in the branched substrates. Attempts to increase the equivalents of diiodomethane, or of both diiodomethane and base, were unsuccessful and further optimization is required for this substrate class.
A Method for the Assessment of Compound Stability to Stationary Phases for Chromatography. The isolation and purification of potentially unstable compounds is an essential skill of the synthetic chemist. Due to the acidic nature of silica gel, decomposition of compounds during silica chromatography can be a common occurrence. While there are several alternative materials that can be employed as stationary phases for chromatography, 42 there is not a method to rapidly and quantitatively compare the performance of these alternatives with regard to the recovery of unstable compounds.
Whereas the majority of the N-Boc iodoaziridines were stable to silica, 25 it was quickly apparent in this study that the N-Ts derivatives behaved significantly differently and compounds 4b and 4c underwent major decomposition. While 4a afforded a good recovery with respect to the yield determined by 1 H NMR, purification of iodoaziridine 4b afforded <50% of the expected recovery. We therefore used compound 4b to study the effect of different stationary phases on the recovery after purification. To achieve this, we developed a simple protocol for assessing the stability of potentially unstable compounds to chromatography, which enabled us to access the iodoaziridines in high yield.
A sample of 4b was prepared as described above, and an internal standard added to obtain a yield by 1 H NMR prior to purification (Table 4, entry 1). To probe the stability of 4b on a range of stationary phases, we subjected crude 4b to conditions that model the experience of the compound during column chromatography, replicating both the solvent conditions and the length of time of a normal purification procedure. Samples of 4b containing the standard were added to a slurry of the relevant stationary phase in EtOAc/hexane and stirred for 30 min. 35 The slurry was then filtered and the filtrate analyzed by 1 H NMR to assess the recovery of the iodoaziridine. On comparison of the yield determined by 1 H NMR, the levels of degradation could be quantified. A selection of stationary phases were compared as indicated in Table 4, in addition to a control experiment where no stationary phase was added. The recovery of iodoaziridine 4b was dramatically affected by changing the stationary phase (Table 4 and Figure 3). Exposure of 4b to bench silica (entry 3) and base-doped silica (1% Et 3 N, entry 4) caused major degradation of the iodoaziridine to iodo(phenyl)acetaldehyde 7 (vide infra). Neutral alumina and basic alumina (activity I) appeared to trap the aziridine, with poor yields being returned for iodoaziridine 4b (entries 5 and 6). However, the stability of the iodoaziridine was greatly enhanced using deactivated basic alumina (activity IV vs activity I), with only a small drop in the recovery observed. Pleasingly, using column chromatography on basic alumina (activity IV) afforded an isolated yield of 48%, which closely resembled that observed in the crude mixture.
By comparison, performing the analysis on phenyl analogue 4a displayed essentially quantitative recovery on all potential stationary phases (Table 5), with the exception of neutral alumina and basic alumina (activity I), which trapped the product (entries 5 and 6). The minor products on bench silica and base-doped silica were assigned to be the corresponding αiodo-aldehyde. This indicated that the method is appropriate, providing good recovery when the compound does not undergo degradation. As a consequence of these results, we used basic alumina (activity IV) for the remainder of the reaction scope above. We believe this protocol may be a useful approach to determine the optimal stationary phase for chromatography of other compounds unstable to silica. An additional advantage compared to directly performing chromotography on different stationary phases was that this protocol enables a more facile investigation into the identity of decomposition products, where these may be missed on collecting fractions.
Stability of N-Ts-iodoaziridines: Rearrangement. During the isolation of more electron-rich iodoaziridines 4b and 4c it was observed that they were subject to rearrangement to form α-iodo imines (Scheme 6). This rearrangement could be achieved in quantitative conversion by submitting neat cisiodoaziridine 4b to mild heating under reduced pressure. 43 We propose this occurs by unimolecular opening of the iodoaziridine and elimination of iodide to afford a benzylic cation, which is trapped by iodide (Scheme 6). Similar rearrangements have been highlighted by Yudin converting αbromoaziridines to α-bromohydrazones. 15 The rearrangement of more electron-rich aromatic N-Ts iodoaziridines (R = (4-tBu)C 6 H 4 , 4c) was also observed by 1 H NMR, but the resulting iodo-imine could not be isolated due to rapid decomposition.
Following the observations made during the stability studies to silica above, we were keen to establish whether iodoaziridine 4b could be converted directly to the iodo-aldehyde, which was observed on stirring crude 4b with silica. Indeed, treating a crude sample of iodoaziridine 4b with bench silica in a mixture of EtOAc/hexane and open to the air, afforded complete rearrangement/hydrolysis of the aziridine to iodoaldehyde 7 in 54% over the 2 steps following chromatography (Scheme 7).
Stereoselective Iodoaziridination with a Chiral N-tert-Butylsulfinyl Imine. We were keen to extend the current protocol of iodoaziridination to chiral N-protecting groups to provide facial selectivity in the initial addition to the imine. The use of Ellman's auxiliary has received significant attention in the stereoselective synthesis of aziridines via the aza-Darzens  approach. 44,45 Attempts to use the comparable toluenesulfinyl group were unsuccessful, as this is known to undergo attack at sulfur with organometallic reagents. 46 Therefore, we investigated the tBu sulfinyl group, which has been shown to offer stabilizing interactions in the functionalization of aziridinyl anions. 47 Phenyl t-butyl sulfinyl imine 9 was prepared by direct condensation using Ti(OEt) 4 (Scheme 8). 48 Sulfinyl imine 8 was then subjected to the reaction conditions optimized for the N-Ts imines (Method A, Table  2). Pleasingly this successfully afforded the desired iodoaziridines 9a and 9b in a 59% yield with diastereoselectivity (dr = 85:15). Characteristic 1 H NMR signals for aziridine protons were observed for both products; doublets at δ 4.54 and 3.71 ppm for the major diastereoisomer and δ 4.83 and 3.30 ppm for the minor diastereoisomer, all with J = 6.0 Hz corresponding to the cis-isomer. Given the well-established models for stereocontrol for the 1,2-addition of organolithiums to aldimines the major and minor diastereoisomers could be predicted (Scheme 8, boxed). 44,49 In this model, the organolithium approaches from the least hindered face of the imine via the lone pair of the sulfinyl group, affording diastereoisomer 9a as the major product. The dr obtained in the addition of diiodomethyllithium is comparable to that obtained for organolithium reagents attacking through an acyclic transition state, for example PhLi addition into N-tert-butylsulfinyl 4-chlorophenyl imine in THF at −78°C, dr = 73: 27. 49 Due to the differing nature of the N-sulfinyl protecting group, stability tests were run to determine the best stationary phase for flash column chromatography in the manner described above. Here, the N-sulfinyl iodoaziridine was found show similar stability to 4a, with the best recovery obtained with basic alumina (activity V, 15% w/w water added). Applying the optimized conditions to tBu-sulfonyl imine 10 (Method A), prepared by oxidation of sulfinyl imine 8, 50 afforded the corresponding N-Bus-iodoaziridine 11 in a moderate 45% yield (Scheme 9).

■ CONCLUSION
We have developed an effective method to install iodide functionality onto a range of alkyl and aromatic substituted N-tosylaziridines. The addition of diiodomethyllithium to imines and imine−HO 2 STol adducts at low temperature, followed by warming, afforded cyclization to the corresponding cis-N-Tsiodoaziridines in a highly diastereoselective fashion and in good yields. The use of the N-Ts protecting group has enabled the formation of alkyl iodoaziridines for the first time. These novel alkyl and aromatic substituted iodoaziridines provide fascinating structures and potential synthetic intermediates for functionalization of the intact aziridine ring. The formation of these iodoaziridines was achieved in conjuction with our new protocol for assessing the best stationary phase for purification of this new class of compound. Rearrangement products of electron-rich aryl iodoaziridines were also discovered, and the formation of an enantioriched N-sulfinyl iodoaziridine was achieved for the first time.

■ EXPERIMENTAL SECTION
General Experimental Considerations. All nonaqueous reactions were run under an inert atmosphere (argon) with flame-dried glassware using standard techniques. Anhydrous solvents were obtained by filtration through drying columns (THF, Et 2 O, CH 2 Cl 2 ). Flash column chromatography was performed using 230− 400 mesh silica or 50−200 μm Brockmann basic alumina (activity IV or activity V) with the indicated solvent system according to standard techniques. Analytical thin-layer chromatography (TLC) was performed on precoated, glass-backed silica gel plates. Visualization of the developed chromatogram was performed by UV absorbance (254 nm), or aqueous potassium permanganate stain. Infrared spectra (ν max , FTIR ATR) were recorded in reciprocal centimeters (cm −1 ). Nuclear magnetic resonance spectra were recorded on 400 or 500 MHz spectrometers. Chemical shifts for 1 H NMR spectra are recorded in parts per million from tetramethylsilane with the solvent resonance as the internal standard (chloroform, δ = 7.27 ppm). Data is reported as follows: chemical shift [multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet and br = broad), coupling constant in Hz, integration]. 13 C NMR spectra were recorded with complete proton decoupling. Chemical shifts are reported in parts per million from tetramethylsilane with the solvent resonance as the internal standard ( 13 CDCl 3 : 77.0 ppm). 19 F NMR spectra were recorded with complete proton decoupling. Chemical shifts are reported in parts per million referenced to the standard monofluorobenzene: −113.5 ppm. J values are reported in Hertz. Assignments of 1 H/ 13 C spectra were made by the analysis of δ/J values, and COSY, HSQC, and HMBC experiments as appropriate. Melting points are uncorrected. Reagents: Commercial reagents were used as supplied or purified by standard techniques where necessary. Compound Handling and Storage: The N-Ts iodoaziridines displayed sensitivity to light and during all handling, exposure of iodoaziridines to light was minimized. However, the N-Ts iodoaziridines displayed a notable increase in stability to exposure to light in comparison to the N-Boc derivatives. Iodoaziridines were stored at −20°C neat for short periods or as a solution in CH 2 Cl 2 or CHCl 3 to prevent decomposition. For example, iodoaziridine 4i was stored in a CDCl 3 solution for >4 months without displaying noticeable decomposition. Deactivated basic alumina: The activity of basic alumina was altered by the addition of water to commercial basic alumina (activity I) and evenly distributed (activity IV: 10% w/w water; activity V: 15% w/w). 51 Imines: Imines 1a,c−d,g,h−i and imine−HSO 2 Tol adducts 5i−l and 5o−p were synthesized according to the method of Chemla and co-workers. Imine 1m was synthesized by a modification of the method of Chemla and co-workers. 39 Imines 1f and 1n by a modification of the method of Proctor, 41 and imines 1b, 1e by the method of Stalick. 40 General Procedure 1: Imines 1a, 1c, 1d, 1g−1i. The relevant aldehyde (10.0 mmol, 1.0 equiv) was added to a solution of ptoluenesulfonamide (1.71 g, 10.0 mmol, 1.0 equiv) and sodium ptoluenesulfinate (1.96 g, 11.0 mmol, 1.1 equiv) in formic acid and water (1:1, 30 mL). The mixture was stirred at rt for 24 h to 7 days at rt, then filtered under reduced pressure and washed successively with water (50 mL) and hexane (50 mL). The resulting imine−HO 2 STol adduct was dissolved in CH 2 Cl 2 (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL) was added. The resulting biphasic solution was vigorously stirred for 2 h at rt. The organic layer was separated, dried (Na 2 SO 4 ) and the solvent was removed under reduced pressure to afford the imine, which was sufficiently pure or further purified where stated.
Method B. For ortho-substituted aromatic imines and sterically hindered imines. Identical to Method A, except the reaction was warmed to rt for 20 min after addition of imine at −78°C.
Method C. nBuLi (2.00 mmol, 4.0 equiv) was added dropwise to a solution of hexamethyldisilazane (420 μL, 2.00 mmol, 4.0 equiv) in THF (7.5 mL) and Et 2 O (3.5 mL) at −78°C. After 30 min, diiodomethane (177 μL, 2.20 mmol, 4.4 equiv) in THF (1.5 mL) was added dropwise to the reaction mixture at −78°C in the dark. After 20 min at −78°C, a solution of the appropriate imine−HO 2 STol adduct (0.50 mmol, 1.0 equiv) in THF (2.0 mL) was added dropwise to the reaction mixture over 5 min. The reaction was then immediately warmed to 0°C in an ice bath and left at this temperature for 15 min. The reaction was then quenched by the addition of saturated aqueous sodium bicarbonate solution (40 mL). The aqueous solution was extracted with CH 2 Cl 2 (3 × 30 mL) and the combined organic layers were dried (Na 2 SO 4 ), and the solvent was removed under reduced pressure. Purification by flash chromatography on deactivated basic alumina (activity IV or activity V) afforded the cis-iodoaziridine.