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 ring-opening 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-Halogen-substituted aziridines introduce additional structural complexity and a further range of reactivity.[6] Halo-aziridines bearing chlorine have been most widely investigated, especially gem-dihalogenated 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 gem-dihalogented aziridines,[10] addition of acid chlorides across 2H-azirines,[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 LiAlH4, leaving the aziridine intact.[9a]

Figure 1

Preparation of mono-C-halogenated aziridines.

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 TsNBr2 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, LiAlH4) 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 aryl-aziridines.[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 cross-coupling of aryl halides with aziridine metal species formed by Bu3Sn–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 gem-diiodide intermediate in a highly diastereoselective manner, to afford aziridines bearing the aryl and iodo groups in a cis-relationship.

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–HSO2Tol 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 electron-withdrawing group, often an ester (e.g., R3 = CO2R 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 MCH2X reagents (R3 = H) being used to afford terminal aziridines. Concellón 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 (MCHI2) 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.

Scheme 1

Comparison of the Stereochemical Outcome in the aza-Darzens Reaction

Since MCHI2 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 (LiCHI2 and NaCHI2) 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 MCHI2 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 (nN–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, MCHI2 reagents were preformed by deprotonation of CH2I2 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:Et2O) 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 LiCHI2 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 1H NMR signals: amino gem-diiodide 3a characterized by signals at δ 5.34, 5.27, and 4.51 ppm (NH; CHI2; 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 gem-diiodide 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 1H NMR of the crude reaction mixture in the presence of an internal standard.

Table 1

Selected Optimization of the Reaction Protocol

								yieldsd (%)
entrya	LiHMDS (equiv)	CH2I2 (equiv)	concn [M]b	time t1c (min)	T2 (°C)	time t2 (min)	additive (equiv)	2a	3a	4a
1	2.2	2.5	0.06	60				15	17	20
2	2.5	10	0.06	60				15	55	16
3	2.5	10	0.04	60				9	11	49
4	2.2	2.5	0.06	60			HMPA (1)	12	8	3
5	2.2	2.5	0.06	60			TMEDA (1)	19	1	48
6	2.2	2.5	0.06	60			DMPU (1)	8	55	19
7	2.2	2.5	0.04	60			DMPU (1)	12	14	54
8	2.0	2.3	0.15	60				8	8	31
9	3.0	3.4	0.15	60				5	15	55
10	4.0	4.5	0.15	60				7	19	63
11	3.0	3.4	0.16	30	0	15		14	0	64
12	3.0	3.4	0.16	–e	0	15		14	0	81

Reaction conditions: imine 1a (0.50 mmol), CH2I2, LiHMDS, THF/Et2O. Deprotonation of CH2I2 over 20 min prior to addition of imine.

Concentration of base prior to addition of imine.

Time at −78 °C following complete addition of imine 1a. Imine added over 5 min at −78 °C.

Yield of 2a, 3a or 4a determined by 1H NMR spectroscopy with reference to an internal standard (1,3,5-trimethoxybenzene).

Reaction warmed immediately following addition of imine.

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 CH2I2 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 4a (entry 2), though the formation of aminal 2a remained at similar levels. Reaction concentration and ratio of THF:Et2O 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 LiCHI2 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:Et2O was optimized, with a mixture of of 2.5:1 THF/Et2O 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% 1H 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 SO2Tol 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- unfavorable. Placing the N-group and iodide in an antiperiplanar fashion appropriate for cyclization therefore provides two possible conformations A- and B-. 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-, the iodide is positioned away from the bulk of the tolyl-sulfonyl group leading to the cis-iodoaziridine.[38] In conformation B-, the unfavorable interaction between the nondisplaced iodide and the large toluenesulfonyl group results in the conformation being disfavored.

Figure 2

Rationale of diastereoselectivity in cyclization to afford cis-iodoaziridines.

Reaction Scope

To explore the scope of the iodoaziridination reaction a range of of N-Ts imines 1 and N-Ts imine–HSO2Tol 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–HSO2Tol adducts, due to the increased stability to hydrolysis and enamine formation compared to the imines.

Scheme 2

Formation of Alkyl Imine–HSO2Tol Adducts and Imines from Corresponding Aldehydes by Chemla’s Two-step Procedure

Scheme 3

Imine Formation by Direct Condensation

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).

Table 2

Scope of Iodoaziridines with Aromatic Imines

Method A: imine (0.50 mmol), nBuLi (1.50 mmol), HMDS (1.50 mmol), CH2I2 (1.70 mmol), THF:Et2O (0.16 M at deprotonation), −78 to 0 °C.

Method B: identical to Method A but reaction warmed to rt for 20 min after addition of imine.

Where >95:5 stated, only the cis-diastereoisomer could be observed by 1H NMR.

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 gem-diiodides (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 cis-iodoaziridine 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 ortho-substituted 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 (Cs2CO3, DMF, rt),[25] only afforded degradation of the starting material.

Scheme 4

Amino gem-Diiodide Formation with 2-Cl(C6H4) Substituted N-Ts Imine and Postulated Coordination Preventing Cyclization

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–HSO2Tol 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–HSO2Tol 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–HSO2Tol 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.

Table 3

Scope of Iodoaziridines with Branched Alkyl Imines and Alkyl Imine–HO2STol Adducts

Method A: imine (0.50 mmol), LiHMDS (1.50 mmol), CH2I2 (1.70 mmol), THF:Et2O (0.16 M at deprotonation), −78 to 0 °C. Method B: identical to Method A but reaction warmed to rt for 20 min after addition of imine. Method C: imine–HO2STol adduct (0.50 mmol), LiHMDS (2.00 mmol), CH2I2 (2.20 mmol), THF:Et2O (0.16 M at deprotonation), −78 to 0 °C.

Where >95:5 stated, only the cis-diastereoisomer could be observed by 1H NMR.

dr = 1.9:1.

Relative configurations not determined.

dr = 1.5:1.

Primary alkyl imine–HO2STol adducts did not perform well under the reaction conditions with nPr and nHex side chains returning only 6 and 4% yields of the corresponding cis-iodoaziridines 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.

Scheme 5

Iodoaziridine Synthesis with Primary Alkyl Imine–HO2STol Adducts

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 1H 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 1H 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 1H NMR to assess the recovery of the iodoaziridine. On comparison of the yield determined by 1H 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.

Table 4

Comparison of the Effect of Different Stationary Phases on the Stability of 4b

entry	stationary phase	recovery of iodoaziridine 4b (%)a	yield of α-iodo-aldehyde 7 (%)a
1	crude	59	0
2	–b	59	0
3	silica gel	25	32
4	silica gel + 1% Et3N	26	30
5	neutral alumina	0	0
6	basic alumina(activity I)c	1	0
7	basic alumina(activity IV)d	53	0
8	florasil	41	15

Yield determined by 1H NMR spectroscopy with reference to an internal standard (1,3,5-trimethoxybenzene).

Sample of crude 4b stirred in 5% EtOAc/hexane.

Basic alumina (activity I), oven-dried for 24 h prior to use.

Basic alumina (activity IV) prepared by addition of water (10% w/w) to basic alumina (activity I).

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% Et3N, 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.

Figure 3

Selected sections of 1H NMR indicating the stability of iodoaziridine 4b to stationary phases.

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 α-iodo-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.

Table 5

Comparison of the Effect of Different Stationary Phases on the Stability of 4a

entry	stationary phase	yield of 4a (%)a
1	crude	80
2	–b	80
3	silica gel	78
4	silica gel + Et3N	77
5	neutral alumina	4
6	basic alumina (activity I)c	0
7	basic alumina (activity IV)d	79
8	florasil	79

Yield determined by 1H NMR spectroscopy with reference to an internal standard (1,3,5-trimethoxybenzene).

Sample of crude 4a stirred in 5% EtOAc/hexane.

Basic alumina (activity I), oven-dried for 24 h prior to use.

Basic alumina (activity IV) prepared by addition of water (10% w/w) to basic alumina (activity I).

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 cis-iodoaziridine 4b to mild heating under reduced pressure.[43]

Scheme 6

Rearrangement of cis-Iodoaziridine 4b to α-Iodo Imine 6

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 α-bromoaziridines to α-bromohydrazones.[15] The rearrangement of more electron-rich aromatic N-Ts iodoaziridines (R = (4-tBu)C6H4, 4c) was also observed by 1H 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).

Scheme 7

Preparation of Iodo-aldehyde 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]

Scheme 8

Preparation of Chiral Sulfinyl Iodoaziridines 9a and 9b

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 1H 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).

Scheme 9

Preparation of N-Bus Iodoaziridine under Optimized Conditions

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–HO2STol adducts at low temperature, followed by warming, afforded cyclization to the corresponding cis-N-Ts-iodoaziridines 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, Et2O, CH2Cl2). 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 (νmax, FTIR ATR) were recorded in reciprocal centimeters (cm–1). Nuclear magnetic resonance spectra were recorded on 400 or 500 MHz spectrometers. Chemical shifts for 1H 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]. 13C 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 (13CDCl3: 77.0 ppm). 19F 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 1H/13C 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 CH2Cl2 or CHCl3 to prevent decomposition. For example, iodoaziridine 4i was stored in a CDCl3 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–HSO2Tol 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 p-toluenesulfonamide (1.71 g, 10.0 mmol, 1.0 equiv) and sodium p-toluenesulfinate (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–HO2STol adduct was dissolved in CH2Cl2 (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 (Na2SO4) and the solvent was removed under reduced pressure to afford the imine, which was sufficiently pure or further purified where stated.

N-[(E)-Phenylmethylidene]-4-methylbenzenesulfonamide (1a)

Prepared according to General Procedure 1 described above, starting from benzaldehyde (1.02 mL, 10.0 mmol). Purification by recrystallization (EtOAc/hexane) afforded imine 1a as colorless crystals (2.06 g, 79%): mp = 106–108 °C (lit.[52] mp = 107 °C); νmax (film)/cm–1 3360, 3263, 3067, 2925, 2259, 1599, 1319, 1155, 1088, 907, 781, 756, 729, 688, 672; 1H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H, CHN), 7.88–7.82 (m, 4H, 2 × SO2Tol-H and 2 × Ph–H), 7.53 (t, J = 7.4 Hz, 1H, Ph–H), 7.40 (t, J = 7.6 Hz, 2H, 2 × Ph–H), 7.28 (d, J = 8.1 Hz, 2H, 2 × SO2Tol-H), 2.35 (s, 3H, SO2Tol-CH3); 13C NMR (101 MHz, CDCl3) δ 169.9 (CHN), 144.4 (SO2Tol-C quat.), 134.7 (SO2TolC-CH3 quat. and Ph–C), 131.9 (Ph–C quat.), 130.9 (2 × Ph–C), 129.5 (2 × SO2Tol-C), 128.8 (2 × Ph–C), 127.7 (2 × SO2Tol-C), 21.3 (SO2Tol-CH3). Observed data was consistent with that reported in the literature.[41]

N-[(E)-4-Methylphenylmethylidene]-4-methylbenzenesulfonamide (1b)

4-Tolualdehyde (2.83 mL, 24.0 mmol, 1.2 equiv) was added to a solution of p-toluenesulfonamide (3.42 g, 20.0 mmol, 1.0 equiv) in toluene (50 mL). The resulting mixture heated under Dean–Stark conditions for 48 h, after which the solvent was removed under reduced pressure. The crude imine was washed with hexane (50 mL), Et2O (50 mL) and then washed with 1 M NaOH (50 mL) to afford imine 1b as a brown solid (1.75 g, 32%): mp = 117–118 °C (lit.[53] mp = 118–119 °C); νmax (film)/cm–1 2922, 1590, 1558, 1447, 1413, 1364, 1315, 1155, 1086, 1018, 871, 791, 760, 667; 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H, CHN), 7.89 (d, J = 8.2 Hz, 2H, 2 × SO2Tol-H), 7.82 (d, J = 8.1 Hz, 2H, 2 × Tol-H), 7.36 (d, J = 8.2 Hz, 2H, 2 × SO2Tol-H), 7.30 (d, J = 8.1 Hz, 2H, 2 × Tol-H), 2.44 (s, 6H, SO2Tol-CH3 and Tol-CH3); 13C NMR (101 MHz, CDCl3) δ 169.9 (CHN), 146.3 (Tol-C quat.), 144.4 (SO2Tol-C quat.), 135.2 (SO2TolC-CH3 quat.), 131.3 (2 × Tol-C), 129.8 (2 × SO2Tol-C), 129.7 (2 × Tol-C and TolC-CH3 quat.), 127.9 (2 × SO2Tol-C), 21.9 (Tol-CH3), 21.5 (SO2Tol-CH3). Observed data was consistent with that reported in the literature.[54]

N-[(E)-4-tert-Butylphenylmethylidene]-4-methylbenzenesulfonamide (1c)

Prepared according to General Procedure 1 described above, starting from 4-tert-butylbenzaldehyde (1.67 mL, 10.0 mmol). Purification by recrystallization (EtOAc/hexane) afforded imine 1c as a white solid (1.72 g, 55%): mp = 114–116 °C (lit.[55] mp = 116–117 °C); νmax (film)/cm–1 2967, 2366, 1741, 1598, 1327, 1159, 1090, 785; 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H, CHN), 7.90–7.85 (m, 4H, 2 × SO2Tol-H and 2 × tBuAr–H), 7.51 (d, J = 8.3 Hz, 2H, 2 × tBuAr–H), 7.34 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 2.44 (s, 3H, SO2Tol-CH3), 1.34 (s, 9H, C(CH3)3); 13C NMR (101 MHz, CDCl3) δ 170.0 (CHN), 159.3 (tBu-CAr quat.), 144.4 (SO2Tol-C quat.), 135.4 (SO2TolC-CH3 quat.), 131.3 (2 × tBuAr–C), 129.8 (tBuAr–C quat.), 129.7 (2 × SO2Tol-C), 128.0 (2 × SO2Tol-C), 126.2 (2 × tBuAr–C), 35.4 (C(CH3)3 quat.), 31.0 (C(CH3)3), 21.6 (SO2Tol-CH3). Observed data was consistent with that reported in the literature.[56]

N-[(E)-2-Methylphenylmethylidene]-4-methylbenzenesulfonamide (1d)

Prepared according to General Procedure 1 described above, starting from 2-tolualdehyde (1.15 mL, 10.0 mmol). Purification by recrystallization (EtOAc/hexane) afforded imine 1d as a white solid (1.65 g, 60%): mp = 93–95 °C (lit.[57] mp = 91–92 °C); νmax (film)/cm–1 1588, 1563, 1321, 1305, 1290, 1156, 1089, 818, 755, 673; 1H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H, CHN), 8.02 (d, J = 8.4 Hz, 1H, Tol-H), 7.90 (d, J = 8.2 Hz, 2H, 2 × SO2Tol-H), 7.51–7.45 (m, 1H, Tol-H), 7.36 (d, J = 8.2 Hz, 2H, 2 × SO2Tol-H), 7.32–7.25 (m, 2H, 2 × Tol-H), 2.62 (s, 3H, Tol-CH3), 2.45 (s, 3H, SO2Tol-CH3); 13C NMR (101 MHz, CDCl3) δ 168.7 (CHN), 144.5 (SO2Tol-C quat.), 142.3 (Tol-C quat.), 135.4 (SO2TolC-CH3 quat.), 134.6 (Tol-C), 131.6 (Tol-C), 130.7 (Tol-C), 130.4 (Tol-C quat.), 129.8 (2 × SO2Tol-C), 128.0 (2 × SO2Tol-C), 126.6 (Tol-C), 21.7 (SO2Tol-CH3), 19.7 (Tol-CH3). Observed data was consistent with that reported in the literature.[57,58]

N-[(E)-1-Napthalenylmethylidene]-4-methylbenzenesulfonamide (1e)

A mixture of p-toluenesulfonamide (7.47 g, 43.6 mmol, 1.0 equiv) and 1-naphthaldehyde (7.10 mL, 52.3 mmol, 1.2 equiv) in toluene (100 mL) was heated under Dean–Stark conditions for 3 days. The resulting mixture was filtered and the solvent was removed under reduced pressure. Purification by recrystallization (EtOAc/hexane) afforded imine 1e as yellow crystals (2.98 g, 22%): mp = 142–144 °C (lit.[59] mp = 139–141 °C); νmax (film)/cm–1 3063, 2925, 2257, 1596, 1564, 1318, 1309, 1153, 1087, 804, 774, 729; 1H NMR (400 MHz, CDCl3) δ 9.63 (s, 1H, CHN), 9.01 (d, J = 8.6 Hz, 1H, Ar–H), 8.19–8.15 (m, 1H, Ar–H), 8.12 (d, J = 8.2 Hz, 1H, Ar–H), 7.99–7.91 (m, 3H, Ar–H and 2 × SO2Tol-H), 7.72–7.66 (m, 1H, Ar–H), 7.64–7.56 (m, 2H, 2 × Ar–H), 7.37 (d, J = 7.9 Hz, 2H, 2 × SO2Tol-H), 2.45 (s, 3H, SO2Tol-CH3); 13C NMR (101 MHz, CDCl3) δ 169.8 (CHN), 144.5 (SO2Tol-C quat.), 136.1 (Ar–C), 135.4 (SO2TolC-CH3 quat.), 135.2 (Ar–C), 133.8 (Ar–C quat.), 131.8 (Ar–C quat.), 129.8 (2 × SO2Tol-C), 129.0 (Ar–C), 128.9 (Ar–C), 128.0 (2 × SO2Tol-C), 127.6 (Ar–C quat.), 127.0 (Ar–C), 125.1 (Ar–C), 124.3 (Ar–C), 21.7 (SO2Tol-CH3). Observed data was consistent with that reported in the literature.[60]

N-[(E)-4-Fluorophenylmethylidene]-4-methylbenzenesulfonamide (1f)

A mixture of p-toluenesulfonamide (1.71 g, 10.0 mmol, 1.0 equiv), toluene (20 mL), 4-fluorobenzaldehyde (1.07 mL, 10.0 mmol, 1.0 equiv) and boron trifluoride THF complex (89 μL, 0.80 mmol, 8 mol %) was heated under reflux for 12 h. After cooling to rt the reaction mixture was quenched with 1 M NaOH (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried (Na2SO4), and the solvent was removed under reduced pressure. The crude imine was then recrystallized (EtOAc/hexane) to afford imine 1f as a white solid (854 mg, 31%): mp = 110–111 °C (lit.[61] mp = 111 °C); νmax (film)/cm–1 1598, 1582, 1509, 1320, 1236, 1156, 1089, 814, 769, 670; 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H, CHN), 7.99–7.94 (m, 2H, 2 × FAr–H), 7.89 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.36 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.22–7.15 (m, 2H, 2 × FAr–H), 2.45 (s, 3H, SO2Tol-CH3); 13C NMR (101 MHz, CDCl3) δ 168.5 (CHN), 166.7 (d, J = 258.4 Hz, ArC-F quat.), 144.6 (SO2Tol-C quat.), 134.9 (SO2TolC-CH3 quat.), 133.7 (d, J = 9.6 Hz, 2 × FAr–C), 129.8 (2 × SO2Tol-C), 128.7 (d, J = 2.8 Hz, FAr–C quat.), 128.0 (2 × SO2Tol-C), 116.5 (d, J = 22.3 Hz, 2 × FAr–C), 21.6 (SO2Tol-CH3). Observed data was consistent with that reported in the literature.[61]

N-[(E)-4-Chlorophenylmethylidene]-4-methylbenzenesulfonamide (1g)

Prepared according to the General Procedure 1 described above, starting from 4-chlorobenzaldehyde (1.41 g, 10.0 mmol). Purification by recrystallization (EtOAc/hexane) afforded imine 1g as colorless crystals (700 mg, 24%): mp = 173–174 °C (lit.[62] mp = 175–176 °C); νmax (film)/cm–1 3067, 2924, 1592, 1560, 1487, 1401, 1316, 1183, 1160, 1083, 1011, 869, 820, 786, 706, 692, 656; 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H, CHN), 7.92–7.80 (m, 4H, 2 × ClAr–H and 2 × SO2Tol-H), 7.47 (d, J = 8.5 Hz, 2H, 2 × ClAr–H), 7.36 (d, J = 8.1 Hz, 2H, 2 × SO2Tol-H), 2.44 (s, 3H, SO2Tol-CH3); 13C NMR (101 MHz, CDCl3) δ 168.6 (CHN), 144.8 (SO2Tol-C quat.), 141.3 (C-ArCl quat.), 134.8 (SO2TolC-CH3 quat.), 132.3 (2 × ClAr–C), 130.7 (ClAr–C quat.), 129.8 (2 × SO2Tol-C), 129.5 (2 × ClAr–C) 128.1 (2 × SO2Tol-C), 21.6 (SO2Tol-CH3). Observed data was consistent with that reported in the literature.[62]

N-[(E)-2-Chlorophenylmethylidene]-4-methylbenzenesulfonamide (1h)

Prepared according to General Procedure 1 described above, starting from 2-chlorobenzaldehyde (1.13 mL, 10.0 mmol) afforded imine 1h as a white solid (2.05 g, 70%): mp = 130–131 °C (lit.[63] mp = 128–129 °C); νmax (film)/cm–1 3090, 1587, 1560, 1435, 1318, 1214, 1154, 1087, 1051, 863, 804, 786, 759, 707, 666; 1H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H, CHN), 8.14 (dd, J = 7.9, 1.6 Hz, 1H, ClAr–H), 7.90 (d, J = 8.4 Hz, 2H, 2 × SO2Tol-H), 7.54–7.50 (m, 1H, ClAr–H), 7.45 (dd, J = 8.1, 1.2 Hz, 1H, ClAr–H), 7.38–7.31 (m, 3H, ClAr–H and 2 × SO2Tol-H), 2.44 (s, 3H, SO2Tol-CH3); 13C NMR (101 MHz, CDCl3) δ 166.7 (CHN), 144.8 (SO2Tol-C quat.), 138.8 (C-ArCl quat.), 135.6 (ClAr–C), 134.5 (SO2TolC-CH3 quat.), 130.4 (ClAr–C), 130.1 (ClAr–C.), 129.8 (2 × SO2Tol-C), 129.6 (ClAr–C quat.) 128.2 (2 × SO2Tol-C), 127.3 (ClAr–C), 21.6 (SO2Tol-CH3). Observed data was consistent with that reported in the literature.[63]

N-[(E)-Cyclohexylmethylidene]-4-methylbenzenesulfonamide (1i)

Cyclohexanecarboxaldehyde (5.45 mL, 45.0 mmol, 1.5 equiv) was added to a stirred solution of p-toluenesulfonamide (5.14 g, 30.0 mmol, 1.0 equiv) and sodium p-toluenesulfinate (6.41 g, 36.0 mmol, 1.2 equiv) in formic acid and water (1:1, 90 mL) at 0 °C. The reaction was then warmed to rt and stirred for 24 h. The reaction mixture was then filtered under reduced pressure and washed successively with water (100 mL) and hexane (100 mL). The solid was then dissolved in CH2Cl2 (300 mL) and saturated aqueous sodium bicarbonate solution (300 mL) was added. The resulting biphasic solution was vigorously stirred for 2 h at rt, after which the organic layer was separated, dried (Na2SO4) and the solvent was removed under reduced pressure. The crude imine was then recrystallized (EtOAc) to afford imine 1i as white crystals (6.39 g, 80%): mp = 109–110 °C (lit.[39] mp = 106 °C); νmax (film)/cm–1 3361, 3265, 2930, 2856, 1627, 1600, 1449, 1317, 1159, 1093, 901, 814, 676; 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 4.4 Hz, 1H, CHN), 7.81 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.34 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 2.46–2.42 (m, 4H, Cy-H and SO2Tol-CH3), 1.92–1.63 (m, 5H, 5 × Cy-H), 1.40–1.18 (m, 5H, 5 × Cy-H); 13C NMR (101 MHz, CDCl3) δ 181.0 (CHN), 144.5 (SO2Tol-C quat.), 134.7 (SO2TolC-CH3 quat.), 129.7 (2 × SO2Tol-C), 128.0 (2 × SO2Tol-C), 43.6 (CH), 28.3 (2 × CH2), 25.6 (CH2), 25.0 (2 × CH2), 21.6 (SO2Tol-CH3). Observed data was consistent with that reported in the literature.[39]

N-[(E)-Cyclohex-3-en-1-ylmethylidene]-4-methylbenzenesulfonamide (1m)

3-Cyclohexene-carboxaldehyde (1.76 mL, 15.0 mmol, 1.5 equiv) was added to a stirred solution of p-toluenesulfonamide (1.71 g, 10.0 mmol, 1.0 equiv) and sodium p-toluenesulfinate (2.14 g, 12.0 mmol, 1.2 equiv) in formic acid and water (1:1, 30 mL) at 0 °C. The reaction was then warmed to rt and stirred for 24 h. The reaction mixture was filtered under reduced pressure and the filter cake washed successively with water (50 mL) and hexane (50 mL). The solid was then dissolved in CH2Cl2 (50 mL) and washed rapidly with aqueous NaOH solution (1 M, 50 mL). The organic layer was separated, dried (Na2SO4), and the solvent was removed under reduced pressure affording imine 1m as a white solid (1.65 g, 63%): mp = 118–119 °C; νmax (film)/cm–1 3028, 2922, 1625, 1597, 1437, 1320, 1291, 1156, 1090, 786, 739, 670; 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 4.3 Hz, 1H, CHN), 7.82 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.35 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 5.73–5.65 (m, 2H, HC=CH), 2.76–2.68 (m, 1H, CH), 2.45 (s, 3H, SO2Tol-CH3), 2.27–2.07 (m, 4H, 2 × CH2), 2.00–1.93 (m, 1H, CH), 1.66–1.55 (m, 1H, CH); 13C NMR (101 MHz, CDCl3) δ 180.6 (CHN), 144.6 (SO2Tol-C quat.), 134.6 (SO2TolC-CH3 quat.), 129.7 (2 × SO2Tol-C), 128.0 (2 × SO2Tol-C), 127.0 (HC=CH), 124.4 (HC=CH), 40.0 (CH), 26.7 (CH2), 24.5 (CH2), 23.8 (CH2), 21.6 (SO2Tol-CH3); HRMS (ESI/TOF) m/z calculated for C14H18NO2S+ [M + H]+: 264.1053; found: 264.1050.

N-[(E)-2,2-Dimethylpropylidene]-4-methylbenzenesulfonamide (1n)

A mixture of p-toluenesulfonamide (1.71 g, 10.0 mmol, 1.0 equiv), toluene (30 mL), pivaldehyde (1.14 mL, 10.5 mmol, 1.05 equiv) and boron trifluoride THF complex (89 μL, 0.80 mmol, 8 mol %) was refluxed for 16 h. After cooling to rt the reaction mixture was quenched with 1 M NaOH (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried (Na2SO4), and the solvent was removed under reduced pressure. Excess sulfonamide was removed by precipitation (CH2Cl2/hexane) then filtration. The filtrate was concentrated under reduced pressure to afford the desired imine 1n as a white solid (916 mg, 38%): mp = 90–94 °C (lit.[60] mp = 84–86 °C, lit.[63] mp = 102–103 °C); νmax (film)/cm–1 3359, 3261, 1741, 1530, 1389, 1305, 1157, 1098, 905, 816, 696; 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H, CHN), 7.66 (d, J = 8.2 Hz, 2H, 2 × SO2Tol-H), 7.19 (d, J = 8.2 Hz, 2H, 2 × SO2Tol-H), 2.26 (s, 3H, SO2Tol-CH3), 0.99 (s, 9H, C(CH3)3); 13C NMR (101 MHz, CDCl3) δ 183.4 (C=N), 144.1 (SO2Tol-C quat.), 134.3 (SO2TolC-CH3 quat.), 129.3 (2 × SO2Tol-C), 127.5 (2 × SO2Tol-C), 37.3 (C(CH3)3 quat.), 25.3 (3 × C(CH3)3), 21.1 (SO2Tol-CH3). Observed data was consistent with that reported in the literature.[63]

Synthesis of Aminal 2a

N-{[Bis(trimethylsilyl)amino](phenyl)methyl}-4-methylbenzene-1-sulfonamide (2a)

A solution of imine 1a (130 mg, 0.50 mmol, 1.0 equiv) in THF (2.0 mL) was added dropwise over 5 min to a solution of LiHMDS (1.0 M solution in THF, 1.50 mL, 1.50 mmol, 3.0 equiv) in THF (5.2 mL) and Et2O (2.7 mL) at −78 °C. The reaction mixture was then quenched by the addition of saturated aqueous sodium bicarbonate solution (40 mL). The aqueous mixture was extracted with CH2Cl2 (3 × 30 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed under reduced pressure affording aminal 2a as a white solid (195 mg, 92%): mp = 110–112 °C; Rf 0.36 (15% EtOAc/hexane); νmax (film)/cm–1 3305, 2959, 1331, 1252, 1160, 965, 909, 869, 829, 813, 734, 698, 664; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.35 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.31–7.20 (m, 5H, 5 × Ph–H), 5.88 (d, J = 7.7 Hz, 1H, NH), 5.17 (d, J = 7.7 Hz, 1H, CHN), 2.46 (s, 3H, SO2Tol-CH3), 0.15 (s, 18H, Si(CH3)2); 13C NMR (101 MHz, CDCl3) δ 143.3 (SO2Tol-C quat.), 143.0 (Ph–C quat.), 136.2 (SO2TolC-CH3 quat.), 129.6 (2 × SO2Tol-C), 128.0 (2 × SO2Tol-C), 127.4 (Ph–C), 127.0 (2 × Ph–C), 126.6 (2 × Ph–C), 69.7 (PhCN), 21.5 (SO2Tol-CH3), 3.1 (Si(CH3)2); HRMS (CI) m/z calculated for C20H36N3O2SSi2+ [M + NH4]+ 438.2061; found 438.2086.

Synthesis of Diiodide 3h

N-[1-(2-Chlorophenyl)-2,2-diiodoethyl]-4-methylbenzenesulfonamide (3h)

Diiodomethane (137 μL, 1.70 mmol, 3.6 equiv) in THF (1.0 mL) was added dropwise to a solution of LiHMDS (1.0 M solution in THF, 1.50 mL, 1.50 mmol, 3.2 equiv) in THF (4.2 mL) and Et2O (2.7 mL) at −78 °C in the dark. After 20 min at −78 °C, a solution of imine 1h (137 mg, 0.47 mmol, 1.0 equiv) in THF (2.0 mL) was added dropwise to the reaction mixture. After a further 10 min at −78 °C, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (40 mL). The aqueous solution was extracted with CH2Cl2 (3 × 30 mL), the combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification by flash chromatography (50% Et2O/hexane) afforded amino gem-diiodide 3h as a white solid (191 mg, 72%): mp = 210–211 °C; Rf 0.20 (50% Et2O/hexane); νmax (film)/cm–1 3237 (NH), 1473, 1437, 1335, 1281, 1160, 1081, 1035, 910, 837, 815, 752; 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 8.1 Hz, 2H, 2 × SO2Tol-H), 7.37 (dd, J = 7.8, 1.5 Hz, 1H, ClAr–H), 7.30 (dd, J = 8.0, 1.4 Hz, 1H, ClAr–H), 7.26 (td, J = 8.0, 1.5 Hz, 1H, ClAr–H), 7.20 (d, J = 8.1 Hz, 2H, 2 × SO2Tol-H), 7.15 (td, J = 7.6, 1.4 Hz, 1H, ClAr–H), 5.40 (d, J = 8.1 Hz, 1H, NH), 5.37 (d, J = 3.2 Hz, 1H, CHI2), 4.37 (dd, J = 8.1, 3.2 Hz, 1H, CHN), 2.37 (s, 3H, SO2Tol-CH3); 13C NMR (125 MHz, CDCl3) δ 143.8 (SO2Tol-C quat.), 136.3 (SO2TolC-CH3 quat), 135.5 (ClAr–C quat.), 132.3 (ClAr–C quat.), 129.8 (ClAr–C), 129.6 (ClAr–C), 129.5 (2 × SO2Tol-C), 129.3 (ClAr–C), 127.5 (2 × SO2Tol-C), 126.7 (ClAr–C), 62.6 (CHN), 21.5 (SO2Tol-CH3), −22.1 (CHI2); HRMS (ESI/TOF) m/z calculated for C15H15ClI2NO2S+ [M + H]+: 561.8596; found: 561.8592.

Synthesis of Imine–HSO2Tol Adducts 5i–l, 5o–p

General Procedure 2: Imine–HSO2Tol Adducts

The relevant aldehyde (15.0 mmol, 1.5 equiv) was added to a stirred solution of p-toluenesulfonamide (1.71 g, 10.0 mmol, 1.0 equiv) and sodium p-toluenesulfinate (2.14 g, 12.0 mmol, 1.2 equiv) in formic acid and water (1:1, 30 mL) at 0 °C. The reaction was then warmed to rt and stirred at this temperature. After 3 days at rt, the reaction mixture was filtered under reduced pressure, washed successively with water (50 mL) and hexane (50 mL) affording the corresponding imine–HO2STol adduct.

N-{2-Methyl-1-[(4-methylphenyl)sulfonyl]cyclohexyl}-4-tolylsulfonamide (5i)

Prepared according to the General Procedure 2 described above, starting from cyclohexanecarboxaldehyde (1.21 mL, 10.0 mmol) afforded imine–HO2STol adduct 5i as a white solid (2.52 g, 60%): mp = 99–102 °C (lit.[64] mp = 101–103 °C); νmax (film)/cm–1 3268, 2933, 2860, 1721, 1600, 1451, 1331, 1303, 1290, 1155, 1081, 906, 812, 731, 705, 661; 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.2 Hz, 2H, 2 × SO2Tol-H), 7.45 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.23 (d, J = 8.2 Hz, 2H, 2 × SO2Tol-H), 7.17 (d, J = 8.2 Hz, 2H, 2 × SO2Tol-H), 5.17 (d, J = 10.7 Hz, 1H, NH), 4.47 (dd, J = 10.7, 2.9 Hz, 1H, HC-NH), 2.45 (s, 3H, SO2Tol-CH3), 2.42 (s, 3H, SO2Tol-CH3), 2.40–2.34 (m, 1H, Cy-H), 2.07–1.99 (m, 1H, Cy-H), 1.80–1.59 (m, 4H, 4 × Cy-H), 1.36–1.28 (m, 2H, 2 × Cy-H), 1.10–0.95 (m, 3H, 3 × Cy-H); 13C NMR (101 MHz, CDCl3) δ 145.0 (SO2Tol-C quat.), 143.5 (SO2Tol-C quat.), 138.1 (SO2TolC-CH3 quat.), 134.1 (SO2TolC-CH3 quat.), 129.7 (2 × SO2Tol-C), 129.5 (2 × SO2Tol-C), 129.3 (2 × SO2Tol-C), 126.6 (2 × SO2Tol-C), 77.5 (CHN), 37.3 (CH), 31.0 (CH2), 27.1 (CH2), 26.2 (CH2), 25.63 (CH2), 25.61 (CH2), 21.8 (SO2Tol-CH3), 21.6 (SO2Tol-CH3). Observed data was consistent with that reported in the literature.[64]

N-{2-Methyl-1-[(4-methylphenyl)sulfonyl]propyl}-4-tolylsulfonamide (5j)

Prepared according to General Procedure 2 described above, starting from isobutyraldehyde (0.91 mL, 10.0 mmol) afforded imine–HO2STol adduct 5j as a white solid (2.00 g, 52%): mp = 86–88 °C; νmax (film)/cm–1 3283, 2968, 1598, 1442, 1332, 1290, 1160, 1132, 1082, 890, 813, 779, 702, 670; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.0 Hz, 2H, 2 × SO2Tol-H), 7.50 (d, J = 8.2 Hz, 2H, 2 × SO2Tol-H), 7.26 (d, J = 8.0 Hz, 2H, 2 × SO2Tol-H), 7.18 (d, J = 8.2 Hz, 2H, 2 × SO2Tol-H), 5.38 (d, J = 10.6 Hz, 1H, NH), 4.52 (dd, J = 10.6, 2.7 Hz, 1H, HC-NH), 2.71 (dqq, J = 6.9, 2.7 Hz, 1H, CH), 2.45 (s, 3H, SO2Tol-CH3), 2.41 (s, 3H, SO2Tol-CH3), 1.05 (d, J = 6.9 Hz, 3H, CH3), 0.87 (d, 3H, J = 6.9 Hz, CH3); 13C NMR (101 MHz, CDCl3) δ 145.0 (SO2Tol-C quat.), 143.4 (SO2Tol-C quat.), 138.0 (SO2TolC-CH3 quat.), 133.9 (SO2TolC-CH3 quat.), 129.6 (2 × SO2Tol-C), 129.4 (2 × SO2Tol-C) 129.2 (2 × SO2Tol-C), 126.6 (2 × SO2Tol-C), 77.5 (HC-NH), 27.6 (CH), 21.7 (SO2Tol-CH3), 21.5 (SO2Tol-CH3), 20.8 (CH3), 16.5 (CH3). The above compound is previously reported without characterization data.[39]

N-{1-[(4-Methylphenyl)sulfonyl]pentan-2-yl}-4-tolylsulfonamide (5k)

Prepared according to General Procedure 2 described above, starting from 2-ethylbutyraldehyde (1.85 mL, 15.0 mmol) afforded imine–HO2STol adduct 5k as a white solid (3.01 g, 73%): mp = 63–64 °C (lit.[64] mp = 56–57 °C); νmax (film)/cm–1 3265, 2965, 2876, 1598, 1450, 1332, 1154, 1129, 1084, 1083, 1067, 885, 810, 703, 676; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.52 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.28 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.20 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 5.23 (d, J = 10.6 Hz, 1H, NH), 4.68 (dd, J = 10.6, 2.0 Hz, 1H, HC-NH), 2.46 (s, 3H, SO2Tol-CH3), 2.42 (s, 3H, SO2Tol-CH3), 2.10–2.01 (m, 1H, CH), 1.89–1.79 (m, 1H, CH2), 1.57–1.47 (m, 1H, CH2), 1.15–1.03 (m, 1H, CH2), 0.97–0.90 (m, 4H, CH2 and CH3), 0.87 (t, J = 7.3 Hz, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 145.0 (SO2Tol-C quat.), 143.5 (SO2Tol-C quat.), 138.0 (SO2TolC-CH3 quat.), 134.1 (SO2TolC-CH3 quat.), 129.7 (2 × SO2Tol-C), 129.4 (2 × SO2Tol-C) 129.2 (2 × SO2Tol-C), 126.5 (2 × SO2Tol-C), 74.4 (HC-NH), 41.4 (CH), 22.7 (CH2), 22.0 (CH2), 21.7 (SO2Tol-CH3), 21.5 (SO2Tol-CH3), 11.9 (CH3), 11.7 (CH3). Observed data was consistent with that reported in the literature.[64]

N-{1-[(4-Methylphenyl)sulfonyl]butan-2-yl}-4-tolylsulfonamide (5l)

Prepared according to General Procedure 2 described above, starting from 2-methylbutyraldehyde (1.61 mL, 15.0 mmol) afforded imine–HO2STol adduct 5l as a white solid (2.38 g, 60%): mp = 86–87 °C; νmax (film)/cm–1 3227, 2929, 1599, 1454, 1334, 1292, 1131, 1083, 813, 763, 669; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.1 Hz, 2H, 2 × SO2Tol-H), 7.50 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.27 (d, J = 8.1 Hz, 2H, 2 × SO2Tol-H), 7.19 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 5.19 (d, J = 10.6 Hz, 1H, NH), 4.63 (dd, J = 10.6, 2.0 Hz, 1H, HC-NH), 2.46–2.42 (m, 1H, CH(CH3)CH2CH3), 2.46 (s, 3H, SO2Tol-CH3), 2.42 (s, 3H, SO2Tol-CH3), 1.21–1.09 (m, 2H, CH(CH3)CH2CH3), 1.05 (d, J = 6.8 Hz, 3H, CH(CH3)CH2CH3) 0.87 (t, J = 7.3 Hz, 3H, CH(CH3)CH2CH3); 13C NMR (101 MHz, CDCl3) δ 145.0 (SO2Tol-C quat.), 143.5 (SO2Tol-C quat.), 138.0 (SO2TolC-CH3 quat.), 134.0 (SO2TolC-CH3 quat.), 129.7 (2 × SO2Tol-C), 129.4 (2 × SO2Tol-C) 129.2 (2 × SO2Tol-C), 126.5 (2 × SO2Tol-C), 75.8 (HC-NH), 33.9 (CH), 27.4 (CH2), 21.8 (SO2Tol-CH3), 21.5 (SO2Tol-CH3), 14.1 (CHCH3), 11.5 (CH2CH3). HRMS (ESI/TOF) m/z calculated for C19H24NO4S2+ [M – H]+: 394.1141; found: 394.1137.

N-{1-[(4-Methylphenyl)sulfonyl]butyl}-4-tolylsulfonamide (5o)

Prepared according to General Procedure 2 described above, starting from butyraldehyde (1.34 mL, 15.0 mmol) afforded imine–HO2STol adduct 5o as a white solid (3.42 g, 90%): mp = 118–119 (lit.[64] mp = 119–120 °C); νmax (film)/cm–1 3214, 2932, 1597, 1460, 1441, 1334, 1291, 1210, 1166, 1127, 1078, 922, 815, 667; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.1 Hz, 2H, 2 × SO2Tol-H), 7.54 (d, J = 8.1 Hz, 2H, 2 × SO2Tol-H), 7.28 (d, J = 8.1 Hz, 2H, 2 × SO2Tol-H), 7.21 (d, J = 8.1 Hz, 2H, 2 × SO2Tol-H), 4.96 (d, J = 10.2 Hz, 1H, NH), 4.59 (dt, J = 10.2, 3.8 Hz, 1H, HC-NH), 2.45 (s, 3H, SO2Tol-CH3), 2.43 (s, 3H, SO2Tol-CH3), 2.17–2.08 (m, 1H, CH2), 1.70–1.62 (m, 1H, CH2), 1.45–1.38 (m, 1H, CH2), 1.29–1.19 (m, 1H, CH2), 0.87 (t, J = 7.3 Hz, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 145.2 (SO2Tol-C quat.), 143.6 (SO2Tol-C quat.), 137.8 (SO2TolC-CH3 quat.), 132.7 (SO2TolC-CH3 quat.), 129.7 (2 × SO2Tol-C), 129.6 (2 × SO2Tol-C) 129.5 (2 × SO2Tol-C), 126.7 (2 × SO2Tol-C), 73.6 (HC-NH), 27.6 (CH2), 21.7 (SO2Tol-CH3), 21.5 (SO2Tol-CH3), 18.4 (CH2), 13.5 (CH3). Observed data was consistent with that reported in the literature.[64]

N-{1-[(4-Methylphenyl)sulfonyl]heptyl}-4-tolylsulfonamide (5p)

Prepared according to General Procedure 2 described above, starting from 1-heptanal (2.09 mL, 15.0 mmol) afforded imine–HO2STol adduct 5p as a white solid (2.67 g, 64%): mp = 76–77 °C; νmax (film)/cm–1 3261, 2925, 1597, 1451, 1334, 1301, 1161, 1129, 1081, 1038, 1010, 901, 813, 676; 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.55 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.30 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.22 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 5.11 (d, J = 10.3 Hz, 1H, NH), 4.53 (dt, J = 10.3, 3.6 Hz, 1H, HC-NH), 2.45 (s, 3H, SO2Tol-CH3), 2.42 (s, 3H, SO2Tol-CH3), 2.19–2.01 (m, 1H, CH2), 1.69–1.60 (m, 2H, 2 × CH2), 1.22–1.07 (m, 7H, 7 × CH2), 0.84 (t, J = 7.3 Hz, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 145.3 (SO2Tol-C quat.), 143.6 (SO2Tol-C quat.), 137.9 (SO2TolC-CH3 quat.), 132.6 (SO2TolC-CH3 quat.), 129.7 (4 × SO2Tol-C), 129.5 (2 × SO2Tol-C), 126.7 (2 × SO2Tol-C), 73.8 (HC-NH), 31.3 (CH2), 28.6 (CH2), 28.0 (CH2), 24.5 (CH2), 22.3 (CH2), 21.8 (SO2Tol-CH3), 21.5 (SO2Tol-CH3), 14.0 (CH3). The above compound is previously reported without characterization data.[65]

Synthesis of cis-Iodoaziridines 4

Method A

nBuLi (1.50 mmol, 3.0 equiv) was added dropwise to a solution of hexamethyldisilazane (315 μL, 1.50 mmol, 3.0 equiv) in THF (5.7 mL) and Et2O (2.7 mL) at −78 °C. After 30 min, diiodomethane (135 μL, 1.70 mmol, 3.4 equiv) in THF (1.0 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 (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 CH2Cl2 (3 × 30 mL), then the combined organic layers were dried (Na2SO4) 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.

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 Et2O (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–HO2STol 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 CH2Cl2 (3 × 30 mL) and the combined organic layers were dried (Na2SO4), 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.

cis-(±)-2-Iodo-3-phenyl-1-(4-tolylsulfonyl)aziridine (4a)

Prepared according to Method A described above, starting from imine 1a (130 mg, 0.50 mmol). Purification by flash chromatography (10% EtOAc/hexane) on deactivated basic alumina (activity IV) afforded cis-iodoaziridine 4a as a yellow oil (152 mg, 76%): Rf 0.24 (15% Et2O/hexane); νmax (film)/cm–1 3035, 2928, 1600, 1499, 1453, 1330, 1157, 1088, 902, 813, 763, 727, 696, 683, 666; 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.5 Hz, 2H, 2 × SO2Tol-H), 7.42–7.33 (m, 5H, 3 × Ph–H and × SO2Tol-H), 7.31–7.25 (m, 2H, 2 × Ph–H), 4.89 (d, J = 6.1 Hz, 1H, CHI), 3.89 (d, J = 6.1 Hz, 1H, CHPh), 2.47 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 145.3 (SO2C-Tol quat.), 134.1 (SO2TolC-CH3 quat.), 132.9 (PhC quat.), 129.9 (2 × SO2Tol-C), 128.7 (Ph–C), 128.1 (2 × SO2Tol-C), 127.8 (2 × Ph–C), 127.5 (2 × Ph–C), 44.9 (PhCN), 21.7 (SO2Tol-CH3), 16.4 (CHI); HRMS (ESI/TOF) m/z calculated for C15H15INO2S+ [M + H]+ 399.9863; found 399.9856.

cis-(±)-2-Iodo-3-(4-tolyl)-1-(4-tolylsulfonyl)aziridine (4b)

Prepared according to Method A described above, starting from imine 1b (137 mg, 0.50 mmol). Purification by flash chromatography (5% EtOAc/hexane) on deactivated basic alumina (activity IV) afforded cis-iodoaziridine 4b as a yellow oil (100 mg, 48%): Rf 0.16 (10% EtOAc/hexane); νmax (film)/cm–1 3022, 2923, 1616, 1598, 1517, 1329, 1292, 1242, 1158, 1089, 1037, 1019, 905, 842, 810, 766; 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.2 Hz, 2H, 2 × SO2Tol-H), 7.38 (d, J = 8.2 Hz, 2H, 2 × SO2Tol-H), 7.18–7.14 (m, 4H, 4 × Tol-H), 4.87 (d, J = 6.1 Hz, 1H, CHI), 3.84 (d, J = 6.1 Hz, 1H, CHAr), 2.46 (s, 3H, SO2Tol-CH3), 2.35 (s, 3H, Tol-CH3); 13C NMR (101 MHz, CDCl3) δ 145.2 (SO2Tol-C quat.), 138.6 (TolC quat.), 134.2 (SO2TolC-CH3 quat.), 129.9 (2 × SO2Tol-C), 129.8 (TolC quat.), 128.9 (2 × Tol-C), 127.8 (2 × SO2Tol-C), 127.4 (2 × Tol-C), 44.9 (CHN), 21.7 (SO2Tol-CH3), 21.2 (Tol-CH3), 16.8 (CHI); HRMS (ESI/TOF) m/z calculated for C16H17INO2S+ [M + H]+: 414.0019; found: 414.0037.

cis-(±)-2-Iodo-3-(4-tert-butylphenyl)-1-(4-tolylsulfonyl)aziridine (4c)

Prepared according to Method A described above, starting from imine 1c (158 mg, 0.50 mmol). Purification by flash chromatography (hexane to 5% EtOAc/hexane) on deactivated basic alumina (activity IV) afforded cis-iodoaziridine 4c as a yellow oil (131 mg, 58%): Rf 0.13 (15% EtOAc/hexane); νmax (film)/cm–1 2966, 2908, 2871, 1602, 1333, 1242, 1159, 1089, 1020, 905, 839, 810, 753, 727, 671; 1H NMR (500 MHz, CDCl3) δ 7.92–7.88 (m, 2H, 2 × SO2Tol-H), 7.40–7.35 (m, 4H, 2 × SO2Tol-H and 2 × tBuAr–H), 7.22–7.18 (m, 2H, 2 × tBuAr–H), 4.88 (d, J = 6.1 Hz, 1H, CHI), 3.85 (d, J = 6.1 Hz, 1H, CHAr), 2.47 (s, 3H, SO2Tol-CH3), 1.32 (s, 9H, C(CH3)3); 13C NMR (125 MHz, CDCl3) δ 151.8 (tBu-CAr quat.), 145.2 (SO2Tol-C quat.), 134.3 (SO2TolC-CH3 quat.), 129.9 (2 × SO2Tol-C), 129.8 (tBuAr–C quat.), 127.9 (2 × SO2Tol-C), 127.2 (2 × tBuAr–C), 125.1 (2 × tBuAr–C), 44.9 (CHN), 34.6 (C(CH3)3 quat.), 31.2 (C(CH3)3), 21.7 (SO2Tol-CH3), 16.6 (CHI); HRMS (ESI/TOF) m/z calculated for C19H23INO2S+ [M + H]+ 456.0489; found 456.0490.

cis-(±)-2-Iodo-3-(2-tolyl)-1-(4-tolylsulfonyl)aziridine (4d)

Prepared according to Method B described above, starting from imine 1d (137 mg, 0.50 mmol). Purification by flash chromatography (hexane to 5% EtOAc/hexane) on deactivated deactivated basic alumina (activity IV) afforded cis-iodoaziridine 4d as a yellow oil (141 mg, 68%): Rf 0.13 (5% EtOAc/hexane); νmax (film)/cm–1 3030, 2923, 2860, 1597, 1492, 1460, 1331, 1240, 1158, 1089, 906, 754, 734, 713, 684, 667; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.40 (d, J = 8.2 Hz, 2H, 2 × SO2Tol-H), 7.31–7.24 (dt, J = 7.4, 1.6 Hz, 1H, Tol-H), 7.22–7.09 (m, 3H, 3 × Tol-H), 4.92 (d, J = 6.0 Hz, 1H, CHI), 3.89 (d, J = 6.0 Hz, 1H, CHAr), 2.47 (s, 3H, SO2Tol-CH3), 2.35 (s, 3H, Tol-CH3); 13C NMR (101 MHz, CDCl3) δ 145.3 (SO2C-Tol quat.), 136.1 (Tol-C quat.), 134.2 (SO2TolC-CH3 quat.), 131.8 (Tol-C quat.), 130.0 (2 × SO2Tol-C), 129.8 (Tol-C), 128.6 (Tol-C), 127.9 (2 × SO2Tol-C), 127.4 (Tol-C), 125.7 (Tol-C), 44.5 (TolCN), 21.7 (SO2Tol-CH3), 19.0 (Tol-CH3), 15.3 (CHI); HRMS (ESI/TOF) m/z calculated for C16H17INO2S+ [M + H]+ 414.0019; found 414.0024.

cis-(±)-2-Iodo-3-(1-napthyl)-1-(4-tolylsulfonyl)aziridine (4e)

Prepared according to Method B described above, starting from imine 1e (155 mg, 0.50 mmol). Purification by flash chromatography (5% EtOAc/hexane) on deactivated basic alumina (activity IV) afforded cis-iodoaziridine 4e as a yellow oil (176 mg, 78%): Rf 0.40 (15% EtOAc/hexane); νmax (film)/cm–1 3287, 3054, 2926, 2259, 1922, 1722, 1600, 1511, 1330, 1157, 1088, 905, 801, 779, 758, 725, 682, 667; 1H NMR (400 MHz, CDCl3) δ 8.01–7.95 (m, 3H, Ar–H and 2 × SO2Tol-H), 7.95–7.90 (d, J = 8.1 Hz, 1H, Ar–H), 7.87 (d, J = 8.1 Hz, 1H, Ar–H), 7.63–7.53 (m, 2H, 2 × Ar–H), 7.45–7.35 (m, 4H, 2 × Ar–H and 2 × SO2Tol-H), 5.07 (d, J = 6.0 Hz, 1H, CHI), 4.38 (d, J = 6.0 Hz, 1H, CHAr), 2.48 (s, 3H, SO2Tol-CH3); 13C NMR (101 MHz, CDCl3) δ 145.4 (SO2Tol-C quat.), 134.2 (SO2TolC–CH3 quat.), 133.1 (Ar–C quat.), 130.7 (Ar–C quat.), 130.0 (2 × SO2Tol-C), 129.4 (Ar–C quat.), 129.0 (Ar–C), 128.8 (Ar–C), 128.0 (2 × SO2Tol-C), 126.7 (Ar–C), 126.1 (Ar–C), 125.8 (Ar–C), 125.1 (Ar–C), 122.6 (Ar–C), 44.4 (ArCN), 21.7 (SO2Tol-CH3), 15.2 (CHI); HRMS (ESI/TOF) m/z calculated for C19H17INO2S+ [M + H]+ 450.0019; found 450.0024.

cis-(±)-2-Iodo-3-(4-fluorophenyl)-1-(4-tolylsulfonyl)aziridine (4f)

Prepared according to Method A described above, starting from imine 1f (139 mg, 0.50 mmol). Purification by flash chromatography (5% EtOAc/hexane) on deactivated basic alumina (activity IV) afforded cis-iodoaziridine 4f as a yellow oil (97 mg, 47%): Rf 0.24 (15% EtOAc/hexane); νmax (film)/cm–1 3029, 2933, 2259, 1905, 1604, 1512, 1334, 1240, 1158, 1089, 904, 835, 814, 735, 706, 680, 666; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.40 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.28–7.22 (m, 2H, 2 × FAr–H), 7.08–7.01 (m, 2H, 2 × FAr–H), 4.85 (d, J = 6.1 Hz, 1H, CHI), 3.85 (d, J = 6.1 Hz, 1H, CHAr), 2.48 (3 H, s, SO2Tol-CH3); 13C NMR (101 MHz, CDCl3) δ 163.0 (d, J = 248 Hz, F-CAr quat.), 145.5 (SO2Tol-C quat.), 134.1 (SO2TolC-CH3 quat.), 130.1 (2 × SO2Tol-C), 129.4 (d, J = 8.5 Hz, 2 × FAr–C), 128.8 (d, J = 3.1 Hz, FAr–C quat.), 128.0 (2 × SO2Tol-C), 115.4 (d, J = 22 Hz, 2 × FAr–C), 44.3 (ArCN), 21.8 (SO2Tol-CH3), 16.5 (CHI); 19F NMR (377 MHz, CDCl3) δ −112.3 (Ar–F); HRMS (ESI/TOF) m/z calculated for C15H14FINO2S+ [M + H]+ 417.9768; found 417.9783.

cis-(±)-2-Iodo-3-(4-chlorophenyl)-1-(4-tolylsulfonyl)aziridine (4g)

Prepared according to Method A described above, starting from imine 1g (147 mg, 0.50 mmol). Purification by flash chromatography (10% EtOAc/hexane) afforded cis-iodoaziridine 4g as a yellow oil (123 mg, 57%): Rf 0.13 (10% EtOAc/hexane); νmax (film)/cm–1 3022, 2923, 1596, 1493, 1332, 1305, 1241, 1158, 1088, 1036, 1014, 903, 844, 805, 735, 688, 668; 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.2 Hz, 2H, 2 × SO2Tol-H), 7.38 (d, J = 8.2 Hz, 2H, 2 × SO2Tol-H), 7.32 (d, J = 8.5 Hz, 2H, 2 × ClAr–H), 7.20 (d, J = 8.5 Hz, 2H, 2 × ClAr–H), 4.85 (d, J = 6.1 Hz, 1H, CHI), 3.83 (d, J = 6.1 Hz, 1H, CHAr), 2.46 (s, 3H, SO2Tol-CH3); 13C NMR (101 MHz, CDCl3) δ 145.5 (SO2Tol-C quat.), 134.7 (ClAr–C quat.), 133.9 (SO2TolC-CH3 quat.), 131.4 (ClAr–C quat.), 130.0 (2 × SO2Tol-C), 128.8 (2 × ClAr–C), 128.4 (2 × ClAr–C), 127.8 (2 × SO2Tol-C), 44.2 (CHN), 21.7 (SO2Tol-CH3), 16.1 (CHI); HRMS (ESI/TOF) m/z calculated for C15H15ClINO2S+ [M + H]+: 433.9473; found: 433.9467.

cis-(±)-2-Iodo-3-cyclohexyl-1-(4-tolylsulfonyl)aziridine (4i)

Prepared according to Method A described above, starting from imine 1i (133 mg, 0.50 mmol). Purification by flash chromatography (10% Et2O/hexane) afforded cis-iodoaziridine 4i as a colorless oil (137 mg, 68%): Rf 0.18 (10% Et2O/hexane); νmax (film)/cm–1 2926, 2851, 1598, 1450, 1330, 1242, 1158, 1090, 968, 900, 883, 814, 732, 669; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.2 Hz, 2H, 2 × SO2Tol-H), 7.37 (d, J = 8.2 Hz, 2H, 2 × SO2Tol-H), 4.53 (d, J = 6.0 Hz, 1H, CHI), 2.47 (s, 3H, SO2Tol-CH3), 2.26 (dd, J = 9.4, 6.0 Hz, 1H, CHCy), 1.84–1.71 (m, 2H, 2 × Cy-H), 1.70–1.62 (m, 2H, 2 × Cy-H), 1.60–1.53 (m, 1H, Cy-H), 1.33–0.99 (m, 6H, 6 × Cy-H); 13C NMR (101 MHz, CDCl3) δ 145.0 (SO2Tol-C quat.), 134.4 (2 × SO2TolC–CH3 quat.), 129.8 (2 × SO2Tol-C), 128.0 (2 × SO2Tol-C), 47.8 (Cy-CHN), 40.1 (Cy-CH), 30.3 (Cy-CH2), 28.3 (Cy-CH2), 25.9 (Cy-CH2), 25.2 (Cy-CH2), 25.1 (Cy-CH2), 21.7 (SO2Tol-CH3), 13.5 (CHI); HRMS (ESI/TOF) m/z calculated for C15H21INO2S+ [M + H]+: 406.0332; found: 406.0328.

cis-(±)-2-Iodo-3-(propan-2-yl)-1-(4-tolylsulfonyl)aziridine (4j)

Prepared according to Method C described above, starting from imine–HO2STol adduct 5j (191 mg, 0.50 mmol). Purification by flash chromatography (5% EtOAc/hexane) on deactivated basic alumina (activity IV) afforded cis-iodoaziridine 4j as a yellow oil (114 mg, 63%): Rf 0.21 (10% EtOAc/hexane); νmax (film)/cm–1 2963, 2931, 2874, 1597, 1466, 1403, 1329, 1244, 1156, 1089, 1026, 954, 885, 831, 813, 734, 684, 667; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.36 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 4.54 (d, J = 5.9 Hz, 1H, CHI), 2.46 (s, 3H, SO2Tol-CH3), 2.20 (dd, J = 9.7, 5.9 Hz, 1H, CHN), 1.92 (dqq, J = 9.7, 6.7, 6.7 Hz, 1H, CH(CH3)2), 0.99 (d, J = 6.7 Hz, 3H, CH(CH3)2), 0.92 (d, J = 6.7 Hz, 3H, CH(CH3)2); 13C NMR (101 MHz, CDCl3) δ 145.1 (SO2Tol-C quat.), 134.3 (SO2TolC-CH3 quat.), 129.8 (2 × SO2Tol-C), 128.0 (2 × SO2Tol-C), 49.3 (CHN), 31.5 (CH(CH3)2), 21.7 (SO2Tol-CH3), 20.0 (CH3), 17.9 (CH3), 13.8 (CHI); HRMS (ESI/TOF) m/z calculated for C12H17INO2S+ [M + H]+: 366.0019; found: 366.0034.

cis-(±)-2-Iodo-3-(pentan-3-yl)-1-(4-tolylsulfonyl)aziridine (4k)

Prepared according to Method C described above, starting from imine–HO2STol adduct 5k (205 mg, 0.50 mmol). Purification by flash chromatography (5% EtOAc/hexane) on deactivated basic alumina (activity IV) afforded cis-iodoaziridine 4k as a yellow oil (123 mg, 63%): Rf 0.31 (10% EtOAc/hexane); νmax (film)/cm–1 2963, 2930, 2877, 1597, 1458, 1330, 1244, 1157, 1089, 976, 887, 835, 813, 731, 667; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.36 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 4.55 (d, J = 5.9 Hz, 1H, CHI), 2.46 (s, 3H, SO2Tol-CH3), 2.39 (dd, J = 9.6, 5.9 Hz, 1H, CHN), 1.53–1.20 (m, 5H, 2 × CH2 and CH), 0.97 (t, J = 7.4 Hz, 3H, CH3), 0.84 (t, J = 7.4 Hz, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 145.0 (SO2Tol-C quat.), 134.3 (SO2TolC-CH3 quat.), 129.8 (2 × SO2Tol-C), 127.9 (2 × SO2Tol-C), 47.1 (CHN), 42.1 (CH(CH2CH3)CH2CH3), 23.7 (CH(CH2CH3)CH2CH3), 22.3 (CH(CH2CH3)CH2CH3), 21.7 (SO2Tol-CH3), 15.0 (CHI), 10.6 (CH(CH2CH3)CH2CH3), 10.1 (CH(CH2CH3)CH2CH3); HRMS (ESI/TOF) m/z calculated for C14H21INO2S+ [M + H]+: 394.0332; found: 394.0332.

cis-(±)-2-Iodo-3-(butan-2-yl)-1-(4-tolylsulfonyl)aziridine (4l)

Prepared according to Method C described above, starting from imine–HO2STol adduct 5l (198 mg, 0.50 mmol). Purification by flash chromatography (5% EtOAc/hexane) on deactivated basic alumina (activity IV) afforded a mixture of cis-iodoaziridines 4l (1.9:1 major:minor) as a yellow oil (115 mg, 61%): Rf 0.24 (10% EtOAc/hexane); νmax (film)/cm–1 2963, 2926, 1597, 1459, 1402, 1330, 1243, 1157, 1089, 1019, 940, 871. 813, 733, 686; major1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.36 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 4.58 (d, J = 6.0 Hz, 1H, CHI), 2.46 (s, 3H, SO2Tol-CH3), 2.26 (d, J = 9.7, 6.0 Hz, 1H, CHN), 1.56–1.20 (m, 3H, CH and CH2), 0.96 (t, J = 7.4 Hz, 3H, CH2CH3), 0.90 (d, J = 6.7 Hz, 3H, CHCH3); 13C NMR (101 MHz, CDCl3) δ 145.1 (SO2Tol-C quat.), 134.3 (SO2TolC-CH3 quat.), 129.8 (2 × SO2Tol-C), 128.0 (2 × SO2Tol-C), 48.7 (CHN), 37.4 (CH), 25.8 (CH2), 21.7 (SO2Tol-CH3), 17.0 (CH2CH3), 14.6 (CHI), 11.1 (CHCH3); minor1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.36 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 4.50 (d, J = 6.0 Hz, 1H, CHI), 2.46 (s, 3H, SO2Tol-CH3), 2.29 (dd, J = 10.3, 6.0 Hz, 1H, CHN), 1.56–1.20 (m, 3H, CH and CH2), 0.97 (d, J = 6.7 Hz, 3H, CH2CH3), 0.86 (t, J = 7.4 Hz, 3H, CHCH3); 13C NMR (101 MHz, CDCl3) δ 145.1 (SO2Tol-C quat.), 134.3 (SO2TolC-CH3 quat.), 129.8 (2 × SO2Tol-C), 127.9 (2 × SO2Tol-C), 48.1 (CHN), 37.0 (CH), 27.6 (CH2), 21.7 (SO2Tol-CH3), 14.5 (CHI), 13.9 (CH2CH3), 10.7 (CHCH3); HRMS (ESI/TOF) m/z calculated for C13H19INO2S+ [M + H]+: 380.0176; found: 380.0186.

cis-(±)-2-Iodo-3-(cyclohex-3-en-1-yl)-1-(4-tolylsulfonyl)aziridine (4m)

Prepared according to Method A described above, starting from imine 1m (132 mg, 0.50 mmol). Purification by flash chromatography (5% EtOAc/hexane) on deactivated basic alumina (activity IV) afforded a mixture of cis-iodoaziridines (1.5:1 major:minor) 4m as a yellow oil (105 mg, 52%): Rf 0.33 (10% EtOAc/hexane); νmax (film)/cm–1 3025, 2920, 1597, 1436, 1330, 1242, 1158, 1090, 1019, 957, 934, 893, 814, 732; major1H NMR (400 MHz, CDCl3) δ 7.84–7.81 (m, 2H 2 × SO2Tol-H), 7.39–7.36 (m, 2H, 2 × SO2Tol-H), 5.73–5.56 (m, 2H, HC=CH), 4.57 (d, J = 6.0 Hz, 1H, CHI), 2.47 (s, 3H, SO2Tol-CH3), 2.38 (dd, J = 9.7, 6.0 Hz, 1H, CHN), 2.26–1.39 (m, 7H, 3 × CH2 and CH); 13C NMR (101 MHz, CDCl3) δ 145.1 (SO2Tol-C quat.), 134.2 (SO2TolC-CH3 quat.), 129.8 (2 × SO2Tol-C), 128.0 (2 × SO2Tol-C), 127.0 (HC=CH), 125.2 (HC=CH), 47.0 (CHN), 36.2 (CH), 28.6 (CH2), 24.0 (CH2), 23.6 (CH2), 21.7 (SO2Tol-CH3), 13.2 (CHI); minor1H NMR (400 MHz, CDCl3) δ 7.84–7.81 (m, 2H, 2 × SO2Tol-H), 7.39–7.36 (m, 2H, 2 × SO2Tol-H), 5.73–5.56 (m, 2H, HC=CH), 4.54 (d, J = 6.0 Hz, 1H, CHI), 2.47 (s, 3H, SO2Tol-CH3), 2.40 (dd, J = 9.7, 6.0 Hz, 1H, CHN), 2.26–1.39 (m, 7H, 3 × CH2 and CH); 13C NMR (101 MHz, CDCl3) δ 145.1 (SO2Tol-C quat.), 134.2 (SO2TolC-CH3 quat.), 129.8 (2 × SO2Tol-C), 128.0 (2 × SO2Tol-C), 127.4 (HC=CH), 124.2 (HC=CH), 46.9 (CHN), 36.1 (CH), 26.6 (CH2), 25.7 (CH2), 23.6 (CH2), 21.7 (SO2Tol-CH3), 13.7 (CHI); HRMS (ESI/TOF) m/z calculated for C15H19INO2S+ [M + H]+: 404.0176; found: 404.0183.

cis-(±)-2-Iodo-3-(tert-butyl)-1-(4-tolylsulfonyl)aziridine (4n)

Prepared according to Method B described above, starting from imine 1n (120 mg, 0.50 mmol). Purification by flash chromatography (5% EtOAc/hexane) on deactivated basic alumina (activity IV) afforded cis-iodoaziridine 4n as a yellow oil (132 mg, 70%): Rf 0.17 (15% EtOAc/hexane); νmax (film)/cm–1 2964, 2874, 1600, 1330, 1258, 1158, 1089, 953, 931, 852, 734, 677, 667; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.2 Hz, 2H, 2 × SO2Tol-H), 7.36 (d, J = 8.2 Hz, 2H, 2 × SO2Tol-H), 4.36 (d, J = 6.4 Hz, 1H, CHI), 2.45 (s, 3H, SO2Tol-CH3), 2.43 (d, J = 6.4, 1H, CHN) 0.98 (s, 9H, C(CH3)3); 13C NMR (101 MHz, CDCl3) δ 145.0 (SO2Tol-C quat.), 134.1 (SO2TolC-CH3 quat.), 129.7 (2 × SO2Tol-C), 128.0 (2 × SO2Tol-C), 50.2 (HCC(CH3)3), 31.4 (C(CH3)3 quat.), 27.0 (C(CH3)3), 21.7 (SO2Tol-CH3), 6.6 (CHI); HRMS (ESI/TOF) m/z calculated for C13H19INO2S+ [M + H]+ 380.0176; found 380.0203.

cis-(±)-2-Iodo-3-propyl-1-(4-tolylsulfonyl)aziridine (4o)

Prepared according to Method C described above, starting from imine–HO2STol adduct 5o (191 mg, 0.50 mmol). Purification by flash chromatography (5% EtOAc/hexane) on deactivated basic alumina (activity IV) afforded cis-iodoaziridine 4o as a yellow oil (11 mg, 6%): Rf 0.23 (10% EtOAc/hexane); νmax (film)/cm–1 2960, 2931, 2873, 1598, 1331, 1245, 1160, 1090, 902, 717; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.37 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 4.55 (d, J = 5.9 Hz, 1H, CHI), 2.58 (m, 1H, CHN), 2.47 (s, 3H, SO2Tol-CH3), 1.65–1.34 (m, 4H, CH2CH2), 0.95 (t, J = 7.3 Hz, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 145.1 (SO2Tol-C quat.), 134.5 (SO2TolC-CH3 quat.), 129.8 (2 × SO2Tol-C), 127.9 (2 × SO2Tol-C), 43.7 (CHN), 33.5 (CH2), 21.7 (SO2Tol-CH3), 19.7 (CH2), 14.5 (CH3), 13.7 (CHI); HRMS (ESI/TOF) m/z calculated for C12H17INO2S+ [M + H]+: 366.0019; found: 366.0031.

cis-(±)-2-Iodo-3-hexyl-1-(4-tolylsulfonyl)aziridine (4p)

Prepared according to Method C described above, starting from imine–HO2STol adduct 5p (212 mg, 0.50 mmol). Purification by flash chromatography (5% EtOAc/hexane) on deactivated basic alumina (activity IV) afforded cis-iodoaziridine 4p as a yellow oil (9 mg, 4%): Rf 0.24 (10% EtOAc/hexane); νmax (film)/cm–1 2955, 2927, 2858, 1597, 1458, 1402, 1334, 1246, 1161, 1091, 717. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 7.37 (d, J = 8.3 Hz, 2H, 2 × SO2Tol-H), 4.56 (d, J = 6.0 Hz, 1H, CHI), 2.54 (dt, J = 7.3, 6.0 Hz, 1H, CHN), 2.47 (s, 3H, SO2Tol-CH3), 1.65–1.46 (m, 2H, CH2), 1.39–1.17 (m, 8H, 4 × CH2), 0.88 (t, J = 7.1 Hz, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 145.1 (SO2Tol-C quat.), 134.5 (SO2TolC-CH3 quat.), 129.8 (2 × SO2Tol-C), 127.9 (2 × SO2Tol-C), 43.9 (CHN), 31.6 (CH2), 28.7 (CH2), 26.2 (CH2), 22.4 (CH2), 21.7 (SO2Tol-CH3), 14.5 (CH3), 14.0 (CHI); HRMS (ESI/TOF) m/z calculated for C15H23INO2S+ [M + H]+: 408.0489; found: 408.0509.

Synthesis of Rearrangement Products 6 and 7

N-[(1E)-2-Iodo-2-(4-methylphenyl)ethylidene]-4-methylbenzenesulfonamide (6)

Neat cis-iodoaziridine 4b (95 mg, 0.23 mmol) was stirred under reduced pressure (∼2 mbar) for 5 h at 20 °C and 1 h at 35 °C, where cis-iodoaziridine 4b rearranged to α-iodo-imine 6 (93 mg, 99%): Rf 0.15 (10% EtOAc/hexane); νmax (film)/cm–1 3031, 2921, 1611, 1512, 1449, 1320, 1157, 1088, 910, 812, 786, 731, 675; 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 8.3 Hz, 1H, CHN), 7.82 (d, J = 8.2 Hz, 2H, SO2Tol-H), 7.39–7.35 (m, 4H, 2 × SO2Tol-H and 2 × Tol-H), 7.16 (d, J = 7.9 Hz, 2H, 2 × Tol-H), 5.90 (d, J = 8.3 Hz, 1H, CHI), 2.45 (s, 3H, SO2Tol-CH3), 2.33 (s, 3H, Tol-CH3); 13C NMR (101 MHz, CDCl3) δ 170.4 (C=N), 145.1 (SO2Tol-C quat.), 139.7 (Tol-C quat.), 133.9 (SO2TolC-CH3 quat.), 132.1 (Tol-C quat.), 130.1 (2 × Tol-C), 129.9 (2 × SO2Tol-C), 128.3 (2 × Tol-C), 128.2 (2 × SO2Tol-C), 28.5 (CHI), 21.7 (SO2Tol-CH3), 21.3 (Tol-CH3); HRMS (ESI/TOF) m/z calculated for C16H15INO2S– [M – H]−: 411.9874; found: 411.9869.

Iodo(phenyl)acetaldehyde (7)

Crude iodoaziridine 4b was prepared by Method A starting from imine 1b (0.50 mmol). The crude cis-iodoaziridine was dissolved in CH2Cl2 (5 mL) and then added to a stirred suspension of silica (150 g) in a mixture of hexane/EtOAc (300 mL). The resulting suspension was stirred in the dark for 3 h, filtered, washed with CH2Cl2 (100 mL) and the solvent was removed under reduced pressure. Purification by flash chromatography (5% EtOAc/hexane) afforded iodo-aldehyde 7 as a yellow oil (70 mg, 54% over 2 steps): Rf 0.16 (5% EtOAc/hexane); νmax (film)/cm–1 3024, 2956, 1715, 1608, 1511, 1449, 1383, 1275, 1181, 1045, 1004, 813, 772, 715, 672; 1H NMR (400 MHz, CDCl3) δ 9.46 (d, J = 3.8 Hz, 1H, CHO), 7.38 (d, J = 8.0 Hz, 2H, 2 × Tol-H), 7.18 (d, J = 8.0 Hz, 2H, 2 × Tol-H), 5.58 (d, J = 3.8 Hz, 1H, CHI), 2.34 (s, 3H, Tol-CH3); 13C NMR (101 MHz, CDCl3) δ 189.6 (C=O), 139.4 (Tol-C quat.), 131.0 (Tol-C quat.), 129.9 (2 × Tol-C), 129.2 (2 × Tol-C), 35.4 (CHI), 21.3 (Tol-CH3); HRMS (CI) m/z calculated for C9H13INO+ [M + NH4]+: 278.0036; found: 278.0049.

Determination of Stationary Phase for Chromatography

Crude iodoaziridines 4a and 4b were prepared by Method A starting from imines 1a/b (0.50 mmol). The crude cis-iodoaziridine was dissolved in CH2Cl2 (16 mL) and c.a. 30 mg of 1,3,5-trimethoxybenzene, as an internal standard, was added to the crude mixture. The mixture was then split into 2 mL portions and each portion was added to a slurry of a different stationary phase (30 g stationary phase/75 mL eluant) and stirred for 30 min to replicate a purification procedure. After 30 min, the slurry was filtered, eluting with CH2Cl2 (50 mL). The solvent was then removed under reduced pressure to afford the recovered sample, which was analyzed by 1H NMR against the internal standard to determine the recovery of the iodoaziridine. A typical screening process involved the following stationary phases: (A) control (sample stirring in solvent system, 5% EtOAc/hex); (B) silica gel; (C) silica gel +1% NEt3; (D) neutral alumina; (E) basic alumina (activity I); (F) basic alumina (activity IV); (G) florasil.

Synthesis of N-Bus Imine 10

(R)-(+)-2-Methyl-N-(phenylmethylidene)propane-2-sulfinamide (8)

Ti(OEt)4 (2.05 g, 9.0 mmol, 3.0 equiv), benzaldehyde (306 μL, 3.0 mmol, 1.0 equiv) and (R)-(+)-2-methyl-2-propanesulfinamide (364 mg, 3.0 mmol, 1.0 equiv) were sequentially added to THF (6 mL). The reaction was stirred at rt for 24 h, after which brine (6 mL) was added, while stirring vigorously. The resulting suspension was filtered through Celite and was washed with EtOAc (100 mL). The filtrate was transferred to a separating funnel, water was added (10 mL) and the aqueous layer was extracted with EtOAc (3 × 30 mL). The organic layers were washed with brine, dried (Na2SO4) and the solvent was removed under reduced pressure to afford sulfinylimine 8 as a colorless oil (625 mg, 99%), which was used without further purification: Rf 0.29 (25% EtOAc/hexane); [α]28D −103.0° (c 2.00, CHCl3); νmax (film)/cm–1 3063, 2961, 2925, 2868, 1606, 1573, 1450, 1363, 1216, 1171, 1084, 1026, 855, 759, 729, 691; 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H, CHN), 7.89–7.84 (m, 2H, 2 × Ph–H), 7.56–7.45 (m, 3H, 3 × Ph–H), 1.28 (s, 9H, C(CH3)3); 13C NMR (101 MHz, CDCl3) δ 162.7 (C=N), 134.0 (Ph–C quat.), 132.4 (Ph–C), 129.4 (2 × Ph–C), 128.9 (2 × Ph–C), 57.8 (C(CH3)3 quat.), 22.6 (C(CH3)3). Observed data was consistent with that reported in the literature.[48]

2-Methyl-N-(phenylmethylidene)propane-2-sulfonamide (10)

Prepared according to the procedure of Ruano,[50]mCPBA (227 mg, 1.31 mmol, 1.1 equiv) was added at rt in one portion to a solution of sulfinylimine 8 (254 mg, 1.19 mmol, 1.0 equiv) in CH2Cl2 (6 mL). After 5 min, the reaction was diluted with CH2Cl2 (12 mL) and then washed with saturated aqueous sodium bicarbonate solution (3 × 10 mL). The organic layer was dried (Na2SO4) and the solvent was removed under reduced pressure, affording sulfonylimine 10 as a colorless oil (268 mg, 99%), which was used without further purification: Rf 0.43 (30% EtOAc/hexane); νmax (film)/cm–1 2984, 1608, 1575, 1479, 1452, 1397, 1366, 1299, 1222, 1176, 1124, 1074, 1023, 862, 810, 786, 760, 681; 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H, CHN), 7.95 (d, J = 7.8 Hz, 2H, 2 × Ph–H), 7.63 (t, J = 7.6 Hz, 1H, Ph–H), 7.51 (t, J = 7.7 Hz, 2H, 2 × Ph–H), 1.48 (s, 9H, C(CH3)); 13C NMR (101 MHz, CDCl3) δ 172.8 (C=N), 134.9 (Ph–C), 132.3 (Ph–C quat.), 131.0 (2 × Ph–C), 129.1 (2 × Ph–C), 58.2 (C(CH3)3 quat.), 23.9 (C(CH3)3). Observed data was consistent with that reported in the literature.[66]

(2R,3S)-2-Iodo-1-[(R)-2-methylpropane-2-sulfinyl]-3-phenylaziridine (major, 9a) and (2S,3R)-2-Iodo-1-[(R)-2-methylpropane-2-sulfinyl]-3-phenylaziridine (minor, 9b)

Prepared according to Method A described above, starting from imine 8 (105 mg, 0.50 mmol). Purification by flash chromatography (5% EtOAc/hexane) on deactivated basic alumina (activity V) afforded a mixture of cis-iodoaziridines 9a (major; 85:15) and 9b (minor) as a yellow oil (103 mg, 59%): Rf = 0.36 (25% EtOAc/hexane); [α]18D −21.3° (c 0.66, CHCl3); νmax (film)/cm–1 2960, 2867, 1605, 1495, 1475, 1454, 1363, 1312, 1238, 1170, 1080, 1026, 906, 847, 817, 791, 758, 699, 676; major1H NMR (400 MHz, CDCl3) δ 7.43–7.33 (m, 5H, 5 × Ph–H), 4.54 (d, J = 6.0 Hz, 1H, CHI), 3.71 (d, J = 6.0 Hz, 1H, CHPh), 1.20 (s, 9H, C(CH3)3); 13C NMR (101 MHz, CDCl3) δ 133.8 (Ph–C quat.), 128.5 (Ph–C), 128.2 (2 × Ph–C), 128.1 (2 × Ph–C), 57.5 (CHPh), 35.4 (C(CH3)3), 22.6 (C(CH3)3), 17.8 (CHI); minor1H NMR (400 MHz, CDCl3) δ 7.43–7.33 (m, 5H, 5 × Ph–H), 4.83 (d, J = 5.9 Hz, 1H, CHI), 3.30 (d, J = 5.9 Hz, 1H, CHPh), 1.41 (s, 9H, C(CH3)3); 13C NMR (101 MHz, CDCl3) δ 134.7 (Ph–C quat.), 128.4 (Ph–C), 128.0 (2 × Ph–C), 127.7 (2 × Ph–C), 58.6 (CHPh), 38.6 (C(CH3)3), 23.3 (C(CH3)3), 15.4 (CHI); HRMS (ESI/TOF) m/z calculated for C12H17INOS+ [M + H]+ 350.0070; found 350.0078.

cis-(±)-2-Iodo-1-(2-methylpropane-2-sulfonyl)-3-phenylaziridine (11)

Prepared according to Method A described above, starting from imine 10 (113 mg, 0.50 mmol). Purification by flash chromatography (5% EtOAc/hexane) on deactivated basic alumina (activity IV) afforded cis-iodoaziridine 11 as a yellow oil (82 mg, 45%): Rf = 0.24 (15% Et2O/hexane); νmax (film)/cm–1 2987, 1457, 1314, 1249, 1175, 1126, 905, 862, 765, 730, 699, 670; 1H NMR (400 MHz, CDCl3) δ 7.46–7.35 (m, 5H, 5 × Ph–H), 4.90 (d, J = 6.0 Hz, 1H, CHI), 3.86 (d, J = 6.0 Hz, 1H, CHPh), 1.58 (s, 9H, C(CH3)3); 13C NMR (101 MHz, CDCl3) δ 133.1 (Ph–C quat.), 128.9 (Ph–C), 128.3 (2 × Ph–C), 127.7 (2 × Ph–C), 60.1 (C(CH3)3 quat.), 43.3 (CHN), 24.0 (C(CH3)3), 19.0 (CHI); HRMS (ESI/TOF) m/z calculated for C12H17INO2S+ [M + H]+ 366.0019; found 366.0021.