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

Article

pubs.acs.org/joc

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

Tom Boultwood, Dominic P. Aﬀron, Aaron D. Trowbridge, and James A. Bull*

Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom

S

* Supporting Information

ABSTRACT: 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.

low temperatures, aﬀording the cis-chloroaziridine (Figure

1A).^9aSince this seminal investigation, α-chloroaziridines

have been accessed via reductive halogenation from gem-

dihalogented aziridines,¹⁰addition of acid chlorides across 2H-

azirines,¹¹nitrene addition to chloroalkenes,¹²and trapping of

metalated aziridines with an electrophilic source of chlorine

(Figure 1B).¹³Chlorinated 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

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-bromi-

nation sequence (Figure 1C).^14aThese 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.¹⁴More recently,

Yudin adopted a nitrogen-transfer approach, generating

nitrenes from N-aminophthalimide with PhI(OAc)₂in the

presence of bromoalkenes (Figure 1D).¹⁵Huang has formed

bromoaziridines through a multiple electrophilic addition of

TsNBr₂to ene-ynoates.¹⁶Bromoaziridines have also been

reported as intermediates, formed by the reaction of a

INTRODUCTION

■

Aziridines, the smallest saturated aza-heterocycles, are im-

portant and common synthetic intermediates in organic

chemistry.^1,2The 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.³Aziridines

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.^4,5C-Halogen-

substituted aziridines introduce additional structural complexity

and a further range of reactivity.⁶Halo-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,⁷and other suitable

methods.^6,8,9These 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.⁶Pioneering 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

Received: May 2, 2013

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Figure 1. Preparation of mono-C-halogenated aziridines.

silyldibromomethyllithium with imines, from which bromide

was displaced in situ (RMgX, LiAlH₄) leaving the aziridine

intact.¹⁷Dibromoaziridines have been recently reported by Li

through addition of bromoform to imines followed by

cyclization.¹⁸Mono and diﬂuoroaziridines have also been

reported recently.¹⁹

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 iodoazir-

idines. 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 stereochemi-

cally pure N-sulﬁnyl imine. In addition, we report a protocol for

determining the optimal stationary phase to use in chromatog-

raphy 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.

There has been signiﬁcant recent interest in the function-

alization 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.²⁰Deprotonation of unstabilized monosub-

stituted 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.²¹Functional group exchange has also been

demonstrated to be an eﬀective method for generating

aziridinyl anions, which react with electrophiles at the

predeﬁned position.^13,22In addition, the palladium-catalyzed

cross-coupling of intact aziridines has recently been achieved;

separately Vedejs,²³and ourselves²⁴have 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 trans-

metalation to zinc and aﬀorded retention of stereochemistry

at the reacting center.

We are interested in methods for the functionalization of

intact aziridines.²⁴We 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).²⁵This 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.

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).^2cCommonly 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. Concellon has reported the

enantioselective preparation of terminal aziridines using

iodomethyllithium and enantioenriched imines.²⁶Chlorome-

thyllithium 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

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THF:Et₂O) was selected due to the stabilizing eﬀect on the

carbenoid reagent.^28,30Early studies varied the base used for

deprotonation and workup procedures to ensure stability of the

products.³⁴The use of LiHMDS as base to aﬀord LiCHI₂was

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.²⁵The ratio of products was determined by

¹H 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 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.³⁵The formation of aminal 2a was irreversible

under the reaction conditions,³⁶and 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.

Scheme 1. Comparison of the Stereochemical Outcome in

the aza-Darzens Reaction

determines the diastereochemistry of the aziridine product

through selecting one of two potential iodide leaving groups.

Since MCHI₂reagents were ﬁrst described by Seyferth and

Lambert in 1973,²⁸they 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 (LiCHI₂and 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.³⁰⁻³²Initial investigations

were undertaken on the addition of MCHI₂to 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, MCHI₂reagents were preformed by

deprotonation of CH₂I₂for 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

Increasing the excess of diiodomethane employed to 10

equiv did aﬀord a signiﬁcant increase in the formation of 3a and

Table 1. Selected Optimization of the Reaction Protocol

d

yields (%)

a

b

c

entry

LiHMDS (equiv)

CH₂I₂(equiv)

concn [M]

time t₁(min)

T₂(°C)

time t₂(min)

additive (equiv)

2a

3a

4a

1

2.2

2.5

2.2

2.0

3.0

4.0

3.0

2.5

10

0.06

0.04

0.06

0.04

0.15

0.16

60

30

15

9

17

55

11

8

20

16

49

3

2

3

10

4

2.5

2.3

3.4

4.5

3.4

HMPA (1)

TMEDA (1)

DMPU (1)

12

19

8

5

1

48

19

54

31

55

63

64

81

6

55

14

8

7

12

8

9

5

15

19

0

10

11

12

7

0

15

14

e

−

0

a

b

d

Reaction conditions: imine 1a (0.50 mmol), CH₂I₂, LiHMDS, THF/Et₂O. Deprotonation of CH₂I₂over 20 min prior to addition of imine.

c

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.

e

1

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

immediately following addition of imine.

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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 LiCHI₂present

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

Figure 2. Rationale of diastereoselectivity in cyclization to aﬀord cis-

iodoaziridines.

Reaction Scope. To explore the scope of the iodoaziridi-

nation 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

Scheme 2. Formation of Alkyl Imine−HSO₂Tol Adducts and

Imines from Corresponding Aldehydes by Chemla’s Two-

step Procedure

1

Scheme 3. Imine Formation by Direct Condensation

standard conditions for further study, aﬀording an 81% 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,²⁵and for cis-N-Boc bromoaziridines by Ziegler and

co-workers.¹⁴To 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-trans unfavorable. Placing the N-group

and iodide in an antiperiplanar fashion appropriate for

cyclization therefore provides two possible conformations A-

cis 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.³⁷We 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-iodoazir-

idine.³⁸In conformation B-trans, the unfavorable interaction

between the nondisplaced iodide and the large toluenesulfonyl

group results in the conformation being disfavored.

3).³⁹⁻⁴¹Certain 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.

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 diiodome-

thyllithium 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

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Table 2. Scope of Iodoaziridines with Aromatic Imines

Scheme 4. Amino gem-Diiodide Formation with 2-Cl(C₆H₄)

Substituted N-Ts Imine and Postulated Coordination

Preventing Cyclization

(Cs₂CO₃, DMF, rt),²⁵only aﬀorded degradation of the starting

material.

In our previous work on N-Boc iodoaziridines, alkyl imines

were unsuccessful.²⁵Pleasingly 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 diaster-

eoselectivity 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−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.

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,⁴²there is not a method

a

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

b

c

1

cis-diastereoisomer could be observed by H NMR.

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 decom-

position. 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

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Table 3. Scope of Iodoaziridines with Branched Alkyl Imines and Alkyl Imine−HO₂STol Adducts

a

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

b

(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

c

d

e

1

observed by H NMR. dr = 1.9:1. Relative conﬁgurations not determined. dr = 1.5:1.

Scheme 5. Iodoaziridine Synthesis with Primary Alkyl

Imine−HO₂STol Adducts

Table 4. Comparison of the Eﬀect of Diﬀerent Stationary

Phases on the Stability of 4b

recovery of iodoaziridine

yield of α-iodo-

a

entry stationary phase

4b (%)

aldehyde 7 (%)

1

2

3

4

crude

59

25

26

0

b

−

silica gel

32

30

silica gel + 1%

Et₃N

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,²⁵it 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

5

6

7

8

neutral

0

1

0

alumina

basic alumina

(activity I)

c

basic alumina

(activity IV)

53

0

d

1

ﬂorasil

41

15

good recovery with respect to the yield determined by H

a

1

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.

Yield determined by H 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

b

c

d

water (10% w/w) to basic alumina (activity I).

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.³⁵The slurry was then ﬁltered and the ﬁltrate analyzed by

¹H NMR to assess the recovery of the iodoaziridine. On

A sample of 4b was prepared as described above, and an

1

internal standard added to obtain a yield by 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

1

comparison of the yield determined by H NMR, the levels of

degradation could be quantiﬁed. A selection of stationary

F

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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

Table 5. Comparison of the Eﬀect of Diﬀerent Stationary

Phases on the Stability of 4a

a

entry

stationary phase

yield of 4a (%)

1

2

3

4

5

6

7

8

crude

80

78

77

4

b

−

silica gel

silica gel + Et₃N

neutral alumina

basic alumina (activity I)

c

0

d

basic alumina (activity IV)

79

ﬂorasil

a

1

Yield determined by H NMR spectroscopy with reference to an

b

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

c

d

water (10% w/w) to basic alumina (activity I).

decomposition products, where these may be missed on

collecting fractions.

Stability of N-Ts-iodoaziridines: Rearrangement. Dur-

ing 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

Figure 3. Selected sections of ¹H NMR indicating the stability of

iodoaziridine 4b to stationary phases.

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.

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

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.¹⁵The 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).

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

G

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Scheme 7. Preparation of Iodo-aldehyde 7

Scheme 8. Preparation of Chiral Sulﬁnyl Iodoaziridines 9a and 9b

approach.^44,45Attempts to use the comparable toluenesulﬁnyl

group were unsuccessful, as this is known to undergo attack at

sulfur with organometallic reagents.⁴⁶Therefore, we inves-

tigated the tBu sulﬁnyl group, which has been shown to oﬀer

stabilizing interactions in the functionalization of aziridinyl

anions.⁴⁷Phenyl t-butyl sulﬁnyl imine 9 was prepared by direct

condensation using Ti(OEt)₄(Scheme 8).⁴⁸

Scheme 9. Preparation of N-Bus Iodoaziridine under

Optimized Conditions

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 iodoazir-

idines 9a and 9b in a 59% yield with diastereoselectivity (dr =

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 functional-

ization 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.

1

85:15). Characteristic 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 stereo-

control for the 1,2-addition of organolithiums to aldimines the

major and minor diastereoisomers could be predicted (Scheme

8, boxed).^44,49In 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 diiodomethyl-

lithium 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).

EXPERIMENTAL SECTION

■

General Experimental Considerations. All nonaqueous reac-

tions 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

(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 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

CONCLUSION

We have developed an eﬀective method to install iodide

functionality onto a range of alkyl and aromatic substituted N-

■

H

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The Journal of Organic Chemistry

Article

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

CH₃and 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-CH₃quat.), 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-methylbenzenesulfona-

mide (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.⁵⁵mp = 116−117

°C); ν_max(ﬁlm)/cm⁻¹2967, 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-CH₃quat.), 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)₃quat.), 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-methylbenzenesulfona-

mide (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.⁵⁷mp = 91−92

°C); ν_max(ﬁlm)/cm⁻¹1588, 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-CH₃quat.),

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

1

are reported in Hertz. Assignments of H/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 CH₂Cl₂or

CHCl₃to prevent decomposition. For example, iodoaziridine 4i was

stored in a CDCl₃solution 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).⁵¹Imines: 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.³⁹Imines

1f and 1n by a modiﬁcation of the method of Proctor,⁴¹and 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)-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.⁵⁹mp = 139−141 °C); ν_max(ﬁlm)/cm⁻¹3063, 2925,

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.⁵²mp = 107 °C);

ν_max(ﬁlm)/cm⁻¹3360, 3263, 3067, 2925, 2259, 1599, 1319, 1155,

1

2257, 1596, 1564, 1318, 1309, 1153, 1087, 804, 774, 729; H 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-

CH₃quat.), 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

1

1088, 907, 781, 756, 729, 688, 672; H 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-CH₃quat. 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-methylbenzenesulfona-

mide (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.⁵³mp

= 118−119 °C); ν_max(ﬁlm)/cm⁻¹2922, 1590, 1558, 1447, 1413, 1364,

N-[(E)-4-Fluorophenylmethylidene]-4-methylbenzenesulfona-

mide (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.⁶¹mp = 111 °C); ν_max(ﬁlm)/cm⁻¹1598, 1582,

1

1315, 1155, 1086, 1018, 871, 791, 760, 667; H 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-

1

1509, 1320, 1236, 1156, 1089, 814, 769, 670; H NMR (400 MHz,

I

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The Journal of Organic Chemistry

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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-

CH₃quat.), 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

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;

ν_max(ﬁlm)/cm⁻¹3028, 2922, 1625, 1597, 1437, 1320, 1291, 1156,

1

1090, 786, 739, 670; H 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-CH₃quat.), 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.⁶⁰mp = 84−86 °C, lit.⁶³mp = 102−103 °C); ν_max(ﬁlm)/

cm⁻¹3359, 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

N-[(E)-4-Chlorophenylmethylidene]-4-methylbenzenesulfona-

mide (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.⁶²mp = 175−

176 °C); ν_max(ﬁlm)/cm⁻¹3067, 2924, 1592, 1560, 1487, 1401, 1316,

1

1183, 1160, 1083, 1011, 869, 820, 786, 706, 692, 656; H 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-CH₃quat.), 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-methylbenzenesulfona-

mide (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.⁶³mp = 128−129 °C); ν_max(ﬁlm)/cm⁻¹3090, 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-CH₃quat.),

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.³⁹mp = 106 °C);

ν_max(ﬁlm)/cm⁻¹3361, 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

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-

CH₃quat.), 129.3 (2 × SO₂Tol-C), 127.5 (2 × SO₂Tol-C), 37.3

(C(CH₃)₃quat.), 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; R_f0.36 (15% EtOAc/hexane);

ν_max(ﬁlm)/cm⁻¹3305, 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-CH₃quat.), 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-diiodoeth-

yl]-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

quat.), 134.7 (SO₂TolC-CH₃quat.), 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-methylbenzenesulfona-

mide (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

J

dx.doi.org/10.1021/jo400956x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

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; R_f0.20 (50% Et₂O/hexane); ν_max

(ﬁlm)/cm⁻¹3237 (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-CH₃quat), 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.

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, CH₂and 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-CH₃quat.), 134.1

(SO₂TolC-CH₃quat.), 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; ν_max(ﬁlm)/cm⁻¹3227, 2929, 1599, 1454, 1334, 1292, 1131,

1

1083, 813, 763, 669; H 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-CH₃quat.), 134.0 (SO₂TolC-CH₃quat.), 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

N-{2-Methyl-1-[(4-methylphenyl)sulfonyl]cyclohexyl}-4-tolylsulfo-

namide (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.⁶⁴mp = 101−103 °C); ν_max(ﬁlm)/cm⁻¹

3268, 2933, 2860, 1721, 1600, 1451, 1331, 1303, 1290, 1155, 1081,

1

+

906, 812, 731, 705, 661; H NMR (400 MHz, CDCl₃) δ 7.65 (d, J =

(ESI/TOF) m/z calculated for C₁₉H₂₄NO₄S₂[M − H]⁺: 394.1141;

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-CH₃quat.), 134.1

(SO₂TolC-CH₃quat.), 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

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.⁶⁴mp =

119−120 °C); ν_max(ﬁlm)/cm⁻¹3214, 2932, 1597, 1460, 1441, 1334,

1

1291, 1210, 1166, 1127, 1078, 922, 815, 667; H 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-CH₃quat.), 132.7

(SO₂TolC-CH₃quat.), 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-{2-Methyl-1-[(4-methylphenyl)sulfonyl]propyl}-4-tolylsulfona-

mide (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; ν_max(ﬁlm)/cm⁻¹3283, 2968, 1598, 1442, 1332, 1290, 1160,

1

1132, 1082, 890, 813, 779, 702, 670; H 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-CH₃quat.), 133.9 (SO₂TolC-CH₃quat.), 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.⁶⁴mp = 56−57 °C); ν_max(ﬁlm)/cm⁻¹3265, 2965, 2876,

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; ν_max(ﬁlm)/

cm⁻¹3261, 2925, 1597, 1451, 1334, 1301, 1161, 1129, 1081, 1038,

1

1010, 901, 813, 676; H 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-CH₃quat.), 132.6 (SO₂TolC-CH₃quat.), 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),

K

dx.doi.org/10.1021/jo400956x | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article

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.

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%): R_f0.13

(15% EtOAc/hexane); ν_max(ﬁlm)/cm⁻¹2966, 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-CH₃quat.), 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)₃quat.), 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). Pre-

pared 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%): R_f0.13 (5% EtOAc/hexane); ν_max(ﬁlm)/cm⁻¹3030, 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.

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%): R_f0.24 (15% Et₂O/

hexane); ν_max(ﬁlm)/cm⁻¹3035, 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

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

pared 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%): R_f0.40 (15% EtOAc/

hexane); ν_max(ﬁlm)/cm⁻¹3287, 3054, 2926, 2259, 1922, 1722, 1600,

1

1511, 1330, 1157, 1088, 905, 801, 779, 758, 725, 682, 667; H 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−CH₃quat.), 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.

Hz, 1H, CHI), 3.89 (d, J = 6.1 Hz, 1H, CHPh), 2.47 (s, 3H, CH₃); ¹³

C

NMR (101 MHz, CDCl₃) δ 145.3 (SO₂C-Tol quat.), 134.1

(SO₂TolC-CH₃quat.), 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-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%): R_f0.24 (15% EtOAc/

hexane); ν_max(ﬁlm)/cm⁻¹3029, 2933, 2259, 1905, 1604, 1512, 1334,

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

pared 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%): R_f0.16 (10% EtOAc/

hexane); ν_max(ﬁlm)/cm⁻¹3022, 2923, 1616, 1598, 1517, 1329, 1292,

1

1240, 1158, 1089, 904, 835, 814, 735, 706, 680, 666; H NMR (400

1242, 1158, 1089, 1037, 1019, 905, 842, 810, 766; H 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-CH₃quat.), 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.

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

L

dx.doi.org/10.1021/jo400956x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

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%): R_f0.13 (10% EtOAc/hexane); ν_max(ﬁlm)/cm⁻¹3022,

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-CH₃quat.), 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). Pre-

pared 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%): R_f0.18 (10% Et₂O/hexane); ν_max(ﬁlm)/cm⁻¹2926, 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−CH₃quat.), 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-(butan-2-yl)-1-(4-tolylsulfonyl)aziridine (4l). Pre-

pared 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%): R_f0.24 (10% EtOAc/

hexane); ν_max(ﬁlm)/cm⁻¹2963, 2926, 1597, 1459, 1402, 1330, 1243,

1157, 1089, 1019, 940, 871. 813, 733, 686; major 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), 4.58 (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-CH₃quat.), 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); minor 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), 4.50 (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-CH₃quat.), 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%): R_f0.33 (10% EtOAc/hexane); ν_max(ﬁlm)/

cm⁻¹3025, 2920, 1597, 1436, 1330, 1242, 1158, 1090, 1019, 957, 934,

1

893, 814, 732; major H NMR (400 MHz, CDCl₃) δ 7.84−7.81 (m,

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%): R_f0.21 (10% EtOAc/hexane); ν_max(ﬁlm)/cm⁻¹2963, 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

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 × CH₂and CH); ¹³C NMR (101 MHz, CDCl₃) δ 145.1

(SO₂Tol-C quat.), 134.2 (SO₂TolC-CH₃quat.), 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

1

(SO₂Tol-CH₃), 13.2 (CHI); minor H 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 × CH₂and CH); ¹³C NMR (101 MHz, CDCl₃)

δ 145.1 (SO₂Tol-C quat.), 134.2 (SO₂TolC-CH₃quat.), 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.

(SO₂TolC-CH₃quat.), 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%): R_f0.31 (10% EtOAc/hexane); ν_max(ﬁlm)/cm⁻¹2963, 2930,

2877, 1597, 1458, 1330, 1244, 1157, 1089, 976, 887, 835, 813, 731,

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

pared 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%): R_f0.17 (15% EtOAc/

hexane); ν_max(ﬁlm)/cm⁻¹2964, 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-CH₃quat.), 129.7

(2 × SO₂Tol-C), 128.0 (2 × SO₂Tol-C), 50.2 (HCC(CH₃)₃), 31.4

(C(CH₃)₃quat.), 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.

1

667; H 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 × CH₂and 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-CH₃quat.), 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-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

M

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The Journal of Organic Chemistry

Article

(activity IV) aﬀorded cis-iodoaziridine 4o as a yellow oil (11 mg, 6%):

R_f0.23 (10% EtOAc/hexane); ν_max(ﬁlm)/cm⁻¹2960, 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-CH₃quat.), 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%): R_f

0.24 (10% EtOAc/hexane); ν_max(ﬁlm)/cm⁻¹2955, 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-CH₃quat.), 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%): R_f

0.15 (10% EtOAc/hexane); ν_max(ﬁlm)/cm⁻¹3031, 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-CH₃quat.), 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.

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: R_f0.29 (25%

EtOAc/hexane); [α]²⁸−103.0° (c 2.00, CHCl₃); ν_max(ﬁlm)/cm⁻¹

D

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)₃quat.), 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,⁵⁰mCPBA (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: R_f0.43 (30% EtOAc/hexane); ν_max(ﬁlm)/cm⁻¹2984,

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)₃quat.), 23.9 (C(CH₃)₃). Observed data was consistent

with that reported in the literature.⁶⁶

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): R_f0.16 (5% EtOAc/hexane); ν_max(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.),

(2R,3S)-2-Iodo-1-[(R)-2-methylpropane-2-sulﬁnyl]-3-phenylaziri-

dine (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%): R_f= 0.36 (25% EtOAc/hexane); [α]¹⁸−21.3° (c 0.66,

D

CHCl₃); ν_max(ﬁlm)/cm⁻¹2960, 2867, 1605, 1495, 1475, 1454, 1363,

1312, 1238, 1170, 1080, 1026, 906, 847, 817, 791, 758, 699, 676;

major ¹H 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),

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.

1

35.4 (C(CH₃)₃), 22.6 (C(CH₃)₃), 17.8 (CHI); minor H 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

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

N

dx.doi.org/10.1021/jo400956x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(5% EtOAc/hexane) on deactivated basic alumina (activity IV)

aﬀorded cis-iodoaziridine 11 as a yellow oil (82 mg, 45%): R_f= 0.24

(15% Et₂O/hexane); ν_max(ﬁlm)/cm⁻¹2987, 1457, 1314, 1249, 1175,

(8) (a) Kimpe, N. De; Verhe, R.; Buyck, L. De; Schamp, N. J. Org.

Chem. 1981, 46, 2079. (b) Zaugg, H. E.; DeNet, R. W. J. Org. Chem.

1971, 36, 1937. (c) Li, Y.; Zheng, T.; Wang, W.; Xu, W.; Ma, Y.;

Zhang, S.; Wang, H.; Sun, Z. Adv. Synth. Catal. 2012, 354, 308.

(9) (a) Deyrup, J. A.; Greenwald, R. B. J. Am. Chem. Soc. 1965, 87,

4538. (b) Deyrup, J. A.; Greenwald, R. B. Tetrahedron Lett. 1965, 6,

321. (c) Deyrup, J. A.; Greenwald, R. B. Tetrahedron Lett. 1966, 7,

5091.

1

1126, 905, 862, 765, 730, 699, 670; H 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)₃quat.), 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.

(10) Yamanaka, H.; Kikui, J.; Teramura, K.; Ando, T. J. Org. Chem.

1976, 41, 3794.

(11) Hassner, A.; Burke, S. S.; Cheng-fan, I, J. J. Am. Chem. Soc. 1975,

97, 4692.

(12) Pellacani, L.; Persia, F.; Tardella, P. A. Tetrahedron Lett. 1980,

ASSOCIATED CONTENT

■

S

* Supporting Information

21, 4967.

¹H and ¹³C NMR spectra for new compounds (PDF). This

material is available free of charge via the Internet at http://

pubs.acs.org.

(13) Vedejs, E.; Moss, W. O. J. Am. Chem. Soc. 1993, 115, 1607.

(14) (a) Ziegler, F. E.; Belema, M. J. Org. Chem. 1994, 59, 7962.

(b) Ziegler, F. E.; Berlin, M. Y. Tetrahedron Lett. 1998, 39, 2455.

(c) Ziegler, F. E.; Belema, M. J. Org. Chem. 1997, 62, 1083.

(15) Krasnova, L. B.; Yudin, A. K. Org. Lett. 2006, 8, 2011.

(16) Shen, R.; Huang, X. Org. Lett. 2009, 11, 5698.

(17) Yagi, K.; Shinokubo, H.; Oshima, K. Org. Lett. 2004, 6, 4339.

(18) Li, Y.; Ma, Y.; Lu, Z.; Wang, L.; Ren, X.; Sun, Z. Tetrahedron

Lett. 2012, 53, 4711.

AUTHOR INFORMATION

■

Corresponding Author

*E-mail: j.bull@imperial.ac.uk.

Notes

(19) Van Hende, E.; Verniest, G.; Surmont, R.; De Kimpe, N. Org.

Lett. 2007, 9, 2935.

The authors declare no competing ﬁnancial interest.

(20) (a) Florio, S. Synthesis 2012, 44, 2872. (b) Florio, S.; Luisi, R.

Chem. Rev. 2010, 110, 5128. (c) Satoh, T. Chem. Rev. 1996, 96, 3303.

(21) (a) Beak, P.; Wu, S.; Yum, E. K.; Jun, Y. M. J. Org. Chem. 1994,

59, 276. (b) Hodgson, D. M.; Humphreys, P. G.; Ward, J. G. Org. Lett.

2005, 7, 1153. (c) Hodgson, D. M.; Humphreys, P. G.; Miles, S. M.;

Brierley, C. A. J.; Ward, J. G. J. Org. Chem. 2007, 72, 10009.

(d) Schmidt, F.; Keller, F.; Vedrenne, E.; Aggarwal, V. K. Angew.

Chem., Int. Ed. 2009, 48, 1149. (e) Musio, B.; Clarkson, G. J.; Shipman,

M.; Florio, S.; Luisi, R. Org. Lett. 2009, 11, 325. (f) Affortunato, F.;

Florio, S.; Luisi, R.; Musio, B. J. Org. Chem. 2008, 73, 9214.

(22) (a) Wiedner, S. D.; Vedejs, E. Org. Lett. 2010, 12, 4030.

(b) Satoh, T.; Fukuda, Y. Tetrahedron 2003, 59, 9803. (c) Vedejs, E.;

Little, J. J. Am. Chem. Soc. 2002, 124, 748. (d) Aggarwal, V. K.; Alonso,

E.; Ferrara, M.; Spey, S. E. J. Org. Chem. 2002, 67, 2335. (e) Satoh, T.;

Matsue, R.; Fujii, T.; Morikawa, S. Tetrahedron 2001, 57, 3891.

(f) Satoh, T.; Sato, T.; Oohara, T.; Yamakawa, K. J. Org. Chem. 1989,

54, 3973.

ACKNOWLEDGMENTS

■

For ﬁnancial support we gratefully acknowledge the EPSRC

(Career Acceleration Fellowship to J.A.B.; EP/J001538/1), the

Ramsay Memorial Trust (Research Fellowship 2009−2011 to

J.A.B.), the Royal Society for a research grant, and Imperial

College London. Thank you to Prof. Alan Armstrong for

generous support and advice.

REFERENCES

■

(1) (a) Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247. (b) Aziridines

and Epoxides in Organic Synthesis; Yudin, A. K, Ed.; Wiley-VCH: New

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dx.doi.org/10.1021/jo400956x | J. Org. Chem. XXXX, XXX, XXX−XXX

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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

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