Studies on the synthesis of α-iodoaziridines and improved conditions for the synthesis of alkyl-α-iodoaziridines using ClMgCHI2

Article abstract of DOI:10.1016/j.tet.2015.05.098

α-Iodoaziridines are unusual motifs and intriguing structures for further functionalisation of the intact aziridine. The preparation of N-protected α-iodoaziridines is achieved through an addition-cyclisation reaction of LiCHI₂ with imines. The effects of varying the N-group and using different carbenoids are investigated. Excellent cis-stereochemistry is achieved, except for N-carbamates containing aryl groups. Using the mixed carbenoid LiCHICl, the iodide leaving group is selected for cyclisation affording chloroaziridines only, as a cis/trans mixture. More convenient and higher yielding conditions for the preparation of alkyl N-Ts α-iodoaziridines are developed, using ClMgCHI₂. Additionally, the formation of the problematic primary alkyl α-iodoaziridines is achieved.

Full text of DOI:10.1016/j.tet.2015.05.098

Tetrahedron 71 (2015) 4949e4957
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Studies on the synthesis of a-iodoaziridines and improved
conditions for the synthesis of alkyl-
ClMgCHI2
a
-iodoaziridines using
*
Tom Boultwood, Dominic P. Affron, James A. Bull
Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
a
-Iodoaziridines are unusual motifs and intriguing structures for further functionalisation of the intact
Received 28 March 2015
Received in revised form 18 May 2015
Accepted 26 May 2015
aziridine. The preparation of N-protected -iodoaziridines is achieved through an addition-cyclisation
a
reaction of LiCHI2 with imines. The effects of varying the N-group and using different carbenoids are
investigated. Excellent cis-stereochemistry is achieved, except for N-carbamates containing aryl groups.
Using the mixed carbenoid LiCHICl, the iodide leaving group is selected for cyclisation affording chlor-
oaziridines only, as a cis/trans mixture. More convenient and higher yielding conditions for the prepa-
Available online 3 June 2015
Keywords:
Aziridines
Carbenoids
Diiodomethyllithium
Diiodomethylmagnesium chloride
Cyclisation
ration of alkyl N-Ts
a-iodoaziridines are developed, using ClMgCHI2. Additionally, the formation of the
problematic primary alkyl
a
-iodoaziridines is achieved.
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
Inspired by this latter approach, we hypothesised that iodo-
substituted aziridines might provide interesting precursors for
the further functionalisation of intact aziridine rings. Towards this
goal, we have recently developed protocols for the synthesis of N-
Aziridines are important motifs in organic chemistry as a result
of the inherent strain in the three-membered heterocycle.1 This
feature is central to their use as synthetic intermediates in ring
opening processes to provide important nitrogen-containing
compounds,2,3 and also to the mode of biological action of azir-
idine containing natural products.4 For the synthetic chemist the
small ring structure of aziridines is a fascinating target for new
methodology development, and there continues to be important
advances in the stereoselective synthesis of aziridines.5 Conceptu-
ally there are several strategies for the preparation of aziridine
derivatives. These include the transfer of carbenoid reagents or
equivalents to imines.6 The direct nitrogen transfer to alkenes can
be achieved using nitrenoid derivatives.7 Aziridines can also be
Boc14 and N-Ts15
a-iodoaziridines, the first examples of this func-
tional group (Scheme 1A). Both of these methods employ the ad-
dition of diiodomethyllithium, formed via the deprotonation of
diiodomethane with LiHMDS, to N-protected imines, often formed
accessed by cyclisation of
formed effectively via addition of nucleophiles to
b
-functionalised amines,8 which may be
-haloimines.9 An
a
alternative, divergent strategy is to prepare an aziridine by one of
these approaches, and then to couple that intact aziridine, forming
a bond directly to the aziridine ring.10 This has been achieved by
metalation of aziridines and reaction with electrophiles,11,12 as well
as palladium-catalysed cross-coupling of the intact aziridines.13
* Corresponding author. Tel.: þ44 20 7594 5811; e-mail address: j.bull@imperial.
Scheme 1. Synthesis of a-iodoaziridines and functionalisation via aziridinyllithium.
ac.uk (J.A. Bull).
http://dx.doi.org/10.1016/j.tet.2015.05.098
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

4950
T. Boultwood et al. / Tetrahedron 71 (2015) 4949e4957
in situ from their sulfinic acid adducts, followed by highly stereo-
selective cyclisation.
a major reaction pathway. The Cbz-protected a-iodoaziridine 4 was
observed in the 1H NMR spectrum of the crude reaction mixture, as
The formation of N-Boc
substituted imines.14 With N-Ts imines, both alkyl and aryl
substituted -iodoaziridines could be accessed in moderate to good
yields, though unbranched, primary alkyl imines only afforded very
low yields.15a The temperature at which cyclisation occurred varied
depending on the nature of the N-protecting group, but excellent
a
-iodoaziridines was successful for aryl
a mixture of diastereoisomers (cis:trans, 2.5:1), but could not be
isolated (CHI: cis,
d
4.76, J¼5.4 Hz vs trans, 4.31, J¼1.9 Hz). In both
d
a
cases, isolation of aziridine-like products proved problematic, with
decomposition apparent on a variety of stationary phases. In-
terestingly, the use of the benzoyl N-protecting group (COPh) led to
a reverse in the diastereoselectivity of the cyclisation step, with the
trans-product now the major product 5 (trans:cis¼2.4:1). Un-
fortunately, decomposition again occurred on attempted purifica-
tion and the aziridine products could not be isolated.
cis-selectivity was achieved in all cases. These
a-iodoaziridines
were shown to be stable on isolation and could be purified by
chromatography when the stationary phase was judiciously se-
lected.15 Furthermore, we demonstrated that N-Ts
a
-iodoaziridines
Our hypothesis for the cis-stereochemical outcome of the cyc-
lisation is that interactions of the non-displaced iodide with the N-
protecting groups disfavour the trans-aziridine cyclisation transi-
tion state (Scheme 1A).14 In all of the cases depicted in Scheme 2,
could be used to generate aziridinyllithium species by LieI ex-
change (Scheme 1B).16 The aziridinyllithium was then trapped with
electrophiles, affording N-sulfonyl aziridine derivatives in high
yields and with complementary regio- and stereochemistry to
deprotonation approaches.
we observed exclusively the cis-
N-groups containing aromatic rings were employed (Cbz and
benzylamide). This suggests a favourable interaction between
a-iodoaziridines, apart from when
Halomethylmetal reagents, in particular chloromethyllithium,
have received significant attention in synthetic chemistry, as they
can display both nucleophilic and electrophilic reactivity.17e19
Dihalomethylmetal reagents have been investigated to a lesser
p-p
the aryl groups may be occurring, promoting formation of the
trans-compound in these cases.
degree.20e22 Integral to the approach to
a-iodoaziridines has been
the use of diiodomethyllithium.14,15 Unlike traditional aza-Darzens
reactions, whereby the diastereoselectivity of aziridine products is
determined in the initial carbenoid addition step, here due to the
symmetrical nature of LiCHI2, the cyclisation step is diaster-
eodetermining. We considered that using alternative reagents
(changing either the nature of the N-group, or the nature of the
carbenoid reagent (MCHI2)), could afford a different stereochemical
outcome, provide improved yields for the more challenging sub-
strates, or provide insight into the factors that affect
stereoselectivity.
Here we report our investigations into the effect of variation of
the N-protecting group and the carbenoid reagents employed in the
synthesis of
outcome. We report an improved procedure for the preparation of
alkyl substituted N-Ts -iodoaziridines with improved yields,
through the use of ClMgCHI2, and study the problematic un-
branched primary alkyl -iodoaziridine examples.
a-iodoaziridines, and relevance to the stereochemical
a
a
a
Scheme 2. Effect of N-protecting group on
a-iodoaziridine formation.
Reaction
2. Results and discussion
conditions: imineeHO2STol adduct (0.50e0.65 mmol), CH2I2 (3.0 equiv), LiHMDS
b
(2.6 equiv), THF:Et2O (3:1), ꢀ78 ꢁC (10 min), then warm (10 min). Product not iso-
c
2.1. Role of N-protecting group
lated, unstable to chromatography. Reaction conditions: imine (0.50 mmol), CH2I2
(3.4 equiv), LiHMDS (3 equiv), THF:Et2O (3:1), ꢀ78 ꢁC (10 min), then warm (15 min).
We first assessed the effect of changing the N-protecting group
on the a-iodoaziridine reaction, using imines formed from benz-
We next assessed bulky sulfonyl protecting groups, under
slightly different reaction conditions; 1.0 equiv imine, 3.4 equiv
aldehyde. Diiodomethyllithium was formed by deprotonation of
CH2I2 with LiHMDS over 20 min in a THF/Et2O mixture at ꢀ78 ꢁC,
prior to the addition of the imineeHSO2Tol adduct. Within the
carbamate series (2.4 equiv CH2I2, 2.6 equiv LiHMDS), the reaction
CH2I2, 3.0 equiv LiHMDS. We had previously reported N-Ts
a-
iodoaziridine 6, formed in 76% on warming the reaction mixture to
0 ꢁC to promote cyclisation, exclusively as the cis-aziridine. The tert-
butylsulfonyl protecting group, in similar fashion, also gave rise
with the N-Boc imine gave 83% isolated yield of a
-iodoaziridine 1.14
exclusively to the cis-a-iodoaziridine 7 in 45% yield.
The reaction required warming to 30 ꢁC to give full cyclisation and
prevent elimination from the intermediate diiodide.23 Only the cis-
a
-iodoaziridine was observed. In moving to the ethyl and methyl
2.2. Mixed halo-carbenoids: chloroiodomethyllithium
carbamates, the products (2 and 3, respectively) were obtained in
reduced yields, presumably due to attack of the nucleophile at the
carbonyl. However, very high diastereoselectivity was maintained,
despite the decrease in steric bulk; again only the ciseproduct was
observed. Rapid warming from ꢀ78 ꢁC to ambient temperatures
was required to minimize the formation of unwanted side products
and to ensure full cyclisation of the amino gem-diiodide in-
termediates. The reaction with phenyl carbamate yielded a com-
plex mixture of products. The imine formed from N-benzyl
carbamate also afforded a complicated mixture of products under
the reaction conditions. Elimination of iodide from the gem-diio-
dide intermediate to form the corresponding vinyl iodide was
Reacting LiCHBr2, in place of LiCHI2, with imineeHSO2Tol adduct
8 afforded cis-N-Boc bromoaziridine 9 in 30% yield (Scheme 3).14
Deyrup demonstrated that chloroaziridines also show a complete
preference for cis-stereochemistry.20 However, mixed dihalo-
carbenoid systems of the form LiCHXY (XsY) have not been pre-
viously investigated, posing interesting questions about the
reactivity of the proposed intermediate and the diaster-
eoselectivity. Chloroiodomethane was chosen as a suitable carbe-
noid precursor to investigate this, due to cost and availability. Being
unsymmetrical, the initial nucleophilic addition of LiCHICl would
determine the relative stereochemistry of a particular product,

T. Boultwood et al. / Tetrahedron 71 (2015) 4949e4957
4951
Scheme 3. Effect of using mixed dihalocarbenoids on chemo- and diastereoselectivity in formation of a-haloaziridines.
however, there would be a choice for the cyclisation. Preference for
cis-configuration in the aziridine products would give a mixture of
cis-chloro and cis-a-iodoaziridines. On the other hand, preference
for the displacement of iodide from the dihalogenated intermediate
as the better leaving group would give exclusively chloroaziridines,
as a mixture of cis- and trans-substituted products.
To test this, using phenyl N-Boc imine precursor 8, LiCHICl was
formed using LiHMDS and CH2ICl under reaction conditions de-
iodoaziridines. Consequently, a more facile procedure to improve
both the yield and ease of purification of the reaction was required.
Therefore we examined alternative protocols for the formation of
MCHI2 reagents, where full formation of the reagent could be
achieved.
Under the standard conditions involving deprotonation of CH2I2,
a 63% yield of a
-iodoaziridine 15 was obtained (Table 1, entry 1).15
The product could also be obtained starting from iodoform,
employing n-BuLi at low temperature to generate diiodome-
thyllithium by LieI exchange, over 3 min prior to the addition of the
imine (entry 2). While the yield was comparable, in the absence of
veloped for
substituted
of the corresponding
vs trans,
a
-iodoaziridines (Scheme 3). Both cis- and trans-
-chloroaziridines were formed (10 and 11), but none
-iodoaziridines (CHCl: cis,
4.77, J¼5.1 Hz
a
a
d
d
4.53, J¼1.8 Hz). This indicated a preference for the system
LiHMDS, we found that
using conventional silica gel chromatography. Using MeLi provided
no desired -iodoaziridine under the reaction conditions (entry 3).
a-iodoaziridine 15 could now be purified
to displace the better leaving group, rather than for the cis-ste-
reochemistry. However, the yield for the cis-product was higher
than that for the trans (dr¼3.3:1 10:11 in crude reaction mixture).
The intermediate dihalides (12) were formed in 1.6:1 dr when the
reaction was quenched at low temperature, and were isolated in
a
Interestingly 1,1-diiodoethane (16) was observed as the only re-
action product due to the reaction of MeI with diiodomethyllithium
after the initial LieI exchange with iodoform (Eq. 1).
low yield.24 The dr enhancement in the formation of the cis-
a-
chloroaziridine, suggests that the cyclisation to the cis-product may
remain a lower energy pathway. Finally, the observation of aminal
species 13, suggests the chloroiodomethane is not fully deproto-
nated under the reaction conditions. The corresponding product
(1)
Next we considered magnesium carbenoids, which display
similar reactivity to lithium carbenoids but may show increased
was also observed in our studies with N-Ts a
-iodoaziridines.15
Table 1
2.3. Using diiodomethylmagnesium: an improved protocol
for the preparation of alkyl- -iodoaziridines
Optimisation of improved procedure for N-Ts
diiodomethyl-metal reagents
a-iodoaziridine formation varying
a
In our studies to date, the use of LiHMDS to deprotonate diio-
domethane had provided the highest yield of -iodoaziridines. In
the synthesis of N-Ts -iodoaziridines, the addition of LiHMDS di-
a
a
rectly to the imine was a significant side product,25 implying in-
complete deprotonation of diiodomethane in the 20 min reaction
time prior to addition of the imine. This was confirmed by deu-
teration studies, whereby treatment of diiodomethane with
LiHMDS under our standard protocol and quenching with d4-MeOD
after 20 min, revealed only 30% D-incorporation. However, in-
Entrya
1c
2
3
4
CHXI2 (equiv)
ReM (equiv)
Yield 15 (%)b
CH2I2 (4.4)
CHI3 (4.0)
CHI3 (4.0)
CHI3 (4.0)
CHI3 (4.0)
CHI3 (3.0)
LiHMDS (4.0)
n-BuLi (4.0)
MeLi (4.0)
i-PrMgCl (4.0)
EtMgCl (4.0)
EtMgCl (3.0)
63
(65)d
0e
75
87
85
5
6
creasing the deprotonation time led to lower overall yields of
iodoaziridines. Furthermore, the presence of the aminal side-
product required a more involved purification of the -iodoazir-
idines. Degradation of the aminal to benzaldehyde occurred upon
silica gel, which co-eluted with the desired N-Ts -iodoaziridines
a-
a
Reaction conditions unless specified: imineeHO2STol adduct (0.50 mmol), CHI3,
ReM, THF (0.26 M at exchange), ꢀ78 ꢁCe0 ꢁC.
a
b
Yield determined by 1H NMR spectroscopy with reference to an internal stan-
dard (1,3,5-trimethoxybenzene).
a
c
Reaction conditions: imineeHO2STol adduct (0.50 mmol), n-BuLi (2.00 mmol),
during chromatography. Therefore purification was performed
with deactivated basic alumina.
HMDS (2.00 mmol), CH2I2 (2.20 mmol), THF:Et2O (0.16 M at deprotonation),
ꢀ78 ꢁCe0 ꢁC.
d
Due to ongoing further studies using the N-Ts
a-iodoaziridines
Isolated yield.
Diiodoethane formed (see Eq. 1).
e
in particular, we required multi gram-quantities of alkyl N-Ts
a
-

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T. Boultwood et al. / Tetrahedron 71 (2015) 4949e4957
thermal and configurational stability.17b,c,26 Methodology de-
veloped by Seyferth and Lambert18b to form ClMgCHI2 by MgeI
exchange between iodoform and i-PrMgCl at low temperature, has
recently been adapted by Schmidt for addition to aldehydes.26a
Formation of ClMgCHI2 using 4.0 equiv of both i-PrMgCl and
CHI3 at ꢀ78 ꢁC, followed by addition of the imine precursor 14 and
cyclisation by warming (10 min, ꢀ78 ꢁC, then 15 min, 0 ꢁC) was
very promising (entry 4). We observed an improved yield of 75%
for a-iodoaziridine 15. This was further improved when employing
EtMgCl under otherwise identical reaction conditions (entry 5).
Finally, we were able to reduce the equivalents of both iodoform
and EtMgCl (entry 6), and maintain a good yield of 15. The pre-
viously employed dual solvent system (THF/Et2O) was not re-
quired for the formation and stability of the magnesium
carbenoid, meaning THF alone could be used, simplifying the
Scheme 6. Formation of primary alkyl a-iodoaziridines using ClMgCHI2.
protocol. a-Iodoaziridine 15 was isolated in 85% yield on 3 mmol
scale (vs 63% using LiCHI2).15 These improved conditions were
applied to other secondary and tertiary-alkyl N-Ts imines enabling
the preparation of N-Ts a-iodoaziridines 17 and 18 in high yield
and purity, exclusively as their cis-diastereoisomers (Scheme 4).
Notably the excellent cis-stereoselectivity remained for the tert-
butyl example 18.
only gave a very slight improvement in yield (13% as determined by
1H NMR). We were pleased to find that the use of diiodome-
thylmagnesium chloride afforded excellent conversion of imine
precursor 25 to the corresponding diiodide 26 after 15 min at 0 ꢁC,
though only minor conversion to a-iodoaziridine 27 was observed
(Scheme 6B). However, a sampling study indicated that while
prolonged reaction times at 0 ꢁC did increase conversion to
a
-
-
iodoaziridine 27, the rate of cyclisation was slow and the desired
a
iodoaziridine product rearranged to iodo-imine 29 (Scheme 7).28
Scheme 7. Postulated mechanism for rearrangement of
imine 29.
a-iodoaziridine 27 to iodo-
Scheme 4. Scope of secondary alkyl substituted
a-iodoaziridines utilizing Mg-
carbenoids. Reaction conditions: imineeHO2STol adduct/imine (3.00 mmol), CHI3
This rearrangement is presumed to occur via a unimolecular
aziridine-ring opening process, affording cation 28,29 which is
subsequently trapped with iodide affording iodo-imine 29. Similar
aziridine rearrangements have previously been reported by Yudin,
converting bromoaziridines to bromohydrazones,30 and ourselves
(9.00 mmol), EtMgCl (9.00 mmol), THF (0.26 M at exchange), ꢀ78 ꢁCe0 ꢁC.
Next we examined the effect of employing ClMgCHI2 with chiral
imine 19, bearing Ellman’s auxiliary (Scheme 5). Using LiCHI2 gave
rise to a mixture of two enantiopure cis-a-iodoaziridines, 20 and 21,
in an 85:15 diastereomeric ratio.15a Treatment of imine 19 with
ClMgCHI2 afforded a mixture of aziridines 20 and 21, exclusively the
cis-diastereoisomers. The major isomer 20 was the same in both
cases, here with a reduced 71:29 ratio of diastereoisomers. The
addition is proposed to occur via an open transition state.27 With
the Grignard reagent, a chelated, cyclic transition state is plausible,
which is likely to reduce the dr, though not dominate due to
competing coordination of the THF solvent.
in the rearrangement of electron rich N-Ts
a-iodoaziridines to iodo-
imines.15a,31 Attempting to control the conversion to the desired
a-
iodoaziridine and prevent rearrangement to the corresponding
iodo-imine, we examined the influence of reaction time at different
temperatures with imineeHSO2Tol adduct 22 (Table 2).
Table 2
Optimisation of improved procedure for primary N-Ts
a-iodoaziridine using
ClMgCHI2
Entrya
T1/ꢁC
t1 (min)
Yield (%)b
Scheme 5. Effect of changing MCHI2 reagent on the reaction with chiral imines.
30
23
31
1
2
3
4
5
0
0
0
15
30
15
30
45
15
15
81
77
69
41
15
16
22
31
18
7
0
0
0
5
10
2.4. Primary alkyl
a-iodoaziridines
Under our reaction conditions for the formation of N-Ts
a-
iodoaziridines, primary alkyl imine-sulfinic acid adducts suffered
from very poor yields and competing nucleophilic addition by
LiHMDS, (6% yield for the imine derived from butanal, Scheme 6A).
However, generating LiCHI2 by LieI exchange using n-BuLi/CHI3
a
Reaction conditions: imineeHO2STol adduct (0.50 mmol), CHI3 (4.0 equiv), i-
PrMgCl (4.0 equiv), THF (0.26 M at exchange).
b
Yield determined by 1H NMR spectroscopy with reference to an internal stan-
dard (1,3,5-trimethoxybenzene).

T. Boultwood et al. / Tetrahedron 71 (2015) 4949e4957
4953
Increasing the time at 0 ꢁC from 15 min to 45 min led to an
increase in the proportion of cyclised product (entries 1e3). How-
ever, increased times led to degradation and rearrangement. Un-
fortunately, warming to 15 ꢁC (entry 4), led to significant
degradation of the reaction mixture, with a lower recovery ob-
served. The thermal instability of the reaction mixture was further
more straightforward procedure provided improved yields and
workup procedure. The perfect cis-selectivity is maintained. This
protocol has enabled the synthesis of primary, secondary and ter-
tiary alkyl substituted
a-iodoaziridines. Further reactivity of these
a-iodoaziridines will be reported in due course.
evident with warming to 30 ꢁC for 15 min (entry 5), with
a-
4. Experimental section
4.1. General
iodoaziridine 23 rearranging to iodo-imine 31.
We therefore examined the possibility of isolating diiodide 30 to
perform cyclisation in a second step. Under conditions outlined in
Table 2 (entry 1), the crude reaction mixture (5:1 30:23) was sub-
jected to purification using deactivated basic alumina (activity IV).
All nonaqueous reactions were run under an inert atmosphere
(argon) with flame-dried glassware using standard techniques.
Anhydrous solvents were obtained by filtration through drying
columns (THF, Et2O, CH2Cl2, hexane). Flash column chromatogra-
To our surprise, this resulted in cyclization to the desired
a-
iodoaziridine, promoted by the basic solid phase, in a modest, but
much improved, 44% yield (Scheme 8).
phy was performed using 230e400 mesh silica or 50e200
mm
Brockmann basic alumina (activity IV) with the indicated solvent
system according to standard techniques. Analytical thin-layer
chromatography (TLC) was performed on precoated, glass-backed
silica gel plates. Visualisation of the developed chromatogram
was performed by UV absorbance (254 nm), aqueous potassium
permanganate stain, ninhydrin solution in ethanol, phosphomo-
lybdic acid solution in ethanol, or a vanillin solution. Infrared
spectra (nmax, FTIR ATR) were recorded in reciprocal centimeters
(cmꢀ1). Nuclear magnetic resonance spectra were recorded on
400 MHz spectrometers. Chemical shifts for 1H NMR spectra are
recorded in parts per million from tetramethylsilane with the sol-
Scheme 8. Formation of primary alkyl N-Ts
deactivated basic alumina (activity IV).
a-iodoaziridine 23 via treatment with
vent resonance as the internal standard (chloroform,
d
¼7.27 ppm).
Data is reported as follows: chemical shift [multiplicity (s¼singlet,
d¼doublet, t¼triplet, m¼multiplet and br¼broad), coupling con-
stant in Hz, integration, assignment]. 13C NMR spectra were recor-
ded with complete proton decoupling. Chemical shifts are reported
in parts per million from tetramethylsilane with the solvent reso-
nance as the internal standard (13CDCl3: 77.0 ppm). J values are
reported in Hz. Assignments of 1H/13C spectra were made by the
Pleasingly this was similarly successful with imine adduct 25
(Scheme 9). With warming to 0 ꢁC we observed minimal cyclisation
in the crude reaction mixture with diiodide 26 as the major prod-
uct. Passing this mixture through a column of basic alumina (ac-
tivity IV) again promoted cyclisation to the desired a-iodoaziridine
27 in a 44% isolated yield. Small quantities of remaining diiodide 26
were also isolated. This approach represents a significant im-
provement to the reaction protocol for primary imines versus the
same imineeHSO2Tol adduct with LiCHI2, which only yielded 6% of
analysis of
appropriate.
d
/J values, and COSY, HSQC, and HMBC experiments as
-Iodoaziridines and diiodides decomposed upon
a
heating (>100 ꢁC), therefore accurate melting points have not been
determined. Reagents: HMDS was freshly distilled over KOH pellets
under an Ar atmosphere prior to use. All other commercial reagents
were used as supplied, or purified by standard techniques where
necessary. Procedure for obtaining deactivated basic alumina: Com-
mercial alumina is classed as activity I. To alter the activity to basic
alumina (activity IV),10% w/v water must be added to basic alumina
(activity I) and evenly distributed.15,32 Imine synthesis: N-Carba-
mate imineeHSO2Tol adducts were prepared according to
the procedure of Jacobsen.33 N-[(E)-Phenylmethylidene]-4-
methyl-benzenesulfonamide was prepared according to
the method of Chemla.34,15 2-Methyl-N-(phenylmethylidene)-pro-
pane-2-sulfonamide was prepared by oxidation of (R)-
(þ)-2-methyl-N-(phenylmethylidene)propane-2-sulfinamide 1935
according to the procedure of Ruano.36
corresponding a-iodoaziridine 23.
Scheme 9. Formation of primary alkyl N-Ts
a-iodoaziridine 27 via treatment with
deactivated basic alumina (activity IV).
3. Conclusion
In conclusion we have demonstrated that a variety of N-groups
(carbamate, sulfonyl and sulfinyl) are suitable for the synthesis of
a-
4.2. General procedure A: synthesis of N-carbamate a-iodoa-
iodoaziridines, often in excellent cis-selectivity. The exception is
ziridines using LiHMDS
when carbamates contain aromatic rings, which afforded an in-
crease in the trans-product possibly due to
p
-p
interactions. The use
Diiodomethane (145 mL, 1.80 mmol, 3.0 equiv) in THF (1.6 mL)
of LiCHICl also led to the formation of aziridines, as a mixture of cis
and trans-chloroaziridines. The corresponding iodides are not ob-
served indicating a strong preference for cyclisation through the
better leaving group, rather than an essential preference for cis-
stereochemistry. These observations are supportive of our model
that the usual cis preference is due to unfavourable steric in-
teractions in the transition state that would lead to the trans-
product.
was added dropwise to a solution of LiHMDS (1 M solution in THF,
1.56 mL, 1.56 mmol, 2.6 equiv) in THF (6.0 mL) and Et2O (3.0 mL) at
ꢀ78 ꢁC in the dark. After 20 min at ꢀ78 ꢁC, a solution of the imi-
neeHSO2Tol adduct (0.60 mmol, 1.0 equiv) in THF (2.0 mL) was
added dropwise to the reaction mixture. After 10 min at ꢀ78 ꢁC, the
reaction flask was transferred to a water bath at the specified
temperature for 10 min and then quenched by the addition of
saturated aqueous sodium bicarbonate solution (30 mL). The
aqueous mixture was extracted with CH2Cl2 (3ꢂ30 mL). The or-
ganic extracts were combined, dried (Na2SO4), filtered and the
The use of ClMgCHI2 has been shown to be superior to the use of
LiCHCI2 for the synthesis of alkyl N-Ts a-iodoaziridines. A modified,

4954
T. Boultwood et al. / Tetrahedron 71 (2015) 4949e4957
solvent removed under reduced pressure. Purification by flash
chromatography afforded the cis- -iodoaziridine.
dine (11). Prepared according to general procedure A described
above, starting from chloroiodomethane (131 L, 1.80 mmol,
a
m
3.0 equiv) and imineeHSO2Tol adduct 8 (217 mg, 0.60 mmol,
4.2.1. cis-(ꢃ)-2-Iodo-3-phenyl-1-tert-butoxycarbonylaziridine
(1). Prepared according to general procedure A described above,
starting from imineeHO2STol adduct 8 (217 mg, 0.60 mmol),
warming to 30 ꢁC. Purification by flash chromatography (10% Et2O/
1.0 equiv), warming to 30 ꢁC. Purification by flash chromatography
(hexane grading to 10% EtOAc/hexane) afforded trans-
oaziridine 11 (11 mg, 7%) as a yellow oil, followed by cis-
oaziridine 10 (55 mg, 36%) as a yellow oil.
a
-chlor-
-chlor-
a
hexane) afforded cis-
a
-iodoaziridine 1 (172 mg, 83%) as a colourless
11: Rf¼0.44 (10% EtOAc/hexane); nmax (film)/cmꢀ1 2878, 1726
(C]O), 1483, 1457, 1394, 1369, 1309, 1252, 1228, 1154, 1080, 1042,
oil: Rf¼0.37 (20% Et2O/hexane); nmax (film)/cmꢀ1 2981, 1724 (C]O),
1610, 1496, 1478, 1458, 1399, 1372, 1320, 1306, 1285, 1258, 1230,
942, 841, 733, 697; 1H NMR (400 MHz, CDCl3)
d 7.36e7.33 (m, 3H,
1147, 1078, 1029; 1H NMR (400 MHz, CDCl3)
d
7.43e7.34 (m, 5H, 5ꢂ
PheH), 4.72 (d, J¼5.4 Hz, 1H, CHI), 3.59 (d, J¼5.4 Hz, 1H, CHPh), 1.51
(s, 9H, C(CH3)3); 13C NMR (101 MHz, CDCl3)
159.6 (C]O quat.),
3ꢂ PheH), 7.27e7.25 (m, 2H, 2ꢂ PheH), 4.53 (d, J¼1.8 Hz,1H, CHCl),
3.67 (d, J¼1.8 Hz, 1H, CHPh), 1.42 (s, 9H, C(CH3)3); 13C NMR
d
(101 MHz, CDCl3) d 156.9 (C]O quat.), 133.7 (PheC quat.), 128.64
134.8 (PheC quat.), 128.4 (PheC), 128.0 (2ꢂ PheC), 127.5 (2ꢂ
PheC), 82.9 (C(CH3)3 quat.), 43.1 (PhCHN), 27.9 (C(CH3)3), 18.2
(CHI); HRMS (ESIþ) m/z Calculated for C13H17INOþ2 [MþH]þ:
346.0298; Found: 346.0295.
(PheC), 128.62 (2ꢂ PheC), 126.8 (2ꢂ PheC), 82.9 (C(CH3)3 quat.),
52.1 (CHCl), 477 (CHN), 27.8 (C(CH3)3); HRMS (CI) m/z Calculated for
C
13H20ClN2Oþ2 [MþNH4]þ: 271.1206; Found: 271.1213.
10: Rf¼0.30 (10% EtOAc/hexane); nmax (film)/cmꢀ1 2982, 1728
(C]O), 1396, 1370, 1321, 1283, 1257, 1150, 853, 748, 696; 1H NMR
4.2.2. cis-(ꢃ)-2-Iodo-3-phenyl-1-ethoxycarbonylaziridine
(2). Prepared according to general procedure A described above,
starting from [(phenyl-(toluene-4-sulfonyl)-methyl]-ethyl-carba-
mate (200 mg, 0.60 mmol, 1.0 equiv), warming to rt. Purification by
(400 MHz, CDCl3)
d
7.42e7.35 (m, 5H, 5ꢂ PheH), 4.77 (d, J¼5.1 Hz,
1H, CHCl), 3.78 (d, J¼5.1 Hz, 1H, CHPh), 1.52 (s, 9H, C(CH3)3); 13C
NMR (101 MHz, CDCl3)
d 159.4 (C]O quat.), 132.3 (PheC quat.),
128.3 (PheC), 128.1 (2ꢂ PheC), 127.9 (2ꢂ PheC), 83.0 (C(CH3)3
quat.), 54.4 (CHCl), 44.9 (CHN), 27.9 (C(CH3)3); HRMS (CI) m/z Cal-
culated for C13H17ClNOþ2 [MþH]þ: 254.0948; Found: 254.0946.
flash chromatography (10% Et2O/hexane) afforded cis-a-iodoazir-
idine 2 (114 mg, 60%) as a colourless oil: Rf¼0.32 (20% EtOAc/hex-
ane); nmax (film)/cmꢀ1 2989, 1727 (C]O), 1610, 1458, 1401, 1369,
1301, 1268, 1226, 1183, 1100, 1025, 757, 698; 1H NMR (400 MHz,
4.3. General procedure B: synthesis of N-sulfonyl a-iodoazir-
CDCl3)
d
7.43e7.34 (m, 5H, 5ꢂ PheH), 4.76 (d, J¼5.4 Hz, 1H, CHI),
idines using LiHMDS
4.29 (q, J¼7.1 Hz, 2H, OCH2CH3), 3.65 (d, J¼5.4 Hz,1H, CHPh),1.34 (t,
J¼7.1 Hz, 3H, OCH2CH3); 13C NMR (101 MHz, CDCl3)
d
160.8 (C]O
n-BuLi (1.50 mmol, 3.0 equiv) was added dropwise to a solution
quat.), 134.4 (PheC quat.), 128.5 (PheC), 128.1 (2ꢂ PheC), 127.4 (2ꢂ
PheC), 63.4 (OCH2CH3), 43.2 (PhCHN), 17.8 (CHI), 14.3 (OCH2CH3);
HRMS (ESIþ) m/z Calculated for C11H13INOþ2 [MþH]þ: 317.9991;
Found: 317.9998.
of hexamethyldisilazane (315 mL, 1.50 mmol, 3.0 equiv) in THF
(5.7 mL) and Et2O (2.7 mL) at ꢀ78 ꢁC. After 30 min, diiodomethane
(135 mL, 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
(3ꢂ30 mL), then the combined organic layers were dried (Na2SO4),
filtered and the solvent removed under reduced pressure. Purifi-
cation by flash chromatography on deactivated basic alumina (ac-
4.2.3. cis-(ꢃ)-2-Iodo-3-phenyl-1-methoxycarbonylaziridine
(3). Prepared according to general procedure A described above,
starting from [(phenyl-(toluene-4-sulfonyl)-methyl]-methyl-car-
bamate37 (202 mg, 0.63 mmol), warming to rt. Purification by flash
chromatography (10% Et2O/hexane) afforded cis-a-iodoaziridine 3
(107 mg, 56%) as a colourless oil: Rf¼0.32 (20% EtOAc/hexane); nmax
(film)/cmꢀ1 2956, 1725 (C]O), 1508, 1437, 1403, 1319, 1301, 1270,
1225, 1196, 1015, 963, 915, 813, 750, 698; 1H NMR (400 MHz, CDCl3)
d
7.41e7.34 (m, 5H, 5ꢂ PheH), 4.77 (d, J¼5.4 Hz, 1H, CHI), 3.83 (s,
tivity IV or activity V) afforded the cis-a-iodoaziridine.
3H, OCH3), 3.67 (d, J¼5.4 Hz, 1H, CHPh); 13C NMR (101 MHz, CDCl3)
d
161.2 (C]O quat.), 134.2 (PheC quat.), 128.5 (PheC), 128.1 (2ꢂ
4.3.1. cis-(ꢃ)-2-Iodo-3-phenyl-1-(4-tolylsulfonyl)aziridine
(6). Prepared according to general procedure B described above,
starting from N-[(E)-phenylmethylidene]-4-methyl-benzene-sul-
fonamide (130 mg, 0.50 mmol). Purification by flash chromatog-
raphy (10% EtOAc/hexane) on deactivated basic alumina (activity
PheC), 127.4 (2ꢂ PheC), 54.1 (OCH3), 43.2 (PhCHN), 17.6 (CHI);
HRMS (ESIþ) m/z Calculated for C10H11INO2 [MþH]þ: 303.9834;
Found: 303.9848.
4.2.4. cis-(ꢃ)-2-Bromo-3-phenyl-1-tert-butoxycarbonylaziridine
(9). Prepared according to general procedure A described above,
IV) afforded cis-a-iodoaziridine 6 (152 mg, 76%) as a yellow oil:
Rf¼0.24 (15% Et2O/hexane); nmax (film)/cmꢀ1 3035, 2928, 1600,
starting from dibromomethane (126
m
L, 1.80 mmol, 3.0 equiv) and
1499, 1453, 1330, 1157, 1088, 902, 813, 763, 727, 696, 683, 666; 1H
imineeHSO2Tol adduct 8 (217 mg, 0.60 mmol, 1.0 equiv), warming
NMR (400 MHz, CDCl3)
d
7.92 (d, J¼8.5 Hz, 2H, 2ꢂ SO2ToleH),
to 30 ꢁC. Purification by flash chromatography (10% EtOAc/hexane)
7.42e7.33 (m, 5H, 3ꢂ PheH and 2ꢂ SO2ToleH), 7.31e7.25 (m, 2H,
afforded cis-a-bromoaziridine 9 (53 mg, 30%) as a colourless oil:
2ꢂ PheH), 4.89 (d, J¼6.1 Hz, 1H, CHI), 3.89 (d, J¼6.1 Hz, 1H, CHPh),
Rf¼0.25 (10% EtOAc/hexane); nmax (film)/cmꢀ1 2982, 1726 (C]O),
2.47 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3)
d 145.3 (SO2CeTol
1303, 1279, 1257, 1233, 1156, 907, 730, 698; 1H NMR (400 MHz,
quat.), 134.1 (SO2TolCeCH3 quat.), 132.9 (PhC quat.), 129.9 (2ꢂ
SO2ToleC), 128.7 (PheC), 128.1 (2ꢂ SO2ToleC), 127.8 (2ꢂ PheC),
127.5 (2ꢂ PheC), 44.9 (PhCN), 21.7 (SO2ToleCH3), 16.4 (CHI); HRMS
(ESIþ) m/z Calculated for C15H15INO2Sþ [MþH]þ 399.9863; Found
399.9856.
CDCl3)
d
7.43e7.35 (m, 5H, 5ꢂ PheH), 4.87 (d, J¼5.1 Hz, 1H, CHBr),
3.75 (d, J¼5.1 Hz, 1H, CHPh), 1.52 (s, 9H, C(CH3)3); 13C NMR
(101 MHz, CDCl3)
d 159.3 (C]O quat.), 133.2 (PheC quat.), 128.4
(PheC), 128.0 (2ꢂ PheC), 127.8 (2ꢂ PheC), 83.0 (C(CH3)3 quat.),
44.7 (CHBr), 44.1 (CHN), 27.9 (C(CH3)3); HRMS (CI) m/z Calculated
79
for C
H
Br NOþ2 [MþH]þ: 298.0443; Found: 298.0450.
4.3.2. cis-(ꢃ)-2-Iodo-1-(2-methylpropane-2-sulfonyl)-3-
phenylaziridine (7). Prepared according to general procedure B
described above, starting from 2-methyl-N-(phenylmethylidene)
propane-2-sulfonamide (113 mg, 0.50 mmol). Purification by flash
13 17
4.2.5. cis-(ꢃ)-2-Chloro-3-phenyl-1-tert-butoxycarbonylaziridine
(10) and trans-(ꢃ)-2-chloro-3-phenyl-1-tert-butoxycarbonylaziri

T. Boultwood et al. / Tetrahedron 71 (2015) 4949e4957
4955
chromatography (5% EtOAc/hexane) on deactivated basic alumina
methyl-benzenesulfonamide (718 mg, 3.00 mmol, 1.0 equiv).
(activity IV) afforded cis-
a
-iodoaziridine 7 (82 mg, 45%) as a yellow
Purification by flash chromatography (hexane grading to 10%
oil: Rf¼0.24 (15% Et2O/hexane); nmax (film)/cmꢀ1 2987, 1457, 1314,
EtOAc/hexane) afforded cis-a-iodoaziridine 18 (553 mg, 49%) as
1249, 1175, 1126, 905, 862, 765, 730, 699, 670; 1H NMR (400 MHz,
a yellow oil: Rf¼0.31 (10% EtOAc/hexane); nmax (film)/cmꢀ1
CDCl3)
d
7.46e7.35 (m, 5H, 5ꢂ PheH), 4.90 (d, J¼6.0 Hz, 1H, CHI),
2964, 2874, 1600, 1330, 1258, 1158, 1089, 953, 931, 852, 734,
3.86 (d, J¼6.0 Hz, 1H, CHPh), 1.58 (s, 9H, C(CH3)3); 13C NMR
677, 667; 1H NMR (400 MHz, CDCl3)
SO2ToleH), 7.36 (d, J¼8.2 Hz, 2H, 2ꢂ SO2ToleH), 4.36 (d,
J¼6.4 Hz, 1H, CHI), 2.45 (s, 3H, SO2ToleCH3), 2.43 (d, J¼6.4, 1H,
HCC(CH3)3), 0.98 (s, 9H, C(CH3)3); 13C NMR (101 MHz, CDCl3)
d
7.82 (d, J¼8.2 Hz, 2H, 2ꢂ
(101 MHz, CDCl3)
d
133.1 (PheC quat.), 128.9 (PheC), 128.3 (2ꢂ
PheC), 127.7 (2ꢂ PheC), 60.1 (C(CH3)3 quat.), 43.3 (CHN), 24.0
(C(CH3)3), 19.0 (CHI); HRMS (ESIþ) m/z Calculated for C12H17INO2Sþ
[MþH]þ 366.0019; Found 366.0021.
d
145.0 (SO2ToleC quat.), 134.1 (SO2TolCeCH3 quat.), 129.7 (2ꢂ
SO2ToleC), 128.0 (2ꢂ SO2ToleC), 50.2 (HCC(CH3)3), 31.4
(C(CH3)3 quat.), 27.0 (C(CH3)3), 21.7 (SO2ToleCH3), 6.6 (CHI);
HRMS (ESIþ) m/z Calculated for C13H19INO2Sþ [MþH]þ
380.0181; Found 380.0203.
4.4. General procedure C: synthesis of N-sulfonyl iodoazir-
idines using ClMgCHI2
EtMgCl (2 M in THF, 4.50 mL, 9.00 mmol, 3.0 equiv) was added
dropwise over 2 min to a solution of iodoform (3.54 g, 9.00 mmol,
3.0 equiv) in THF (34 mL) at ꢀ78 ꢁC in the dark. After 10 min at
ꢀ78 ꢁC, a solution of the appropriate imine or imineeHSO2Tol
adduct (3.00 mmol, 1.0 equiv) in THF (8 mL) was added dropwise
over 3 min. The reaction was left for 10 min at ꢀ78 ꢁC and then
warmed to 0 ꢁC in an ice/water bath. After 15 min at 0 ꢁC, the re-
action was quenched by the addition of saturated aqueous sodium
bicarbonate solution (100 mL). The aqueous solution was extracted
with CH2Cl2 (3ꢂ100 mL) and the organic extracts were combined,
dried (Na2SO4), filtered and the solvent removed under reduced
pressure. Purification by flash chromatography (silica, hexane
4.4.4. (2R,3S)-2-Iodo-1-[(R)-2-methylpropane-2-sulfinyl]-3-
phenylaziridine (major, 20) and (2S,3R)-2-iodo-1-[(R)-2-
methylpropane-2-sulfinyl]-3-phenylaziridine (minor, 21). Using
ClMgCHI2: Prepared according to general procedure C described
above, starting from imine 19 (105 mg, 0.50 mmol). Purification by
flash chromatography (hexane grading to 10% EtOAc/hexane) on
silica gel afforded a mixture of cis-a-iodoaziridines (71:29 major:-
minor) 20 and 21 (101 mg, 58%) as a yellow oil:
Using LiCHI2: Prepared according to general procedure B de-
scribed above, starting from imine 19 (105 mg, 0.50 mmol). Puri-
fication by flash chromatography (5% EtOAc/hexane) on deactivated
grading to 10% EtOAc/hexane) afforded the cis-
a-iodoaziridine.
basic alumina (activity V) afforded a mixture of cis-a-iodoaziridines
(85:15 major:minor) 20 and 21 (103 mg, 59%) as a yellow oil.
4.4.1. cis-(ꢃ)-2-Iodo-3-(propan-2-yl)-1-(4-tolylsulfonyl)aziridine
(15). Prepared according to general procedure C described above,
starting from imineeHO2STol adduct 14 (1.14 g, 3.00 mmol). Puri-
fication by flash chromatography (10% EtOAc/hexane) afforded cis-
Rf¼0.36 (25% EtOAc/hexane); ½a D18
ꢄ
e21.3ꢁ (c 0.66, CHCl3; 85:15
major:minor); nmax (film)/cmꢀ1 2960, 2867, 1605, 1495, 1475, 1454,
1363, 1312, 1238, 1170, 1080, 1026, 906, 847, 817, 791, 758, 699, 676;
20: 1H NMR (400 MHz, CDCl3)
d
7.43e7.33 (m, 5H, 5ꢂ PheH), 4.54
(d, J¼6.0 Hz, 1H, CHI), 3.71 (d, J¼6.0 Hz, 1H, CHPh), 1.20 (s, 9H,
C(CH3)3); 13C NMR (101 MHz, CDCl3)
133.8 (PheC quat.), 128.5
a
-iodoaziridine 15 (930 mg, 85%) as a yellow solid: Rf¼0.21 (10%
EtOAc/hexane); nmax (film)/cmꢀ1 2963, 2931, 2874,1597,1466,1403,
d
1329, 1244, 1156, 1089, 1026, 954, 885, 831, 813, 734, 684, 667; 1H
(PheC), 128.2 (2ꢂ PheC), 128.1 (2ꢂ PheC), 57.5 (CHPh), 35.4
NMR (400 MHz, CDCl3)
d
7.82 (d, J¼8.3 Hz, 2H, 2ꢂ SO2ToleH), 7.36
(C(CH3)3), 22.6 (C(CH3)3), 17.8 (CHI); 21: 1H NMR (400 MHz, CDCl3)
(d, J¼8.3 Hz, 2H, 2ꢂ SO2ToleH), 4.54 (d, J¼5.9 Hz, 1H, CHI), 2.46 (s,
3H, SO2ToleCH3), 2.20 (dd, J¼9.7, 5.9 Hz, 1H, CHN), 1.92 (dqq, J¼9.7,
6.7, 6.7 Hz, 1H, CH(CH3)2), 0.99 (d, J¼6.7 Hz, 3H, CH(CH3)2), 0.92 (d,
d
7.43e7.33 (m, 5H, 5ꢂ PheH), 4.83 (d, J¼5.9 Hz, 1H, CHI), 3.30 (d,
J¼5.9 Hz, 1H, CHPh), 1.41 (s, 9H, C(CH3)3); 13C NMR (101 MHz,
CDCl3)
d
134.7 (PheC quat.), 128.4 (PheC), 128.0 (2ꢂ PheC), 127.7
J¼6.7 Hz, 3H, CH(CH3)2); 13C NMR (101 MHz, CDCl3)
d
145.1
(2ꢂ PheC), 58.6 (CHPh), 38.6 (C(CH3)3), 23.3 (C(CH3)3), 15.4 (CHI);
HRMS (ESIþ) m/z Calculated for C12H17INOSþ [MþH]þ 350.0070;
Found 350.0078.
(SO2ToleC quat.), 134.3 (SO2TolCeCH3 quat.), 129.8 (2ꢂ SO2ToleC),
128.0 (2ꢂ SO2ToleC), 49.3 (CHN), 31.5 (CH(CH3)2), 21.7
(SO2ToleCH3), 20.0 (CH3), 17.9 (CH3), 13.8 (CHI); HRMS (ESIþ) m/z
Calculated for C12H17INO2Sþ [MþH]þ: 366.0019; Found: 366.0034.
4.4.5. cis-(ꢃ)-2-Iodo-3-propyl-1-(4-tolylsulfonyl)aziridine
(23). EtMgCl (2 M in THF, 0.75 mL, 1.50 mmol, 3.0 equiv) was added
dropwise over 2 min to a solution of iodoform (591 mg, 1.50 mmol,
3.0 equiv) in THF (6 mL) at ꢀ78 ꢁC in the dark. After 10 min at
4.4.2. cis-(ꢃ)-2-Iodo-3-cyclohexyl-1-(4-tolylsulfonyl)aziridine
(17). Prepared according to general procedure C described above,
starting from N-[(E)-cyclohexylmethylidene]-4-methyl-benzene-
sulfonamide (796 mg, 3.00 mmol). Purification by flash chroma-
ꢀ78 ꢁC,
a solution of imineeHO2STol adduct 22 (191 mg,
0.50 mmol) in THF (2 mL) was added dropwise over 3 min. The
reaction was left for 10 min at ꢀ78 ꢁC and then warmed to 0 ꢁC in an
ice/water bath. After 15 min at 0 ꢁC, the reaction was quenched by
the addition of saturated aqueous sodium bicarbonate solution
(20 mL). The aqueous solution was extracted with CH2Cl2
(3ꢂ30 mL) and the organic extracts were combined, dried (Na2SO4),
filtered and the solvent removed under reduced pressure. Purifi-
cation by flash chromatography (hexane grading to 10% EtOAc/
tography (10% EtOAc/hexane) afforded cis-a-iodoaziridine 17
(999 mg, 82%) as a yellow solid: Rf¼0.18 (10% Et2O/hexane); nmax
(film)/cmꢀ1 2926, 2851,1598,1450,1330,1242,1158,1090, 968, 900,
883, 814, 732, 669; 1H NMR (400 MHz, CDCl3)
d
7.82 (d, J¼8.2 Hz,
2H, 2ꢂ SO2ToleH), 7.37 (d, J¼8.2 Hz, 2H, 2ꢂ SO2ToleH), 4.53 (d,
J¼6.0 Hz, 1H, CHI), 2.47 (s, 3H, SO2ToleCH3), 2.26 (dd, J¼9.4, 6.0 Hz,
1H, CHCy), 1.84e1.71 (m, 2H, 2ꢂ CyeH), 1.70e1.62 (m, 2H, 2ꢂ
CyeH), 1.60e1.53 (m, 1H, CyeH), 1.33e0.99 (m, 6H, 6ꢂ CyeH); 13
C
hexane) on deactivated basic alumina (activity IV) afforded cis-a-
NMR (101 MHz, CDCl3)
d
145.0 (SO2ToleC quat.), 134.4
iodoaziridine 23 (80 mg, 44%) as a yellow oil: Rf¼0.23 (10% EtOAc/
(SO2TolCeCH3 quat.), 129.8 (2ꢂ SO2ToleC), 128.0 (2ꢂ SO2ToleC),
47.8 (CHN), 40.1 (CH), 30.3 (CH2), 28.3 (CH2), 25.9 (CH2), 25.2 (CH2),
25.1 (CH2), 21.7 (SO2ToleCH3), 13.5 (CHI); HRMS (ESIþ) m/z Calcu-
lated for C15H21INO2Sþ [MþH]þ: 406.0332; Found: 406.0328.
hexane); nmax (film)/cmꢀ1 2960, 2931, 2873, 1598, 1331, 1245, 1160,
1090, 902, 717; 1H NMR (400 MHz, CDCl3)
d
7.83 (d, J¼8.3 Hz, 2H,
2ꢂ SO2ToleH), 7.37 (d, J¼8.3 Hz, 2H, 2ꢂ SO2ToleH), 4.55 (d,
J¼6.0 Hz, 1H, CHI), 2.60e2.55 (m, 1H, CHN), 2.47 (s, 3H,
SO2ToleCH3), 1.57e1.40 (m, 4H, 2ꢂ CH2), 0.95 (t, J¼7.3 Hz, 3H, CH3);
4.4.3. cis-(ꢃ)-2-Iodo-3-(tert-butyl)-1-(4-tolylsulfonyl)aziridine
13C NMR (101 MHz, CDCl3)
d 145.0 (SO2ToleC quat.), 134.5
(18). Prepared according to general procedure
C
described
(SO2TolCeCH3 quat.), 129.8 (2ꢂ SO2ToleC), 127.9 (2ꢂ SO2ToleC),
above,
starting
from
N-[(E)-2,2-dimethylpropylidene]-4-
43.6 (CHN), 33.5 (CH2), 21.7 (SO2ToleCH3), 19.7 (CH2), 14.5 (CH3),

4956
T. Boultwood et al. / Tetrahedron 71 (2015) 4949e4957
13.6 (CHI); HRMS (ESIþ) m/z Calculated for C12H17INO2Sþ [MþH]þ:
3. For ring expansion and rearrangements: (a) Ilardi, E. A.; Njardarson, J. T. J. Org.
Chem. 2013, 78, 9533; (b) Dauban, P.; Malik, G. Angew. Chem., Int. Ed. 2009, 48,
9026.
366.0019; Found: 366.0031.
4. (a) Ismail, F. M. D.; Levitsky, D. O.; Dembitsky, V. M. Eur. J. Med. Chem. 2009, 44,
3373; (b) Kasai, M.; Kono, M. Synlett 1992, 778; (c) Danishefsky, S. J.; Schker-
yantz, J. M. Synlett 1995, 475; (d) Williams, R. M.; Rajski, S. R.; Rollins, S. B.
Chem. Biol. 1997, 4, 127.
5. (a) Degennaro, L.; Trinchera, P.; Luisi, R. Chem. Rev. 2014, 114, 7881; (b) Pel-
lissier, H. Adv. Synth. Catal. 2014, 356, 1899; (c) Smith, D. T.; Njardarson, J. T.
Angew. Chem., Int. Ed. 2014, 53, 4278; (d) Callebaut, G.; Meiresonne, T.; De
Kimpe, N.; Mangelinckx, S. Chem. Rev. 2014, 114, 7954.
6. For aza-Darzens reactions: (a) Sweeney, J. Eur. J. Org. Chem. 2009, 4911; (b)
Huang, L.; Wulff, W. D. J. Am. Chem. Soc. 2011, 133, 8892; (c) Moragas, T.;
Churcher, I.; Lewis, W.; Stockman, R. A. Org. Lett. 2014, 16, 6290; (d) Zhang, Y.;
Lu, Z.; Wulff, W. D. Synlett 2009, 2715; (e) Johnston, J. N.; Muchalski, H.; Troyer,
T. L. Angew. Chem., Int. Ed. 2010, 49, 2290.
4.4.6. cis-(ꢃ)-2-Iodo-3-(2-methylpropyl)-1-(4-tolylsulfonyl)aziridine
(27) and N-(1,1-diiodo-4-methylpentan-2-yl)-4-tolyl-1-sulfonamide
(26). EtMgCl (2 M in THF, 0.75 mL, 1.50 mmol, 3.0 equiv) was added
dropwise over 2 min to a solution of iodoform (591 mg, 1.50 mmol,
3.0 equiv) in THF (6 mL) at ꢀ78 ꢁC in the dark. After 10 min at
ꢀ78 ꢁC,
a solution of imineeHO2STol adduct 25 (198 mg,
0.50 mmol) in THF (2 mL) was added dropwise over 3 min. The
reaction was left for 10 min at ꢀ78 ꢁC and then warmed to 0 ꢁC in an
ice/water bath. After 15 min at 0 ꢁC, the reaction was quenched by
the addition of saturated aqueous sodium bicarbonate solution
(20 mL). The aqueous solution was extracted with CH2Cl2
(3ꢂ30 mL) and the organic extracts were combined, dried (Na2SO4),
filtered and the solvent removed under reduced pressure. Purifi-
cation by flash chromatography (hexane grading to 10% EtOAc/
7. For N-transfer to alkenes: (a) Jat, J. L.; Paudyal, M. P.; Gao, H.; Xu, Q.-L.; You-
€
sufuddin, M.; Devarajan, D.; Ess, D. H.; Kurti, L.; Falck, J. R. Science 2014, 343, 61;
(b) Watson, I. D. G.; Yu, L.; Yudin, A. K. Acc. Chem. Res. 2006, 39, 194; (c) Lebel,
H.; Parmentier, M. Pure Appl. Chem. 2010, 82, 1827; (d) Lebel, H.; Spitz, C.;
Leogane, O.; Trudel, C.; Parmentier, M. Org. Lett. 2011, 13, 5460 For organo-
catalytic approaches: (e) Pesciaioli, F.; De Vincentiis, F.; Galzerano, P.; Benci-
venni, G.; Bartoli, G.; Mazzanti, A.; Melchiorre, P. Angew. Chem., Int. Ed. 2008, 47,
hexane) on deactivated basic alumina (activity IV) afforded cis-a-
€
8703; (f) Jung, N.; Brase, S. Angew. Chem., Int. Ed. 2012, 51, 5538; (g) Deiana, L.;
iodoaziridine 27 (83 mg, 44%) as a yellow oil, followed by amino
gem-diiodide 26 (40 mg, 16%) as a white solid.
ꢀ
Dziedzic, P.; Zhao, G.-L.; Vesely, J.; Ibrahem, I.; Rios, R.; Sun, J.; Cordova, A. Chem.
dEur. J. 2011, 17, 7904; (h) Armstrong, A.; Pullin, R. D. C.; Jenner, C. R.; Foo, K.;
White, A. J. P.; Scutt, J. N. Tetrahedron: Asymmetry 2014, 25, 74.
26: Rf¼0.17 (10% EtOAc/hexane); nmax (film)/cmꢀ1 3243, 2959,
8. For examples, see: (a) Li, X.; Chen, N.; Xu, J. Synthesis 2010, 3423; (b) Olofsson,
B.; Wijtmans, R.; Somfai, P. Tetrahedron 2002, 58, 5979; (c) Cardillo, G.; Gen-
1417, 1330, 1162, 1093, 1036, 962, 917, 814, 665; 1H NMR (400 MHz,
ꢀ
tilucci, L.; Tolomelli, A. Aldrichimica Acta 2003, 36, 39; (d) Viso, A.; Fernandez De
CDCl3)
d
7.79 (d, J¼7.9 Hz, 2H, 2ꢂ SO2ToleH), 7.34 (d, J¼7.9 Hz, 2H,
ꢀ
~
La Pradilla, R.; Urena, M.; Bates, R. H.; Del Aguila, M. A.; Colomer, I. J. Org. Chem.
2012, 77, 525; (e) Kawamoto, A. M.; Wills, M. J. Chem. Soc., Perkin Trans. 1 2001,
1916; (f) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599.
2ꢂ SO2ToleH), 5.27e5.26 (m, 1H, CHI2), 4.93 (d, J¼8.3 Hz, 1H, NH),
2.91e2.84 (m, 1H, CHN), 2.46 (s, 3H, SO2ToleCH3), 1.70e1.60 (m, 1H,
CH), 1.47e1.35 (m, 2H, CH2), 0.88 (t, J¼6.4 Hz, 3H, CH3), 0.66 (t,
ꢀ
9. (a) De Kimpe, N.; Schamp, N.; Verhe, R. Synth. Commun. 1975, 5, 403; (b) De
Kimpe, N.; Verhe, R.; Buyck, L. De; Schamp, N. J. Org. Chem. 1980, 45, 5319; (c)
J¼6.3 Hz, 3H, CH3); 13C NMR (101 MHz, CDCl3)
d 144.1 (SO2ToleC
ꢀ
De Kimpe, N.; Sulmon, P.; Schamp, N. Angew. Chem., Int. Ed. Engl. 1985, 24, 881;
(d) De Kimpe, N.; Moens, L. Tetrahedron 1990, 46, 2965; (e) Denolf, B.; Man-
quat.), 137.3 (SO2TolCeCH3 quat.), 129.9 (2ꢂ SO2ToleC), 127.1 (2ꢂ
SO2ToleC), 59.1 (CHN), 43.2 (CH2), 24.1 (CH), 23.3 (CH3), 21.6
(SO2ToleCH3), 21.2 (CH3), ꢀ11.6 (CHI2).
€
gelinckx, S.; Tornroos, K. W.; De Kimpe, N. Org. Lett. 2006, 8, 3129; (f) Denolf, B.;
Leemans, E.; De Kimpe, N. J. Org. Chem. 2007, 72, 3211; (g) Hodgson, D. M.;
Kloesges, J.; Evans, B. Synthesis 2009, 1923.
27: Rf¼0.31 (10% EtOAc/hexane); nmax (film)/cmꢀ1 2956, 2872,
1597, 1467, 1329, 1246, 1158, 1089, 999, 904, 813, 714; 1H NMR
10. (a) Florio, S.; Luisi, R. Chem. Rev. 2010, 110, 5128; (b) Satoh, T. Chem. Rev. 1996,
96, 3303; (c) Hodgson, D. M.; Humphreys, P. G.; Hughes, S. P. Pure Appl. Chem.
2007, 79, 269.
(400 MHz, CDCl3)
d
7.82 (d, J¼8.3 Hz, 2H, 2ꢂ SO2ToleH), 7.36 (d,
11. For approaches via functional group exchange, see: (a) Satoh, T.; Fukuda, Y.
Tetrahedron 2003, 59, 9803; (b) Satoh, T.; Matsue, R.; Fujii, T.; Morikawa, S.
Tetrahedron 2001, 57, 3891; (c) Satoh, T.; Ozawa, M.; Takano, K.; Chyouma, T.;
Okawa, A. Tetrahedron 2000, 56, 4415; (d) Satoh, T.; Sato, T.; Oohara, T.; Ya-
makawa, K. J. Org. Chem. 1989, 54, 3973; (e) Vedejs, E.; Moss, W. O. J. Am. Chem.
Soc. 1993, 115, 1607; (f) Vedejs, E.; Little, J. J. Am. Chem. Soc. 2002, 124, 748; (g)
Vedejs, E.; Little, J. D.; Seaney, L. M. J. Org. Chem. 2004, 69, 1788; (h) Wiedner, S.
D.; Vedejs, E. Org. Lett. 2010, 12, 4030; (i) Aggarwal, V. K.; Alonso, E.; Ferrara, M.;
Spey, S. E. J. Org. Chem. 2002, 67, 2335; (j) Aggarwal, V. K.; Ferrara, M. Org. Lett.
2000, 2, 4107.
12. (a) Beak, P.; Wu, S.; Yum, E. K.; Jun, Y. M. J. Org. Chem. 1994, 59, 276; (b) Vedejs,
E.; Kendall, J. T. J. Am. Chem. Soc. 1997, 119, 6941; (c) Vedejs, E.; Bhanu Prasad, A.
S.; Kendall, J. T.; Russel, J. S. Tetrahedron 2003, 59, 9849; (d) Capriati, V.; Florio,
S.; Luisi, R.; Musio, B. Org. Lett. 2005, 7, 3749; (e) Hodgson, D. M.; Humphreys, P.
G.; Xu, Z.; Ward, J. G. Angew. Chem., Int. Ed. 2007, 46, 2245; (f) Hodgson, D. M.;
Humphreys, P. G.; Ward, J. G. Org. Lett. 2005, 7, 1153; (g) Hodgson, D. M.;
Hughes, S. P.; Thompson, A. L.; Heightman, T. D. Org. Lett. 2008, 10, 3453; (h)
Musio, B.; Clarkson, G. J.; Shipman, M.; Florio, S.; Luisi, R. Org. Lett. 2009, 11, 325;
(i) Huang, J.; Moore, S. P.; O’Brien, P.; Whitwood, A. C.; Gilday, J. Org. Biomol.
Chem. 2009, 7, 335.
J¼8.3 Hz, 2H, 2ꢂ SO2ToleH), 4.54 (d, J¼5.9 Hz, 1H, CHI), 2.63 (dt,
J¼7.0, 6.1 Hz, 1H, CHN), 2.46 (s, 3H, SO2ToleCH3), 1.77e1.67 (m, 1H,
CH), 1.51e1.42 (m, 2H, CH2), 0.98 (t, J¼6.7 Hz, 3H, CH3), 0.95 (t,
J¼6.7 Hz, 3H, CH3); 13C NMR (101 MHz, CDCl3)
d 145.0 (SO2ToleC
quat.), 134.5 (SO2TolCeCH3 quat.), 129.8 (2ꢂ SO2ToleC), 127.8 (2ꢂ
SO2ToleC), 42.6 (CHN), 40.1 (CH2), 26.3 (CH), 22.5 (CH3), 22.3 (CH3),
21.7 (SO2ToleCH3), 14.9 (CHI); HRMS (ESIþ) m/z Calculated for
C
13H19INO2Sþ [MþH]þ: 380.0176; Found: 380.0195.
Acknowledgements
For financial support we gratefully acknowledge the Engineer-
ing and Physical Sciences Research Council (Career Acceleration
Fellowship to J.A.B.; EP/J001538/1), the Ramsay Memorial Trust
(Research Fellowship 2009e2011 to J.A.B.), the Royal Society for
a research grant (RG2014/R1, RG130648), and Imperial College
London. Thank you to Marcel Schlegel for preliminary studies and
to Prof. Alan Armstrong for generous support.
13. (a) Hughes, M.; Boultwood, T.; Zeppetelli, G.; Bull, J. A. J. Org. Chem. 2013, 78,
844; (b) Nelson, J. M.; Vedejs, E. Org. Lett. 2010, 12, 5085; (c) Theddu, N.; Vedejs,
E. J. Org. Chem. 2013, 78, 5061.
14. Bull, J. A.; Boultwood, T.; Taylor, T. A. Chem. Commun. 2012, 12246.
15. (a) Boultwood, T.; Affron, D. P.; Trowbridge, A. D.; Bull, J. A. J. Org. Chem. 2013,
78, 6632; (b) Boultwood, T.; Affron, D. P.; Bull, J. A. J. Vis. Exp. 2014, 87, e51633.
16. Boultwood, T.; Bull, J. A. Org. Lett. 2014, 16, 2740.
Supplementary data
17. For recent reviews of carbenoid reagents: (a) Capriati, V.; Florio, S. Chem.
dEur. J. 2010, 16, 4152; (b) Satoh, T. Chem. Soc. Rev. 2007, 36, 1561; (c) Satoh,
T. Heterocycles 2012, 85, 1; (d) Boche, G.; Lohrenz, J. C. W. Chem. Rev. 2001,
101, 697.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.05.098.
€
18. (a) Kobrich, G.; Flory, K.; Drischel, W. Angew. Chem., Int. Ed. Engl. 1964, 3, 513;
(b) Seyferth, D.; Lambert, R. L., Jr. J. Organomet. Chem. 1973, 54, 123; (c) Char-
References and notes
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4957
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ꢀ
Boc imine, this has been indicated by a broad singlet observed at
d
5.78 cor-
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ꢀ
mixture and integration of signals at
d 5.53 and d 5.39 presumed to correspond
to the CHICl protons. See Supplementary data for 1H NMR spectrum.