Terminal aziridines by addition of Grignard reagents or organoceriums to an (α-chloro)sulfinylimine

Article abstract of DOI:10.1055/s-0029-1216799

Reaction of N-(2-chloroethylidene)-tert-butylsulfinamide with Grignard reagents or organoceriums gives terminal N-tert-butylsulfinyl aziridines in good yields and (mainly with organoceriums) good diastereomeric ratios. Oxidation of terminal N-tert-butylsu

Full text of DOI:10.1055/s-0029-1216799

FEATURE ARTICLE
1923
Terminal Aziridines by Addition of Grignard Reagents or Organoceriums to
an (a-Chloro)sulfinylimine
T
ermina
l
A
ziridine
a
s
from an(
v
a
-Chloro)sul
i
finylim
d
ine M. Hodgson,*a Johannes Kloesges,a Brian Evansb
a
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
Fax +44(1865)285002; E-mail: david.hodgson@chem.ox.ac.uk
b
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Received 29 March 2009
velopment of several new transformations of terminal
aziridines proceeding by a-lithiation, including trapping
of electrophiles, dimerisation, and intramolecular cyclo-
propanation of terminal N-Bus (Bus = tert-butylsulfonyl)
Abstract: Reaction of N-(2-chloroethylidene)-tert-butylsulfin-
amide with Grignard reagents or organoceriums gives terminal N-
tert-butylsulfinyl aziridines in good yields and (mainly with orga-
noceriums) good diastereomeric ratios. Oxidation of terminal N-
tert-butylsulfinyl aziridines provides synthetically useful terminal aziridines 2 (Scheme 2).10 The Bus protecting group was
N-Bus (Bus = tert-butylsulfonyl) aziridines.
originally introduced by Weinreb and co-workers as a
base-stable (acid-labile) protecting group for nitrogen,11
Key words: aziridines, chiral auxiliaries, imines, nucleophilic
addition, organoceriums
and we have found the Bus group uniquely suited for the
range of chemistry shown in Scheme 2.
.
NBus
Facilitating ways to introduce nitrogen-containing organ-
ic fragments into organic molecules is an important goal
in synthetic chemistry. Aziridines, typically when bearing
an electron-withdrawing/-activating group on nitrogen,
are becoming increasingly important electrophiles.1 Ter-
minal aziridines 1 are probably the most useful aziridines
of all, because of the ease, generality and predictable re-
gioselectivity with which they undergo ring-opening reac-
tions with nucleophiles.2 Five strategically different ways
that have been used to access terminal aziridines are out-
lined in Scheme 1.1b,3 In the context of asymmetric syn-
thesis, all of these strategies have been pursued with
varying degrees of success, but it remains the case that
there is currently no general and straightforward method
to access highly enantioenriched 2-substituted (particular-
ly 2-alkyl-substituted) aziridines in an efficient manner.4,5
E
R
E+
NHBus
lithium
amide
NBus
NBus
Li
R
R
R
R
2
NHBus
NHBus
R =
Bus = tert-butylsulfonyl
Scheme 2 Reactions of a-lithiated terminal N-Bus aziridines10
Where we used enantioenriched terminal N-Bus aziri-
dines 2 in the chemistry in Scheme 2, the aziridines were
typically prepared using t-BuSO2NH2 in a three-step re-
gioselective epoxide ring-opening/aziridine ring-closure
sequence, with the starting enantiopure terminal epoxides
being accessed by Jacobsen’s hydrolytic kinetic resolu-
tion protocol.10d With the aim of developing a more direct
asymmetric synthesis of terminal N-Bus aziridines which
avoided a resolution step, we were attracted to a report in
2006 by De Kimpe and co-workers concerning an asym-
metric synthesis of 2,2,3-trisubstituted aziridines 4 by ad-
dition of Grignard reagents to nonenolisable a-
chloroaldimines 3 (Scheme 3).12,13 Successful adaptation
of this latter chemistry to make terminal N-Bus aziridines
2 would require: (i) straightforward access to the N-tert-
butylsulfinyl imine of a-chloroacetaldehyde 3 (R1 = H),
(ii) development of conditions for the efficient and highly
diastereoselective addition of organometallics to this imi-
ne (which avoid enolisation and/or chloride displacement)
followed by ring-closure (ideally in situ), and (iii) sulfinyl
to sulfonyl oxidation while preserving the terminal aziri-
dine. The present article describes the realisation of these
goals.14
PG
N
PG
N
NHPG
LG
R
+
R
R
1
ring closure1b
metallation/
E
+ trapping9
PG
N
+
PG
+
N
R
R
N
CH2
additions
to azirines8
nitrene
transfer6
R
carbene
transfer7
PG = protecting group
LG = leaving group
Scheme 1 Synthetic approaches to terminal aziridines
We became aware of current limitations for the asymmet-
ric synthesis of terminal aziridines during our recent de-
SYNTHESIS 2009, No. 11, pp 1923–1932
x
x.
x
x
.
2
0
0
9
Advanced online publication: 12.05.2009
DOI: 10.1055/s-0029-1216799; Art ID: Z05109SS
© Georg Thieme Verlag Stuttgart · New York

1924
D. M. Hodgson et al.
FEATURE ARTICLE
of cheap 1,3-dioxolan-2-one (5) in CCl4.17 Although reac-
tion of t-BuSONH2 with anhydrous a-chloroacetaldehyde
in the presence of Ti(OEt)4 led to decomposition, milder
conditions using anhydrous CuSO418 did generate the de-
sired imine 8; the latter reaction is essentially quantitative
and requires no further purification following filtration
and solvent removal.
NSOt-Bu
Cl
R2MgBr
NSOt-Bu
43–99%
up to 99:1 dr
R2
R1
CH2Cl2 or PhMe
R1 R1
R1
3
4
R1 = Me, Et, –(CH2)5–
Scheme 3 Addition of Grignard reagents to a-chloroaldimines 312
De Kimpe and co-workers prepared their a-chloroald-
imines 3 (R1 = alkyl) by condensation of commercially
available t-BuSONH2 with the corresponding a-chloroal-
dehydes using Ti(OEt)4 in THF at reflux, where the Lewis
acid also acts as a trap for the generated water. As a-chlo-
roacetaldehyde (7) is supplied in aqueous solution, which
only gives the hemiacetal on extraction with organic sol-
vents, we first attempted to prepare our desired imine 8
from commercially available chloroacetaldehyde dimeth-
yl acetal and t-BuSONH2; however, no reaction was seen
in the presence of Ti(OEt)4, whereas decomposition was
observed using TiCl4. Among the reported methods to ac-
cess anhydrous a-chloroacetaldehyde (7),15,16 in our hands
only Et3NHCl-catalysed loss of CO2 from 4-chloro-1,3-
dioxolan-2-one (6) proved viable (Scheme 4).16 Dioxol-
anone 6 is commercially available (but now expensive);
however, it can be conveniently prepared by chlorination
O
NSOt-Bu
O
Et3N (1 drop)
180 °C
t-BuSONH2
O
O
Cl
Cl
78%
CuSO4, CH2Cl2
7
8
98%
X
5 (X = H)
6 (X = Cl)
Cl2, UV-light, CCl4
73%
Scheme 4 Synthesis of imine 8
Initial application of De Kimpe’s conditions (CH2Cl2,
–78 °C, 2 h)12 using BuMgCl (1.1 equiv) as a representa-
tive Grignard reagent led to complete consumption of imi-
ne 8 and cleanly gave chloroamine 9 (80%); however,
virtually no diastereoselectivity was observed (53:47, by
GC of crude reaction mixture). Diastereoselectivity was
not significantly improved by switching to THF as sol-
Biographical Sketches
David M. Hodgson ob- sons) and a research posi- he is now a Professor of
tained his first degree in tion at Schering, he was Chemistry. His research in-
Chemistry at Bath Universi- appointed in 1990 to a lec- terests are broadly in the de-
ty. After
a
Ph.D. at tureship at Reading Univer- velopment and application
Southampton University in sity. In 1995 he moved to of synthetic methods.
the field of natural product the Chemistry Department
synthesis (with P. J. Par- at Oxford University, where
Johannes Kloesges ob- which included a final-year ration with GlaxoSmith-
tained his first degree in project on aminohydroxyla- Kline, are concerned with
Chemistry at Oxford Uni- tion with Tim Donohoe. His aziridines.
versity (Oriel College), graduate studies, in collabo-
Brian Evans obtained his he joined Glaxo-Allenburys receptors
first degree in Chemistry at Research in 1977 and stayed ondansetron),
(sumatriptan,
adenosine
the University of Liverpool. with Glaxo under the vari- receptors, b-stimulants (ser-
After a research position at ous name changes. His re- event),
Allen & Hanburys, and a search activities have receptors,
neurokinin
combinatorial
Ph.D. at Liverpool on por- encompassed histamine H2 chemistry, and early-phase
phyrins (with K. M. Smith), blockers (zantac), serotonin drug discovery.
Synthesis 2009, No. 11, 1923–1932 © Thieme Stuttgart · New York

FEATURE ARTICLE
Terminal Aziridines from an (a-Chloro)sulfinylimine
1925
vent, or by the use of additives such as dioxane (potential-
ly driving the Schlenk equilibrium towards Bu2Mg), LiCl
(potential chelation of Li+ to N and Cl), or CeCl3, whereas
using BuLi simply resulted in decomposition of imine 8.
Nevertheless, allowing a reaction under the original con-
ditions to warm to room temperature did lead to ring-clo-
sure and isolation of terminal aziridine 10a in 78% yield
and unchanged diastereomeric ratio (51:49) (Scheme 5).
In De Kimpe’s study, imine 3 (R1 = Me) was reduced with
i-PrMgCl,12 whereas in the present work less-hindered
imine 8 efficiently gave aziridine 10b [81%, only traces of
the corresponding reduced imine, N-(2-chloroethyl)-tert-
butylsulfinamide,9 were detected], but the diastereoselec-
tivity (57:43 dr) remained similar to that seen with
BuMgCl. However, t-BuMgCl gave aziridine 10c (88%)
with significant diastereocontrol (94:6 dr) and PhMgBr
gave aziridine 10d (76%) with 83:17 dr.
Cl MgHal
R
H
H
Cl
Cl
S
(Mg)O
N
S
N
H
N
Mg
O
R
Mg
O R
Hal
Hal
TS-A
TS-B
TS-C
Figure 1 Possible transition states for addition of RMgHal to imine
(RS)-8
1) mesitylMgBr
t-BuMgCl
NBus 1)
S
O
N
PhMe, –78 °C,
then HCl,
2) KOH, then NaOH
t-Bu
(R)-2c 84%
2) MCPBA
Cl
(RS)-8
CS2
S
mesitylMgBr
mesitylMgBr
PhMe
–78 °C to r.t.
PhMe, –78 °C,
then HCl
HN
S
NSOt-Bu
NH3X–
Cl
1123 77%
10e 57%, >99:1 dr
NHSOt-Bu
NSOt-Bu
NSOt-Bu
RMgHal (1.1 equiv)
CH2Cl2, –78 °C to r.t.
BuMgCl
–78 °C
12 (X = Cl) 71%
13 (X– = picrate) 76%
aq NaOH, Et2O
then picric acid, C6H6
Cl
Cl
R
Bu
9
8
10a (R = Bu) 78%, 51:49 dr
10b (R = i-Pr) 81%, 57:43 dr
10c (R = t-Bu) 88%, 94:6 dr
10d (R = Ph) 76%, 83:17 dr
80%, 53:47 dr
Scheme 6 Addition of Grignard reagents to imine (RS)-8
During the course of our initial studies discussed above,
Crimmins and Shamszad reported in a synthesis of thiaz-
olidinethione 11 an isolated example of an addition to
imine (RS)-8, using mesitylmagnesium bromide (mesi-
tylMgBr, 5 equiv) at –78 °C in toluene and which
occurred with high/complete diastereoselectivity
(Scheme 6).23,24 While re-examination of the above three
alkyl Grignard reagents (5 equiv) with imine 8 in toluene
did not change the efficiency, or the magnitude (or sense)
of stereoinduction found for aziridine formation in
CH2Cl2, we were intrigued that Crimmins and Shamszad
had noted the opposite sense of asymmetric induction
with mesitylMgBr to that which we had determined with
t-BuMgCl. We confirmed the remarkable complete rever-
sal of asymmetric induction between these two hindered
Grignard reagents by X-ray crystallographic analysis of
picrate 13.25 Picrate 13 was derived from addition of mes-
itylMgBr to imine (RS)-8 with quenching at low tempera-
ture (the corresponding aziridine 10e was formed in 57%
yield and >99:1 dr if the reaction was allowed to warm to
room temperature), followed by counter-anion exchange
from the hydrochloride salt 12 (Scheme 6). Perhaps the
more sterically demanding mesityl group prevents coordi-
nation to the a-chloro group, resulting in reaction pro-
ceeding by way of TS-A (Figure 1).26
Scheme 5 Addition of Grignard reagents to imine 8
Repeating the reaction with t-BuMgCl, but using imine
(RS)-8 [prepared as before, but using commercially avail-
able (RS)-t-BuSONH2]19 provided an opportunity to both
study the viability of the desired subsequent sulfinyl to
sulfonyl oxidation step, as well as establish the predomi-
nant sense of asymmetric induction [as the specific rota-
tion of N-Bus aziridine (R)-2c is known].10d MCPBA has
previously been reported to oxidise 2,3-disubstituted N-
tert-butylsulfinyl aziridines to N-Bus aziridines,20 and in
the present case efficient oxidation of the sulfinyl aziri-
dine from t-BuMgCl and imine (RS)-8 gave N-Bus aziri-
dine (R)-2c (84%, Scheme 6), which illustrates
asymmetric access to synthetically valuable terminal N-
Bus aziridine functionality. The sense of asymmetric in-
duction found using imine 8 with t-BuMgCl is opposite to
that observed with non-functionalised tert-butylsulfinyl
aldimines, but parallels that observed in De Kimpe’s
study (and in most other reports concerning N-sulfinyl
imines containing a-coordinating groups).12,13 With non-
functionalised aldimines, the sense of asymmetric induc-
tion has been rationalised by invoking a chair-like transi-
tion state involving chelation of the incoming nucleophile
to the sulfinyl oxygen of the E-imine, with the sterically
demanding t-Bu group residing equatorial (TS-A,
Figure 1). To explain the reversal with a-coordinating
groups, it has been proposed that such groups either over-
ride sulfinyl oxygen chelation (TS-B),21 or additionally
chelate (TS-C),22 the latter only being possible following
to E- to Z-imine isomerisation under the reaction condi-
tions.
The addition of Grignard reagents to imine 8 furnished the
desired aziridines 10 in good yields. However, aside from
the significant diastereocontrol observed with the bulky
t-Bu and mesityl Grignard reagents, there was an obvious
shortfall in diastereoselectivity seen for the simple alkyl-
substituted aziridines and for which efficient asymmetric
access was a principal goal of the current study. Ellman
and co-workers, in their seminal studies on additions of
organometallics to simple N-tert-butylsulfinyl-substituted
aldimines, noted in a single example (8, Me instead of Cl)
Synthesis 2009, No. 11, 1923–1932 © Thieme Stuttgart · New York

1926
D. M. Hodgson et al.
FEATURE ARTICLE
that MeCeCl2 (THF, –78 °C) was inferior to MeMgBr nyl cerium reagents (entries 6–10). Entries 5, 6, 8, and 10
(CH2Cl2, –48 °C) with respect to diastereoselectivity illustrate the ability to carry additional functionality into
(78:22 compared with 97:3, respectively).27 However, en- the aziridine 10. Similarly to BuCeCl2, the absence of
couraged by Denmark and co-workers’ earlier report on 10% DMPU was shown to result in significantly lower
organocerium additions to SAMP-hydrazones,28 we ex- diastereomeric ratios for methyl-, allyl- and phenylcerium
amined BuCeCl2 (1.2 equiv) with imine 8 in THF or Et2O additions [83% yield (63:37 dr), 91% yield (85:15 dr), and
at –78 °C and were pleased to observe significant rises in 90% (70:30 dr), respectively].
diastereoselectivity (93:7 and 87:13, respectively); allow-
ing these reactions to warm to room temperature led to
MCPBA oxidation of sulfinyl aziridine 10f, formed from
addition of C10H21CeCl2 to imine (RS)-8 (Table 1, entry
ring-closure and isolation of terminal aziridine 10a in
3), gave known N-Bus aziridine (R)-2 (R = C10H21)10d
82% and 77% yield, respectively, and unchanged diaste-
(87%, 96:4 er by chiral HPLC); this result indicates the
reomeric ratios. The diastereoselectivity in THF could be
sense of asymmetric induction for reaction of
further improved to >99:1 (GC analysis) by addition of
C10H21CeCl2 with imine (RS)-8 is the same as that seen
earlier for t-BuMgCl. The same predominant sense of
asymmetric induction was also observed for phenylceri-
HMPA or DMPU,29 and warming to room temperature
gave terminal aziridine 10a in 83 and 86% yields, respec-
tively and in unchanged diastereomeric ratio (Table 1, en-
um and 4-chlorophenylcerium (Table 1, entry 8). For phe-
try 1). Use of 10% DMPU in THF also improved the
nylcerium, the absolute sense of asymmetric induction
diastereomeric ratio as reported by Ellman and co-work-
was established using imine (RS)-8 by chemical correla-
tion of sign of specific rotation following MCPBA oxida-
tion to the corresponding N-Bus phenyl aziridine (R)-2d,
ers in the addition of MeCeCl2 to imine 8 (Me instead of
Cl) from 78:22 (89% yield)27 to 96:4 (75% yield).
with the latter being also derived from (R)-phenylglycine
methyl ester hydrochloride (14) (Scheme 7). For 4-chlo-
Table 1 Aziridines 10 from a-Chloroimine 8 Using Organoceriums
NSOt-Bu
NSOt-Bu
RCeCl2
rophenylcerium, the relative stereochemistry of the major
diastereomer of sulfinylaziridine 10j was determined to
be RS*,R* by X-ray crystallographic analysis.30 As phe-
nylcerium was observed to give the same predominant
sense of asymmetric induction with imine 8 as was found
earlier with PhMgBr (Scheme 5), then [now knowing
both the absolute sense of asymmetric induction with phe-
nylcerium and with mesitylMgBr (Scheme 6)] this estab-
lishes that PhMgBr gives the opposite sense of
asymmetric induction to mesitylMgBr.
Cl
R
DMPU–THF (1:10)
–78 to 25 °C
8
10
Entry
Organocerium reagent
Aziridine Yield (%) dra
1
2
10a
10c
86
76
>99:1
>99:1
CeCl2
t-BuCeCl2
CeCl2
9
3b
10f
78
97:3
4
MeCeCl2
10g
10h
10i
81c
83
91:9
99:1
86:14
92:8
O
t-Bu
S
92%
92:8 dr
5
CeCl2
N
S
PhCeCl2
t-Bu
(RS,R)-10d
MCPBA, CH2Cl2
NBus
O
N
Ph
6
75c
92
DMPU–THF (1:10)
–78 to 25 °C
CeCl2
Cl
(RS)-8
7d
PhCeCl2
10d
CeCl2
X
8
10j
84
85:15
1) LiAlH4, THF
2) Ms2O, Et3N
Ph
CO2Me
Ph
Cl
CeCl2
85% from 10d
69% from 15
(R)-2d
14 (X = NH3Cl)
15 (X = NHBus)
9
10k
10l
81
82
92:8
1) t-BuSOCl, py
2) MCPBA, CH2Cl2
S
98%
10
85:15
Ph
CeCl2
Scheme 7 Determination of sense of asymmetric induction with
PhCeCl2 and imine (RS)-8
a By GC of crude reaction mixture.
b Using (RS)-8.
c Isolated as the corresponding N-Bus aziridine 2 following oxidation.
d Using HMPA instead of DMPU gave 10d in 93% yield, 92:8 dr.
The above chemistry was exemplified in the preparation
of highly enantioenriched unsaturated N-Bus terminal
aziridine (R)-2m (Scheme 8). Aziridine 2m has previous-
ly been shown to undergo the range of chemistry outlined
in Scheme 2, with (S)-2m being obtained by the epoxide
resolution strategy discussed earlier.10d Reaction of ho-
moallylcerium with imine (RS)-8 gave sulfinylaziridine
(RS,R)-10m (64%, 99:1 dr). While oxidation of sulfinyl-
aziridine (RS,R)-10m using MCPBA was complicated by
concomitant epoxidation, chemoselective oxidation at
The scope of this reaction was then examined with a range
of organocerium reagents (Table 1). The organocerium
reagents were prepared from the corresponding organo-
lithiums and CeCl3. Alkyl- and allylcerium reagents add-
ed with essentially complete diastereocontrol, with the
exception of MeCeCl2 (entries 1–5). The reaction was less
diastereoselective for alkenyl, aryl, heteroaryl, and alky-
Synthesis 2009, No. 11, 1923–1932 © Thieme Stuttgart · New York

FEATURE ARTICLE
Terminal Aziridines from an (a-Chloro)sulfinylimine
1927
t-Bu
minal N-Bus aziridine functionality in high enantiomeric
ratio, and that deprotection of a terminal N-tert-butylsulfi-
nyl aziridine can be achieved (and without erosion of
enantiopurity).
CeCl2
NSOt-Bu
S
O
N
DMPU–THF (1:10)
–78 to 25 °C
Cl
(RS,R)-10m 64%, 99:1 dr
(RS)-8
cat. TPAP
NMO, MeCN
40 °C
Reactions were performed in flame-dried glassware under an atmo-
sphere of dry argon. MeCN and CH2Cl2 were degassed and dried
over activated alumina under N2. THF was distilled from sodium
benzophenone ketyl in a continuous still under N2. DMPU and
HMPA were distilled from CaH2 and stored over CaH2 and 3 Å mo-
lecular sieves; all other reagents were used as received, unless indi-
cated otherwise. Flash column chromatography was performed with
silica gel (BDH, 0.040–0.063 mm or Machery-Nagel Kieselgel
60M). Petroleum ether (PE) refers to the fraction of petrol boiling
in the range of 30–40 °C. Melting points were obtained in capillary
tubes using a Griffin melting point apparatus and are uncorrected.
NBus
(R)-2m 72%
Scheme 8 Synthesis of unsaturated N-Bus aziridine (R)-2m
sulfur was achieved using using catalytic TPAP/NMO in
MeCN31 to give unsaturated N-Bus aziridine (R)-2m,
(72%). Similar conditions were found to be required for
oxidation of vinyl aziridine 10i (Table 1, entry 6).
T
Specific rotations [a]D were measured with a cell of path length
10.0 cm at T °C and are given in 10-1 deg cm2g-1 with concentrations
c given in g/100 mL. Gas chromatographic analysis was performed
using a Phenomenex Zebron ZB-5 high performance 5% polydi-
methylsiloxane column with He as carrier gas.
Although deprotection of several tert-butylsulfinyl azir-
idines have been reported, typically using HCl in dioxane,
in our hands these methods did not prove viable with ter-
minal aziridines.32–36 In particular, we sought deprotection
conditions for alkyl-substituted terminal aziridines with-
out degradation of enantiopurity.37 With decylaziridine
(RS,R)-10f as a representative substrate, other methods
previously reported for the deprotection of t-BuSO, Bus,
and tosyl amines/aziridines were also examined, but with-
out success;11,38 our attempts either resulted in no reaction
or decomposition of the starting aziridine. Finally, we
considered the use of HI, anticipating it to be both capable
of initiating deprotection by protonation on nitrogen39 and
SN2 ring-opening by iodide of any putative transient azir-
idinium ion(s), thus leading to an intermediate a-iodo hy-
droiodide, which could be ring-closed to the desired NH
Further details about instrumentation, techniques and experimental
details/characterisation data for aziridines not described below can
be found in the supporting information of ref. 14.
4-Chloro-1,3-dioxolan-2-one (6)17
A solution of 1,3-dioxolan-2-one 5 (Huntsman Ultrapure® 200 g,
2.27 mol) in CCl4 (300 mL) was irradiated with a sun-lamp (Osram
Ultra-Vitalux®, 300 W) and Cl2 gas was passed into the solution at
a rate slow enough for the reaction mixture to remain colourless. Af-
ter 5 h, 1H NMR analysis indicated a mixture comprising 4-chloro-
1,3-dioxolan-2-one (80%), 1,3-dioxolan-2-one (10%), and 4,5-
dichloro-1,3-dioxolan-2-one (10%). The solvent was removed un-
der reduced pressure and distillation of the residue (N2-bleed inlet)
gave the title compound [bp 96–98 °C/9 mbar (Lit.17 bp 130–
139 °C/39 Torr)] as a clear colourless liquid (203 g, 73%) in >95%
aziridine on subsequent addition of base. In line with this purity by 1H NMR spectrum.
1H NMR (400 MHz, CDCl3): d = 6.45 (dd, J = 5.7, 1.8 Hz, 1 H,
CHCl), 4.84 (dd, J = 10.3, 5.7 Hz, 1 H, CHH¢), 4.63–4.60 (m, 1 H,
CHH¢).
13C NMR (100 MHz, CDCl3): d = 152.4 (C=O), 85.3 (CHCl), 73.8
(CHH¢).
analysis, reaction of decylaziridine (RS,R)-10f with HI fol-
lowed by addition of aqueous KOH gave deprotected azir-
idine 16 in good yield and without any loss of
enantiointegrity (Scheme 9).
MS (CI): m/z (%) = 140.0 (100, [M + NH4]+).
HRMS-CI: m/z [M + NH4]+ calcd for C3H7ClNO3: 140.0114; found:
O
S
NH
N
t-Bu
HI, THF
C10H21
140.0116.
C10H21
then aq KOH
16
84%, 97:3 er
(RS,R)-10f
2-Chloroacetaldehyde (7)16
(97:3 dr)
Et3N (one drop) was added to 4-chloro-1,3-dioxolan-2-one (6; 7.35
g, 60 mmol) in a 25 mL round-bottomed flask equipped with a short
path distillation kit. After heating the reaction to 180 °C (oil-bath
temperature), distillation commenced and collection of the fraction
boiling between 87–89 °C (Lit.16b bp 84–86 °C/760 Torr) furnished
the title compound as a pale yellow-green liquid of acrid odour
(3.67 g, 78%). The material thus obtained was analytically pure by
1H NMR and 13C NMR analyses and was used without further puri-
fication.
Scheme 9 Deprotection of aziridine 10f
In conclusion, we have described the direct formation of
terminal N-tert-butylsulfinyl aziridines 10 from addition
of Grignard reagents or organoceriums to readily prepared
t-BuSONH2-derived N-(2-chloroethylidene)-tert-butyl-
sulfinamide (8). The reactions proceed in good yields and
(mainly with organoceriums) good diastereomeric ratios.
Oxidation at sulfur of terminal N-tert-butylsulfinyl azir-
idines 10, including selective oxidation in the presence of
unsaturation, provides terminal N-Bus aziridines 2 of
demonstrated10 synthetic utility. By using one of the com-
mercially available t-BuSONH2 enantiomers we have also
demonstrated that the chemistry provides an entry to ter-
IR (neat): 2967, 2360, 2341, 1826, 1430, 1348, 1061, 1017, 763
cm–1.
1H NMR (250 MHz, C6D6): d = 8.92 (br t, 1 H, CHO), 3.38 (br d, 2
H, CH2Cl).
13C NMR (100 MHz, CDCl3): d = 193.3 (CHO), 48.6 (CH2Cl).
MS (FI): m/z (%) = 77.9 (100, [M]+).
Synthesis 2009, No. 11, 1923–1932 © Thieme Stuttgart · New York

1928
D. M. Hodgson et al.
FEATURE ARTICLE
HRMS-FI: m/z [M]+ calcd for C2H3Cl: 77.9872; found: 77.9874.
pale yellow oil (0.16 g, 78%, 51:49 dr by GC); Rf = 0.45 (PE–Et2O,
4:1).
N-(2-Chloroethylidene)-2-methylpropane-2-sulfinamide (8)23
To a solution of t-BuSONH2 (3.64 g, 20 mmol) and anhyd CuSO4
(9.58 g, 60 mmol) in CH2Cl2 (300 mL) was added dropwise anhyd
2-chloroacetaldehyde (7; 1.88 g, 24 mmol). After complete con-
sumption of the t-BuSONH2 (~8 h, TLC monitoring), the reaction
mixture was filtered through a pad of Celite® and the filter cake
washed with CH2Cl2 (4 × 20 mL). Evaporation of the solvent in
vacuo afforded the title compound (3.57 g, 98%) as a pale yellow
oil. The material thus obtained, pure by 1H and 13C NMR analyses,
was used without further purification; Rf = 0.28 (PE–Et2O, 2:1).
IR (neat): 2958, 2930, 2962, 1458, 1398, 1260, 1080, 923, 869, 628
cm–1.
1H NMR (400 MHz, CDCl3): d (RS*,R*) = 2.56 (d, J = 6.7 Hz, 1 H,
CHH¢), 2.06–2.04 (m, 1 H, CHN), 1.63 (d, J = 4.1 Hz, 1 H, CHH¢),
1.51–1.22 (m, 6 H, CH2CH2CH2CH3), 1.21 [s, 9 H, C(CH3)3], 0.90
(br t, 3 H, CH3); d (RS*,S*) = 2.64–2.61 (m, 1 H, CHN), 2.01 (d,
J = 6.7 Hz, 1 H, CHH¢), 1.81 (d, J = 3.9 Hz, 1 H, CHH¢), 1.51–1.22
(m, 6 H, CH2CH2CH2CH3), 1.19 [s, 9 H, C(CH3)3], 0.90 (br t, 3 H,
CH3).
13C NMR (100 MHz, CDCl3): d (RS*,R*) = 56.9 [C(CH3)3], 33.5
(CHN), 31.5 (CH2N), 28.8 (CH2CH2CH2CH3), 25.0
(CH2CH2CH2CH3), 22.7 [C(CH3)3], 22.4 (CH2CH2CH2CH3), 13.9
(CH2CH2CH2CH3); d (RS*,S*) = 56.3 [C(CH3)3], 30.6 (CHN), 28.8
(CH2CH2CH2CH3), 28.0 (CH2N), 25.0 (CH2CH2CH2CH3), 22.6
[C(CH3)3], 22.2 (CH2CH2CH2CH3), 13.9 (CH2CH2CH2CH3).
MS (ESI): m/z (%) = 203.9 (100, [M + H]+).
HRMS-ESI: m/z [M + Na]+ calcd for C10H21NOS + Na: 226.1236;
IR (neat): 2963, 1831, 1623, 1475, 1364, 1253, 1091, 720, 657, 582
cm–1.
1H NMR (200 MHz, CDCl3): d = 8.02 (s, 1 H, CHN), 4.32 (d,
J = 4.6 Hz, 2 H, CHCl), 1.21(s, 9 H, t-C4H9).
13C NMR (100 MHz, CDCl3): d = 162.3 (CHN), 57.3 [C(CH3)3],
43.4 (CH2Cl), 22.2 [C(CH3)3].
MS (CI): m/z (%) = 199.1 (100, [M + NH4]+), 182.3 (60, [M + H]+).
HRMS-CI: m/z [M + NH4]+ calcd for C6H16ClN2OS: 199.0672;
found: 226.1234.
found: 199.0676.
1-(tert-Butylsulfinyl)-2-isopropylaziridine (10b)
(RS)-N-(2-Chloroethylidene)-2-methylpropane-2-sulfinamide
[(RS)-8]
Prepared according to Typical Procedure A, using i-PrMgCl (2.0 M
in THF, 0.55 mL, 1.1 mmol); purification by column chromatogra-
phy (SiO2, PE–Et2O, 5:1) gave aziridine 10b as a pale yellow oil
(0.153 g, 81%, 57:43 dr by GC); Rf = 0.45 (PE–Et2O, 4:1).
Prepared as above, but using (RS)-t-BuSONH2 (Aldrich, 98% ee);
[a]D22 –351.1 (c 2.00, CHCl3) {Lit.23 [a]D27 –295 (c 2.90, CH2Cl2)}.
IR (neat): 2960, 2935, 1455, 1383, 1265, 1263, 1084, 941, 872, 642
cm–1.
N-(1-Chlorohexan-2-yl)-2-methylpropane-2-sulfinamide (9)
BuMgCl (20 wt% in THF–toluene, 0.64 mL, 1.1 mmol) was added
dropwise to a stirred solution of imine 8 (0.18 g, 1 mmol) in CH2Cl2
(5 mL) at –78 °C and the reaction mixture stirred for 2 h, then
quenched with MeOH (5 mL) and warmed to r.t. Sat. aq NH4Cl (10
mL) was added and, after extracting the aqueous layer with Et2O
(2 × 10 mL), the combined organic layers were washed with H2O
(2 × 15 mL) and brine (15 mL), dried (Na2SO4), and evaporated in
vacuo. Purification of the residue by column chromatography
(SiO2, PE–EtOAc, 2:1) gave the title compound as a pale yellow oil
(0.19 g, 80%, 53:47 dr by GC); Rf = 0.40 (PE–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): d = 2.58–2.55 (m, 1 H, CHN), 2.54 (d,
J = 6.7 Hz, 1 H, CHH¢), 1.90 (d, J = 6.9 Hz, 1 H, CHH¢), 1.90 (d,
J = 4.3 Hz, 1 H, CHH¢), 1.86–1.81 (m, 1 H, CHN), 1.67 (d, J = 4.1
Hz, 1 H, CHH¢), 1.52–1.34 (m, 2 H, CH), 1.20 [s, 9 H, C(CH3)3],
1.19 [s, 9 H, C(CH3)3], 1.01–0.79 [m, 12 H, CH(CH3)2].
13C NMR (100 MHz, CDCl3): d = 56.9 and 56.2 [C(CH3)3], 39.3 and
36.2 (CHN), 30.3 and 27.6 (CH), 25.1 and 24.0 (CH2N), 22.7 and
22.5 [C(CH3)3], 20.2, 19.3, 18.9, and 17.1 (CH3).
MS (CI): m/z (%) = 190.1 (100, [M + H]+).
HRMS-CI: m/z [M + H]+ calcd for C9H20NOS: 190.1266; found:
IR (neat): 3171, 2958, 2932, 2871, 1530, 1458, 1391, 1306, 1195,
1134, 1043, 931, 895 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.91–3.60 (m, 6 H, CH2Cl and
CH), 3.51–3.48 (m, 1 H, NH), 3.36 (d, J = 5.9 Hz, 1 H, NH), 1.81–
1.26 (m, 12 H, CH2CH2CH2), 1.23 [s, 9 H, C(CH3)3], 1.22 [s, 9 H,
C(CH3)3], 0.92–0.88 (m, 6 H, CH3).
13C NMR (100 MHz, CDCl3): d = 57.2 and 56.9 (CHN), 56.2 and
56.1 [C(CH3)3], 49.9 and 48.8 (CH2Cl), 31.9 and 32.9
(CHNCH2CH2CH2), 27.8 and 27.8 (CHNCH2CH2CH2), 22.6 and
22.4 [C(CH3)3], 22.3 and 22.3 (CHNCH2CH2CH2), 14.0 and 13.9
(CH3).
190.1258.
2-tert-Butyl-1-(tert-butylsulfinyl)aziridine (10c)
Prepared according to Typical Procedure A, using t-BuMgCl (2.0 M
in Et2O, 0.55 mL, 1.1 mmol); purification by column chromatogra-
phy (SiO2, PE–Et2O, 4:1 with 3% Et3N) gave aziridine 10c as a pale
yellow oil (0.17 g, 88%, 94:6 dr by GC); Rf = 0.3 (PE–Et2O, 4:1).
IR (neat): 2963, 2935, 1451, 1388, 1265, 1087, 943, 859, 640 cm–1.
1H NMR (400 MHz, CDCl3): d [major (RS*,R*)] = 2.46 (d, J = 6.8
Hz, 1 H, CHH¢), 1.89 (dd, J = 6.8, 4.3 Hz, 1 H, CHN), 1.73 (d,
J = 4.3 Hz, 1 H, CHH¢), 1.19 [s, 9 H, SOC(CH3)3], 0.87 [s, 9 H,
C(CH3)3]; d [discernible data for minor (RS*,S*)] = 1.20 [s, 9 H,
SOC(CH3)3], 0.91 [s, 9 H, C(CH3)3].
MS (CI): m/z (%) = 240.1 (100, [M + H]+).
HRMS-CI: m/z [M + H]+ calcd for C10H23ClNOS: 240.1187; found:
240.1189.
13C NMR (100 MHz, CDCl3): d (RS*,R*) = 57.0 [SOC(CH3)3], 41.9
[C(CH3)3], 30.0 (CHN), 26.1 (CH2N), 22.6 [C(CH3)3], 22.0
[SOC(CH3)3]; d (RS*,S*) = 56.0 [SOC(CH3)3], 42.3 [C(CH3)3], 29.4
(CHN), 25.2 (CH2N), 22.5 [C(CH3)3], 21.9 [SOC(CH3)3].
MS (CI): m/z (%) = 204.2 (100, [M + H]+).
HRMS-ESI: m/z [M + H]+ calcd for C10H22NOS: 204.1422; found:
Aziridines 10 from Grignard Reagents; 2-Butyl-1-(tert-butyl-
sulfinyl)aziridine (10a); Typical Procedure A
BuMgCl (20 wt% in THF–toluene, 0.64 mL, 1.1 mmol) was added
dropwise to a stirred solution of imine 8 (0.18 g, 1 mmol) in CH2Cl2
(5 mL) at –78 °C and the reaction mixture was allowed to warm to
r.t. overnight. Sat. aq NH4Cl (10 mL) was added and after extracting
the aqueous layer with Et2O (2 × 10 mL), the combined organic lay-
ers were washed with H2O (2 × 15 mL) and brine (15 mL), dried
(MgSO4), and evaporated in vacuo. Purification of the residue by
column chromatography (SiO2, PE–Et2O, 4:1) gave aziridine 10a as
204.1421.
(R)-2-tert-Butyl-1-(tert-butylsulfonyl)aziridine [(R)-2c]10d
MCPBA (0.38 g, 2.2 mmol) was added to a solution of sulfinyl azir-
idine 10c (prepared according to the Typical Procedure A from im-
Synthesis 2009, No. 11, 1923–1932 © Thieme Stuttgart · New York

FEATURE ARTICLE
Terminal Aziridines from an (a-Chloro)sulfinylimine
1929
ine (RS)-8, 0.29 g, 1.0 mmol) in CH2Cl2 (10 mL). After 3 h, sat. aq
NaHSO3 (10 mL) was added and the reaction mixture stirred for 15
min; the layers were separated and the aqueous phase extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were washed
with H2O (10 mL), sat. aq NaHCO3 (10 mL) and brine (10 mL),
dried (MgSO4), and concentrated in vacuo. Purification of the resi-
due by column chromatography (PE–Et2O, 5:1) gave N-Bus azir-
1H NMR (500 MHz, acetone-d6): d = 8.70 (s, 2 H, picrate CH), 6.97
(s, 2 H, Mes CH), 5.67 (dd, J = 10.3, 4.4 Hz, 1 H, CHN), 4.46–4.41
(m, 1 H, CHH¢), 4.04 (dd, J = 12.4, 4.4 Hz, 1 H, CHH¢), 2.45 (s, 6
H, o-CH3), 2.25 (s, 3 H, p-CH3).
13C NMR (126 MHz, acetone-d6): d = 162.3 (CO), 143.2 (p-CNO2),
140.1 (o-CNO2), 139.9 (br, quat), 137.6 [o-C(CH3)], 131.8 [p-
C(CH3)], 129.1 (Mes CH), 126.1 (picrate CH), 63.3 (CHN), 43.9
(CH2Cl), 20.4 (o-CH3), 20.3 (p-CH3).
25
idine (R)-2c (0.19 g, 84%) as a clear, colourless oil; [a]D –81.0
(c 1.00, CHCl3) {Lit.10d for pure (R): [a]D25 –87.5 (c 1.00, CHCl3)};
Rf = 0.3 (SiO2, PE–Et2O, 5:1).
(S)-1-[(R)-tert-Butylsulfinyl]-2-mesitylaziridine (10e)
1H NMR (400 MHz, CDCl3): d = 2.64 (dd, J = 7.1, 4.8 Hz, 1 H,
CHN), 2.49 (dd, J = 7.0 Hz, 1 H, CHH¢), 2.19 (d, J = 4.8 Hz, 1 H,
CHH¢), 1.50 [s, 9 H, SO2C(CH3)3], 0.95 [9 H, s, C(CH3)3].
13C NMR (100 MHz, CDCl3): d = 59.4 [SO2C(CH3)2], 45.0
[C(CH3)3], 32.9 (CHN), 30.3 (CH2N), 26.3 [SO2C(CH3)2], 24.3
[C(CH3)3].
MS (CI): m/z (%) = 220.1 (100, [M + H]+).
HRMS-CI: m/z [M + H]+ calcd for C10H22NO2S: 220.1371; found:
To a solution of imine (RS)-8 (0.55 g, 3 mmol) in toluene (15 mL)
at –78 °C was added mesitylene magnesium bromide (1.0 M in
Et2O, 15 mL, 15 mmol), and the reaction mixture slowly warmed to
r.t. overnight. After quenching with MeOH (5 mL), then aq HCl (1
M, 5 mL), and partitioning, the aqueous layer was extracted with
Et2O (3 × 15 mL), and the combined organic layers washed with
H2O (2 × 20 mL) and brine (20 mL), dried (MgSO4), and concen-
trated in vacuo. Column chromatography (SiO2, PE–Et2O, 6:1) of
the residue gave the title compound as a pale yellow oil (0.45 g,
57%); [a]D25 +74.1 (c 1.00, CHCl3); Rf = 0.6 (PE–Et2O, 3:1).
220.1370.
IR (neat): 2960, 2923, 2733, 1612, 1573, 1475, 1456, 1376, 1260,
1189, 1084, 1030, 958, 851, 802, 739 cm–1.
1H NMR (500 MHz, C6D6): d = 6.67 (s, 2 Harom), 3.84, (br s, 1 H,
CHN), 2.36 (s, 6 H, o-CH3), 2.02 (s, 3 H, p-CH3), 2.00 (br d, 2 H,
CH2), 1.06 [s, 9 H, C(CH3)3].
13C NMR (126 MHz, C6D6): d = 138.2 (br, quat), 137.1 [br, o-
C(CH3)], 130.8 [br, p-C(CH3)3], 130.7 (CH), 56.4 [C(CH3)3], 29.2
(br, CHN), 22.6 (br, CH2), 22.5 [C(CH3)3], 20.8 (p-CH3), 20.3 (o-
CH3).
(S)-2-Chloro-1-mesitylethanaminium Chloride (12)
To a solution of imine (RS)-8 (0.55 g, 3 mmol) in toluene (15 mL)
at –78 °C was added mesitylene magnesium bromide (1.0 M in
Et2O; 15 mL, 15 mmol); the reaction mixture stirred for 3 h,
quenched with MeOH (5 mL) and warmed to r.t. After addition of
aq HCl (6 M, 5 mL) and stirring for 3 h, the mixture was partitioned,
washed with Et2O (10 mL), and 15% aq NaOH added to the aqueous
layer until pH 11. The aqueous layer was extracted with EtOAc
(3 × 20 mL) and the combined organic layers dried (Na2SO4), con-
centrated in vacuo, dissolved in ice-cold dioxane (10 mL), treated
with HCl gas until pH 1, stirred for 10 min, and concentrated in
vacuo. Recrystallisation of the residue from boiling hexane–chloro-
form gave the title compound as an off-white, crystalline solid (0.49
g, 71%); mp 176–177 °C; [a]D25 +13.7 (c 1.00, CHCl3).
MS (CI): m/z (%) = 266.2 (100, [M + H]+).
HRMS-CI: m/z [M + H]+ calcd for C15H24NOS: 266.1579; found:
266.1577.
Anhydrous CeCl3 Slurry for Organocerium Reagents
CeCl3·7H2O (Aldrich 99.999%, 0.45 g, 1.2 mmol) was placed in a
Schlenk flask equipped with an ellipsoid stirrer bar fitted exactly to
the inner diameter of the flask. After connection to high vacuum
(<0.1 mbar), the flask was heated at 165 °C for 2 h (oil-bath temper-
ature) with slight stirring; the anhyd CeCl3 should be a snow-white,
fine powder. The Schlenk flask was then disconnected from the vac-
uum, filled with argon whilst still hot and allowed to cool to r.t. Af-
ter addition of anhyd THF (7 mL), the suspension was vigorously
stirred for 2 h and employed in Typical Procedure B, described be-
low.
IR (KBr): 3374, 3209, 2973, 1657, 1559, 1475, 1442, 1392, 1161,
1033, 943, 767 cm–1.
+
1H NMR (500 MHz, CDCl3): d = 9.06 (br s, 3 H, NH3 ), 6.89 (s, 2
Harom), 4.93 (dd, J = 6.3, 2.7 Hz, 1 H, CHN), 4.24 (dd, J = 11.9, 2.9
Hz, 1 H, CHH¢), 3.82 (dd, J = 11.9, 5.7 Hz, 1 H, CHH¢), 2.44 (s, 6
H, o-CH3), 2.26 (s, 3 H, p-CH3).
13C NMR (126 MHz, CDCl3): d = 139.2 (quat), 136.6 [br, o-
C(CH3)], 130.1 [br, p-C(CH3)], 126.8 (CH), 53.2 (CHN), 43.2
(CH2Cl), 21.4 (br, o-CH3), 20.8 (p-CH3).
(S)-2-Chloro-1-mesitylethanaminium 2,4,6-trinitrophenolate
(13)
Aziridines 10 from Organoceriums; 2-Butyl-1-(tert-butylsulfi-
nyl)aziridine (10a); Typical Procedure B
A solution of 12 (0.09 g, 0.4 mmol) in Et2O (5 mL) was adjusted to
pH 12 with 15% aq NaOH and vigorously stirred for 10 min. After
partitioning, and extraction of the aqueous layer with EtOAc
(2 × 10 mL), the combined organic layers were dried (Na2SO4), and
concentrated in vacuo. The residual oil was dissolved in benzene (3
mL) and a dry sat. soln of picric acid in benzene [picric acid (1.5 g)
was dissolved in benzene (25 mL) with gentle warming and the re-
sulting, bright yellow solution dried (MgSO4), filtered and used im-
mediately] added dropwise, until no further precipitation occurred
(pH 2). The precipitated yellow crystals were collected by filtration,
washed with cold benzene and dried in vacuo. Recrystallisation
from boiling benzene–hexane gave the title compound as an in-
tensely yellow, crystalline solid (0.13 g, 76%). A single crystal suit-
able for X-ray crystallographic analysis25 was grown by slow
n-BuLi (1.6 M in hexanes, 0.75 mL, 1.2 mmol) in THF (5 mL) was
added dropwise to a stirred slurry of anhyd CeCl3 (0.30 g, 1.2 mmol,
prepared as described above) in THF (7 mL) at –78 °C under argon.
After 45 min, DMPU (1.5 mL) was added, followed after 15 min by
a solution of imine 8 (0.18 g, 1 mmol) in THF (3 mL) and the reac-
tion mixture was then allowed to warm to r.t. overnight. Sat. aq
NH4Cl (10 mL) and Et2O (5 mL) were added, the mixture filtered
through a pad of Celite and the filter cake washed thoroughly with
Et2O (3 × 10 mL). The combined organic layers were washed with
H2O (2 × 15 mL) and brine (15 mL), dried (MgSO4), and evaporat-
ed in vacuo. Purification by column chromatography (SiO2, PE–
Et2O, 4:1) afforded the title compound as pale yellow oil (0.18 g,
86%, >99:1 dr by GC); Rf = 0.3 (PE–Et2O, 4:1).
25
evaporation of a CHCl3–MeOH solution; mp 189–190 °C; [a]D
+15.0 (c 1.00, MeOH).
IR (neat): 2958, 2930, 2962, 1458, 1398, 1260, 1080, 923, 869, 628
cm–1.
IR (KBr): 2973, 1612, 1567, 1536, 1428, 1362, 1320, 1272, 1164,
1081, 914, 702, 648 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.61 (d, J = 6.7 Hz, 1 H, CHN),
2.05–2.04 (m, 1 H, CHH¢), 1.65 (d, J = 4.1 Hz, 1 H, CHH¢), 1.41–
Synthesis 2009, No. 11, 1923–1932 © Thieme Stuttgart · New York

1930
D. M. Hodgson et al.
FEATURE ARTICLE
1.22 [m, 15 H, C(CH3)3 and CH2CH2CH2CH3], 0.92 (br t, 3 H,
CH2CH2CH2CH3).
13C NMR (63 MHz, CDCl3): d = 57.0 [C(CH3)3], 33.6 (CHN), 31.6
(CH2N), 28.8 (CH2CH2CH2CH3), 25.1 (CH2CH2CH2CH3), 22.8
[C(CH3)3], 22.3 (CH2CH2CH2CH3), 14.0 (CH2CH2CH2CH3).
MS (ESI): m/z (%) = 203.9 (100, [M + H]+).
HRMS-ESI: m/z [M + Na]+ calcd for C10H21NOS + Na: 226.1236;
(R)-1-[(R)-tert-Butylsulfinyl]-2-phenylaziridine [(RS,R)-10d]
PhLi (2.0 M in Bu2O, 0.6 mL, 1.2 mmol) and imine (RS)-8 were re-
acted following Typical Procedure B. Purification by column chro-
matography (SiO2, PE–Et2O, 4:1) afforded the title compound as a
colourless oil (0.21 g, 92%, 92:8 dr by GC), which solidified upon
20
standing; mp 54–55 °C; [a]D25 –313.1 (c 0.80, CHCl3) {Lit.40 [a]D
–320.0 (c 0.5, CHCl3); Lit.34 [a]D –335.0 (c 0.6, CHCl3)}; Rf = 0.32
(PE–Et2O, 4:1).
IR (KBr): 2927, 1461, 1308, 1216, 1130, 865, 709 cm–1.
found: 226.1234.
1H NMR (500 MHz, CDCl3): d [major (RS,R)] = 7.34–7.25 (m, 5
1-(tert-Butylsulfonyl)-2-methylaziridine (2; R = Me)
Harom), 3.11–3.09 (m, 1 H, CHN), 2.98 (d, J = 6.8 Hz, 1 H, CHH¢),
MeLi (1.6 M in Et2O, 0.75 mL, 1.2 mmol) was used following Typ-
ical Procedure B. GC-MS analysis indicated the formation of
1-(tert-butylsulfinyl)-2-methylaziridine (10g) in 91:9 dr, which was
immediately oxidised to 2 (R = Me) as follows. Crude sulfinyl azir-
idine 10g was dissolved in CH2Cl2 (5 mL), cooled to 0 °C and
MCPBA (0.46 g, 3 mmol) added. After warming to r.t., and stirring
for 4 h, the reaction was quenched with sat. aq NaHSO3 (10 mL),
partitioned, and the aqueous layer extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were washed with sat. aq
NaHCO3 (20 mL), H2O (20 mL) and brine (20 mL), dried (MgSO4),
and concentrated in vacuo. Column chromatography (SiO2, PE–
Et2O, 3:1) provided the title compound as a clear, colourless oil
(0.14 g, 81%); Rf = 0.3 (PE–Et2O, 3:1).
1.99 (d, J = 4.0, 1 H, CHH¢), 1.28 [s, 9 H, C(CH3)3]; d [discernible
data for minor (RS,S)] = 3.60–3.59 (m, 1 H, CHN), 2.44 (d, J = 6.8
Hz, 1 H, CHH¢), 2.16 (d, J = 4.0 Hz, 1 H, CHH¢), 1.16 [s, 9 H,
C(CH3)3].
13C NMR (126 MHz, CDCl3): d [major (RS,R)] = 137.7 (quat),
128.4 (quat), 127.7, 126.3 (arom), 57.4 [C(CH3)3], 34.8 (CHN),
28.7 (CH2N), 22.8 [C(CH3)3]; d [discernible data for minor
(RS,S)] = 56.9 [C(CH3)3], 31.9 (CHN), 31.4 (CH2N).
MS (CI): m/z (%) = 224.1 (100, [M + H]+).
HRMS-CI: m/z [M + H]+ calcd for C12H18NOS: 224.1109; found:
224.1110.
IR (neat): 2973, 1657, 1559, 1475, 1442, 1394, 1161, 1091, 1033,
943, 767 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.81 (m, 1 H, CHN), 2.64 (d,
J = 7.0 Hz, 1 H, CHH¢), 2.15 (d, J = 4.6 Hz, 1 H, CHH¢), 1.48 [s, 9
H, C(CH3)3], 1.42 (m, 3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 59.7 [C(CH3)3], 39.6 (CHN), 33.7
(CH2N), 24.2 [C(CH3)3], 21.8 (CH3).
MS (CI): m/z (%) = 178.1.1 (100, [M + H]+).
(R)-1-(tert-Butylsulfonyl)-2-phenylaziridine (2d)
MCPBA (0.38 g, 2.2 mmol) was added to a solution of sulfinyl azir-
idine (RS,R)-10d (0.24 g, 1.0 mmol) in CH2Cl2 (10 mL). After 3 h,
sat. aq NaHSO3 (10 mL) was added and the reaction mixture stirred
for 15 min; the layers were separated and the aqueous phase extract-
ed with CH2Cl2 (3 × 10 mL). The combined organic layers were
washed with H2O (10 mL), sat. aq NaHCO3 (10 mL) and brine (10
mL), dried (MgSO4), and concentrated in vacuo. Purification of the
residue by column chromatography (PE–Et2O, 10:1) gave N-Bus
aziridine 2d as a clear, colourless oil (0.20 g, 85%); [a]D25 –165.0
(c 0.50, CHCl3) {Lit.41 (>98% ee, R) [a]D25 –184.5 (c 1.0, CHCl3)}.
HRMS-CI: m/z [M + H]+ calcd for C7H16NO2S: 178.0902; found:
178.0898.
IR (KBr): 2956, 2933, 1466, 1308, 1216, 1130, 950, 865, 709 cm–1.
1-(tert-Butylsulfonyl)-2-vinylaziridine (2; R = vinyl)
1H NMR (500 MHz, CDCl3): d = 7.36–7.29 (m, 5 Harom), 3.63 (dd,
J = 7.1, 4.4 Hz, 1 H, CHN), 2.97 (d, J = 7.2 Hz, 1 H, CHH¢), 2.36
(d, J = 4.4 Hz, 1 H, CHH¢), 1.47 [s, 9 H, C(CH3)3].
13C NMR (126 MHz, CDCl3): d = 135.3 (quat), 128.7 (p-CH), 128.3
(CH), 126.3 (CH), 59.4 [C(CH3)3], 41.5 (CHN), 34.7 (CH2N), 24.1
[C(CH3)3].
MS (CI): m/z (%) = 257.1 (100, [M + NH4]+), 240.1 (80, [M + H]+).
HRMS-CI: m/z [M + H]+ calcd for C12H18NO2S: 240.1058; found:
Freshly distilled tributyl(vinyl)stannane (0.46 g, 1.5 mmol) in Et2O
(5 mL) was cooled to –78 °C in a Schlenk flask and n-BuLi (1.6 M
in hexanes, 0.94 mL, 1.5 mmol) added dropwise. After stirring for
1 h, the temperature was elevated to r.t. and the mixture stirred for
a further 2 h, the solvent concentrated in vacuo, and the residue con-
taining vinyllithium dissolved in THF (4 mL) and used immediately
following Typical Procedure B. GC-MS analysis indicated the for-
mation of 1-(tert-butylsulfinyl)-2-vinylaziridine (10i) in 86:14 dr,
which was immediately oxidised to aziridine 2 (R = vinyl) as fol-
lows. Crude sulfinyl aziridine 10i was dissolved in anhyd MeCN (5
mL) and, after the addition of NMO (0.35 g, 3 mmol), crushed 4 Å
molecular sieves (0.75 g) and TPAP (0.035 g, 10 mol%), heated to
40 °C overnight. The mixture was cooled to r.t. and concentrated
onto silica gel. Column chromatography (SiO2, PE–Et2O, 5:1) pro-
vided the title compound as a clear, colourless oil (0.16 g, 75%);
Rf = 0.3 (PE–Et2O, 5:1).
240.1057.
Methyl (R)-2-(1,1-Dimethylethylsulfonamido)-2-phenylacetate
(15)
t-Butylsulfinyl chloride (1.41 mL, 10 mmol) was added to a solu-
tion of (R)-phenylglycine methyl ester hydrochloride (14; 2.02 g, 10
mmol) in anhyd pyridine (25 mL) and the mixture stirred overnight.
After the addition of EtOAc (50 mL), and adjusting to pH 5 using
aq 5 M HCl, the aqueous layer was extracted with EtOAc (3 × 15
mL). The combined organic layers were washed with aq 2 m HCl
(30 mL), sat. aq CuSO4 (20 mL), H2O (30 mL) and brine (30 mL),
dried (MgSO4), and concentrated in vacuo. To an ice-cold solution
of the residue in CH2Cl2 (50 mL) was added MCPBA (3.45 g, 20
mmol) and mixture stirred for 6 h. After quenching with sat. aq
NaHSO3 (30 mL), the aqueous layer was extracted with Et2O
(3 × 15 mL) and the combined organic layers were washed with
15% aq NaOH (25 mL), H2O (25 mL) and brine (25 mL), dried
(MgSO4), and concentrated in vacuo to yield the title compound as
a white crystalline solid, which was used without further purifica-
tion (2.80 g, 98%); mp 139–140 °C; [a]D25 –102.6 (c 0.50, CHCl3).
IR (neat): 2374, 2256, 2140, 1307, 1130, 933, 842, 742, 690 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.61–5.51 (m, 2 H, C=CHH¢),
5.34–5.31 (m, 1 H, CH=CHH¢), 3.17 (ddd, J = 7.1, 4.4, 2.6 Hz, 1 H,
CHN), 2.77 (d, J = 7.1 Hz, 1 H, CHH¢), 2.22 (d, J = 4.4 Hz, 1 H,
CHH¢).
13C NMR (100 MHz, CDCl3): d = 133.6 (CH2=CH), 120.4
(CH2=CH), 59.3 [C(CH3)3], 41.5 (CHN), 32.5 (CH2N), 24.1
[C(CH3)3].
MS (CI): m/z (%) = 190.1 (100, [M + H]+).
HRMS-ESI: m/z [M + H]+ calcd for C8H16NO2S: 190.0902; found:
190.0899.
Synthesis 2009, No. 11, 1923–1932 © Thieme Stuttgart · New York

FEATURE ARTICLE
Terminal Aziridines from an (a-Chloro)sulfinylimine
1931
IR (KBr): 3410, 2980, 2913, 1709, 1466, 1308, 1216, 1130, 1051,
950, 893, 865, 709 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.38–7.35 (m, 5 Harom), 5.28 (d,
J = 8.8 Hz, 1 H, NH), 5.22 (d, J = 8.8 Hz, 1 H, CH), 3.75 (s, 3 H,
CH3), 1.30 [s, 9 H, C(CH3)3].
mixture was cooled to r.t. and concentrated onto SiO2. Column
chromatography (PE–Et2O, 5:1) provided the title compound as a
25
clear, colourless oil (0.10 g, 72%); [a]D –51.9 (c 1.0, CHCl3)
{Lit.10d pure S: [a]D25 +66.9 (c 1.0, CHCl3); Rf = 0.3 (PE–Et2O, 5:1).
IR (neat): 2982, 2932, 1641, 1455, 1366, 1130, 914, 870, 712 cm–1.
13C NMR (100 MHz, CDCl3): d = 171.6 (CO2CH3), 136.6 (quat),
129.0 (p-CH), 128.7 (CH), 127.1 (CH), 60.0 [C(CH3)3], 53.1
(CO2CH3), 24.0 [C(CH3)3].
MS (CI): m/z (%) = 303.1 (100, [M + NH4]+), 286.1 (20, [M + H]+).
HRMS-CI: m/z [M + NH4]+ calcd for C13H23N2O4S: 303.1379;
1H NMR (400 MHz, CDCl3): d = 5.83 (ddt, J = 10.4, 6.6, 3.6 Hz, 1
H, CH=CHH¢), 5.10–5.00 (m, 2 H, CH=CHH¢), 2.78–2.72 (m, 1 H,
CHN), 2.59 (d, J = 7.1 Hz, 1 H, CHH¢N), 2.23–2.19 (m, 2 H,
CH2CH2CH=CHH¢), 2.09 (d, J = 4.5 Hz, 1 H, CHH¢N), 1.77–1.55
(m, 2 H, CH2CH2CH=CHH¢), 1.49 [s, 9 H, C(CH3)3].
13C NMR (100 MHz, CDCl3): d = 137.1 (CH=CHH¢), 115.5
(CH=CHH¢), 59.2 [C(CH3)3], 37.7 (CHN), 34.2 (CH2N), 30.7
(CH2CH2CH=CHH¢), 30.6 (CH2CH2CH=CHH¢), 24.2 [C(CH3)3].
found: 303.1386.
(R)-1-(tert)-Butylsulfonyl-2-phenylaziridine (2d)
To and ice-cold solution of ester 15 in THF (30 mL) was added
LiAlH4 (0.76 g, 20 mmol) in small portions, and the reaction mix-
ture then stirred overnight while allowing to warm to r.t. After cool-
ing to 0 °C, the reaction was quenched with H2O (0.8 mL), 15% aq
NaOH (0.8 mL) and H2O (2.5 mL), the suspension filtered through
a pad of Celite® and the filter cake washed with EtOAc (3 × 50 mL).
The filtrate, combined with the washings was concentrated in vac-
uo. To an ice-cold solution of the residue in CH2Cl2 (50 mL) was
added mesyl anhydride (1.74 g, 10 mmol), then Et3N (1.51 g, 15
mmol) and the mixture stirred overnight. After quenching with sat.
aq NH4Cl (15 mL), the mixture was partitioned and the aqueous lay-
er extracted with Et2O (3 × 20 mL). The combined organic layers
were washed with aq NaOH (15%, 20 mL), H2O (20 mL) and brine
(20 mL), dried (MgSO4), and concentrated in vacuo. Purification of
the residue by column chromatography furnished the title com-
pound as a white solid (1.64 g, 69%); mp 54–56 °C; [a]D25 –194.0
(c 0.50, CHCl3). All other data as described for 2d earlier.
MS (CI): m/z (%) = 218.1 (100, [M + H]+).
HRMS-CI: m/z [M + H]+ calcd for C10H20NO2S: 218.1215; found:
218.1218.
Acknowledgment
We thank the EPSRC (DTA) and GlaxoSmithKline for financial
support of this work. We also thank the EPSRC National Mass
Spectrometry Service Centre (Swansea) for mass spectra, Dr. A.
Thompson (Oxford) for X-ray crystallographic analyses, Dr. C. J.
R. Bataille (Oxford) for chiral GC analyses, Dr. K. Darragas
(Huntsman Performance Products) for a generous sample of ethyl-
ene carbonate, and Dr. R. P. C. Cousins (GlaxoSmithKline) and
Prof. A. Fürstner (Max-Planck-Institut für Kohlenforschung,
Mülheim) for useful discussions.
References
(R)-2-(But-3-enyl)-1-[(R)-tert-butylsulfinyl]aziridine (10m)
4-Iodobut-1-ene42 (passed through a plug of basic, activated alumi-
na immediately before use; the liquid obtained must be colourless,
0.24 g, 1.3 mmol) was dissolved in pentane (3 mL) and Et2O (2 mL)
and cooled to –78 °C, then t-BuLi (1.5 M in pentane, 1.9 mL, 2.86
mmol) was added dropwise. After 15 min, the cold bath was re-
placed by an ice bath, the reaction mixture slowly warmed to r.t.,
stirred for 2 h, the reaction solvent removed in vacuo, and the resi-
due redissolved in anhyd THF (4 mL). This solution of
homoallyllithium43 and imine (RS)-8 were reacted following Typi-
cal Procedure B. Purification of the residue by column chromatog-
raphy (SiO2, PE–EtOAc, 5:1) gave the title compound as a pale
yellow oil (0.13 g, 64%, 99:1 dr by GC); [a]D –265.7 (c 0.40,
CCl4); Rf = 0.3 (PE–EtOAc, 4:1).
IR (neat): 2926, 2855, 1640, 1461, 1310, 1131, 938, 867, 709 cm–1.
1H NMR (500 MHz, C6D6): d = 5.65 (ddt, J = 10.2, 6.8, 3.2 Hz, 1 H,
CH=HH¢), 4.98–4.92 (m, 1 H, CH=HH¢), 3.91 (dd, J = 14.4, 7.3 Hz,
1 H, CH=CHH¢), 2.64 (d, J = 6.6 Hz, 1 H, CHH¢), 2.03–1.90 (m, 1
H, CHN), 1.41–1.12 (m, 5 H, CH2CH2 and CHH¢), 1.09 [s, 9 H,
C(CH3)3].
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Synthesis 2009, No. 11, 1923–1932 © Thieme Stuttgart · New York

1932
D. M. Hodgson et al.
FEATURE ARTICLE
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Synthesis 2009, No. 11, 1923–1932 © Thieme Stuttgart · New York