On the α-lithiation-rearrangement of N-toluensulfonyl aziridines: Mechanistic and synthetic aspects

Article abstract of DOI:10.1016/j.tet.2003.09.024

A detailed study of the rearrangement of five cycloalkene N-toluenesulfonyl (tosyl) aziridines using sec-butyllithium (with and without added ligands such as (-)-sparteine and TMEDA) has been carried out. Allylic sulfonamides were the main products from the cyclopentene and cyclohexene aziridines whereas bicyclic sulfonamides were obtained from the cycloheptene and cyclooctene aziridines. In most cases, p-toluenesulfonamide (TsNH ₂) was produced as a by-product and a mechanistic explanation for its formation is forwarded. These reactions are believed to involve α-lithiation to a lithiated aziridine which can then partition through two pathways: (i) rearrangement to allylic or bicyclic sulfonamides via C-H insertion reactions or (ii) reductive alkylation to alkenes via attack by sec-butyllithium and subsequent elimination of TsNH₂. In the (-)-sparteine reactions, the products were generated with 38-66% ee and the sense of asymmetric induction involved lithiation of the S-aziridine stereocentre. This is opposite to that observed with epoxides.

Full text of DOI:10.1016/j.tet.2003.09.024

Tetrahedron 59 (2003) 9779–9791
On the a-lithiation-rearrangement of N-toluensulfonyl aziridines:
mechanistic and synthetic aspects
a
b
Peter O’Brien,a Clare M. Rosser and Darren Caine
,
*
aDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK
bGlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Received 17 July 2003; accepted 5 September 2003
Abstract—A detailed study of the rearrangement of five cycloalkene N-toluenesulfonyl (tosyl) aziridines using sec-butyllithium (with and
without added ligands such as (2)-sparteine and TMEDA) has been carried out. Allylic sulfonamides were the main products from the
cyclopentene and cyclohexene aziridines whereas bicyclic sulfonamides were obtained from the cycloheptene and cyclooctene aziridines. In
most cases, p-toluenesulfonamide (TsNH2) was produced as a by-product and a mechanistic explanation for its formation is forwarded. These
reactions are believed to involve a-lithiation to a lithiated aziridine which can then partition through two pathways: (i) rearrangement to
allylic or bicyclic sulfonamides via C–H insertion reactions or (ii) reductive alkylation to alkenes via attack by sec-butyllithium and
subsequent elimination of TsNH2. In the (2)-sparteine reactions, the products were generated with 38–66% ee and the sense of asymmetric
induction involved lithiation of the S-aziridine stereocentre. This is opposite to that observed with epoxides.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
For some time, we have been intrigued by the prospect of
developing suitable reagents/conditions for the direct
conversion of aziridines into allylic amines, exemplified
by the rearrangement of 1 into 2 (Scheme 1). The analogous
rearrangement of epoxides to allylic alcohols is well
known and has been widely studied using chiral lithium
amide bases,14,15 including contributions from our group.16
However, there are only three reports11,17,18 of the direct,
one-step transformation of aziridines into protected allylic
amines and lithium amides alone have not been reported
to carry out this interconversion.16a Of these, Scheffold17
used a Vitamin B12-catalysed process whilst the two most
recent reports (Mu¨ller11 and Mordini18a) utilised strong
bases (e.g. sec-butyllithium/(2)-sparteine, LDA/potassium
tert-butoxide or n-butyllithium/potassium tert-butoxide) to
convert N-tosyl aziridine 1 (R¼Ts) into allylic sulfonamide
2 (R¼Ts).
Lithiated epoxides (oxiranyl anions) were first identified as
reaction intermediates by Cope in 1951 to explain the
conversion of cyclooctatetraene into 2,4,6-cyclooctatrien-1-
one.1 Since then, the chemistry of lithiated epoxides has
blossomed into a significant research area with major world-
wide interest.2,3 Of recent interest, Hodgson and co-workers
have developed elegant and useful asymmetric method-
ology based on enantioenriched lithiated epoxides, gener-
ated by direct a-lithiation of epoxides using alkyllithiums
in the presence of chiral ligands such as (2)-sparteine and
bisoxazolines.3–5 In contrast, the chemistry of lithiated
aziridines (aziridinyl anions) produced by direct a-lithia-
tion/deprotonation has received much less attention.2 Of the
known examples, most lithiated aziridines are generated
from aziridines equipped with an anion stabilising group
(e.g. acyl,6 alkenyl,7 oxazolinyl,8 benzotriazoyl9 or sulfo-
nyl10 groups) attached directly. However, there are three
reported instances of lithiated aziridines generated from
aziridines lacking an anion stabilising group: Mu¨ller’s
a-lithiation-rearrangement of N-toluenesulfonyl (tosyl)
aziridines,11 Vedejs’ a-lithiation of borane complexes of
N-alkyl aziridines12 and Beak’s a-lithiation-in situ trapping
of N-Boc aziridines.13 It is these reports that attracted our
attention for the present study.
In his original report, Mu¨ller reported three examples of the
rearrangement of N-tosyl aziridines (e.g. 1, R¼Ts) using
Keywords: aziridines; sulfonamides; rearrangement; lithiation; carbenes
and carbenoids.
*
Corresponding author. Tel.: þ44-1904-432535; fax: þ44-1904-432516;
e-mail: paob1@york.ac.uk
Scheme 1.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.024

9780
P. O’Brien et al. / Tetrahedron 59 (2003) 9779–9791
sec-butyllithium/(2)-sparteine.11 By analogy with the
extensive literature on epoxides,2,3 it is likely that sec-
butyllithium/(2)-sparteine would cause aziridines 1 to
undergo irreversible a-lithiation to give lithiated aziridines
3 (aziridinyl anions) which will presumably possess
carbenoid character (Scheme 1). Subsequent insertion into
an adjacent C–H bond either directly or via the carbene 4
(generated by a-elimination of lithiated aziridine 3) would
then produce allylic amines 2. It may well be that Mordini’s
reactions18a of N-tosyl aziridines with LDA/postassium tert-
butoxide or n-butyllithium/potassium tert-butoxide also
proceed via a similar a-lithiation mechanism, although
Mordini suggests a b-elimination process (reactions
of lithium amides with epoxides can proceed via a- or
b-lithiation mechanisms, depending strongly on the epoxide
structure and reaction conditions19). Due to our ongoing
interest in sparteine-like diamines20 and aziridines,16a,21
coupled with our desire to develop the aziridine to allylic
amine reaction, we became interested in further exploiting
Mu¨ller’s seminal contribution. Thus, we have carried out a
study on the reaction of alkyllithiums with five cycloalkene
N-tosyl aziridines and full results are presented in this
paper.22 Of particular significance, we have established the
sense of asymmetric induction in the lithiation of N-tosyl
aziridines with (2)-sparteine and we have rationalised the
formation of p-toluenesulfonamide (TsNH2) as a by-product
in these reactions. The formation of TsNH2 has allowed us
to provide evidence in support of the intermediacy of
lithiated aziridines 3 in the rearrangement reactions
discussed. Additionally, our results indicate a significant
ligand effect and this has allowed us to draw some important
synthetic conclusions.
procedure was less successful with cyclooctene, resulting
in a lower yield (20%) of aziridine 10 (Scheme 2).
As a starting point in our study, we selected cyclohexene
N-tosyl aziridine 8 and conditions that were essentially the
same as those reported by Mu¨ller and Nury for their
aziridine rearrangements.11 Thus, a diethyl ether solution
of N-tosyl aziridine 8 was added to 2.9 equiv. of sec-
butyllithium/(2)-sparteine in diethyl ether at 2788C. After
4 h at 2788C, the solution was allowed to warm to room
temperature (over approximately 1 h) and worked up.
Purification by flash chromatography furnished allylic
sulfonamide (R)-11 in 67% yield (38% ee by chiral
HPLC) and p-toluenesulfonamide (TsNH2) in 10% yield
(Scheme 3). The enantioselectivity was virtually identical to
that reported by Mu¨ller but there were some differences:
(i) our isolated yield (typically 60–70%) was approximately
30% higher than that reported by Mu¨ller; (ii) we have no
evidence for the generation of the isomeric enamide 12
(despite having run the reaction many times and carefully
analysing the crude product mixtures by 1H NMR
spectroscopy) and (iii) our reaction was always
accompanied by the formation of some TsNH2. Upon
subsequent re-examination by Mu¨ller and co-workers, all of
our observations (i)–(iii) listed above have now been
verified.26
Scheme 3. Reagents and conditions: (i) 2.9 equiv. sBuLi, 2.9 equiv.
(2)-sparteine, Et2O, 2788C, 4 h then to rt over 1 h.
2. Results and discussion
As substrates for the detailed a-lithiation rearrangement
study, we have utilised N-tosyl aziridines cis-6 and 7–10
and the aziridines were prepared in one step from the
corresponding cycloalkenes. Of the methods available
(e.g. iodinane-based procedures23 and Chloramine-T-based
conditions24,25), we prefer the Sharpless protocol25 (Chlora-
mine-T, phenyltrimethylammonium tribromide, aceto-
nitrile, room temperature) as it is a generally high yielding
and simple method. For example, alkene 5 was converted
into a separable mixture of aziridines cis and trans-6
(relative stereochemistry established by independent syn-
thesis from a known epoxide21) in a high 86% combined
yield using the Sharpless conditions (Scheme 2). In a similar
way, simpler N-tosyl aziridines 7–9 were prepared in high
yields (63–88%, Scheme 2) but, unfortunately, this
The major enantiomer of allylic sulfonamide 11 generated
from the sec-butyllithum/(2)-sparteine reaction was estab-
lished as (R) using two different reaction sequences
(Scheme 4). In a first sequence, we attempted to prepare
allylic sulfonamide (R)-11 via a Mitsunobu route using
Weinreb’s TsNHBoc reagent27 and allylic alcohol (S)-14.
Thus, cyclohexene oxide 11 was rearranged using the chiral
Scheme 4. Reagents and conditions: (i) 2 equiv. (1R,2S)-N-methyl-1-
phenyl-2-(1-pyrrolidinyl)-1-propanamine, 2 equiv. nBuLi, THF, 08C to rt
over 1 h then 16 h at rt; (ii) 1.5 equiv. TsNHBoc, 2.5 equiv. DEAD,
3.0 equiv. PPh3, THF, rt, 10 h; (iii) TFA, CH2Cl2, 08C to rt over 1 h;
(iv) 1.1 equiv. Boc2O, 1.1 equiv. Et3N, 0.1 equiv. DMAP, CH2Cl2, rt, 16 h;
(v) 10 equiv. Na, NH3, THF, 2788C for 1 h then rt for 1 h.
Scheme 2. Reagents and conditions: (i) 1.1 equiv. TsNCl2Naþ·3H2O,
0.1 equiv. PhMe3NþBr23 , MeCN, rt, 16 h.

P. O’Brien et al. / Tetrahedron 59 (2003) 9779–9791
9781
lithium amide derived from (1R,2S)-N-methyl-1-phenyl-2-
(1-pyrrolidinyl)-1-propanamine (independently developed
by ourselves28 and Ahlberg29) to give allylic alcohol (S)-14
of 81% ee (determined by Mosher’s ester formation).
The moderate isolated yield (37%) of allylic alcohol (S)-14
presumably reflects its volatility. Then, (S)-14 was sub-
jected to a standard Mitsunobu reaction with TsNHBoc to
generate a high yield (95%) of protected allylic sulfonamide
(R)-15. Subsequent Boc deprotection gave allylic sulfona-
mide (R)-11 in 50% yield but of only 18% ee (by chiral
HPLC). We suggest that the enantiomeric excess of (S)-14 is
compromised significantly during the Mitsunobu reaction
by a competing SN20 reaction in this sterically unbiased
system. This has precedent in related Mitsunobu reactions
with carboxylic acids.30 In contrast, in sterically biased
systems, Mitsunobu reactions of cyclic allylic alcohols
proceed with essentially complete stereochemical integrity,
as we have observed for other nitrogen-based Mitsunobu
reactions.16a Due to this non-stereospecific Mitsunobu
reaction, we sought unequivocal assignment of absolute
stereochemistry in allylic sulfonamide 11 and a straight-
forward second route was investigated. Allylic sulfonamide
11 of 38% ee was Boc protected to give (R)-15 from which
(R)-16 was formed by tosyl deprotection using sodium in
liquid ammonia. The absolute stereochemistry of Boc
protected allylic amine (R)-16 was assigned by comparison
of its optical rotation {[a]D¼þ30.0 (c 1.1 in CHCl3), 38%
ee assumed} with the literature value17 {[a]D¼þ101 (c 2.8
in CHCl3) for (R)-16, 95% ee}. Hence, the major
enantiomer generated from the rearrangement of N-tosyl
aziridine 8 was unequivocally assigned as allylic sulfona-
mide (R)-11.
5. Thus, Boc protection gave (R)-18 and subsequent tosyl
deprotection generated Boc protected allylic amine (R)-19.
Comparison of its optical rotation {[a]D¼þ38.8 (c 1.0 in
CH2Cl2), 64% ee assumed} with that reported in the
literature17 {[a]D¼þ77.0 (c 5.1 in CH2Cl2) for (R)-19, 87%
ee} enabled the stereochemistry to be assigned.
At this stage, it is appropriate to consider the likely
mechanisms that could account for the formation of the
allylic sulfonamides (R)-11 and (R)-17 as well as the TsNH2
by-product. The formation of TsNH2 had not been noted in
Mu¨ller’s original report11 and we were especially keen to
rationalise the generation of TsNH2 as both of the C–N
bonds of the aziridines must have been cleaved. A proposed
mechanistic outline is delineated in Scheme 6. Irreversible
a-lithiation of the N-tosyl aziridines 7 and 8 by sec-
butyllithium/(2)-sparteine would produce lithiated aziri-
dines 20. Subsequent insertion into the adjacent C–H bond
either directly or via the carbenes 21 (generated by
a-elimination of lithiated aziridines 20) would produce
the allylic sulfonamides (R)-17 and (R)-11 after aqueous
work-up. However, by analogy with their epoxide cousins,
lithiated aziridines 20 are also likely to possess significant
electrophilic character and this opens up another possible
reaction pathway. Attack of lithiated aziridines 20 by a
second equivalent of sec-butyllithium would lead to
dilithiated adducts 22 from which elimination of TsNLi2
would generate alkenes 23 and TsNH2 after aqueous work-
up (Scheme 6). We believe that this is the mechanistic
process that accounts for the generation of TsNH2 in our
reactions. Such a reductive alkylation process is well
documented for lithiated epoxides and was first proposed
by Crandall and Lin in 1967.31 Since then, Mioskowski32,33
and, more recently, Hodgson3,5a,b,34 have widely utilised
this type of reductive alkylation process with lithiated
epoxides in synthetic applications. Of particular relevance
to our mechanistic conjecture, Mioskowski et al. reported
the conversion of epoxides into substituted alkenes via
reductive alkylation of lithiated epoxides with concomitant
elimination of Li2O.32
Next, the previously unstudied cyclopentene N-tosyl
aziridine 7 was rearranged using 2.9 equiv. of sec-
butyllithium/(2)-sparteine (same conditions as in Scheme
3). In this case, a 39% yield of allylic sulfonamide (R)-17
(64% ee by chiral HPLC) was obtained (Scheme 5).
Compared to the cyclohexene aziridine 8, the yield of
allylic sulfonamide (R)-17 was lower (39%) and was
accompanied by an increase in the yield of the TsNH2
by-product (47%); the enantioselectivity was higher (64%
ee) and the same sense of asymmetric induction was
observed. The major enantiomer of allylic sulfonamide 17
was assigned as (R) using the sequence outlined in Scheme
Scheme 6.
The reductive alkylation of lithiated aziridines (and hence
the formation of TsNH2) has not been described previously.
Unfortunately, we have been unable to isolate alkenes 23
(n¼0 and 1) from the sec-butyllithium/(2)-sparteine
reactions of aziridines 7 and 8. Thus, in order to provide
Scheme 5. Reagents and conditions: (i) 2.9 equiv. sBuLi, 2.9 equiv.
(2)-sparteine, Et2O, 2788C, 4 h then to rt over 1 h; (ii) 1.1 equiv. Boc2O,
1.1 equiv. Et3N, 0.1 equiv. DMAP, CH2Cl2, rt, 16 h; (iii) 10 equiv. Na,
NH3, THF, 2788C for 1 h then rt for 1 h.

9782
P. O’Brien et al. / Tetrahedron 59 (2003) 9779–9791
diastereomeric products. Using Hodgson’s conditions,4
cyclooctene oxide 26 was rearranged with sec-butyl-
lithium/(2)-sparteine to give bicyclic alcohol (1S,3aR,
6aR)-27 (69% ee by chiral HPLC of a derivative) in 84%
yield. In order to generate the same relative stereochemistry
in bicyclic sulfonamide 25, initial inversion of the hydroxyl
configuration in 27 followed by substitution with an amino
group (i.e. a second inversion) would be required.
s
Scheme 7. Reagents and conditions: (i) 2.9 equiv. BuLi, Et2O or THF,
2788C, 4 h then to rt over 1 h.
Thus, alcohol (1S,3aR,6aR)-27 was converted into the
2,4-dinitrobenzoate 28 using a Mitsunobu reaction and
thence into alcohol 29 upon treatment with potassium
hydroxide. Introduction of the amino group was achieved
using a Mitsunobu reaction with TsNHBoc to give
sulfonamide 30 in 16% yield. The low yield of this reaction
(despite an extended reaction time of 64 h) reflects the
difficulty in carrying out SN2 substitution on the sterically
hindered endo face of the bicyclic system. An interesting
reactivity comparison was obtained when the same
Mitsunobu reaction was carried out with the diastereomeric
alcohol 27—in this case, we isolated a satisfactory 50%
yield of the Mitsunobu adduct 31 (clearly distinguishable
from 30 by 1H and 13C NMR spectroscopic data—see
Section 4) via SN2 attack on the more accessible exo face.
Deprotection of the Boc group in sulfonamide 30 gave
(1S,3aR,6aR)-25 (70% ee by chiral HPLC) of known
further evidence in support of our mechanistic rationale, we
decided to study the reaction of N-tosyl aziridine cis-6 as
this should generate a non-volatile alkene 24. Based on
Mioskowski’s precedent with epoxides,32 it appeared likely
that the reductive alkylation pathway would be dominant if
the reaction was carried out in the absence of ligand.
Therefore, aziridine cis-6 was treated with 2.9 equiv. of
sec-butyllithium alone in Et2O under the usual reactions
conditions and, after work-up and chromatography, a 76%
yield of substituted alkene 24 (50:50 mixture of dia-
stereomers) was isolated. The same reaction proceeded with
70% yield in THF. From both of these reactions, TsNH2 was
also produced and there was no evidence for the formation
of any allylic sulfonamide. These are the first examples of
the preparation of substituted alkenes by the reductive
alkylation of lithiated aziridines and this type of process
could have useful synthetic applications. Of greater
significance to the present work, the reactions with aziridine
cis-6 strongly support our mechanistic speculation regard-
ing the generation of TsNH2.
1
absolute and relative stereochemistry. As expected, its H
and 13C NMR spectra were identical to the bicyclic
sulfonamide generated from the sec-butyllithium/(2)-spar-
teine rearrangement of aziridine 10. However, its sign of
optical rotation was opposite to that obtained from the
aziridine rearrangement reaction. For final confirmation of
the relative stereochemistry, 31 was Boc deprotected to give
The sec-butyllithium/(2)-sparteine reactions of the cyclo-
heptene and cyclooctene N-tosyl aziridines (9 and 10) have
also been studied. Surprisingly, under the usual conditions
with sec-butyllithium/(2)-sparteine, the cycloheptene
aziridine 9 did not produce any allylic sulfonamide and
we were unable to isolate any meaningful products from
this reaction. In contrast, the cyclooctene aziridine 10 was
well-behaved and underwent rearrangement to the bicyclic
sulfonamide 25, as expected based on previous epoxide4 and
aziridine11 results. From the reaction of aziridine 10, a 71%
yield of bicyclic sulfonamide (1R,3aS,6aS)-25 (66% ee by
chiral HPLC) was isolated after chromatography. There was
no evidence of TsNH2 being generated from this reaction
and our reaction exhibits comparable yield and enantio-
selectivity to those reported by Mu¨ller.11
The relative and absolute stereochemistry of the bicyclic
sulfonamide 25 generated from the (2)-sparteine reaction
was established via a series of Mitsunobu reactions starting
from alcohol (1S,3aR,6aR)-27, as outlined in Scheme 9. It is
worth emphasising that in all of these Mitsunobu reactions,
there was no evidence for the formation of other
Scheme 9. (i) 2.4 equiv. sBuLi, 2.4 equiv. (2)-sparteine, Et2O, 2788C, 5 h
then to rt over 16 h; (ii) 1.5 equiv. 2,4-dinitrobenzoic acid, 2.5 equiv.
DEAD, 3.0 equiv. PPh3, THF, rt, 64 h; (iii) KOH, water–MeOH–THF,
08C, 30 min; (iv) 1.5 equiv. TsNHBoc, 2.5 equiv. DEAD, 3.0 equiv. PPh3,
THF, rt, 64 h; (v) TFA, CH2Cl2, 08C to rt then rt for 2.5 h.
Scheme 8. Reagents and conditions: (i) 2.9 equiv. sBuLi, 2.9 equiv.
(2)-sparteine, Et2O, 2788C, 4 h then to rt over 1 h.

P. O’Brien et al. / Tetrahedron 59 (2003) 9779–9791
9783
1
bicyclic sulfonamide 32, whose H and 13C NMR spectra
were different to those of 25 recorded by us and reported by
Mu¨ller11 (for 25, CHN signal is at dH 3.62–3.51 (m) and dC
57.0;11 for 32, CHN signal is at dH 3.13 (br quin., J¼7.0 Hz)
and dC 61.4).
The sense of asymmetric induction in the rearrangement of
aziridines 7, 8 and 10 using sec-butyllithium/(2)-sparteine
has been unequivocally established in the work presented so
far. In each case, the sense of induction is the same:
preferential lithiation of the S-aziridine stereocentre occurs
to give lithiated aziridines 20 (Fig. 1) In the one example
where the stereoselectivity was established, Mu¨ller11 found
that a norbornene-derived N-tosyl aziridine rearranged via
lithiated aziridine 35 (Fig. 1), also generated by lithiation of
the S-aziridine stereocentre. Although we do not yet have a
model to account for this sense of induction, we note that
opposite stereoselectivity is observed with aziridines and
epoxides. This is most apparent in the results presented in
Scheme 9 where alcohol (1S,3aR,6aR)-27 (generated by an
epoxide rearrangement using (2)-sparteine) was converted
into sulfonamide (1S,3aR,6aR)-25, enantiomeric to that
generated by rearrangement of aziridine 10 using
(2)-sparteine (see Scheme 8). In all of the examples
reported to date from the Hodgson group,4,5 the use of
(2)-sparteine as a ligand leads to preferential lithiation of
the R-stereocentre (to varying degrees, depending on the
substrate) thus generating lithiated epoxides 33 and 34.
Clearly, the presence of a N-tosyl group in aziridines
permits a complete changeover of the enantiodiscriminating
Figure 1.
interactions between the alkyllithium-(2)-sparteine complex
and the substrate. With N-tosyl aziridines, it is conceivable
that the first step in the mechanism is stereoselective
complexation of the alkyllithium to the oxygen of one of the
enantiotopic SvO groups and this could be the source of
the reversal in stereoselectivity compared to epoxides. Two
other unpublished results from Mu¨ller and co-workers26
are also consistent with preferential lithiation of the
S-stereocentre in N-tosyl aziridines using sec-butyllithum/
(2)-sparteine.
We have also carried out a preliminary study on the scope
and limitations of the rearrrangement of aziridines 7–10
using sec-butyllithium. This included replacing (2)-spar-
teine by TMEDA and trying the reactions in the absence of
any ligand (in both THF and diethyl ether). The TMEDA
reactions were carried out in the same way as the
(2)-sparteine ones described previously (i.e. an aziridine
solution was added to the sec-butyllithium/ligand solution at
2788C). However, for reactions with no ligand present, it
was experimentally easier to add the sec-butyllithium to a
solution of the aziridine at 2788C and so this procedure was
adopted. The full results of this study are presented in
Scheme 10 and Table 1.
Scheme 10.
Table 1. Rearrangement of N-tosyl aziridines using sec-butyllithium under different conditionsa
Entry
SM (n)b
Ligand
Solvent
Product
Yield (%)c
ee (%)d
TsNH2 (%)e
SM (%)f
1
2
3
4
5
6
7
8
7 (0)
7 (0)
7 (0)
7 (0)
8 (1)
8 (1)
8 (1)
8 (1)
9 (2)
9 (2)
10 (3)
10 (3)
10 (3)
10 (3)
(2)-Sparteine
TMEDA
–
–
(2)-Sparteine
TMEDA
–
–
(2)-Sparteine
–
(2)-Sparteine
TMEDA
Et2O
Et2O
Et2O
THF
Et2O
Et2O
Et2O
THF
Et2O
Et2O
Et2O
Et2O
Et2O
THF
(R)-17
rac-17
rac-17
rac-17
(R)-11
rac-11
rac-11
rac-11
39
23
8
10
67
22
57
4
64
–
–
–
38
–
–
–
–
–
47
38
69
56
10
ndg
30
56
–
31
–
–
–
–
–
–
–
–
–
–
–
–
–
17
–
–
23
–
h
9
–
–
10
11
12
13
14
rac-36
25
rac-25
rac-25
rac-25
23
71
26
34
36
66
–
–
–
–
–
a
Conditions: 2.9 equiv. sBuLi, 2.9 equiv. ligand (if applicable), Et2O or THF, 2788C, 4 h then rt over 1 h.
Starting material.
Isolated yield of product after chromatography.
Enantiomeric excess determined by chiral HPLC.
Isolated yield of TsNH2 after chromatography.
Isolated yield of recovered starting material after chromatography.
Not determined.
No isolable compounds (including starting material) were obtained.
b
c
d
e
f
g
h

9784
P. O’Brien et al. / Tetrahedron 59 (2003) 9779–9791
As mentioned previously, rearrangement of the cyclohep-
tene N-tosyl aziridine 9 using sec-butyllithium/(2)-spar-
teine generated no isolable compounds, including starting
material (entry 9). In contrast, cyclopropylsulfonamide 36
(23% yield) was isolated from the analogous reaction in
diethyl ether in the absence of ligand. Evidence for the
formation of the cyclopropyl ring in 36 was provided by
characteristic upfield resonances at dH 0.94–0.82, 0.46 and
rearrangement products (R)-11, (R)-17 and (1R,3aS,6aS)-25
are generated via lithiation of the S-aziridine stereocentre.
For the cyclooctene aziridine (10) and epoxide (26), the
results described in this paper provide a direct comparison
as almost equal and opposite asymmetric induction are
observed under near-identical conditions: aziridine 10 gave
(1R,3aS,6aS)-25 in 71% yield and 66% ee (Scheme 8)
whereas epoxide 26 gave (1S,3aR,6aR)-25 in 84% yield and
69% ee (Scheme 9) using sec-butyllithium/(2)-sparteine.
Three other examples of N-tosyl aziridines rearrangement
reactions, reported by Mu¨ller and co-workers,11,26 also pro-
ceed via lithiation of the S-aziridine stereocentre.
1
0.08 ppm in the H NMR spectrum and at dC 15.9 (CH),
12.5 (CH) and 8.0 (CH2) in the 13C NMR spectrum. The
relative stereochemistry of 36 has not been established
unequivocally. However, we assigned a cis relationship
between the NHTs group and the cyclopropane ring based
on the precedent in the corresponding cycloheptene oxide
rearrangement reaction35 and by comparing the likely
conformations for C–H insertion in the cyclooctene and
cycloheptene N-tosyl aziridines, 37 and 38, respectively
(Fig. 2).
Secondly, we have rationalised the formation of TsNH2
(to varying degrees) in the rearrangement reactions by
considering attack by a second equivalent of sec-butyl-
lithium on the electrophilic lithiated aziridines. Specifically,
the conversion of N-tosyl aziridine cis-6 into alkene 24
(together with the formation of TsNH2) is the first example
of the reductive alkylation of lithiated aziridines and may
have useful synthetic applications, as both Hodgson5a,b,34
and Mioskowski32,33 have demonstrated with epoxides.
Thirdly, there is a significant ligand effect in the N-tosyl
aziridine reactions and our results suggest that a ligand (e.g.
(2)-sparteine or TMEDA) is not required for a-lithiation but
has a key role in determining the fate of the lithiated
aziridine. Hodgson et al. have recently noted dramatic ligand
effects in some related epoxide reactions.5a The highest
yields of allylic sulfonamides 11 and 17 were obtained from
the reactions in the presence of sterically hindered (2)-
sparteine. We suggest that the use of the less hindered
TMEDA or no ligand (diethyl ether or THF presumably
coordinated to the lithium) allows the alternative reductive
alkylation pathway (generating alkenes and TsNH2) to occur
preferentially. Most of the lower yielding reactions (Table 1,
entries 1–4, 8, and 10) are accompanied by higher yields of
TsNH2. Fourthly, reductive alkylation is most pronounced
with cyclopentene N-tosyl aziridines cis-6 and 7 compared to
the cyclohexene, cycloheptene and cyclooctene analogues.
Figure 2.
Some important and interesting trends can be identified
from the results presented in Table 1. Apart from the
cycloheptene N-tosyl aziridine 9, the highest yields of
rearrangement products were obtained in the presence
of (2)-sparteine (entries 1, 5, and 11). In contrast, use of
TMEDA or no ligand generally led to lower product yields
and an increase in the amount of TsNH2 that was generated
(entries 2, 3, 4, and 8). To explain this, we suggest that in
the absence of the sterically hindered (2)-sparteine ligand,
the lithiated aziridines are more susceptible to nucleophilic
attack by a second equivalent of sec-butyllithium, as
outlined in Scheme 6. This alternative process appears to
occur more readily for the cyclopentene N-tosyl aziridine 7
(and also for the cyclopentene N-tosyl aziridine cis-6,
Scheme 7). However, the reaction of cyclohexene N-tosyl
aziridine 8 with sec-butyllithium in diethyl ether (entry 7)
appears anomalous as a 57% isolated yield of allylic
sulfonamide rac-11 was obtained. In the reactions of
cyclooctene N-tosyl aziridine 10, we have never observed
the formation of any TsNH2 (entries 11–14) and the low
yielding reactions in the absence of ligand (entries 12–14)
are presumably due to another competing process that we
have not yet identified. Finally, we note that the highest
enantioselectivity was observed with the cyclooctene
N-tosyl aziridine 10 (entry 11).
Finally, from a synthetic viewpoint, we recommend the use
of a bulky diamine ligand in diethyl ether as a way of
generating rearrangement products and the use of no ligand
in THF or diethyl ether as a means of producing reductive
alkylation products. Further work is required to fully
understand these reactions. However, it is hoped that the
results and conclusions presented in this paper provide a
strong foundation for future developments in the syn-
thetic utility of lithiated aziridines generated by direct
a-lithiation/deprotonation.
4. Experimental
4.1. General
3. Conclusion
The reactions between sec-butyllithium and the five
cycoalkene N-tosyl aziridines presented in this paper have
allowed us to draw some important synthetic, mechanistic
and stereochemical conclusions. Firstly, the predominant
sense of asymmetric induction in the lithiation-rearrange-
ment of N-tosyl aziridines 7, 8 and 10 using (2)-sparteine is
opposite to the corresponding epoxides: the R-epoxide
stereocentre is lithiated preferentially but the aziridine
Water is distilled water. Et2O and THF were freshly distilled
from sodium benzophenone ketyl whereas CH2Cl2 was
freshly distilled from calcium hydride. All non-aqueous
reactions were carried out under oxygen-free nitrogen using
oven-dried glassware. Petrol refers to the fraction of
petroleum ether boiling in the range 40–608C. Brine refers
to a saturated aqueous solution of NaCl.

P. O’Brien et al. / Tetrahedron 59 (2003) 9779–9791
9785
Flash column chromatography was carried out using ICN
˚
Biomedicals GmbH silica (60 A) or Fisher Matrex silica 60,
The combined Et2O extracts were dried (Na2SO4) and
evaporated under reduced pressure to give the crude
product.
70–200 mm. Thin layer chromatography was carried out
using commercially available Merck F254 aluminium-
backed silica plates. Proton (270 or 400 MHz) and carbon
(67.9 or 100.6 MHz) NMR spectra were recorded on a Jeol
EX-270 or a Jeol ECX-400 instrument using an internal
deuterium lock. All samples were recorded as solutions in
CDCl3 and chemical shifts are quoted in parts per million
downfield of tetramethylsilane. Carbon NMR spectra were
recorded with broad band proton decoupling and were
assigned using DEPT experiments. Melting points
were measured on a Gallenkamp melting point apparatus
and are uncorrected. Infrared spectra were recorded on an
ATI Matteson Genesis FT-IR spectrometer. Chemical
ionisation and high resolution mass spectra were recorded
on a Fisons Analytical (VG) Autospec spectrometer. Optical
rotations were recorded at 208C on a Jasco DIP-370
polarimeter (using the sodium D line; 589 nm) and [a]D
are given in 1021 deg cm2 g21. Microanalyses were carried
out at the University of Newcastle on a Carlo Erba 1106
elemental analyser and weighed using a Mettler MT 5
microbalance.
4.2. tert-Butyl(diphenyl)silyl 3-cyclopenten-1-yl ether 5
Imidazole (404 mg, 5.9 mmol) and tert-butyldiphenylsilyl
chloride (654 mg, 2.4 mmol) were added in portions to a
stirred solution of 3-cyclopenten-1-ol (200 mg, 2.4 mmol)
in CH2Cl2 (6 mL) at rt under nitrogen. After stirring for
16 h, water (5 mL) was added and the layers were separated.
The aqueous layer was extracted with CH2Cl2 (3£5 mL) and
the combined CH2Cl2 extracts were washed with brine
(10 mL), dried (Na2SO4) and evaporated under reduced
pressure to give the crude product. Purification by flash
chromatography on silica with petrol–Et2O (95:5) as eluent
gave alkene 5 (768 mg, 100%) as a cloudy oil, RF(99:1
petrol–Et2O) 0.6; IR (CH2Cl2) 3072, 2933, 2858, 1427,
1
1109 cm21; H NMR (270 MHz; CDCl3) 7.70–7.68 (m,
4H), 7.47–7.36 (m, 6H), 5.63 (br s, 2H), 4.61–4.53 (m, 1H),
2.44–2.40 (m, 4H), 1.07 (s, 9H); 13C NMR (67.9 MHz;
CDCl3) 135.7, 134.5, 129.5, 128.3, 127.5, 73.5, 42.4, 26.9,
19.1; MS (CI, NH3) 323 (MþH)þ, 282, 265, 216, 199;
HRMS (CI, NH3) m/z calcd for C21H26OSi (MþH)þ
323.1831, found 323.1833.
n-Butyllithium and sec-butyllithium were titrated against
N-benzylbenzamide before use.36 (2)-Sparteine, TMEDA
and (1R,2S)-N-methyl-1-phenyl-2-(1-pyrrolidinyl)-1-propa-
namine were purified by Kugelrohr distillation immediately
prior to use. 3-Cyclopenten-1-ol is commercially available
from Astatech Inc., Philadelphia (USA). (1R,2S)-N-Methyl-
1-phenyl-2-(1-pyrrolidinyl)-1-propanamine28b and TsNHBoc37
were prepared according to the literature procedures.
4.3. 3-{[tert-Butyl(diphenyl)silyl]oxy}-6-[(4-methyl-
phenyl)sulfonyl]-6-azabicyclo[3.1.0]hexane trans-6 and
cis-6
Using general procedure A, alkene 5 (500 mg, 1.55 mmol),
Chloramine-T trihydrate (480 mg, 1.70 mmol) and PhMe3-
NþBr23 (60 mg, 0.16 mmol) in MeCN (20 mL) gave the
crude product which contained a 37:63 mixture of aziridines
4.1.1. General procedure A: preparation of N-tosyl
aziridines. PhMe3NþBr23 (0.1 equiv.) was added to a
stirred solution of alkene (0.16 mmol) and Chloramine-T
(1.1 equiv.) in MeCN (2 mL) at rt under N2. After stirring for
16 h at rt, the reaction mixture was filtered through a plug of
silica and washed well with Et2O. Then, the filtrate was
evaporated under reduced pressure to give the crude product.
1
trans-6 and cis-6 (by H NMR spectroscopy). Purification
by flash chromatography on silica with petrol–Et2O (7:3) as
eluent gave aziridine trans-6 (271 mg, 36%) as a white
solid, mp 118–1198C (from EtOAc); RF(7:3 petrol–Et2O)
0.3; IR (CDCl3) 3072, 3052, 2962, 1429, 1159, 1090, 758,
1
652 cm21; H NMR (270 MHz; CDCl3) 7.70 (br d, 2H,
J¼8.5 Hz), 7.63–7.58 (m, 4H), 7.48–7.28 (m, 8H), 4.12
(quin., 1H, J¼7.5 Hz), 3.29 (br s, 2H), 2.43 (s, 3H), 2.18
(dd, 2H, J¼7.5, 14.0 Hz), 1.76 (dddd, 2H, J¼0.5, 1.5, 7.5,
14.0 Hz), 1.01 (s, 9H); 13C NMR (67.9 MHz; CDCl3) 144.1,
135.6, 135.4, 133.6, 129.7, 129.6, 127.62, 127.58, 70.7,
45.0, 36.3, 26.8, 21.6, 18.9; MS (CI, NH3) 492 (MþH)þ,
434, 338, 216, 196, 82; HRMS (CI, NH3) m/z calcd for
C28H33NO3SiS (MþH)þ 492.2029, found 492.2023. Anal.
calcd for C28H33NO3SiS: C, 68.39; H, 6.76; N, 2.85; found:
C, 67.5; H, 6.9; N, 2.5 and aziridine cis-6 (378 mg, 50%) as
a white solid, mp 89–908C (from EtOAc); RF(7:3 petrol–
Et2O) 0.2; IR (CDCl3) 3695, 3072, 3053, 2960, 2931, 2860,
4.1.2. General procedure B: rearrangement of aziridines
using
sec-butyllithium/diamine.
sec-Butyllithium
(2.9 equiv. of 1.2 M solution in cyclohexane) was added
dropwise to a stirred solution of (2)-sparteine or TMEDA
(2.9 equiv.) in Et2O (3 mL) at 278 8C under N2. After
stirring for 15 min, a solution of aziridine (0.5 mmol) in
Et2O (2 mL) was added dropwise via cannula. After stirring
for 4 h at 278 8C, the solution was allowed to warm to rt and
saturated NH4Cl(aq) (10 mL) was added. The layers were
separated and the aqueous layer was extracted with Et2O
(3£10 mL). The combined Et2O extracts were dried
(Na2SO4) and evaporated under reduced pressure to give
the crude product.
1
2260, 1159, 1093 cm21; H NMR (270 MHz; CDCl3) 7.94
(br d, 2H, J¼8.5 Hz), 7.64–7.59 (m, 4H), 7.46–7.31 (m,
8H), 4.36 (br t, 1H, J¼6.5 Hz), 3.36 (br s, 2H), 2.47 (s, 3H),
2.03 (dd, 2H J¼1.0, 15.0 Hz), 1.89 (br dd, 2H, J¼6.5,
15.0 Hz), 1.03 (s, 9H); 13C NMR (67.9 MHz; CDCl3) 143.9,
136.4, 135.8, 134.0, 129.5, 129.4, 127.6, 127.5, 72.7, 46.3,
37.9, 26.7, 21.6, 19.0; MS (CI, NH3) 492 (MþH)þ, 434,
338, 216, 196, 82; HRMS (CI, NH3) m/z calcd for
C28H33NO3SiS (MþH)þ 492.2029, found 492.2021. Anal.
calcd for C28H33NO3SiS: C, 68.39; H, 6.76; N, 2.85; found:
C, 68.1; H, 6.9; N, 2.6.
4.1.3. General procedure C: rearrangement of aziridines
using sec-butyllithium. sec-Butyllithium (2.9 equiv. of
1.2 M solution in cyclohexane) was added dropwise to a
stirred solution of aziridine (0.5 mmol) in Et2O or THF
(5 mL) at 2788C under N2. After stirring for 4 h at 2788C,
the solution was allowed to warm to rt and saturated
NH4Cl(aq) (10 mL) was added. The layers were separated
and the aqueous layer was extracted with Et2O (3£10 mL).

9786
P. O’Brien et al. / Tetrahedron 59 (2003) 9779–9791
4.4. 6-[(4-Methylphenyl)sulfonyl]-6-azabicyclo[3.1.0]-
hexane 7
Purification by flash chromatography on silica with
pentane–EtOAc (8:2) as eluent gave allylic sulfonamide
(R)-11 (85 mg, 67%, 38% ee by chiral HPLC) as a white
solid, mp 99–1008C (lit.,11 104–1068C); [a]D¼ þ27.8 (c
1.0 in CHCl3)(lit.,11 [a]D¼þ19.8 (c 1.5 in CHCl3) for 39%
ee); HPLC: Chiralcel AD-H, pentane–EtOH–TFA
(75:25:0.1), 1.0 mL min21, 230 nm, 12.5 min [(R)-11],
14.6 [(S)-11] and TsNH2 (9 mg, 10%) as a white solid.
Spectroscopic data of (R)-11 identical to that reported in the
literature.11,18a
Using general procedure A, cyclopentene (500 mg,
7.34 mmol), Chloramine-T trihydrate (2.3 g, 8.1 mmol)
and PhMe3NþBr32 (276 mg, 0.73 mmol) in MeCN
(30 mL) gave the crude product. Purification by flash
chromatography on silica with petrol–EtOAc (9:1) as eluent
gave aziridine 7 (1.54 g, 88%) as a white solid, mp 71–728C
(lit.,25 71–728C). Spectroscopic data identical to that
reported in the literature.18a,25
4.9. (1S)-2-Cyclohexen-1-ol (S)-14
4.5. 7-[(4-Methylphenyl)sulfonyl]-7-azabicyclo[4.1.0]-
heptane 8
n-Butyllithium (9.4 mL of a 2.2 M solution in hexanes,
20.4 mmol) was added dropwise to a stirred solution of
(1R,2S)-N-methyl-1-phenyl-2-(1-pyrrolidinyl)-1-propana-
mine28b (4.39 g, 20.4 mmol) in THF (100 mL) at 08C under
N2. After stirring for 30 min at 08C, cyclohexene oxide 13
(1.00 g, 10.2 mmol) was added dropwise and the resulting
solution was allowed to warm to rt. After stirring for 16 h at
rt, saturated NH4Cl(aq) (60 mL) was added and the layers
were separated. The aqueous layer was extracted with Et2O
(3£50 mL) and the combined Et2O extracts were washed
with 2 M HCl(aq) (2£50 mL), dried (Na2SO4) and evapo-
rated under reduced pressure (water bath ,408C) to give
the crude product. Purification by distillation gave alcohol
(S)-14 (370 mg, 37, 81% ee by Mosher’s ester formation)
as a colourless liquid, bp 62–638C/15 mm Hg(lit.,40 75–
768C/23 mm Hg); [a]D¼2132.9 (c 1.0 in CHCl3)(lit.,41
[a]D¼þ130.6 (c 1.21 in CHCl3) for (R)-14 of 99% ee).
Spectroscopic data identical to that reported in the
literature.42
Using general procedure A, cyclohexene (500 mg,
6.1 mmol), Chloramine-T trihydrate (1.89 g, 6.7 mmol)
and PhMe3NþBr32 (229 mg, 0.61 mmol) in MeCN
(30 mL) gave the crude product. Purification by flash
chromatography on silica with petrol–EtOAc (9:1) as eluent
gave aziridine 8 (1.13 g, 74%) as a white solid, mp 55–568C
(lit.,23a 55–568C). Spectroscopic data identical to that
reported in the literature.23a
4.6. 8-[(4-Methylphenyl)sulfonyl]-8-azabicyclo[5.1.0]-
octane 9
Using general procedure A, cycloheptene (500 mg,
5.2 mmol), Chloramine-T trihydrate (1.61 g, 5.3 mmol)
and PhMe3NþBr32 (195 mg, 0.52 mmol) in MeCN
(30 mL) gave the crude product. Purification by flash
chromatography on silica with petrol–EtOAc (9:1) as eluent
gave aziridine 9 (870 mg, 63%) as a white solid, mp 75–
768C; RF(1:1 petrol–Et2O) 0.4; IR (CHCl3) 3060, 2958,
4.10. N-[(1R)-2-Cyclohexen-1-yl]-4-methylbenzene-
sulfonamide (R)-11
2879, 1421, 1401, 1318, 1248, 1155, 1090 cm21 1H
;
NMR (270 MHz, CDCl3) 7.82 (br d, 2H, J¼8.5 Hz), 7.32
(br d, 2H, J¼8.5 Hz), 3.00–2.89 (m, 2H), 2.45 (s, 3H),
1.94–1.73 (m, 4H), 1.64–1.37 (m, 6H); 13C NMR
(67.9 MHz, CDCl3) 143.8, 135.7, 129.4, 127.3, 44.1, 30.8,
27.9, 25.0, 21.4; MS (CI, NH3) 266 (MþH)þ; HRMS (CI,
NH3) m/z calcd for C14H19NO2S (MþH)þ 266.1215, found
266.1214.
DEAD (404 mL, 2.56 mmol) was added dropwise to a
stirred solution of alcohol (S)-14 (100 mg, 1.20 mmol, 81%
ee), PPh3 (801 mg, 3.06 mmol) and TsNHBoc38 (446 mg,
1.53 mmol) in THF (3 mL) at rt under N2. After stirring for
10 h at rt, the solvent was evaporated under reduced
pressure to give the crude product. Purification by flash
chromatography on silica with petrol–EtOAc (8:2) as eluent
gave Boc protected allylic sulfonamide (R)-15 (340 mg,
95%) as an off-white solid. Spectroscopic data identical to
that described below.
4.7. 9-[(4-Methylphenyl)sulfonyl]-9-azabicyclo[6.1.0]-
nonane 10
Using general procedure A, cis-cyclooctene (3.00 g,
27.2 mmol), Chloramine-T trihydrate (8.44 g, 29.9 mmol)
and PhMe3NþBr32 (1.02 g, 2.7 mmol) in MeCN (150 mL)
gave the crude product. Purification by flash chromato-
graphy on silica with petrol–EtOAc (9:1) as eluent and then
recrystallisation from petrol–EtOAc gave aziridine 10
(1.50 g, 20%) as white needles, mp 124–1258C (lit.,38
1258C). Spectroscopic data identical to that reported in the
literature.39
TFA (263 mL, 3.41 mmol) was added dropwise to a stirred
solution of Boc protected allylic sulfonamide (R)-15
(100 mg, 0.29 mmol) in CH2Cl2 (1 mL) at 08C under N2.
The resulting solution was allowed to warm to rt. After
stirring for 1 h at rt, 5% NaHCO3(aq) (5 mL) was added and
the layers were separated. The aqueous layer was extracted
with CH2Cl2 (2£5 mL) and the combined CH2Cl2 extracts
were dried (Na2SO4) and evaporated under reduced pressure
to give the crude product. Purification by flash chroma-
tography on silica with petrol–EtOAc (8:2) as eluent gave
allylic sulfonamide (R)-11 (36 mg, 50%, 18% ee by chiral
HPLC) as a white solid, [a]D¼þ11.6 (c 1.0 in CHCl3);
HPLC: Chiralcel AD-H, pentane–EtOH–TFA (75:25:0.1),
1.0 mL min21, 230 nm, 12.3 min [(R)-11], 14.4 [(S)-11].
Spectroscopic data identical to that reported in the
literature.11,18a
4.8. N-[(1R)-2-Cyclohexen-1-yl]-4-methylbenzene-
sulfonamide (R)-11
Using general procedure B, aziridine 8 (126 mg, 0.5 mmol),
sec-butyllithium (1.19 mL of a 1.2 M solution in cyclo-
hexane, 1.45 mmol) and (2)-sparteine (333 mL,
1.45 mmol) in Et2O (5 mL) gave the crude product.

P. O’Brien et al. / Tetrahedron 59 (2003) 9779–9791
9787
4.11. tert-Butyl 2-cyclohexen-1-yl[(4-methylphenyl)-
sulfonyl]carbamate (R)-15
47%) as a white solid. Spectroscopic data of (R)-17 identical
to that reported in the literature.18a,43
A solution of di-tert-butyl dicarbonate (100 mg, 0.46 mmol)
in CH2Cl2 (0.8 mL) was added dropwise to a stirred solution
of allylic sulfonamide (R)-11 (100 mg, 0.4 mmol, 38% ee),
Et3N (61 mL, 0.44 mmol) and DMAP (5 mg, 40 mmol) in
CH2Cl2 (0.5 mL) at rt under nitrogen. After stirring for 16 h
at rt, the solvent was evaporated under reduced pressure.
EtOAc (2.5 mL) and 20% HCl(aq) (5 mL) were added and
the layers were separated. The organic layer was washed
with water (5 mL) and brine (5 mL), dried (Na2SO4) and
evaporated under reduced pressure to give the crude
product. Purification by flash chromatography on silica
with petrol–EtOAc (8:2) as eluent gave Boc-protected
allylic sulfonamide (R)-15 (122 mg, 87, 38% ee assumed)
as a white solid, mp 91–928C (from EtOAc); RF(8:2
petrol–EtOAc) 0.7; [a]D¼þ10.7 (c 1.0 in CHCl3); IR
(CH2Cl2) 3061, 2983, 2939, 2868, 1727, 1354, 1245,
4.14. tert-Butyl (1R)-2-cyclopenten-1-yl[(4-methyl-
phenyl)sulfonyl]carbamate (R)-18
A solution of di-tert-butyl dicarbonate (185 mg, 0.85 mmol)
in CH2Cl2 (2 mL) was added dropwise to a stirred solution
of allylic sulfonamide (R)-17 (175 mg, 0.74 mmol, 64% ee),
Et3N (113 mL, 0.81 mmol) and DMAP (9 mg, 73 mmol) in
CH2Cl2 (1 mL) at rt under nitrogen. After stirring for 16 h at
rt, the solvent was evaporated under reduced pressure.
EtOAc (5 mL) and 20% HCl(aq) (10 mL) were added and the
layers were separated. The organic layer was washed with
water (10 mL) and brine (10 mL), dried (Na2SO4) and
evaporated under reduced pressure to give the crude
product. Purification by flash chromatography on silica
with petrol–EtOAc (8:2) as eluent gave Boc-protected
allylic sulfonamide (R)-18 (172 mg, 69, 64% ee assumed) as
a white solid, mp 85–868C (from Et2O); RF(8:2 petrol–
EtOAc) 0.4; [a]D¼þ51.2 (c 1.0 in CHCl3); IR (CHCl3)
1
1153 cm21; H NMR (270 MHz, CDCl3) 7.82 (br d, 2H,
J¼8.5 Hz), 7.31 (br d, 2H, J¼8.5 Hz), 5.80–5.70 (m, 1H),
5.51 (br d, 1H, J¼10.0 Hz), 5.16–5.05 (m, 1H), 2.44 (s,
3H), 2.30–1.65 (m, 6H), 1.35 (s, 9H); 13C NMR
(100.6 MHz, CDCl3) 150.5, 143.8, 137.7, 129.2, 128.7,
128.2, 127.6, 83.9, 56.2, 28.3, 27.8, 23.9, 22.5, 21.5; MS
(CI, NH3) 369 (MþNH4)þ, 313, 269; HRMS (CI, NH3) m/z
calcd for C18H25NO4S (MþNH4)þ 369.1848, found
369.1851.
1
3022, 2983, 1724, 1352, 1151 cm21; H NMR (270 MHz,
CDCl3) 7.82 (br d, 2H, J¼8.5 Hz), 7.33 (br d, 2H, J¼
8.5 Hz), 5.95–5.84 (m, 1H), 5.69–5.55 (m, 2H), 5.16–5.05
(m, 1H), 2.71–2.53 (m, 1H), 2.48–2.26 (m, 2H), 2.44 (s,
3H), 2.16–1.92 (m, 1H), 1.32 (s, 9H); 13C NMR
(100.6 MHz, CDCl3) 150.6, 143.8, 137.9, 133.0, 129.7,
129.2, 127.6, 84.0, 64.6, 31.7, 28.7, 27.8, 21.6; MS (CI,
NH3) 355 (MþNH4)þ, 338, 299; HRMS (CI, NH3) m/z
calcd for C17H23NO4S (MþNH4)þ 355.1692, found
355.1693.
4.12. tert-Butyl (1R)-2-cyclohexen-1-ylcarbamate (R)-16
A solution of Boc-protected allylic sulfonamide (R)-15
(122 mg, 0.35 mmol) in THF (4 mL) was added dropwise to
a stirred solution of sodium (80 mg, 3.47 mmol) in ammonia
(approx. 20 mL) at 2788C under N2. After stirring for 1 h at
2788C, the solution was allowed to warm to rt and stirred at
rt for 1 h. Then, the solvent was allowed to evaporate by
removing the cold-trap condenser. Saturated NH4Cl(aq)
(10 mL) and EtOAc (10 mL) were added and the layers
were separated. The organic layer was washed with 0.1 M
NaOH(aq) (2£10 mL) and brine (10 mL), dried (Na2SO4)
and evaporated under reduced pressure to give the crude
product. Purification by flash chromatography on silica with
petrol–EtOAc (9:1) as eluent gave carbamate (R)-16
(35 mg, 51%, 38% ee assumed) as a white solid, mp 52–
538C (lit.,17 488C); RF(9:1 petrol–EtOAc) 0.3; [a]D¼þ30.0
(c 1.1 in CHCl3)(lit.,17 [a]D¼þ101 (c 2.8 in CHCl3) for (R)-
16 of 95% ee). Spectroscopic data identical to that reported
in the literature.17
4.15. tert-Butyl (1R)-2-cyclopenten-1-ylcarbamate (R)-19
A solution of Boc-protected allylic sulfonamide (R)-18
(130 mg, 0.39 mmol) in THF (4 mL) was added dropwise to
a stirred solution of sodium (89 mg, 3.85 mmol) in ammonia
(approx. 20 mL) at 2788C under N2. After stirring for 1 h at
2788C, the solution was allowed to warm to rt and stirred at
rt for 1 h. Then, the solvent was allowed to evaporate by
removing the cold-trap condenser. Saturated NH4Cl(aq)
(10 mL) and EtOAc (10 mL) were added and the layers
were separated. The organic layer was washed with 0.1 M
NaOH(aq) (2£10 mL) and brine (10 mL), dried (Na2SO4)
and evaporated under reduced pressure to give the crude
product. Purification by flash chromatography on silica with
petrol–EtOAc (9:1) as eluent gave carbamate (R)-19
(50 mg, 69, 64% ee assumed) as a white solid, mp 86–
878C (lit.,17 87.58C); RF(9:1 petrol–EtOAc) 0.2; [a]D¼
þ38.8 (c 1.0 in CH2Cl2)(lit.,17 [a]D¼þ77.0 (c 5.1 in
CH2Cl2) for (R)-19 of 87% ee). Spectroscopic data identical
to that reported in the literature.17
4.13. N-[(1R)-2-Cyclopenten-1-yl]-4-methylbenzene-
sulfonamide (R)-17
Using general procedure B, aziridine 7 (119 mg, 0.5 mmol),
sec-butyllithium (1.19 mL of a 1.2 M solution in cyclo-
hexane, 1.45 mmol) and (2)-sparteine (333 mL,
1.45 mmol) in Et2O (5 mL) gave the crude product.
Purification by flash chromatography on silica with
pentane–EtOAc (8:2) as eluent gave allylic sulfonamide
(R)-17 (46 mg, 39%, 64% ee by chiral HPLC) as a white
solid, mp 73–748C; [a]D¼þ15.4 (c 1.0 in CHCl3); HPLC:
4.16. 3-sec-Butyl-3-cyclopenten-1-yl tert-butyl-
(diphenyl)silyl ether 24
Using general procedure C, aziridine cis-6 (246 mg,
0.5 mmol) and sec-butyllithium (1.16 mL of a 1.25 M
solution in cyclohexane, 1.45 mmol) in Et2O (2.5 mL)
gave the crude product. Purification by flash chromato-
graphy on silica with pentane–Et2O (7:3) as eluent gave a
50:50 mixture (by 1H NMR spectroscopy) of diastereomeric
alkenes 24 (143 mg, 76%) as a colourless oil, RF(7:3
Chiralcel OJ-R, hexane–iPrOH (9:1), 1.0 mL min21
,
230 nm, 7.3 min [(S)-17], 7.6 [(R)-17] and TsNH2 (40 mg,

9788
P. O’Brien et al. / Tetrahedron 59 (2003) 9779–9791
petrol–Et2O) 0.65; IR (CH2Cl2) 3072, 2962, 2931, 2860,
1462, 1427, 1365, 1109 cm21; 1H NMR (270 MHz; CDCl3)
7.74–7.68 (m, 4H), 7.47–7.36 (m, 6H), 5.21 (br s, 1H),
4.58–4.50 (m, 1H), 2.47–2.42 (m, 2H), 2.13 and 2.11
(sextet, 1H, J¼6.5 Hz), 1.47–1.23 (m, 2H), 1.08 (s, 9H),
1.00 and 0.98 (d, 3H, J¼6.5 Hz), 0.85 and 0.81 (t, 3H,
J¼6.5 Hz); 13C NMR (67.9 MHz; CDCl3) 146.8 and 146.7,
135.73 and 135.71, 134.63 and 134.60, 129.4, 127.5, 119.8
and 119.7, 73.9 and 73.8, 42.1 and 42.0, 41.9 and 41.8, 37.0
and 36.8, 27.8 and 27.7, 26.9, 19.1 and 18.9, 18.5, 11.8 and
11.5 (some diastereomeric signals not resolvable); MS (CI,
NH3) 379 (MþH)þ, 123; HRMS (CI, NH3) m/z calcd for
C25H34OSi (MþH)þ 379.2457, found 379.2460.
4.20. (1R,3aR,6aR)-Octahydro-1-pentalenyl 2,4-dinitro-
benzoate (1R,3aR,6aR)-28
DEAD (1.47 mL of 85% purity reagent, 7.9 mmol) was
added dropwise to
a stirred solution of alcohol
(1S,3aR,6aR)-27 (400 mg, 3.2 mmol, 69% ee), PPh3
(2.49 g, 9.5 mmol) and 2,4-dinitrobenzoic acid (1.01 g,
4.75 mmol) in THF (10.5 mL) at rt under N2. After stirring
for 64 h at rt, the solvent was evaporated under reduced
pressure to give the crude product. Purification by flash
chromatography on silica with petrol–Et2O (9:1) as eluent
gave 2,4-dinitrobenzoate ester 28 (687 mg, 67%) as an off-
white solid, mp 57–588C (from Et2O); RF(9:1 petrol–Et2O)
0.2; [a]D¼215.3 (c 1.0 in CHCl3); IR (CH2Cl2) 3105, 3040,
1
4.17. 3-sec-Butyl-3-cyclopenten-1-yl tert-butyl-
(diphenyl)silyl ether 24
2954, 2866, 1733, 1549, 1350, 1288, 766 cm21; H NMR
(270 MHz, CDCl3) 8.76 (d, 1H, J¼2.0 Hz), 8.53 (dd, 1H,
J¼2.0, 8.5 Hz), 7.96 (d, 1H, J¼8.5 Hz), 5.17–5.11 (m, 1H),
2.69–2.47 (m, 2H), 2.01–1.74 (m, 4H), 1.69–1.14 (m, 6H);
13C NMR (100.6 MHz, CDCl3) 163.2, 148.8, 148.3, 133.3,
131.4, 127.3, 119.4, 86.2, 49.4, 41.8, 34.2, 31.5, 30.8, 30.4,
26.8; MS (CI, NH3) 338 (MþNH4)þ; HRMS (CI, NH3) m/z
calcd for C15H16N2O6 (MþNH4)þ 338.1352, found
388.1357.
Using general procedure C, aziridine cis-6 (246 mg,
0.5 mmol) and sec-butyllithium (1.16 mL of a 1.25 M
solution in cyclohexane, 1.45 mmol) in THF (2.5 mL)
gave the crude product. Purification by flash chromato-
graphy on silica with pentane–Et2O (7:3) as eluent gave
alkene 24 (133 mg, 70%) as a colourless oil. Spectroscopic
data identical to that described above.
4.21. (1R,3aR,6aR)-Octahydro-1-pentalenol (1R,3aR,
6aR)-29
4.18. N-[(1R,3aS,6aS)-Octahydro-1-pentalenyl]-4-
methylbenzenesulfonamide (1R,3aS,6aS)-25
1 M KOH(aq) (3 mL, 3.0 mmol) was added dropwise to a
stirred solution of 2,4-dinitrobenzoate ester 28 (637 mg,
2.0 mmol) in THF (5 mL) and MeOH (2 mL) at 08C. After
stirring for 30 min at 08C, the mixture was allowed to warm
to rt and Et2O (15 mL) was added. The layers were
separated and the aqueous layer was extracted with Et2O
(2£15 mL). The combined Et2O extracts were washed with
water (20 mL) and brine (20 mL), dried (Na2SO4) and
evaporated under reduced pressure to give the crude
product. Purification by flash chromatography on silica
using petrol–Et2O (1:1) as eluent gave alcohol 29 (208 mg,
83%) as a pale yellow oil, RF(1:1 petrol–Et2O) 0.2;
[a]D¼211.9 (c 0.3 in CHCl3); IR (CH2Cl2) 3614, 2953,
Using general procedure B, aziridine 10 (126 mg,
0.5 mmol), sec-butyllithium (1.19 mL of a 1.25 M solution
in cyclohexane, 1.45 mmol) and (2)-sparteine (333 mL,
1.45 mmol) in Et2O (5 mL) gave the crude product.
Purification by flash chromatography on silica with
pentane–EtOAc (8:2) as eluent gave bicyclic sulfonamide
(1R,3aS,6aS)-25 (100 mg, 71%, 66% ee by chiral HPLC) as
a white solid, mp 109–1108C (lit.,11 106–1088C);
[a]D¼þ21.2 (c 1.0 in CHCl3)(lit.,11 [a]D¼þ29.1 (c 1.0 in
CHCl3) for 75% ee); HPLC: Chiralcel OD, hexane–iPrOH
(96:4), 1.0 mL min21, 230 nm, 28.5 min [(1S,3aR,6aR)-25],
30.7 [(1R,3aS,6aS)-25]. Spectroscopic data identical to that
reported in the literature.11,18a
1
2864, 1450, 924, 758 cm21; H NMR (270 MHz, CDCl3)
3.90–3.85 (m, 1H), 2.66–2.50 (m, 1H), 2.30–2.17 (m, 1H),
2.04–1.88 (m, 1H), 1.83–1.63 (m, 4H), 1.60–1.34 (m, 3H),
1.30–1.10 (m, 3H); 13C NMR (67.9 MHz, CDCl3) 80.1,
52.6, 41.7, 34.3, 34.1, 31.5, 30.2, 26.5.
4.19. (1S,3aR,6aR)-Octahydro-1-pentalenol (1S,3aR,
6aR)-27
sec-Butyllithium (15 mL of 1.3 M solution in cyclohexane,
19.0 mmol) was added dropwise to a stirred solution of (2)-
sparteine (4.4 mL, 19.0 mmol) in Et2O (40 mL) at 2788C
under N2. After stirring for 30 min at 2788C, a solution of
cyclooctene oxide 26 (1.0 g, 7.9 mmol) in Et2O (20 mL)
was added dropwise via cannula. After stirring for 5 h at
2788C, the solution was allowed to warm to rt over 1 h and
stirred at rt for 16 h. 2 M HCl(aq) (40 mL) was added, the
layers were separated and the aqueous layer was extracted
with Et2O (3£40 mL). The combined Et2O extracts were
washed with saturated NaHCO3(aq) (40 mL) and brine
(40 mL), dried (Na2SO4) and evaporated under reduced
pressure to give the crude product. Purification by flash
chromatography on silica using petrol–Et2O (1:1) as eluent
gave alcohol (1S,3aR, 6aR)-27 (837 mg, 84, 69% ee by
chiral HPLC of the 2,4-dinitrobenzoate4) as a colourless oil,
RF(1:1 petrol–Et2O) 0.4. Spectroscopic data identical to
that reported in the literature.4
4.22. tert-Butyl (1S,3aR,6aR)-octahydro-1-pentalenyl-
[(4-methylphenyl)sulfonyl]carbamate (1S,3aR,6aR)-30
DEAD (620 mL of 85% purity reagent, 3.37 mmol) was
added dropwise to a stirred solution of alcohol 29 (170 mg,
1.35 mmol), PPh3 (1.06 g, 4.04 mmol) and TsNHBoc38
(548 mg, 2.02 mmol) in THF (4 mL) at rt under N2. After
stirring for 64 h at rt, the solvent was evaporated under
reduced pressure to give the crude product. Purification by
flash chromatography on silica with petrol–Et2O (7:3) as
eluent gave Boc protected bicyclic sulfonamide 30 (83 mg,
16%) as a colourless oil, RF(7:3 petrol–Et2O) 0.4; [a]D¼
215.0 (c 1.0 in CHCl3); IR (CDCl3) 2953, 2867, 1722, 1369
1
1155, 924 cm21; H NMR (270 MHz, CDCl3) 7.79 (br d,
2H, J¼8.5 Hz), 7.30 (br d, 2H, J¼8.5 Hz), 4.46 (ddd, 1H,
J¼6.0, 8.0, 12.0 Hz), 2.76 (quin., 1H, J¼8.0 Hz), 2.60–2.37
(m, 2H), 2.44 (s, 3H), 1.97–1.84 (m, 1H), 1.80–1.55 (m,

P. O’Brien et al. / Tetrahedron 59 (2003) 9779–9791
9789
5H), 1.53–1.10 (m, 3H), 1.35 (s, 9H); 13C NMR (67.9 MHz,
CDCl3) 151.6, 143.6, 138.2, 129.1, 127.5, 83.9, 63.2, 46.5,
41.1, 35.4, 29.6, 28.3, 27.8, 27.4, 27.1, 21.5; MS (CI, NH3)
397 (MþNH4)þ, 341, 297; HRMS (CI, NH3) m/z calcd for
C20H29NO4S (MþNH4)þ 397.2161, found 397.2163.
RF(1:1 petrol–Et2O) 0.2; [a]D¼211.0 (c 1.0 in CHCl3); IR
1
(CH2Cl2) 3373, 2954, 1279, 1252, 1155 cm21; H NMR
(270 MHz, CDCl3) 7.79 (br d, 2H, J¼8.0 Hz), 7.30 (br d,
2H, J¼8.0 Hz), 5.19 (d, 1H, J¼7.0 Hz), 3.13 (br quin., 1H,
J¼7.0 Hz), 2.49–2.35 (m, 1H), 2.43 (s, 3H), 2.19–2.08 (m,
1H), 1.90–1.77 (m, 1H), 1.74–1.64 (m, 1H), 1.62–1.15 (m,
7H), 1.12–0.97 (m, 1H); 13C NMR (67.9 MHz, CDCl3)
143.0, 138.0, 129.5, 127.0, 61.4, 50.6, 41.3, 33.7, 33.6, 31.5,
30.8, 25.5, 21.5; MS (CI, NH3) 297 (MþNH4)þ, 280
(MþH)þ; HRMS (CI, NH3) m/z calcd for C15H21NO2S
(MþH)þ 280.1371, found 280.1366.
4.23. N-[(1S,3aR,6aR)-Octahydro-1-pentalenyl]-4-
methylbenzenesulfonamide (1S,3aR,6aR)-25
TFA (207 mL, 2.62 mmol) was added dropwise to a stirred
solution of Boc protected bicyclic sulfonamide 30 (83 mg,
0.22 mmol) in CH2Cl2 (1 mL) at 08C under N2. The
resulting solution was allowed to warm to rt. After stirring
for 2.5 h at rt, the solvent was evaporated under reduced
pressure. Excess TFA was removed by azeotroping with
CHCl3 (4£5 mL) to give the crude product. Purification by
flash chromatography on silica with petrol–Et2O (1:1) as
eluent gave bicyclic sulfonamide (1S,3aR,6aR)-25 (41 mg,
67, 70% ee by chiral HPLC) as a white solid, [a]D¼226.5
(c 1.0 in CHCl3)(lit.,11 [a]D¼þ29.1 (c 1.0 in CHCl3) for
75% ee); HPLC: Chiralcel OD, hexane–iPrOH (96:4),
1.0 mL min21, 230 nm, 28.5 min [(1S,3aR,6aR)-25], 30.7
[(1R,3aS,6aS)-25]. Spectroscopic data identical to that
reported in the literature.11,18a
4.26. N-[2-Cyclopenten-1-yl]-4-methylbenzene-
sulfonamide rac-17
Using general procedure B, aziridine 7 (119 mg, 0.5 mmol),
sec-butyllithium (1.16 mL of a 1.25 M solution in cyclo-
hexane, 1.45 mmol) and TMEDA (222 mL, 1.45 mmol) in
Et2O (5 mL) gave the crude product. Purification by flash
chromatography on silica with pentane–EtOAc (8:2) as
eluent gave allylic sulfonamide rac-17 (27 mg, 23%) as a
colourless oil and TsNH2 (33 mg, 38%) as a white solid.
4.27. N-[2-Cyclopenten-1-yl]-4-methylbenzene-
sulfonamide rac-17
4.24. tert-Butyl (1R,3aR,6aR)-octahydro-1-pentalenyl-
[(4-methylphenyl)sulfonyl]carbamate (1R,3aR,6aR)-31
Using general procedure C, aziridine 7 (119 mg, 0.5 mmol)
and sec-butyllithium (1.16 mL of a 1.25 M solution in
cyclohexane, 1.45 mmol) in Et2O (5 mL) gave the crude
product. Purification by flash chromatography on silica with
pentane–EtOAc (8:2) as eluent gave allylic sulfonamide
rac-17 (9 mg, 8%) as a white solid and TsNH2 (59 mg, 69%)
as a white solid.
DEAD (370 mL of 85% purity reagent, 1.98 mmol) was
added dropwise to a stirred solution of alcohol (1S,3aR,
6aR)-27 (100 mg, 0.79 mmol, 69% ee), PPh3 (624 mg,
2.38 mmol) and TsNHBoc38 (322 mg, 1.19 mmol) in THF
(2.3 mL) at rt under N2. After stirring for 64 h at rt, the
solvent was evaporated under reduced pressure to give
the crude product. Purification by flash chromatography on
silica with petrol–Et2O (8:2) as eluent gave Boc protected
bicyclic sulfonamide 31 (149 mg, 50%) as a white solid, mp
88–898C (from Et2O), RF(8:2 petrol–Et2O) 0.5; [a]D¼
230.2 (c 1.0 in CHCl3); IR (CDCl3) 2951, 2866, 1720, 1350
1153 cm21; 1H NMR (270 MHz, CDCl3) 7.77 (br d, 2H, J¼
8.0 Hz), 7.29 (br d, 2H, J¼8.0 Hz), 4.42–4.29 (m, 1H),
2.96–2.80 (m, 1H), 2.70–2.52 (m, 1H), 2.43 (s, 3H), 2.35–
2.15 (m, 1H), 2.03–1.79 (m, 2H), 1.72–1.48 (m, 5H), 1.44–
1.24 (m, 1H), 1.33 (s, 9H), 1.20–1.00 (m, 1H); 13C NMR
(67.9 MHz, CDCl3) 150.6, 143.6, 138.1, 129.2, 127.5, 84.0,
65.6, 45.6, 42.2, 33.0, 31.5, 31.3, 31.0, 27.9, 24.8, 21.5; MS
(CI, NH3) 397 (MþNH4)þ, 380 (MþH)þ, 280; HRMS (CI,
NH3) m/z calcd for C20H29NO4S (MþH)þ 380.1896, found
380.1893.
4.28. N-[2-Cyclopenten-1-yl]-4-methylbenzene-
sulfonamide rac-17
Using general procedure C, aziridine 7 (119 mg, 0.5 mmol)
and sec-butyllithium (1.16 mL of a 1.25 M solution in
cyclohexane, 1.45 mmol) in THF (5 mL) gave the crude
product. Purification by flash chromatography on silica with
pentane–EtOAc (8:2) as eluent gave allylic sulfonamide
rac-17 (12 mg, 10%) as a white solid and TsNH2 (48 mg,
56%) as a white solid.
4.29. N-[2-Cyclohexen-1-yl]-4-methylbenzene-
sulfonamide rac-11
Using general procedure B, aziridine 8 (126 mg, 0.5 mmol),
sec-butyllithium (1.19 mL of a 1.2 M solution in cyclo-
hexane, 1.45 mmol) and TMEDA (222 mL, 1.45 mmol) in
Et2O (5 mL) gave the crude product. Purification by flash
chromatography on silica with pentane–EtOAc (8:2) as
eluent gave allylic sulfonamide rac-11 (28 mg, 22%) as a
pale yellow oil.
4.25. N-[(1R,3aR,6aR)-Octahydro-1-pentalenyl]-4-
methylbenzenesulfonamide (1R,3aR,6aR)-32
TFA (314 mL, 4.08 mmol) was added dropwise to a stirred
solution of Boc protected bicyclic sulfonamide 31 (129 mg,
0.34 mmol) in CH2Cl2 (1.5 mL) at 08C under N2. The
resulting solution was allowed to warm to rt. After stirring
for 2.5 h at rt, the solvent was evaporated under reduced
pressure. Excess TFA was removed by azeotroping with
CHCl3 (4£5 mL) to give the crude product. Purification by
flash chromatography on silica with petrol–Et2O (1:1) as
eluent gave bicyclic sulfonamide (1R,3aR,6aR)-32 (72 mg,
76, 69% ee assumed) as a white solid, mp 100–1018C;
4.30. N-[2-Cyclohexen-1-yl]-4-methylbenzene-
sulfonamide rac-11
Using general procedure C, aziridine 8 (126 mg, 0.5 mmol)
and sec-butyllithium (1.16 mL of a 1.25 M solution in
cyclohexane, 1.45 mmol) in Et2O (5 mL) gave the crude
product. Purification by flash chromatography on silica with

9790
P. O’Brien et al. / Tetrahedron 59 (2003) 9779–9791
pentane–EtOAc (8:2) as eluent gave allylic sulfonamide
rac-17 (72 mg, 57%) as a white solid and TsNH2 (26 mg,
30%) as a white solid.
0.5 mmol) and sec-butyl-lithium (1.16 mL of a 1.25 M
solution in cyclohexane, 1.45 mmol) in THF (5 mL) gave
the crude product. Purification by flash chromatography on
silica with pentane–EtOAc (8:2) as eluent gave bicyclic
sulfonamide rac-25 (50 mg, 36%) as a white solid.
4.31. N-[2-Cyclohexen-1-yl]-4-methylbenzene-
sulfonamide rac-11
Using general procedure C, aziridine 8 (126 mg, 0.5 mmol)
and sec-butyllithium (1.16 mL of a 1.25 M solution in
cyclohexane, 1.45 mmol) in THF (5 mL) gave the crude
product. Purification by flash chromatography on silica with
pentane–EtOAc (8:2) as eluent gave allylic sulfonamide
rac-17 (5 mg, 4%) as a white solid and TsNH2 (48 mg, 56%)
as a white solid.
Acknowledgements
We thank the EPSRC and GlaxoSmithKline for a CASE
award (to C. M. R.). Professor P. Mu¨ller (University of
Geneva) is especially thanked for exchange of unpublished
results and several useful discussions.
4.32. N-[(1S p,2R p,6R p)-Bicyclo[4.1.0]hept-2-yl]-4-
methylbenzenesulfonamide 36
References
Using general procedure C, aziridine 9 (133 mg, 0.5 mmol)
and sec-butyllithium (1.16 mL of a 1.25 M solution in
cyclohexane, 1.45 mmol) in Et2O (5 mL) gave the crude
product. Purification by flash chromatography on silica with
petrol–Et2O (1:1) as eluent gave aziridine 9 (23 mg, 17%)
as a colourless oil; cyclo-propylsulfonamide 36 (30 mg,
23%) as a colourless oil, RF(1:1 petrol–Et2O) 0.22; IR
1. Cope, A. C.; Tiffany, B. D. J. Am. Chem. Soc. 1951, 73, 4158.
2. Satoh, T. Chem. Rev. 1996, 96, 3303.
3. Hodgson, D. M.; Gras, E. Synthesis 2002, 1625.
4. Hodgson, D. M.; Lee, G. P.; Marriott, R. E.; Thompson, A. J.;
Wisedale, R.; Witherington, J. J. Chem. Soc., Perkin Trans. 1
1998, 2151.
5. For recent examples, see: (a) Hodgson, D. M.; Stent, M. A. H.;
Stefane, B.; Wilson, F. X. Org. Biomol. Chem. 2003, 1, 1139.
(b) Hodgson, D. M.; Maxwell, C. R.; Miles, T. J.; Paruch, E.;
Stent, M. A. H.; Matthews, I. R.; Wilson, F. X.; Witherington,
J. Angew. Chem. Int. Ed. 2002, 41, 4313. (c) Hodgson, D. M.;
Gras, E. Angew. Chem. Int. Ed. 2002, 41, 2376. (d) Hodgson,
D. M.; Cameron, I. D.; Christlieb, M.; Green, R.; Lee, G. P.;
Robinson, L. A. J. Chem. Soc., Perkin Trans. 1 2001, 2161.
(e) Hodgson, D. M.; Robinson, L. A.; Jones, M. L.
Tetrahedron Lett. 1999, 40, 8637. (f) Hodgson, D. M.;
Maxwell, C. R.; Matthews, I. R. Tetrahedron: Asymmetry
1999, 10, 1847.
(CH2Cl2) 3373, 2937, 2864, 1599, 1410, 1329, 1159 cm21
;
1H NMR (400 MHz, CDCl3) 7.80 (br d, 2H, J¼8.0 Hz), 7.30
(br d, 2H, J¼8.0 Hz), 4.47 (d, 1H, J¼8.0 Hz), 3.76–3.66
(m, 1H), 2.43 (s, 3H), 1.89–1.79 (m, 1H), 1.67–1.56 (m,
1H), 1.40–1.23 (m, 2H), 1.18–1.00 (m, 2H), 0.94–0.82 (m,
2H), 0.46 (dt, 1H, J¼5.0, 9.0 Hz), 0.08 (q, 1H, J¼5.0 Hz);
13C NMR (100.6 MHz, CDCl3) 143.1, 138.6, 129.6, 127.0,
50.3, 28.4, 22.6, 21.6, 21.5, 15.9, 12.5, 8.0; MS (CI, NH3)
283 (MþNH4)þ, 266 (MþH)þ; HRMS (CI, NH3) m/z calcd
for C14H19NO2S (MþH)þ 266.1215, found 266.1214; and
TsNH2 (27 mg, 31%) as a white solid.
6. Alezra, V.; Bonin, L.; Micouin, L.; Policar, C.; Husson, H.-P.
Eur. J. Org. Chem. 2001, 2589.
´
7. (a) Quast, H.; Weise Velez, C. A. Angew. Chem., Int. Ed. Engl.
4.33. N-[(1R p,3aS p,6aS p)-Octahydro-1-pentalenyl]-4-
methylbenzenesulfonamide rac-25
´
1974, 13, 342. (b) Quast, H.; Weise Velez, C. A. Angew.
Using general procedure B, aziridine 10 (140 mg,
0.5 mmol), sec-butyllithium (1.2 mL of a 1.2 M solution
in cyclohexane, 1.45 mmol) and TMEDA (219 mL,
1.45 mmol) in Et2O (10 mL) gave the crude product.
Purification by flash chromatography on silica with
pentane–EtOAc (8:2) as eluent gave bicyclic sulfonamide
rac-25 (36 mg, 26%) as a pale yellow oil.
´
Chem., Int. Ed. Engl. 1978, 17, 213. (c) Hayes, J. F.; Prevost,
N.; Prokes, I.; Shipman, M.; Slawin, A. M. Z.; Twin, H. Chem.
Commun. 2003, 1344.
8. Florio, S.; Troisi, V.; Capriati, V.; Ingrosso, G. Tetrahedron
Lett. 1999, 40, 6101.
9. Katritzky, A. R.; Yao, J.; Bao, W.; Qi, M.; Steel, P. J. J. Org.
Chem. 1999, 64, 346.
10. Reutrakul, V.; Prapansiri, V.; Panyachotipun, C. Tetrahedron
Lett. 1984, 25, 1949.
11. Mu¨ller, P.; Nury, P. Helv. Chim. Acta 2001, 84, 662.
12. Vedejs, E.; Kendall, J. T. J. Am. Chem. Soc. 1997, 119, 6941.
13. Beak, P.; Wu, S.; Yum, E. K.; Jun, Y. M. J. Org. Chem. 1994,
59, 276.
4.34. N-[(1R p,3aS p,6aS p)-Octahydro-1-pentalenyl]-4-
methylbenzenesulfonamide rac-25
Using general procedure C, aziridine 10 (140 mg,
0.5 mmol) and sec-butyllithium (1.16 mL of a 1.25 M
solution in cyclohexane, 1.45 mmol) in Et2O (5 mL) gave
the crude product. Purification by flash chromatography on
silica with pentane–EtOAc (8:2) as eluent gave aziridine 10
(32 mg, 23%) as a white solid and bicyclic sulfonamide
rac-25 (48 mg, 34%) as a white solid.
14. For reviews, see: (a) Eames, J. Eur. J. Org. Chem. 2002, 393.
(b) Magnus, A.; Bertilsson, S. K.; Andersson, P. G. Chem. Soc.
Rev. 2002, 31, 223. (c) O’Brien, P. J. Chem. Soc., Perkin
Trans. 1 1998, 1439.
15. For recent examples, see: (a) Johansson, A.; Abrahamsson, P.;
Davidsson, O. Tetrahedron: Asymmetry 2003, 14, 1261.
(b) Malhotra, S. V. Tetrahedron: Asymmetry 2003, 14, 645.
(c) Gayet, A.; Bertilsson, S.; Andersson, P. G. Org. Lett. 2002,
4.35. N-[(1R p,3aS p,6aS p)-Octahydro-1-pentalenyl]-4-
methylbenzenesulfonamide rac-25
¨
4, 3777. (d) Bertilsson, S. K.; Sodergren, M. J.; Andersson,
P. G. J. Org. Chem. 2002, 67, 1567. (e) Pettersen, D.;
Using general procedure C, aziridine 10 (140 mg,

P. O’Brien et al. / Tetrahedron 59 (2003) 9779–9791
9791
Amedjkouh, M.; Nilsson Lill, S. O.; Ahlberg, P. J. Chem. Soc.,
Perkin Trans. 1 2002, 1397. (f) Seki, A.; Asami, M.
Tetrahedron 2002, 58, 4655.
Harris, G. D.; Weinreb, S. M. Tetrahedron Lett. 1989, 30,
5709.
28. (a) de Sousa, S. E.; O’Brien, P.; Steffens, H. C. Tetrahedron
Lett. 1999, 40, 8423. (b) Colman, B.; de Sousa, S. E.; O’Brien,
P.; Towers, T. D.; Watson, W. Tetrahedron: Asymmetry 1999,
10, 4175.
16. For examples and leading references, see: (a) O’Brien, P.;
Pilgram, C. D. Org. Biomol. Chem. 2003, 1, 523. (b) de Sousa,
S. E.; O’Brien, P.; Pilgram, C. D. Tetrahedron 2002, 58, 4643.
17. da Zhang, Z.; Scheffold, R. Helv. Chim. Acta 1993, 76, 2602.
18. (a) Mordini, A.; Russo, F.; Valacchi, M.; Zani, L.;
Degl’Innocenti, A.; Reginato, G. Tetrahedron 2002, 58,
7153. (b) Mordini, A.; Sbaragli, L.; Valacchi, M.; Russo, F.;
Reginato, G. Chem. Commun. 2002, 778.
´
29. Pettersen, D.; Amedjkouh, M.; Nilsson Lill, S. O.; Dahlen, K.;
Ahlberg, P. J. Chem. Soc., Perkin Trans. 2 2001, 1654.
30. Shull, B. K.; Sakai, T.; Nichols, J. B.; Koreeda, M. J. Org.
Chem. 1997, 62, 8294.
31. (a) Crandall, J. K.; Lin, L.-H. C. J. Am. Chem. Soc. 1967, 89,
4526. (b) Crandall, J. K.; Lin, L.-H. C. J. Am. Chem. Soc.
1967, 89, 4527.
19. (a) Morgan, K. M.; O’Connor, M. J.; Humphrey, J. L.;
Buschman, K. E. J. Org. Chem. 2001, 66, 1600. (b) Morgan,
K. M.; Gronert, S. J. Org. Chem. 2000, 65, 1461. (c) Ramirez,
A.; Collum, D. B. J. Am. Chem. Soc. 1999, 121, 11114.
(d) Hodgson, D. M.; Gibbs, A. R. Tetrahedron Lett. 1997, 38,
8907. (e) Morgan, K. M.; Gajewski, J. J. J. Org. Chem. 1996,
61, 820.
32. Doris, E.; Dechoux, L.; Mioskowski, C. Tetrahedron Lett.
1994, 35, 7943.
33. (a) Dechoux, L.; Doris, E.; Mioskowski, C. Chem. Commun.
1996, 549. (b) Doris, E.; Dechoux, L.; Mioskowski, C. Synlett
1998, 337.
20. Dearden, M. J.; Firkin, C. R.; Hermet, J.-P. R.; O’Brien, P.
J. Am. Chem. Soc. 2002, 124, 11870.
34. (a) Hodgson, D. M.; Stent, M. A. H.; Wilson, F. X. Synthesis
2002, 1445. (b) Hodgson, D. M.; Miles, T. J.; Witherington, J.
Synlett 2002, 310. (c) Hodgson, D. M.; Stent, M. A. H.;
Wilson, F. X. Org. Lett. 2001, 3, 3401.
21. Caine, D.; O’Brien, P.; Rosser, C. M. Org. Lett. 2002, 4, 1923.
22. For a preliminary communication on part of this work, see:
O’Brien, P.; Rosser, C. M.; Caine, D. Tetrahedron Lett. 2003,
44, 6613.
35. Boeckman, R. K. Tetrahedron Lett. 1977, 4281.
36. Burchat, A. F.; Chong, J. M.; Nielson, N. J. Organomet. Chem.
1997, 63, 66.
23. (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Am. Chem.
¨
Soc. 1994, 116, 2742. (b) Sodergren, M. J.; Alonso, D. A.;
Bedekar, A. V.; Andersson, P. G. Tetrahedron Lett. 1997, 38,
6897.
37. Neustadt, B. R. Tetrahedron Lett. 1994, 35, 379.
38. Sharpless, K. B. J. Org. Chem. 1978, 43, 2544.
39. Chanda, B. M.; Vyas, R.; Bedekar, A. V. J. Org. Chem. 2001,
66, 30.
24. (a) Ando, T.; Kano, D.; Minakata, S.; Ryu, I.; Komatsu, M.
Tetrahedron 1998, 54, 13485. (b) Ali, S. I.; Nikalje, M. D.;
Sudalai, A. Org. Lett. 1999, 1, 705. (c) Thakur, V. V.; Sudalai,
A. Tetrahedron Lett. 2003, 44, 989.
40. Hill, R. K.; Morgan, J. W. J. Org. Chem. 1968, 33, 927.
41. Fukazawa, T.; Hashimoto, T. Tetrahedron: Asymmetry 1993,
4, 2323.
25. Jeong, J. U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless,
K. B. J. Am. Chem. Soc. 1998, 120, 6844.
42. Saravanan, P.; DattaGupta, A.; Bhuniya, D.; Singh, V. K.
Tetrahedron 1997, 53, 1855.
26. Mu¨ller, P.; Riegert, D.; Bernardinelli, G. Personal communi-
cation.
27. Henry, J. R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.;
43. Kim, D. Y.; Kim, H. S.; Choi, Y. J.; Mang, J. Y.; Lee, K. Synth.
Commun. 2001, 31, 2463.