A stereochemically flexible approach to pyrrolidines based on 5-endo-trig iodocyclisations of homoallylic sulfonamides

Article abstract of DOI:10.1039/b008537p

5-endo-trig Iodocyclisations of the (E)-homoallylic sulfonamides 24 in the presence of potassium carbonate give excellent yields of trans-2,5-disubstituted-3-iodopyrrolidines 36. In the absence of base, these initial kinetic products undergo rapid isomeri

Full text of DOI:10.1039/b008537p

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A stereochemically flexible approach to pyrrolidines based on
5-endo-trig iodocyclisations of homoallylic sulfonamides
Andrew D. Jones,a David W. Knight*ab and David E. Hibbsb
1
a School of Chemistry, Nottingham University, University Park, Nottingham, UK NG7 2RD
b Chemistry Department, Cardiff University, P.O. Box 912, Cardiff, UK CF10 3TB
Received (in Cambridge, UK) 23rd October 2000, Accepted 22nd March 2001
First published as an Advance Article on the web 26th April 2001
5-endo-trig Iodocyclisations of the (E)-homoallylic sulfonamides 24 in the presence of potassium carbonate give
excellent yields of trans-2,5-disubstituted-3-iodopyrrolidines 36. In the absence of base, these initial kinetic products
undergo rapid isomerization to the corresponding cis-2,5-disubstituted pyrrolidines 37 by a ring opening–reclosure
mechanism to these thermodynamic isomers. Octahydroindole derivatives 40 and 41 can be similarly obtained from
the alk-2-enylcyclohexylsulfonamides 31 and 32. Attempted 5-endo-trig cyclisations of homoallylic carbamates
were generally unsuccessful and resulted instead in relatively inefficient 6-exo cyclisations involving the carbamate
carbonyl group. Deiodination provides both trans- and cis-2,5-disubstituted pyrrolidines [49 and 50]; the free amine
derived from trans-2-butyl-5-pentylpyrrolidine 49d is a component of a fire ant defence pheromone. X-Ray
crystallography was carried out for 37f, 36, and 37k.
One of the fundamental tenets of Baldwin’s rules is that 5-exo-
trig cyclisations 1 are amongst the most favoured while 5-endo-
trig processes 2 are the least favoured (Fig. 1).1 However, it is
now well established from results obtained by a number of
groups,2 including ours,3 that 5-endo-trig cyclisations of
(E)-homoallylic alcohols 3 can be induced using both iodonium
and phenylselenenium cations leading to excellent yields of
Fig. 1
tetrahydrofurans [e.g. 4] (Scheme 1). Such cyclisations are
selection.5 As electrophile-driven reactions, these cyclisations
are not exceptions to Baldwin’s rules; indeed, a nucleophilic
centre, when positioned such that it can undergo a competing
5-exo cyclisation will react preferentially, except in exceptional
circumstances.2,3,6 Further, the additional demands present in
such 5-endo cyclisations seem to emphasise the requirement for
the well-ordered and probably late transition state conform-
ation 6,7 of the lowest possible energy, in contrast to the less
Scheme 1
stereoselective 5-exo cyclisations. In the light of the synthetic
utility of these reactions, we asked the perhaps obvious ques-
tion: is it possible to carry out similar cyclisations with homo-
usually highly stereoselective, in contrast to similar 5-exo-trig
cyclisations;4 (Z)-homoallylic alcohols can similarly be con-
allylic amine derivatives 7 and thus define a new and equally
verted into the all-cis-diastereoisomers 5, although in poorer
useful approach to pyrrolidines 8 (Scheme 2)? Herein, we report
Scheme 2
yields.3 These observations can be explained by the transition
state conformation 6 wherein the selective generation of the
in full that this is indeed possible and describe some of the
surprises associated with this chemistry.8
2,5-trans-iodotetrahydrofurans 4 is controlled by the pseudo-
equatorial positioning of the substituent R1. The necessary
‘axial’ position which has to be adopted by the alkene substitu-
ent (Z) accounts for the poorer yields obtained from simple
Results and discussion
(Z)-homoallylic alcohols, although
hydroxy group results in much higher yields and stereo-
a
suitably positioned
Our first consideration was the nature of the nitrogen pro-
tecting group R3 (Scheme 2). That the amine group required
1182
J. Chem. Soc., Perkin Trans. 1, 2001, 1182–1203
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b008537p

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protection seemed plain from studies of the reactions between
amines and molecular iodine which result in N-iodination, the
formation of molecular complexes and, in some cases, unusual
oxidation processes.9 Further, the stability of an iodo-
pyrrolidine with no N-protection was an additional point of
concern. It seemed unlikely that carbamates or N-acyl deriv-
atives would be an optimum choice. The disfavoured nature of
5-endo-trig cyclisations suggested that such substrates as 9 would
5-exo cyclisations seem to be more flexible, as these are possible
with both N-alkylpent-4-enamines24,25 and the correspond-
ing carbamates.26 By careful choice of conditions and
reagents, these can be highly stereoselective, giving the 2,5-trans
diastereoisomers as the kinetic products and the corresponding
2,5-cis isomers under thermodynamic conditions. Interestingly,
an isolated example of a 5-endo cyclisation has been reported:
treatment of N-propylbut-3-enamine with mercury() chloride
in tetrahydrofuran gives 3-chloromercurio-1-propylpyrrol-
idine.24 A similar mechanism probably operates in the gener-
ation of bis-mercuriopyrrolidines by the addition of tosylamine
and mercury() nitrate to 1,4-dienes leading to β-mercurio-
pyrrolidines.27 Direct 5-exo sulfenocyclisation of N-benzoyl-
pent-4-enamines (13; R3 = Ph)28 and of N-tosyl-2-allylanilines29
is also viable, given that an activated sulfenium species is
employed (Scheme 3). Alternatively, the necessary episulfonium
Scheme 3
species can be generated by a prior mercury()-induced cyclis-
ation30 or by the addition of benzenesulfenyl chloride to an
N-alkylbut-3-enamine followed by intramolecular displacement
of the halogen by sulfur.31 In this latter example, the overall
reaction is a 5-endo process. There are also many examples of
palladium-induced 5-exo cyclisations of these types of amine
derivatives (9, 13); an advantage of this methodology is the
range of additional substituents which can be incorporated by
further reactions of the intermediate palladium species.32
In view of the chemistry outlined above, we chose to use the
sulfonamide group for protection of the nitrogen function in
our initial studies of the prospects for effecting 5-endo-trig
iodocyclisations of homoallylic amine derivatives, since we
expected that it would not participate directly in such reactions.
More positively, this functionality had previously been found
to be particularly reactive in electrophile-induced cyclisations,
presumably because of its ability to lower the pKa of the N–H
bond.15,33 Thus, we required a series of sulfonamides 15. As we
preferentially undergo a 6-exo cyclisation (10) to give, at least
initially, the heterocycles 11. Alternatively, loss of the carb-
amate alkyl group, certainly plausible if an N-Boc or Cbz group
were to be used (i.e. R = But or PhCH2), would lead to the cyclic
carbamates 12, also by a 6-exo process. In these considerations,
we were guided by previous reports on the 5-exo-trig cyclisation
of pent-4-enamine derivatives 13, leading to pyrrolidines 14,
and related cyclisations of pent-4-enamides leading, when
successful, to the corresponding 5-membered lactams.4 For
example, conversion of pent-4-enamides into the corresponding
N,O-bis(trimethylsilyl) derivatives10 or thioimidates11 is neces-
sary for the nitrogen to act as the nucleophile, leading to
lactams; similarly, direct iodocyclisation of unsaturated thio-
amides results in sulfur acting as the nucleophilic centre,
leading to tetrahydrothiophene derivatives.12 However, both
N-tosyl-3-hydroxypent-4-enamines13 and related unsaturated
N-alkoxyamines14 undergo smooth iodocyclisations while
various N-acyl derivatives are unreactive,13 perhaps because
of an insufficiently low pKa value of the N–H bond.15 Direct 5-
exo iodocyclisation of an amide is possible in the case of but-3-
enyl-β-lactams to give carbapenems, not surprisingly, as the
alternative cyclisation via oxygen would lead to a rather
strained bridged species.16 Apparent examples of 5-endo
amide cyclisations in a similar system17 or ones which lead to
β-alkoxypyrrolidines18 may, in reality, proceed by a 5-exo pro-
cess6 or by a more complex mechanism, respectively. Similarly,
selenocyclisations of unmodified pent-4-enamides tend to
result in reaction via oxygen rather than nitrogen to give
tetrahydrofuran derivatives.19 However, in contrast, such 5-exo
cyclisations of carbamates 13, derived from pent-4-enamines,
generally work well to give N-alkoxycarbonylpyrrolidines.20
Although free alkenylamines fail to cyclise smoothly, ortho-
allylanilines do undergo selenocyclisation efficiently, as
exemplified in an elegant approach to the mitomycin skeleton.21
Similarly, N-acetylpent-4-enamines (13; R3 = Me)22 and the
corresponding N-pentenylimidates23 cyclise in a 5-exo manner
to give selenomethylpyrrolidines. An attempted 5-endo seleno-
cyclisation of N-acetylbut-3-enamine resulted instead in reac-
tion at oxygen by a 6-exo pathway (cf. 11). Mercury()-induced
had available proven methodology for the formation of the
corresponding homoallylic alcohols 16,3,7 an efficient approach
to such substrates appeared to be by Mitsunobu reaction34
between these and the sulfonamide derivatives 17, as developed
by Weinreb and colleagues.35 As we reported previously,3,7 the
alcohols 16 were readily prepared by sequential Yamaguchi–
Hirao condensation36 between monosubstituted epoxides 18
and acetylenes 19 followed by reduction of the resulting
alcohols 20 using various methods to give either the (Z)- or
(E)-homoallylic alcohols 21 or 22 (Scheme 4). In our hands, the
Weinreb reagents 17 were easily prepared as previously reported
and underwent smooth Mitsunobu reactions with the foregoing
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and 26. The more highly substituted analogues 27b and 28b
were prepared similarly starting from the corresponding
epoxybutanes. Condensation between epoxycyclohexane
and hex-1-yne provided the cyclohexanol 29;7 subsequent
Mitsunobu reaction34 but using phthalimide as the nucleophile
gave the expected product 30a in poor but sufficient yield
(Scheme 5). When the N-Boc-sulfonamides 17 were used in
place of phthalimide, only elimination products were isolated;
various azide displacements were similarly unproductive.37
Protecting group exchange and reductions then gave the
required (E)- and (Z)-isomers 31 and 32. The preparation of
a range of homoallylic amines protected by carbonyl-based
groups was achieved by a different approach (Scheme 6):
enolate Claisen rearrangement38 of the ester 33 led smoothly to
the unsaturated acid 34, a modified Curtius rearrangement of
which using diphenyl phosphorazidate39 gave the Boc-protected
unsaturated amine 35a. Deprotection gave the corresponding
amine 35b; standard acylation methods then gave a series of
derivatives 35c–e.
In our initial studies, we naturally chose to use the conditions
which had been so successful in effecting iodocyclisations of
homoallylic alcohols, i.e. treatment of the appropriate substrate
with three equivalents each of iodine and sodium hydrogen
carbonate in dry acetonitrile at ambient temperature. Our
first experiment proved the viability of the idea, using the
sulfonamide 24a having no distal substituent. We were pleased
to find that cyclisation did occur, although the reaction gave a
number of other products and almost no stereoselection (Table
1). Encouraged by this, we next found that the sulfonamide 24b
underwent smooth and rapid cyclisation to give only the trans-
2,3-iodopyrrolidine 36b. Similarly the phenylsulfonyl derivative
24c gave only the iodopyrrolidine 36c in good yield, a stereo-
selection which reflects the expected anti-addition across the
double bond. However, there was distinctly less stereoselection
when we attempted to form trisubstituted pyrrolidines under
these conditions. Thus, the precursors 24f and 24j, while under-
going encouragingly efficient cyclisations, gave synthetically
uninteresting mixtures of the products 36f–37f and 36j–37j, in
marked contrast to similar cyclisations leading to tetrahydro-
furans.3 Various changes to the conditions including lowering
the temperature to 0 ЊC and even Ϫ78 ЊC and changing the
solvent to ether or dichloromethane did not result in any
improvement. Fortunately, we observed that the isomer ratio
in the products 36f–37f derived from sulfonamide 24f varied
significantly, depending upon the exact method of work up. We
wondered if this could be due to the presence of variable
amounts of acid arising from the cyclisation itself causing an
isomerisation and reasoned that a stronger base might improve
matters. To our satisfaction, changing the base from sodium
hydrogen carbonate to the slightly stronger potassium carbon-
ate resulted in the almost exclusive formation of the iodo-
pyrrolidine 36f from the sulfonamide 24f under conditions
otherwise identical to those used initially. Subsequently, this
was used as the base throughout and, as summarized in Table 1,
all such reactions were highly selective in favour of the 2,5-
trans-isomers 36. A surprise associated with this particular
recipe was the effect of water. In our previous work on the
tetrahydrofuran synthesis, we had deduced that the presence of
water was especially deleterious to cyclisation, due to its com-
peting by attacking the iodonium ion intermediate to give the
corresponding iodohydrins. However, we discovered that, in
marked contrast to this, in the present sulfonamide cyclisations,
when potassium carbonate was used as the base, the addition of
small amounts of water not only improved the yields but also
the stereoselectivity, in favour of isomers 36. We assume that
this is because, under these conditions, the hydrogen iodide
produced is more quickly neutralised by the base and hence
cannot cause isomerization of these initial products (see below)
and that water did not compete as a nucleophile to give
iodohydrins.
Scheme 4
alcohols to give the expected amine derivatives 23 and 25 in
good isolated yields. These were then deprotected using tri-
fluoroacetic acid to give a representative series of precursors 24
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J. Chem. Soc., Perkin Trans. 1, 2001, 1182–1203

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Scheme 5
product 36g, no matter whether base was present or not. The
more highly substituted isomers 27b and 28b also underwent
smooth cyclisation to provide good yields of the iodopyrrol-
idines 38 and 39, essentially as single isomers, whether or not
any base was present. Finally, both the (E)- and (Z)-alkenyl
substituted cyclohexane derivatives 31 and 32 underwent
cyclisation simply by the addition of iodine (i.e. no base was
used) to give the perhydroindole derivatives 40 and 41, in much
the same way as the corresponding octahydrobenzofurans can
be formed from alk-2-enylcycloalkanols.7 However, these last
two cyclisations are no more than proof of concept as the yields
attained during preparation of the precursors were so poor.
We then turned to an examination of similar iodocyclisations
of the related (Z)-sulfonamides 26; the results are summarized
in Table 2. As is evident from this Table, such cyclisations were
not as successful under any of the conditions tried, both in
terms of yields and stereoselection. The products were identi-
fied from NMR spectra of the mixtures obtained, by compar-
isons with pure isomers obtained as indicated in Table 1. These
results are very much in line with those obtained from cyclis-
ations of the related (Z)-homoallylic alcohols (see below).3 The
results from cyclisations of the trisubstituted pyrrolidine pre-
cursor 26c were unexpected. Conformation 6 suggests that the
initial product should be the all-cis isomer 44; however, less of
this was isolated under basic conditions than under acidic
Scheme 6
These results suggested that, in the absence of base, it might
be possible to completely isomerize the presumed initial
products 36 to the isomers 37. We were delighted to find that
when sulfonamide 24f was treated with three equivalents of
iodine in acetonitrile, an extremely rapid cyclisation occurred
from which was isolated only isomer 37f in excellent yield. The
same result was obtained with all of the other arylsulfonamides,
as detailed in Table 1. For reasons which are unclear, it was
fortunate that we chose this particular protecting group. As
shown in Table 1, the corresponding methanesulfonamide 24g
failed to undergo isomerization but instead gave the same
Table 1 Iodocyclisations of (E)-homoallylic sulfonamides 24
Substrate
R1
R2
R3
Time/min
Additive
Yield (%)
Ratio 36 : 37
24a
24b
Me
H
H
Et
Ph
p-Tol
60
10
20
2
10
25
3
NaHCO3
NaHCO3
K2CO3
No base
NaHCO3
K2CO3
No base
No base
NaHCO3
K2CO3
No base
K2CO3
No base
K2CO3
No base
K2CO3
No base
NaHCO3
K2CO3
No base
No base
42
84
73
88
84
85
86
85
76
74
78
72
78
79
74
78
76
76
83
76
81
60 : 40
100 : 0
100 : 0
100 : 0
100 : 0
93 : 7
0 : 100
0 : 100
74 : 26
94 : 6
0 : 100
97 : 3
94 : 6
97 : 3
0 : 100
94 : 6
24c
24d
H
Me
Et
Bu
Ph
p-Tol
24e [(R)-24d]
24f
3
Et
Bu
p-Tol
25
30
3
25
3
25
3
35
15
40
45
10
10
24g
24h
24i
24j
Et
Et
Bu
Et
Bu
Me
Pent
Pent
Ph
p-Tol
p-Tol
p-Tol
0 : 100
65 : 35
94 : 6
0 : 100
0 : 100
24k
Et
Ph
Ph
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conditions, when isomerization was expected, suggesting that
perhaps an alternative conformation is involved.
cyclisations gave mixtures of a number of compounds and are
certainly not synthetically useful, at least under the present sets
of conditions.
The final group of substrates examined were the series of
(E)-N-acyl derivatives 35, which we expected to undergo
competing 6-exo cyclisation to at least some degree, if not com-
pletely (see above; structures 9 to 12). In the event (Table 3),
only small amounts (10%) of the desired pyrrolidines 47 and 48
were formed in all cases. These were identified by comparisons
with foregoing compounds (Table 1). The major products were
tentatively identified as those from 6-exo cyclisations. In the
case of the N-Boc derivative 35a, loss of the tert-butyl group
was evident; other NMR data on the 2 : 1 mixture of isomers
obtained were consistent with the cyclic carbamate structures
45, epimeric at the methyl substituent, given the expected anti-
addition across the double bond. Although this cyclisation is
reasonably efficient, the relative lack of stereoselection rather
detracts from any synthetic utility. Not surprisingly, under
acidic conditions, some of the starting amine 35b was also
obtained. Similar cyclisations of the acetyl and trifluoroacetyl
derivatives 35c and 35d gave the alternative 6-exo products
46c,d, as unstable mixtures of isomers which again were not
fully characterized. This latter mode of cyclisation also
appeared to occur with the methoxycarbonyl derivative 35e,
presumably because loss of a methyl carbocation is much less
favourable than loss of tert-butyl. Overall, most of these
Finally, we briefly examined some reactions of the initial
products 36 and 37. Firstly, deiodination using tributyltin
hydride led smoothly to the expected 2,5-disubstituted pyrrol-
idines 49 and 50 in good yields. In no cases was any isomeriz-
ation observed. A number of such 2,5-dialkylpyrrolidines, with
combinations of C2, C4, C6 and C7 side chains, have been iden-
tified as components in the defence secretions of various fire
ants.40 A specific example is the free amine derived from the
trans-5-butyl-2-pentylpyrrolidine 49d which has previously
been synthesized by low yielding and non-stereoselective
approaches, in which a final step is removal of the N-tolyl-
sulfonyl group using lithium aluminium hydride.41 This present
chemistry therefore could be used to selectively prepare both
possible diastereoisomers of such structures and to obtain
optically pure samples. It also proved possible to effect base-
induced E2 eliminations of the initial products to provide
access to the corresponding 3-pyrrolines 51 and 52; again, no
isomerization occurred in the two examples examined.
Throughout these studies, the structures of the various iso-
meric pyrrolidines were determined in much the same way as in
our work on tetrahydrofuran synthesis.3 Firstly, CHI functions
were identified in 13C spectra from their unique position around
1
20–30 ppm, due to the heavy atom effect.42 Subsequent H–1H
1
and H–13C correlation experiments then allowed full assign-
ment of each resonance and crucially confirmed that the
products were indeed pyrrolidines and not azetidines which
could arise from 4-exo-trig cyclisations. As is typical of five-
membered rings, coupling constant data were not helpful in
determining stereochemistry. In some examples (36f, 36j), the
problem of overlapping resonances was solved by running
1
the H NMR spectra in solvents other than deuteriochloro-
form. However, NOE measurements gave reasonable indi-
cations of the assigned stereochemistries, but were certainly not
definitive, as was the case with the related tetrahydrofurans.3
Definite structural proof was finally achieved by pertinent
1
literature comparisons, especially of H NMR data43 and, in
particular, by single crystal X-ray determinations of the cis-
2,5-dialkyl-3-iodopyrrolidine 37f together with the isomeric
2-phenylpyrrolidines 36j and 37k.44 Although many of the
iodopyrrolidines were obtained as solids, these did not provide
crystals suitable for X-ray analysis from the initial recrystallis-
ations. Suitable samples were eventually obtained by a vapour
Table 2 Iodocyclisations of (Z)-homoallylic sulfonamides 26
R
Time/min
Base
Yield (%)
Product ratio
R = Ts
60
60
60
60
24 h
60
NaHCO3
K2CO3
No base
NaHCO3
K2CO3
40
52
35
45
~0
40
42a : 43a [36b] = 35 : 65
42a : 43a [36b] = 38 : 62
Gross mixture
R = Me
42b : 43b = 50 : 50
No base
Gross mixture
60
60
60
NaHCO3
K2CO3
65
63
57
44 : 36f : 37f =
43 : 30 : 27
44 : 36f : 37f =
27 : 83 : ~0
44 : 36f : 37f =
66 : 19 : 15
No base
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Table 3 Iodocyclisations of homoallylic carbamates and amides 35
R
Time/min
Base
Yield (%)
Product ratio
a) R = Boc
30
30
60
60
60
60
60
60
K2CO3
No base
K2CO3
No base
K2CO3
No base
K2CO3
No base
79
67
57
—
0
67
48
42
45 (66 : 34)
45 (67 : 35) [ϩ15% of amine 35b]
46c (76 : 24) [R = CF3]
Gross mixture
c) R = CF3CO
d) R = CO2Me
e) R = CO2Me
No reaction
46d (76 : 24) [R = Me]
46e (66 : 34) [R = OMe]
46e (66 : 34)
Fig. 2 (2RS,3SR,5SR)-2-Butyl-5-ethyl-3-iodo-1-p-tolylsulfonylpyrrol-
idine 37f.
pseudoaxially and the arylsulfonyl group trans to both
α-substituents. This more stable conformation contrasts with
the minor diastereoisomer (Fig. 5) in which the iodine appears
to be pseudoaxial. Subsequently, we observed, as expected, that
samples of the minor conformation 37k(ii) exhibited spectro-
scopic data (infra-red, 1H and 13C NMR) in solution which were
identical to those displayed by the bulk sample of compound
37k. Despite this amusing complication, comparisons of the
spectral data displayed by these three compounds with all
the other products then completed the structural assignments.
It therefore seemed most likely that the trans-2,5-
disubstituted pyrrolidines 36 obtained from cyclisations under
basic conditions were the kinetic products and that these were
isomerized under acidic conditions to the thermodynamically
more stable cis-2,5-disubstituted pyrrolidines 37.45 There was,
however, a final structural problem associated with this idea:
the trans-disposition of the 2-substituent and the 3-iodo group
in the 2,5-cis-stereoisomers 37 strongly suggested that isomeriz-
ation of the initial trans-isomers 36 was occurring by ring open-
ing and reclosure. However, it was possible that, in some way,
the 5-centre in isomers 36 was undergoing epimerization to give
the more stable cis-isomers 37. As the two possible structures
are enantiomeric [i.e. 37 or 36 with R1 ‘down’ or α-], we were
unable to distinguish these two pathways using the foregoing
diffusion method in which a concentrated ethereal solution of
the particular iodopyrrolidine was stored for up to one month
in an atmosphere of hexane at ambient temperature. The
crystal structure determinations of the iodopyrrolidines 37f
and 36j proceeded uneventfully and confirmed the respective
2,5-cis and 2,5-trans stereochemical assignments made on the
basis of NMR data; these are shown in Figs. 2 and 3. However,
the vapour diffusion crystallisation of iodopyrrolidine 37k
provided an unexpected complication: on close inspection of
the sample, two crystalline forms were apparent, one as orange
clusters (mp 103–104 ЊC) while the other, minor, component
(mp 95–97 ЊC) appeared as colourless rectangles. Fearing either
decomposition of the sample or, worse, an unexpected isomeris-
ation, individual samples were separated by hand and both
were subjected to X-ray analysis. We were surprised and
delighted to find that both confirmed the assigned 2,5-cis stereo-
chemistry of compound 37k and that the two crystal forms
were in fact differing conformations of the same diastereo-
isomer. The major and minor structures observed, 37k(i) and
37k(ii), are presented in Figs. 4 and 5 respectively. In the major
conformation, the phenyl and iodine substituents appear in
pseudoequatorial positions with the ethyl group positioned
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Scheme 7
Fig. 3 (2RS,3SR,5RS)-5-Ethyl-3-iodo-2-phenyl-1-p-tolylsulfonylpyr-
rolidine 36j.
Scheme 8
ation (Scheme 8). Hence, we conclude that isomerization does
indeed occur by cycloreversion and recyclisation and not by
epimerization at the 5-position.
The formation of the trans-pyrrolidines 36 as kinetic
products can be understood by the chair-like conformation 53,
in which the substituent R is positioned equatorially, along
much the same lines as that proposed (6) for the related tetra-
hydrofuran synthesis; the pseudoaxial position of the substitu-
ent ‘Z’ in such a conformation presumably accounts for the
poor returns from cyclisations of the (Z)-homoallylic sulfon-
amides 26. The tetrasubstituted iodopyrrolidines 38 and 39
Fig. 4 (2RS,3SR,5SR)-5-Ethyl-3-iodo-2-phenyl-1-phenylsulfonylpyr-
rolidine 37k(i).
Fig. 5 (2RS,3SR,5SR)-5-Ethyl-3-iodo-2-phenyl-1-phenylsulfonylpyr-
rolidine 37k(ii).
racemates. We therefore prepared the enantiopure homoallylic
sulfonamide 24e [(R)-24d], starting from (S)-epoxypropane,
and subjected this to cyclisation under acidic conditions and
isolated the expected iodopyrrolidine 37e. Cycloreversion by
deiodination using zinc metal in acetic acid then provided the
starting sulfonamide 24e with essentially the same optical
rotation (Scheme 7). As confirmation of this, we found that
selected examples of the trans-stereoisomers 36d,f,j underwent
isomerization to the corresponding cis-isomers 37d,f,j when
exposed to hydrogen iodide; other acids such as sulfuric acid
and trifluoroacetic acid did not cause isomerization although
exposure to 6 M hydrochloric acid resulted in partial isomeriz-
Scheme 9
were resistant to isomerisation. This was not surprising, as a
similar conformation 54 would lead to the cis-isomer 38 from
the anti-sulfonamide 27b which would not gain from such an
isomerisation to a less thermodynamically stable 2,5-trans-
pyrrolidine. The syn-isomer 28b presumably undergoes
cyclisation via conformation 55 in which all substituents are
effectively equatorial to give a product 39 in which each sub-
stituent has a trans relationship to the adjacent groups, thus
1188
J. Chem. Soc., Perkin Trans. 1, 2001, 1182–1203

View Article Online
presumably overcoming any advantage associated with a 2,5-cis
stereochemistry. These considerations should be useful in syn-
thetic design in this area. A limitation of the present method
is that this type of cyclisation, when applied to homoallylic
sulfonamides having a terminal alkene function (24a), gives a
poor yield of a mixture of isomers (36a and 37b). After comple-
tion of these studies, a possible solution to this was reported
in similar iodocyclisations, but of N-9-phenylfluorenyl
homoallylic amines 56, which give good yields of the pyr-
rolidines 57.46 However, the presence of an allylic acetate group
may also assist these cyclisations.5
In summary, this application of the 5-endo-trig method has
provided a flexible approach to both trans- and cis-2,5-
disubstituted pyrrolidines. Optically pure pyrrolidines will be
obtained by starting with single enantiomers of the homoallylic
alcohols 22, as demonstrated in the preparation of the iodo-
pyrrolidine 37e, at least in examples such as this where there is
no opportunity for racemization. One limitation of this present
chemistry is the lack of functionality present in the substitu-
ents. In preliminary studies, we have partly addressed this
deficiency by demonstrating that sulfonamides derived from
α-allylated glycine esters undergo similarly efficient and flexible
iodocyclisations to provide examples of substituted prolines
in a highly stereoselective manner.47 Similarly, selenocyclis-
ations of homoallylic sulfonamides 24 are also highly stereo-
115–117 ЊC); N-tert-butoxycarbonylmethanesulfonamide 17c,
mp 106–107 ЊC (lit.51 mp 108–109 ЊC).
Mitsunobu reactions: general procedure
To a stirred solution of an alkenol 21 or 22 (10 mmol, 1 eq.),
a Mitsunobu sulfonamide reagent 17 (10 mmol, 1 eq.) and
triphenylphosphine (11 mmol, 1.1 eq.) in dry tetrahydrofuran
(60 ml) cooled in an ice-bath was added dropwise diethyl azo-
dicarboxylate (11 mmol, 1.1 eq.). The reaction mixture was
stirred at ambient temperature for 6 h then treated with water
(50 ml) and extracted with dichloromethane (3 × 50 ml). The
combined organic extracts were dried and evaporated to leave
the crude product 23, 25, 27a or 28a which was either purified
by column chromatography (cc) or deprotected without further
purification (see later).
4-[(N-tert-Butoxycarbonylphenyl)sulfonylamino]pent-1-ene
23a. A solution of pent-4-en-2-ol (0.50 g, 5.8 mmol) was reacted
with Mitsunobu reagent 17a (1.50 g, 5.8 mmol) as described in
the general procedure to yield a yellow semi-solid which was
purified by cc (hexane–ethyl acetate 50 : 50) to afford the title
compound 23a (1.40 g, 74%) as a viscous, pale yellow oil: Rf 0.76
(hexane–ethyl acetate 50 : 50); νmax/cmϪ1 2956 (s), 2940 (s), 2880
(s), 1732 (C᎐O), 1456 (s) and 1363 (s); δ (250) 7.93–7.42 (5H,
᎐
H
m, Ph), 5.72 (1H, dddd, J 15.8, 12.2, 6.3 and 6.3, 2-H), 5.10–
4.96 (2H, m, 1-CH2), 4.64–4.58 (1H, m, 4-H), 2.79–2.40 (2H, m,
3-CH2), 1.47 (3H, d, J 8.3, 5-Me) and 1.32 (9H, s, tBu); δC (67.8)
selective, although
a variety of conditions have to be
employed to achieve this.48 No doubt many other side-chain
substituents will be compatible with the foregoing chemistry.
Exceptions may well be when heteroatoms are present in
positions in which these can undergo competing 5-exo cyclis-
ations as, despite the facile nature of the cyclisations described
in this paper, Baldwin’s rules are likely to apply in such com-
petitive situations.
150.4 (C᎐O), 140.8 (Ar-C), 135.1 (Ar-CH), 132.6 (2-CH), 128.6
᎐
(Ar-CH), 127.7 (Ar-CH), 117.6 (1-CH2), 84.0 (tBu-C), 54.9
(4-CH), 39.3 (3-CH2), 27.8 (tBu-Me) and 19.4 (5-Me); m/z (EI)
284 (Mϩ Ϫ C3H5, 30%), 198 (4), 184 (100), 141 (61), 77 (65) and
57 (98).
(E)-3-[(N-tert-Butoxycarbonyl)-p-tolylsulfonylamino]dec-5-
ene 23f. (E)-Dec-5-en-3-ol (0.66 g, 4.20 mmol) was reacted with
Mitsunobu reagent 17b (1.13 g, 4.20 mmol) as described in the
general procedure to give a yellow solid which was purified by
cc (dichloromethane) to afford the title compound 23f (1.20 g,
74%) as a pale yellow, viscous oil: Rf 0.68 (dichloromethane);
Experimental
General details
Melting points were determined on a Köfler hot stage appar-
atus. Optical rotations were measured using an Optical Activity
AA-10 polarimeter and are given in 10Ϫ1 deg cm2 gϪ1. Infrared
spectra were recorded using a Perkin-Elmer 1600 series Fourier
transform spectrometer using thin films between sodium chlor-
ide plates, unless otherwise stated. 1H NMR spectra were
determined using a Bruker WM-250, a JEOL EX-270 or a
Bruker AM-400 spectrometer, operating at the frequencies
indicated [i.e. (250) refers to 250 MHz etc.]. 13C NMR spectra
were determined using any of the latter three instruments,
operating at 62.5, 67.8 and 100.1 MHz respectively, as indicated
after δC. Unless otherwise stated, all spectra were determined
using dilute solutions in deuteriochloroform and tetramethyl-
silane as internal standard. J Values are expressed in hertz.
Mass spectra were measured using either an AEI MS902 or a
VG 7070E instrument, both operating in the electron impact
mode, unless otherwise stated; FAB, electrospray (ES) and
atmospheric pressure chemical ionization (APcI) spectra were
obtained using the latter instrument or were obtained from the
EPSRC Mass Spectrometry Service at UC Swansea.
Unless otherwise stated, all reactions were carried out in
anhydrous solvents which were obtained by the usual
methods.49 All organic solutions from work-ups were dried by
brief exposure to anhydrous magnesium sulfate followed by
filtration. Solvents were removed by rotary evaporation. CC
refers to column chromatography over Sorbsil silica gel using
the eluants specified.
The Mitsunobu reagents 17 were prepared in similar yields to
those previously reported and showed identical spectroscopic
and analytical data: N-tert-butoxycarbonylbenzenesulfonamide
17a, mp 94–95 ЊC (lit.50 mp 93–95 ЊC); N-tert-butoxy-
carbonyltoluene-p-sulfonamide 17b, mp 116–117 ЊC (lit.35 mp
νmax/cmϪ1 2964 (s), 2930 (s), 2874 (w), 1726 (C᎐O), 1589 (w),
᎐
1458 (s) and 1357 (s); δH (400) 7.83 (2H, d, J 8.4, Ar-H), 7.26
(2H, d, J 8.4, Ar-H), 5.50 (1H, dt, J 15.2 and 6.2, 6-H), 5.37
(1H, dt, J 15.2 and 6.3, 5-H), 4.34 (1H, tt, J 7.3 and 6.3, 3-H),
2.61–2.37 (2H, m, 4-CH2), 2.42 (3H, s, Ar-Me), 1.98–1.72 (4H,
m, 2- and 7-CH2), 1.40–1.11 (4H, m, 8- and 9-CH2), 1.38 (9H, s,
tBu), 0.96 (3H, t, J 7.3, 1-Me) and 0.87 (3H, t, J 6.8, 10-Me);
δC (100) 150.7 (C᎐O), 143.6, 137.7 (both Ar-C), 133.5 (᎐CH),
᎐
᎐
128.8, 128.3 (both Ar-CH), 126.5 (᎐CH), 83.5 (tBu-C), 65.3
᎐
(3-CH), 36.6, 32.2, 31.4 (all CH2), 27.9 (tBu-Me), 26.3, 22.2
(both CH2), 21.4 (Ar-Me), 13.9 (10-Me) and 11.5 (13-Me); m/z
(EI) 336 (Mϩ Ϫ C4H9O, 3%), 312 (2), 254 (18), 212 (100), 156
(4), 138 (13) and 91 (38) [Found: Mϩ Ϫ C4H9O, 336.1635.
C18H26NO3S requires M, 336.1633].
(E)-3-[(N-tert-Butoxycarbonyl)methylsulfonylamino]dec-5-
ene 23g. (E)-Dec-5-en-3-ol (0.10 g, 0.65 mmol) was reacted with
Mitsunobu reagent 17c (0.13 g, 0.65 mmol) as described in the
general procedure to give a crude product as a yellow, semi-
solid which was purified by cc (dichloromethane) to afford the
title compound 23g (0.16 g, 76%) as a pale yellow, viscous oil: Rf
0.43 (dichloromethane); νmax/cmϪ1 2965 (s), 2932 (s), 2875 (w),
1724 (C᎐O), 1459 (w), 1395 (w) and 1353 (s); δ (400) 5.46 (1H,
᎐
H
dt, J 15.3 and 6.7, 6-H), 5.32 (1H, dt, J 15.3 and 6.6, 5-H), 4.18
(1H, tt, J 7.2 and 6.3, 3-H), 3.21 (3H, s, SO2Me), 2.61–2.58 (1H,
m, 4-Hα), 2.32–2.21 (1H, m, 4-Hβ), 1.98–1.89 (4H, m, 2- and
7-CH2), 1.65–1.54 (2H, m, 8-CH2), 1.53 (9H, s, tBu), 1.30 (2H,
m, 9-CH2), 0.92 (3H, t, J 7.4, 1-Me) and 0.86 (3H, t, J 7.1,
10-Me); δC (67.8) 133.8, 126.6 (both ᎐CH), 83.9 (tBu-C), 61.2
᎐
(3-CH), 42.1 (SO2Me), 36.4, 32.2, 31.4 (all CH2), 28.0 (tBu-Me),
J. Chem. Soc., Perkin Trans. 1, 2001, 1182–1203
1189

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26.3, 22.1 (both CH2), 13.8 (10-Me) and 11.3 (1-Me); m/z (FAB)
334 (Mϩ ϩ 1, 12%), 298 (54), 278 (100), 234 (18), 154 (20), 136
(47), 126 (10), 83 (35), 57 (90) and 55 (20) [Found: Mϩ ϩ 1,
334.2056. C16H32NO4S requires M, 334.2052].
general procedure to give a dark yellow semi-solid which was
purified by cc (dichloromethane) to yield the title compound 25b
(0.20 g, 80%) as a thick, pale yellow oil: Rf 0.52 (dichloro-
methane); νmax/cmϪ1 3008 (w), 2973 (s), 2935 (s), 2875 (w), 1726
(C᎐O), 1487 (w) and 1355 (s); δ (400) 5.48–5.29 (2H, m, 3- and
᎐
H
(E)-5-[(N-tert-Butoxycarbonyl)-p-tolylsulfonylamino]tridec-
7-ene 23i. (E)-Tridec-7-en-5-ol (1.90 g, 9.60 mmol) was reacted
with Mitsunobu reagent 17b (2.60 g, 9.60 mmol) under the gen-
eral conditions to give a crude product as a yellow semi-solid
which was purified by cc (hexane–ethyl acetate 80 : 20) to yield
the title compound 23i (3.20 g, 71%) as a colourless, viscous oil:
Rf 0.66 (hexane–ethyl acetate 80 : 20); νmax/cmϪ1 2957 (s), 2929
4-H), 3.69 (2H, t, J 7.3, 1-CH2), 3.26 (3H, s, SO2Me), 2.37 (2H,
td, J 7.3 and 7.2, 2-CH2), 2.05 (2H, qd, J 7.5 and 7.3, 5-CH2),
t
1.54 (9H, s, Bu) and 0.95 (3H, t, J 7.5, 6-Me); δC (100) 151.6
(C᎐O), 134.6, 124.1 (both ᎐CH), 84.1 (tBu-C), 45.6 (1-CH ),
᎐
᎐
2
42.0 (SO2Me), 27.8 (tBu-Me), 27.4, 20.3 (both CH2) and 14.0
(6-Me); m/z (FAB) 278 (Mϩ ϩ 1, 36%), 222 (100), 204 (9), 178
(33), 154 (44), 137 (41), 83 (23) and 57 (73) [Found: Mϩ ϩ 1,
278.1429. C12H24NO4S requires M, 278.1426].
(s), 2860 (w), 1726 (C᎐O), 1598 (w), 1356 (s) and 1278 (s); δ
᎐
H
(400) 7.83 (2H, d, J 8.2, Ar-H), 7.28 (2H, d, J 8.2, Ar-H), 5.43
(1H, dt, J 15.3 and 6.8, 8-H), 5.35 (1H, dt, J 15.3 and 6.6, 7-H),
4.48–4.30 (1H, m, 5-H), 2.64–2.37 (2H, m, 6-CH2), 2.43 (3H, s,
Ar-Me), 1.98–1.65 (4H, m, 4- and 9-CH2), 1.38 (9H, s, Bu),
1.34–1.21 (10H, m, 2-, 3-, 10-, 11- and 12-CH2), 0.82 (3H, t,
(1RS,2RS)-2-(Hex-1-ynyl)-1-phthalimidocyclohexane 30a. A
solution of phthalimide (5.20 g, 36.0 mmol) and triphenyl-
phosphine (9.40 g, 36.0 mmol) in dry THF (100 ml) was stirred
under nitrogen at ambient temperature. To this was added
alkynol 29 (2.16 g, 12 mmol)7 and diethyl azodicarboxylate
(5 ml, 36.0 mmol). Stirring was continued for 48 h, after which
time the solvent was evaporated and the crude product purified
by cc (hexane–ether 80 : 20) to furnish the phthalimide 30a (1.50
g, 46%) as a viscous oil: νmax/cmϪ1 1772 (C᎐O), 1714 (C᎐O) and
1330; δH (400) 7.85–7.78 (2H, m, Ar-H), 7.73–7.67 (2H, m,
Ar-H), 4.11 (1H, dt, J 13.0 and 3.6, 1-H), 3.53–3.02 (1H, m),
2.09 (2H, td, J 7.0 and 2.3, 3Ј-CH2), 1.97–1.22 (10H, m) and
0.90 (3H, t, J 7.2, Me); δC (67.8) 168.5 (Ar-C), 133.6, 122.8
(both Ar-CH), 83.5, 79.2 (both C), 55.4, 33.0 (both CH), 31.1,
26.3, 24.9, 22.1, 20.9, 20.7 (all CH2) and 13.40 (Me); m/z (ES)
310 (Mϩ ϩ 1, 100%), 151 (24) and 134 (51) [Found: Mϩ ϩ 1,
310.1807. C20H24NO2 requires M, 310.1806].
t
J 6.8, Me) and 0.79 (3H, t, J 7.0, Me); δC (100) 151.3 (C᎐O),
᎐
143.8 (Ar-C), 137.8 (Ar-C), 133.7 (᎐CH), 128.9 (Ar-CH), 128.4
᎐
(Ar-CH), 126.7 (᎐CH), 83.7 (tBu-C), 60.1 (5-CH), 36.9, 33.7,
᎐
33.1, 32.6, 29.1 (all CH2), 28.0 (tBu-Me), 26.8, 22.5 (both CH2),
21.53 (Ar-Me) and 13.9 (1- and 13-Me); m/z (ES) 452 (Mϩ ϩ 1,
23%), 396 (91), 356 (100) and 245 (34).
᎐
᎐
(E)-4-[(N-tert-Butoxycarbonyl)-p-tolylsulfonylamino]-1-
phenylhex-1-ene 23j. (E)-1-Phenylhex-1-en-4-ol (3.00 g, 17.00
mmol) was reacted with Mitsunobu reagent 17b (4.62 g, 17.00
mmol) under the conditions described in the general procedure
to give the crude product as a yellow semi-solid which was
purified by cc (hexane–ethyl acetate 80 : 20) to afford the title
compound 23j (5.60 g, 81%) as a colourless solid, mp 106–
107 ЊC: Rf 0.51 (hexane–ethyl acetate 80 : 20); νmax/cmϪ1
Boc deprotections: general procedure
(CHCl ) 2962 (s), 2930 (s), 2862 (s), 1727 (C᎐O) and 1462 (s);
᎐
3
To a stirred solution of an N-Boc-arene (or alkane) sulfonamide
(10.0 mmol, 1 eq.) in dichloromethane (50 ml) was added drop-
wise trifluoroacetic acid (11.4 ml, 100 mmol, 10 eq.). The result-
ing mixture was stirred at ambient temperature, typically for
10–20 h. Once the reaction was complete, the mixture was
neutralised using 2 M aqueous sodium carbonate and the
resulting two layers separated. The aqueous layer was extracted
with dichloromethane (3 × 50 ml) and the combined organic
solutions dried and evaporated. The resulting crude product
was purified by column chromatography. In examples of crude
compounds from the Mitsunobu reaction, the yields for the
deprotection step and the quantity of trifluoroacetic acid used
were based on the starting homoallylic alcohol.
δH (250) 7.74 (2H, d, J 8.4, Ar-H), 7.33–7.19 (5H, m, Ph), 6.99
(2H, d, J 8.4, Ar-H), 6.39 (1H, d, J 15.7, 1-H), 6.10 (1H, ddd,
J 15.7, 7.5 and 6.8, 2-H), 4.50 (1H, tdd, J 6.2, 6.2 and 6.1, 4-H),
2.89 (1H, ddd, J 14.0, 7.5 and 6.2, 3-Hα), 2.62 (1H, ddd, J 14.0,
6.8 and 6.1, 3-Hβ), 2.31 (3H, s, Ar-Me), 2.10–1.55 (2H, m,
5-CH2), 1.38 (9H, s, tBu) and 1.01 (3H, t, J 7.7, 6-Me); δC (100)
150.9 (C᎐O), 143.6, 137.5, 136.9 (all Ar-C), 132.7 (Ar-CH),
᎐
128.9 (᎐CH), 128.4, 128.3, 127.3, 127.14 (all Ar-CH), 126.2
᎐
(᎐CH), 83.9 (tBu-C), 61.3 (4-CH), 36.9 (3-CH ), 28.0 (tBu-Me),
᎐
2
26.9 (5-CH2), 21.5 (Ar-Me) and 11.5 (6-Me); m/z (ES) 430
(Mϩ ϩ 1, 100%), 374 (92), 330 (84), 83 (28) and 60 (52) [Found:
C, 66.9; H, 7.4; N, 3.2. C24H31NO4S requires C, 67.1; H, 7.3;
N, 3.2%].
4-(Phenylsulfonylamino)pent-1-ene 24a.52 Boc-Sulfonamide
23a (0.50 g, 1.54 mmol) was deprotected as described in the
general procedure to give the crude product as a yellow oil,
which was purified by cc (hexane–ethyl acetate 60 : 40) to afford
the title compound 24a (0.28 g, 82%) as a viscous, colourless oil:
Rf 0.67 (hexane–ethyl acetate 60 : 40); δH (250) 7.92–7.49 (5H,
m, Ph), 5.57 (1H, ddt, J 15.6, 12.4 and 6.4, 2-H), 5.02–4.87 (2H,
m, 1-CH2), 3.49 (1H, qdd, J 8.4, 6.3 and 6.2, 4-H), 2.20–2.03
(2H, m, 3-CH2) and 1.07 (3H, d, J 8.4, 5-Me); δC (67.8) 140.9
(Ar-C), 133.3 (Ar-CH), 132.4 (2-CH), 128.9, 126.9 (both
Ar-CH), 118.5 (1-CH2), 49.3 (4-CH), 41.3 (3-CH2) and 21.0
(5-Me); m/z (EI) 210 (Mϩ Ϫ 15, 1%), 184 (93), 141 (72), 125 (3),
86 (8), 77 (100) and 59 (7).
(Z)-1-[(N-tert-Butoxycarbonyl)-p-tolylsulfonylamino]hex-3-
ene 25a. (Z)-Hex-3-en-1-ol (0.50 g, 5.0 mmol) was reacted with
Mitsunobu reagent 17b (1.35 g, 5.0 mmol) as described above to
give an orange semi-solid which was purified by cc (dichloro-
methane) to yield the title compound 25a (1.30 g, 74%) as a
viscous, pale yellow oil: Rf 0.62 (dichloromethane); νmax/cmϪ1
3307 (w), 2969 (s), 2933 (s), 1728 (C᎐O), 1356 (s) and 1289 (s);
᎐
δH (400) 7.79 (2H, d, J 8.2, Ar-H), 7.29 (2H, d, J 8.2, Ar-H),
5.51–5.29 (2H, m, 3- and 4-H), 3.86–3.79 (2H, m, 1-CH2), 2.62–
2.45 (2H, m, 2-CH2), 2.44 (3H, s, Ar-Me), 2.11 (2H, qd, J 7.5
and 7.4, 5-CH2) 1.35 (9H, s, tBu) and 0.98 (3H, t, J 7.5, 6-Me);
δC (100) 151.0 (C᎐O), 144.0, 137.7 (both Ar-C), 134.8 (᎐CH),
᎐
᎐
129.2, 127.8 (both Ar-CH), 124.1 (᎐CH), 84.0 (tBu-C), 46.6
᎐
(1-CH2), 28.2 (CH2), 27.9 (tBu-Me), 21.5 (Ar-Me), 20.6 (CH2)
and 14.2 (6-Me); m/z (FAB) 354 (Mϩ ϩ 1, 36%), 298 (100), 280
(7), 254 (17), 184 (13), 155 (33), 139 (10), 126 (30), 91 (17), 82
(13) and 57 (32) [Found: Mϩ ϩ 1, 354.1749. C18H28NO4S
requires M, 354.1739].
(E)-1-(p-Tolylsulfonylamino)hex-3-ene 24b. (E)-Hex-3-en-1-
ol (0.50 g, 5.0 mmol) was reacted with Mitsunobu reagent 17b
(1.35 g, 5 mmol) under the conditions described above to give
the (E)-Boc-sulfonamide 23b as a yellow semi-solid which was
not further purified but which was immediately deprotected.
Crude (E)-Boc-sulfonamide 23b from the Mitsunobu reac-
tion was treated with trifluoroacetic acid (5.7 ml, 50 mmol) as
described above and the crude product purified by cc (hexane–
(Z)-1-[(N-tert-Butoxycarbonyl)methylsulfonylamino]hex-3-
ene 25b. (Z)-Hex-3-en-1-ol (0.10 g, 1.0 mmol) was reacted with
Mitsunobu reagent 17c (0.19 g, 1.0 mmol) as described in the
1190
J. Chem. Soc., Perkin Trans. 1, 2001, 1182–1203

View Article Online
ethyl acetate 60 : 40) to yield the sulfonamide 24b (0.86 g, 67%)
as a colourless, viscous oil: Rf 0.70 (hexane–ethyl acetate
60 : 40); νmax/cmϪ1 3272 (NH), 2968 (s), 2923 (s), 1598 (w) and
1315 (s); δH (250) 7.73 (2H, d, J 8.3, Ar-H), 7.30 (2H, d, J 8.3,
Ar-H), 5.45 (1H, dt, J 15.5 and 6.2, 4-H), 5.16 (1H, dt, J 15.5
and 7.1, 3-H), 4.62 (1H, m, NH), 2.99–2.91 (2H, m, 1-CH2),
2.42 (3H, s, Ar-Me), 2.15–2.08 (2H, m, 2-CH2), 1.93 (2H, qd,
J 7.4 and 6.2, 5-CH2) and 0.90 (3H, t, J 7.4, 6-Me); δC (67.8)
(2R)-(E)-2-(p-Tolylsulfonylamino)non-4-ene
24e.
(2R)-
(E)-Non-4-en-2-ol (0.34 g, 2.40 mmol) was reacted with
Mitsunobu reagent 17b (0.65 g, 2.40 mmol) under the
conditions described above to give (2R)-(E)-2-(N-tert-
butoxycarbonyl-p-tolylsulfonylamino)non-4-ene 23e as
yellow, semi-solid which was not further purified but was
immediately deprotected.
Crude (R)-(E)-Boc-sulfonamide 23e was deprotected with
trifluoroacetic acid (2.9 ml, 24 mmol) as described in the gen-
eral procedure to afford the title compound 24e (0.50 g, 71%) as
a pale yellow, viscous oil: [α]D = ϩ33.5 (c 0.01, CHCl3); other
spectral data were identical to those displayed by the racemic
sulfonamide 24d (see above).
a
143.3, 139.9 (both Ar-C), 135.9 (᎐CH), 129.6, 127.1 (both
᎐
Ar-CH), 124.3 (᎐CH), 42.6 (1-CH ), 32.3, 25.4 (both CH ), 21.5
᎐
2
2
(Ar-Me) and 13.6 (6-Me); m/z (ES) 254 (Mϩ ϩ 1, 100%), 252
(22), 224 (13), 184 (6) and 83 (4) [Found: Mϩ ϩ 1, 254.1214.
C13H20NO2S requires M, 254.1215].
(E)-1-(Phenylsulfonylamino)hex-3-ene 24c. (E)-Hex-3-en-1-ol
(0.21 g, 2.0 mmol) was reacted with Mitsunobu reagent 17a
(0.54 g, 5 mmol) under the conditions described above to
give the (E)-Boc-sulfonamide 23c as a yellow semi-solid
which was not further purified but which was immediately
deprotected.
(E)-3-(p-Tolylsulfonylamino)dec-5-ene 24f. (E)-Boc-Sulfon-
amide 23f (0.50 g, 1.2 mmol) was deprotected as described
above and purified by cc (dichloromethane) to afford the
sulfonamide 24f (0.34 g, 92%) as a viscous, colourless oil: Rf 0.36
(dichloromethane); νmax/cmϪ1 3280 (NH), 2959 (s), 2927 (s),
2872 (w), 1598 (w), 1454 (s) and 1327 (s); δH (400) 7.77 (2H, d,
J 8.3, Ar-H), 7.28 (2H, d, J 8.3, Ar-H), 5.34 (1H, dt, J 15.5 and
6.6, 6-H), 5.10 (1H, dt, J 15.5 and 7.3, 5-H), 4.91 (1H, d, J 7.9,
NH), 3.14 (1H, dtt, J 7.9, 7.3 and 6.5, 3-H), 2.41 (3H, s,
Ar-Me), 2.03 (2H, app. dd, J 7.3 and 6.5, 4-CH2), 1.96–1.82
(2H, m, 7-CH2), 1.44 (2H, dq, J 7.3 and 6.9, 2-CH2), 1.28–1.23
(4H, m, 8- and 9-CH2), 0.87 (3H, t, J 6.9, 1-Me) and 0.81 (3H, t,
Crude (E)-Boc-sulfonamide 23c was treated with trifluoro-
acetic acid (2.3 ml, 20 mmol) as described above and the crude
product purified by cc (hexane–ethyl acetate 60 : 40) to afford
the title compound 24c (0.35g, 70%) as a colourless, viscous oil:
Rf 0.70 (hexane–ethyl acetate 60 : 40); νmax/cmϪ1 3275 (NH),
2970 (s), 2925 (s), 1660 (w), and 1317 (s); δH (250) 7.91–
7.46 (5H, m, Ph), 5.44 (1H, dt, J 15.5 and 6.2, 4-H), 5.22 (1H,
dt, J 15.5 and 7.1, 3-CH), 3.02–2.91 (2H, m, 1-CH2), 2.20–2.08
(2H, m, 2-CH2), 1.93 (2H, qd, J 7.4 and 6.2, 5-CH2) and 0.90
(3H, t, J 7.4, 6-Me); δC (67.8) 139.8 (Ar-C), 135.4 (Ar-CH),
132.3 (᎐CH), 129.2, 126.8 (both Ar-CH), 124.1 (᎐CH), 42.6
J 7.4, 10-Me); δ (100) 142.8, 138.3 (both Ar-C), 134.6 (᎐CH),
᎐
C
129.3, 126.9 (both Ar-CH), 124.4 (᎐CH), 54.9 (3-CH), 37.1,
᎐
32.1, 31.3, 27.3, 22.0 (all CH2), 21.3 (Ar-Me), 13.7 (10-Me) and
9.6 (1-Me), m/z (ES) 310 (Mϩ ϩ 1, 100), 279 (6), 139 (13) and 83
(12) [Found: Mϩ ϩ 1, 310.1843. C17H28NO2S requires M,
310.1841].
᎐
᎐
(1-CH2), 32.2, 25.2 (both CH2) and 13.3 (6-Me); m/z (EI) 240
(Mϩ ϩ 1, 5%), 198 (6), 170 (90), 141 (97), 125 (6), 82 (7), 77
(100), 69 (14), 51 (47) and 41 (44) [Found: Mϩ ϩ 1, 240.1048.
C12H18NO2S requires M, 240.1058].
(E)-3-(Methylsulfonylamino)dec-5-ene 24g. (E)-Boc-Sulfon-
amide 23g (0.20 g, 0.65 mmol) was deprotected as described
above and purified by cc (dichloromethane) to yield the title
compound 24g (0.12 g, 77%) as a pale yellow, viscous oil: Rf 0.39
(dichloromethane); νmax/cmϪ1 3286 (NH), 2960 (s), 2930 (s),
2874 (w), 1581 (w), 1434 (s), 1413 (s) and 1379 (s); δH (270) 5.39
(1H, dt, J 15.2 and 6.6, 6-H), 5.22 (1H, dt, J 15.2 and 7.2, 5-H),
4.22 (1H, d, J 8.3, NH), 3.15 (1H, dtt, J 8.3, 8.0 and 6.9, 3-H),
2.79 (3H, s, SO2Me), 2.08 (2H, dd, J 7.2 and 6.9, 4-CH2), 1.87
(2H, m, 7-CH2), 1.52 (2H, dq, J 8.0 and 7.1, 2-CH2), 1.24–1.03
(4H, m, 8- and 9-CH2), 0.80 (3H, t, J 7.2, 10-Me) and 0.74 (3H,
(E)-2-(p-Tolylsulfonylamino)non-4-ene 24d. Racemic (E)-
non-4-en-2-ol (0.60 g, 4.2 mmol) was reacted with Mitsunobu
reagent 17b (1.14 g, 4.2 mmol) under the conditions described
above to give the sulfonamide 23d (1.20 g, 74%) as a pale yellow,
viscous oil: Rf 0.67 (dichloromethane); νmax/cmϪ1 3010 (w), 2980
(s), 2963 (s), 2880 (s), 1735 (C᎐O), 1384 (s) and 1295 (s);
᎐
δH (250) 7.80 (2H, d, J 8.3, Ar-H), 7.29 (2H, d, J 8.3, Ar-H),
5.46 (1H, dt, J 15.2 and 6.5, 5-H), 5.29 (1H, dt, J 15.2 and
6.6, 4-H), 4.56 (1H, qt, J 6.8 and 6.6, 2-H), 2.68–2.33 (2H,
m, 3-CH2), 2.43 (3H, s, Ar-Me), 1.46 (3H, d, J 6.8, 1-Me),
t, J 7.1, 1-Me); δ (67.8) 135.3, 124.5 (both ᎐CH), 55.5 (3-CH),
᎐
C
41.8 (SO2Me), 38.0, 32.2, 31.4, 27.9, 22.2 (all CH2), 13.8 (10-
Me) and 10.0 (1-Me); m/z (ES) 234 (Mϩ ϩ 1, 100%), 231 (33),
172 (70) and 62 (35) [Found: Mϩ ϩ 1, 234.1530. C11H24NO2S
requires M, 234.1528].
t
1.37 (9H, s, Bu), 1.33–1.26 (4H, m, 7- and 8-CH2) and 0.88
(3H, t, J 8.6, 9-Me); δC (67.8) 150.6 (C᎐O), 143.6, 136.9
᎐
(both Ar-C), 133.7 (᎐CH), 128.9, 127.8 (both Ar-CH), 126.4
᎐
(᎐CH), 83.8 (tBu-C), 55.5 (2-CH), 37.9, 32.2, 31.4 (all CH ),
᎐
2
27.87 (tBu-Me), 22.2 (CH2), 21.5 (Ar-Me), 19.8 (1-Me) and
14.0 (9-Me).
(E)-3-(p-Tolylsulfonylamino)undec-5-ene 24h. (E)-Undec-5-
en-3-ol (1.00 g, 6.3 mmol) was reacted with Mitsunobu reagent
17b (1.71 g, 6.3 mmol) under the conditions described in the
general procedure to give the Boc-sulfonamide 23h as an orange
semi-solid which was not further purified but was immediately
deprotected.
(E)-Boc-Sulfonamide 23d (1.98 g, 5.0 mmol) was deprotected
as described in the general procedure and the product purified
by cc (dichloromethane) to yield the title compound 24d (1.15 g,
78%) as a pale yellow, viscous oil: Rf 0.36 (dichloromethane);
νmax/cmϪ1 3274 (NH), 2963 (s), 2935 (s), 2864 (w), 1603 (w) and
1459 (s); δH (250) 7.75 (2H, d, J 8.3, Ar-H), 7.30 (2H, d, J 8.3,
Ar-H), 5.38 (1H, dt, J 15.2 and 6.6, 5-H), 5.10 (1H, dt, J 15.2
and 7.2, 4-H), 4.33 (1H, d, J 7.2, NH), 3.31 (1H, dqt, J 7.2, 6.5
and 6.2, 2-H), 2.43 (3H, s, Ar-Me), 2.04 (2H, dd, J 7.2 and 6.2,
3-CH2), 1.94–1.91 (2H, m, 6-CH2), 1.38–1.13 (4H, m, 7- and
8-CH2), 1.09 (3H, d, J 6.5, 1-Me) and 0.90 (3H, t, J 7.0, 9-Me);
Crude (E)-Boc-sulfonamide 23h was treated with trifluoro-
acetic acid (7.2 ml, 62 mmol) as described above and the crude
product purified by cc (dichloromethane) to afford the sulfon-
amide 24h (0.14 g, 68%) as a viscous, colourless oil: Rf 0.37
(dichloromethane); νmax/cmϪ1 3280 (NH), 2958 (s), 2927 (s),
2870 (w), 1600 (w), 1453 (s) and 1328 (s); δH (400) 7.77 (2H, d,
J 8.2, Ar-H), 7.28 (2H, d, J 8.2, Ar-H), 5.37 (1H, dt, J 15.4 and
6.6, 6-H), 5.09 (1H, dt, J 15.4 and 7.4, 5-H), 4.55 (1H, d, J 7.9,
NH), 3.14 (1H, dtt, J 7.9, 7.4 and 6.6, 3-H), 2.42 (3H, s,
Ar-Me), 2.03 (2H, dd, J 7.4 and 6.6, 4-CH2), 1.91–1.77 (2H, m,
7-CH2), 1.43 (2H, dq, J 7.4 and 6.9, 2-CH2), 1.39–1.17 (6H, m,
8-, 9- and 10-CH2), 0.87 (3H, t, J 6.9, 1-Me) and 0.82 (3H, t,
J 7.4, 10-Me); δ (100) 143.0, 138.2 (both Ar-C), 135.0 (᎐CH),
δC (100) 143.6, 138.3 (Ar-C), 135.5 (᎐CH), 130.0, 127.5 (both
᎐
Ar-CH), 124.9 (᎐CH), 49.9 (2-CH), 40.5, 32.6, 31.8, 22.6 (all
᎐
CH2), 21.7 (Ar-Me), 19.0 (1-Me) and 14.3 (9-Me); m/z (FAB)
296 (Mϩ ϩ 1, 23%), 289 (15), 254 (6), 198 (18), 154 (100),
137 (70), 120 (12), 107 (21), 95 (6) and 77 (17) [Found: C, 63.5;
H, 8.6; N, 4.5; Mϩ ϩ 1, 296.1693. C16H25NO2S requires C, 64.0;
H, 8.5; N, 4.7%; C16H26NO2S requires M, 296.1684].
᎐
C
129.5, 126.9 (both Ar-CH), 124.3 (᎐CH), 54.9 (3-CH), 37.1,
᎐
J. Chem. Soc., Perkin Trans. 1, 2001, 1182–1203
1191

View Article Online
32.5, 31.4, 29.1, 27.4, 22.4 (all CH2), 21.3 (Ar-Me), 14.0 (10-Me)
and 9.8 (1-Me) [Found: (APcI) Mϩ ϩ 1, 324.1994. C18H30NO2S
requires M, 324.1997].
and 7.3, 5-CH2) and 0.92 (3H, t, J 7.6, 6-Me); δC (100) 143.2,
136.5 (both Ar-C), 135.0 (᎐CH), 129.5, 127.0 (both Ar-CH),
᎐
123.1 (᎐CH), 42.7 (1-CH ), 27.2, 21.3 (both CH ), 20.4 (Ar-Me)
᎐
2
2
and 14.0 (6-Me); m/z (FAB) 254 (Mϩ ϩ 1, 100%), 184 (33), 154
(61), 137 (53), 107 (18), 91 (23) and 77 (15) [Found: Mϩ ϩ 1,
254.1240. C13H20NO2S requires M, 254.1215].
(E)-5-(p-Tolylsulfonylamino)tridec-7-ene 24i. (E)-Boc-Sulfon-
amide 23i (2.20 g, 4.8 mmol) was deprotected as described in
the general procedure and the product purified by cc (hexane–
ethyl acetate 9 : 1) to afford the title compound 24i (1.30 g, 77%)
as a colourless, viscous oil: Rf 0.43 (hexane–ethyl acetate 9 : 1);
νmax/cmϪ1 3278 (NH), 2955 (w), 2929 (s), 2858 (s), 1778 (w),
1598 (w), 1457 (s), 1425 (s) and 1326 (s); δH (250) 7.77 (2H, d,
J 8.3, Ar-H), 7.28 (2H, d, J 8.3, Ar-H), 5.30 (1H, dt, J 15.1 and
6.6, 8-H), 5.05 (1H, dt, J 15.1 and 7.2, 7-H), 4.72 (1H, d, J 7.9,
NH), 3.21 (1H, m, 5-H), 2.47 (3H, s, Ar-Me), 2.15–1.72 (6H,
m, 4-, 6- and 9-CH2), 1.52–1.03 (10H, m, 2-, 3-, 10-, 11- and
12-CH2), 0.97 (3H, t, J 7.2, 1-Me) and 0.86 (3H, t, J 7.1,
(Z)-1-(Methylsulfonylamino)hex-3-ene 26b. (Z)-Boc-Sulfon-
amide 25b (0.21 g, 0.80 mmol) was deprotected as described
above and purified by cc (dichloromethane) to yield the title
compound 26b (0.16 g, 71%) as a colourless, viscous oil: Rf 0.38
(dichloromethane); νmax/cmϪ1 3287 (NH), 2964 (s), 2875 (s),
1655 (w), 1437 (s) and 1317 (s); δH (400) 5.49 (1H, dt, J 10.7 and
7.3, 4-H), 5.24 (1H, dt, J 10.7 and 7.3, 3-H), 4.92–4.79 (1H, br,
s, NH), 3.08 (2H, td, J 6.9 and 6.4, 1-CH2), 2.91 (3H, s, SO2Me),
2.27 (2H, dt, J 7.3 and 6.9, 2-CH2), 2.01 (2H, qd, J 7.5 and 7.3,
5-CH2) and 0.93 (3H, t, J 7.5, 6-Me); δC (100) 135.0, 124.0 (both
13-Me); δ (100) 143.1, 138.4 (both Ar-C), 135.3 (᎐CH), 129.5,
᎐
C
127.1 (both Ar-CH), 124.3 (᎐CH), 54.1 (5-CH), 34.9, 34.8, 31.5,
᎐CH), 42.8 (1-CH ), 39.9 (SO Me), 27.7, 20.5 (both CH ) and
᎐
2 2 2
᎐
31.4, 27.5, 27.4, 24.9, 22.6 (all CH2), 22.5 (Ar-Me) and 13.9
(1- and 13-Me); m/z (ES) 352 (Mϩ ϩ 1, 100%), 350 (46), 312
(42), 172 (78) and 60 (39) [Found: Mϩ ϩ 1, 352.2310.
C20H34NO2S requires M, 352.2310].
14.0 (Me); m/z (FAB) 178 (Mϩ ϩ 1, 43%), 154 (100), 137 (81),
108 (27), 89 (20), 77 (22) and 55 (18).
(Z)-3-(Tolylsulfonylamino)dec-5-ene 26c. (Z)-Dec-5-en-3-ol
(0.40 g, 0.26 mmol) was reacted with Mitsunobu reagent 17b
(0.69 g, 0.26 mmol) under the conditions described above to
afford N-Boc-sulfonamide 25c as a yellow, semi-solid which was
not further purified but which was immediately deprotected.
Crude (Z)-Boc-sulfonamide 25c was treated with trifluoro-
acetic acid (2.9 ml, 26.0 mmol) as described above and the crude
product purified by cc (dichloromethane) to afford the title
compound 26c (0.05 g, 74%) as a viscous, colourless oil: Rf
0.38 (dichloromethane); νmax/cmϪ1 3274 (NH), 2964 (s), 2938
(s), 2862 (w), 1601 (w) and 1500 (s); δH (270) 7.83 (2H, d,
J 7.9, Ar-H), 7.33 (2H, d, J 7.9, Ar-H), 5.47–5.19 (3H, m, NH,
5- and 6-H), 3.25–3.17 (1H, m, 3-H), 2.45 (3H, s, Ar-Me),
2.21–2.16 (2H, m, 4-CH2), 2.07–1.97 (2H, m, 7-CH2), 1.59–
1.29 (6H, m, 2-, 8- and 9-CH2), 0.91 (3H, t, J 6.9, 1-Me)
and 0.84 (3H, t, J 7.4, 10-Me); δC (67.8) 143.2, 138.6 (both
(E)-4-(p-Tolylsulfonylamino)-1-phenylhex-1-ene 24j. (E)-Boc-
Sulfonamide 23j (3.00 g, 7 mmol) was deprotected as described
above using trifluoroacetic acid (7.98 g, 70 mmol) and the
product purified by cc (hexane–ethyl acetate 9 : 1) to yield the
title compound 24j (2.20 g, 95%) as a colourless, crystalline
solid, mp 76–77 ЊC: Rf 0.26 (dichloromethane); νmax/cmϪ1
(CHCl3) 3280 (NH), 2965 (s), 2931 (s), 2875 (w), 1597 (w), 1448
(s), 1422 (s) and 1324 (s); δH (250) 7.74 (2H, d, J 8.2, Ar-H),
7.31–7.19 (7H, m, Ar-H), 6.28 (1H, d, J 15.8, 1-H), 5.86 (1H, dt,
J 15.8 and 7.4, 2-H), 4.69 (1H, d. J 7.2, NH), 3.28 (1H, dtt,
J 7.2, 7.0 and 6.7, 4-H), 2.38 (3H, s, Ar-Me), 2.27 (2H, dd, J 7.4
and 6.7, 3-CH2), 1.54 (2H, qd, J 7.6 and 7.0, 5-CH2) and 0.85
(3H, t, J 7.6, 6-Me); δC (100) 141.6, 136.4, 135.1 (all Ar-C),
131.9 (᎐CH), 128.0, 126.9, 125.8, 125.5, 124.5, (all Ar-CH),
᎐
123.5 (᎐CH), 53.6 (4-CH), 36.3, 26.3 (both CH ), 19.9 (Ar-Me)
Ar-C), 133.4 (᎐CH), 129.7, 127.3 (both Ar-CH), 124.3
᎐
᎐
2
and 8.3 (6-Me); m/z (ES) 330 (Mϩ ϩ 1, 100%), 176 (7) and
159 (19) [Found: C, 69.3; H, 7.3; N, 4.45. C19H23NO2S requires
C, 69.3; H, 7.0; N, 4.25%].
(᎐CH), 55.6 (3-CH), 32.4, 31.9, 27.4, 27.2, 22.5 (all CH ), 21.7
᎐
2
(Ar-Me), 14.2 (10-Me) and 9.9 (1-Me); m/z (FAB) 310 (Mϩ ϩ 1,
53%), 212 (100), 155 (41), 137 (19), 91 (36), 83 (20) and 54
(16) [Found: Mϩ ϩ 1, 310.1846. C17H28NO2S requires M,
310.1840].
(E)-4-Phenylsulfonylamino-1-phenylhex-1-ene 24k. (E)-1-
Phenylhex-1-en-4-ol (2.47 g, 14 mmol) was reacted with the
Mitsunobu reagent 17a (3.59 g, 14 mmol) under the conditions
described in the general procedure to give a crude product 23k
which was deprotected immediately by treatment with trifluoro-
acetic acid (16 g, 140 mmol) as described above. Purification of
the residue by cc (hexane–ethyl acetate 9 : 1) gave the benzene-
sulfonamide 24k (3.175 g, 72%) as a colourless, crystalline
solid, mp 82–83 ЊC: Rf 0.24 (dichloromethane); νmax/cmϪ1
(CHCl3) 3270 (NH), 2980 (s), 2930 (s), 2875 (w), 1600 (w), 1450
(s), 1410 (s) and 1320 (s); δH 7.85–7.14 (10H, m, 2 × Ph), 6.24
(1H, d, J 15.6, 1-H), 5.79 (1H, dt, J 15.6 and 7.3, 2-H), 4.87
(1H, d, J 7.1, NH), 3.23 (1H, dtt, J 7.1, 6.9 and 6.7, 4-H), 2.33
(2H, dd, J 7.3 and 6.7, 3-CH2), 1.55 (2H, qd, J 7.6 and 6.9,
5-CH2) and 0.87 (3H, t, J 7.6, 6-Me); m/z (ES) 316 (Mϩ ϩ 1,
100%) [Found: C, 68.5; H, 6.9; N, 4.5. C18H21NO2S requires C,
68.5; H, 6.7; N, 4.4%].
(2RS,3RS)-(E)-2-(p-Tolylsulfonylamino)-3-methyloct-4-ene
27b. (2SR,3RS)-(E)-3-Methyloct-4-en-2-ol [(E)-syn-alkenol]
(0.80 g, 5.62 mmol), derived from cis-2,3-epoxybutane, was
reacted with Mitsunobu reagent 17b (1.53 g, 5.62 mmol) under
the conditions described in the general procedure to afford
the (E)-anti-Boc-sulfonamide 27a as an orange semi-solid
which was not further purified but which was immediately
deprotected.
A solution of crude (E)-anti-Boc-sulfonamide 27a in dichloro-
methane (50 ml) was deprotected as described above using
trifluoroacetic acid (5.7 g, 56 mmol). The product was purified
by cc (dichloromethane) to afford the sulfonamide 27b (1.32 g,
80%) as a colourless, viscous oil: Rf 0.48 (dichloromethane);
νmax/cmϪ1 3282 (NH), 2973 (s), 2931 (s), 2875 (w), 1581 (w),
1454 (s), 1328 (s) and 1166 (s); δH (250) 7.74 (2H, d, J 8.3,
Ar-H), 7.29 (2H, d, J 8.3, Ar-H), 5.37 (1H, dt, J 15.2 and 6.6,
5-H), 5.12 (1H, ddd, J 15.2, 8.3 and 1.2, 4-H), 4.34 (1H, d, J 8.7,
NH), 3.29–3.20 (1H, m, 2-H), 2.43 (3H, s, Ar-Me), 2.16–2.07
(1H, m, 3-CH), 1.93 (2H, td, J 7.1 and 6.6, 6-CH2), 1.35 (2H, qt,
J 7.4 and 7.1, 7-CH2), 0.97 (3H, d, J 6.7, 1-Me), 0.90 (3H, d,
J 6.8, 3-Me) and 0.86 (3H, t, J 7.4, 8-Me); δC (67.8) 143.6, 139.8
(Z)-1-(p-Tolylsulfonylamino)hex-3-ene 26a. (Z)-Boc-Sulfon-
amide 25a (1.30 g, 3.7 mmol) was deprotected as described
above and the crude product purified by cc (dichloromethane)
to give the sulfonamide 26a (0.70 g, 72%) as a viscous, colourless
oil: Rf 0.43 (dichloromethane); νmax/cmϪ1 3284 (NH), 2964 (s),
2934 (s), 1656 (w), 1598 (w), 1426 (s) and 1325 (s); δH (400) 7.76
(2H, d, J 8.2, Ar-H), 7.30 (2H, d, J 8.2, Ar-H), 5.49 (1H, dt
J 10.8 and 7.3, 4-H), 5.25 (1H, dt J 10.8 and 7.3, 3-H), 5.01 (1H,
t, J 6.1, NH), 2.95 (2H, td, J 6.9 and 6.1, 1-CH2), 2.42 (3H, s,
Ar-Me), 2.20 (2H, dt, J 7.3 and 6.9, 2-CH2), 2.01 (2H, qd, J 7.6
(both Ar-C), 133.1 (Ar-CH), 130.1, 129.6 (both ᎐CH), 127.6
᎐
(Ar-CH), 53.6 (2-CH), 42.2 (3-CH), 34.6, 22.5 (both CH2), 21.5
(Ar-Me), 17.4 (1-Me), 17.1 (3-Me) and 13.6 (8-Me); m/z (FAB)
296 (Mϩ ϩ 1, 93%), 198 (100), 155 (48), 125 (84), 107 (12), 91
(47), 83 (41) and 69 (78) [Found: C, 64.6; H, 8.6; N, 4.55;
1192
J. Chem. Soc., Perkin Trans. 1, 2001, 1182–1203

View Article Online
Mϩ ϩ 1, 296.1734. C16H25NO2S requires C, 65.0; H, 8.5; N,
4.7%; C16H26NO2S requires M, 296.1684].
solution was stirred at ambient temperature for 2 days then
diluted with dichloromethane and washed successively with 2 M
hydrochloric acid (3 × 2 ml), saturated aqueous sodium hydro-
gencarbonate (3 ml) and brine (3 ml). The organic solution was
then dried and evaporated and the residue purified by cc
(hexane–ether 80 : 20) to furnish the (E)-toluene-p-sulfonamide
31 (40 mg, 41%) as a viscous oil: νmax/cmϪ1 1600 (s), 1415 (s) and
1178 (s); δH (400) 7.73 (2H, d, J 8.0, Ar-H), 7.29 (2H, d, J 8.0,
Ar-H), 5.32 (1H, dt, J 15.5 and 6.5, 2Ј-H), 5.23 (1H, dd, J 15.5
and 7.5, 1Ј-H), 4.40 (1H, d, J 7.3, NH), 3.30–3.26 (1H, m, 1-H),
2.43 (3H, s, Ar-Me), 2.20–2.13 (1H, m, 2-H), 1.95–1.90 (2H, m,
3Ј-CH2), 1.63-1.20 (12H, m) and 0.91 (3H, t, J 7.0, Me); δC (100)
(2SR,3RS)-(E)-2-(p-Tolylsulfonylamino)-3-methyloct-4-ene
28b. (2SR,3SR)-(E)-3-Methyloct-4-en-2-ol [(E)-anti-alkenol]
(0.30 g, 2.20 mmol), derived from trans-2,3-epoxybutane, was
reacted with Mitsunobu reagent 17b (0.57 g, 2.20 mmol) under
the conditions described in the general procedure to give
the (E)-syn-Boc-sulfonamide 28a as an orange semi-solid
which was not further purified but which was immediately
deprotected.
A
solution of crude (E)-syn-Boc-sulfonamide 28a in
dichloromethane (20 ml) was deprotected using trifluoroacetic
acid (2.4 ml, 21 mmol) as described above and the product
purified by cc (dichloromethane) to give the title compound 28b
(0.53 g, 86% yield) as a colourless, viscous oil: Rf 0.49 (dichloro-
methane); νmax/cmϪ1 3282 (NH), 2973 (s), 2931 (s), 2882
(s), 1588 (w), 1440 (s) and 1328 (s); δH (400) 7.76 (2H, d, J 8.3,
Ar-H), 7.29 (2H, d, J 8.3, Ar-H), 5.40 (1H, dt, J 15.3 and 6.8,
5-H), 5.74 (1H, ddd, J 15.3, 7.9 and 1.2, 4-H), 4.76 (1H, d, J 7.3,
NH), 3.14 (1H, m, 2-H), 2.42 (3H, s, Ar-Me), 2.10 (1H, m,
3-H), 1.90 (2H, td, J 7.3 and 6.8, 6-CH2), 1.32 (2H, tq, J 7.3 and
7.3, 7-CH2), 0.99 (3H, d, J 6.6, 1-Me), 0.90 (3H, d, J 6.8, 3-Me)
and 0.86 (3H, t, J 7.3, 8-Me); δC (100) 143.0, 138.0 (both Ar-C),
142.7, 137.9 (both Ar-C), 133.6 (᎐CH), 129.3, 128.1 (both
᎐
Ar-CH), 126.8 (᎐CH), 53.5, 42.2 (both CH), 32.2, 31.3, 30.2,
᎐
28.4, 22.6 (all CH2), 22.0 (Ar-Me), 21.1 (CH2) and 13.7 (Me).
(Z)-(1RS,2RS)-2-(Hex-1-en-1-yl)-1-(p-tolylsulfonylamino)-
cyclohexane 32. The tosylated acetylene 30b (54 mg, 0.16 mmol)
was dissolved in ethyl acetate (1 ml) and 5% palladium on
barium sulfate (7 mg, 0.016 mmol) was added. The resulting
suspension was stirred under an atmosphere of hydrogen for
3 h. The catalyst was removed by filtration and the solvent
evaporated to give a crude product which was purified by cc
(hexane–ether 80 : 20) to afford the (Z)-toluene-p-sulfonamide
32 (50 mg, 95%) as a pale yellow oil: νmax/cmϪ1 1721 (m), 1600
(s), 1415 (s) and 1178 (s); δH (400) 7.74 (2H, d, J 8.2, Ar-H), 7.28
(2H, d, J 8.2, Ar-H), 5.48–5.38 (2H, m, 1Ј- and 2Ј-H), 4.49 (1H,
d, J 6.6, NH), 3.35–3.30 (1H, br s, 1-H), 2.61–2.58 (1H, m,
2-H), 2.43 (3H, s, Ar-Me), 1.88–1.85 (2H, m, 3Ј-CH), 1.62–1.11
(12H, m) and 0.88 (3H, t, J 7.0, Me); δC (100) 142.9, 137.9 (both
132.4 (Ar-CH), 130.8, 129.4 (both ᎐CH), 127.0 (Ar-CH), 53.9
᎐
(2-CH), 42.1 (3-CH), 34.5, 22.4 (both CH2), 21.4 (Ar-Me), 18.8
(1-Me), 16.2 (3-Me) and 13.5 (8-Me); m/z (FAB) 296 (Mϩ ϩ 1,
46%), 198 (50), 154 (57), 137 (48), 125 (43), 107 (27), 91 (72), 83
(32) and 69 (100) [Found: Mϩ ϩ 1, 296.1697. C16H26NO2S
requires M, 296.1684].
Ar-C), 133.8 (᎐CH), 129.5, 126.9 (both Ar-CH), 126.7 (᎐CH),
᎐
᎐
(1RS,2RS)-2-(Hex-1-ynyl)-1-(p-tolylsulfonylamino)cyclo-
hexane 30b. To a stirred solution of phthalimide 30a (1.0 g, 3.5
mmol) in ethanol (4 ml) was added hydrazine monohydrate
(3.85 ml). The resulting solution was heated at reflux for 2 h,
then cooled and acidified with concentrated hydrochloric acid.
The phthalhydrazide was removed by filtration and the solid
washed with ethanol (4 × 10 ml). The filtrate was diluted with
water (50 ml), and the solution reduced to 20 ml under reduced
pressure and filtered. The solvent was then completely removed
and the remaining amine salt dissolved in dichloromethane
(10 ml). The resulting solution was treated with toluene-p-
sulfonyl chloride (0.74 g, 3.85 mmol) and triethylamine (1.1 ml,
7.7 mmol) and stirred at ambient temperature for 16 h then
washed successively with 2 M hydrochloric acid (2 × 5 ml),
saturated aqueous sodium hydrogencarbonate (5 ml) and brine
(10 ml). The remaining organic solution was dried and evapor-
ated and the crude product purified by cc (hexane–ether 80 : 20)
to afford the toluene-p-sulfonamide 30b (0.55 g, 47%) as a pale
yellow oil: νmax/cmϪ1 3372 (NH), 1738 (w), 1599 (w), 1415 (s)
and 1331 (s); δH (400) 7.77 (2H, d, J 8.2, Ar-H), 7.27 (2H, d,
J 8.2, Ar-H), 4.89 (1H, d, J 8.2, NH), 3.20–3.17 (1H, m, 1-H),
2.60 (1H, app br s, 2-H), 2.41 (3H, s, Ar-Me), 2.15 (2H, td, J 6.9
and 2.2, 3Ј-CH2), 1.80–1.25 (12H, m) and 0.91 (3H, t, J 7.1,
Me); δC (100) 143.0, 138.5 (both Ar-C), 129.5, 126.7 (both Ar-
CH), 84.9, 77.8 (both C), 55.6, 33.7 (both CH), 31.0, 30.4, 29.7,
24.6, 21.9 (all CH2), 21.4 (Ar-Me), 20.6, 18.2 (both CH2) and
13.6 (Me); m/z (ES) 334 (Mϩ ϩ 1, 100%), 189 (42) and 124 (19)
[Found: Mϩ ϩ 1, 334.1841. C19H28NO2S requires M, 334.1843].
54.2, 37.1 (both CH), 31.8, 30.3, 30.0, 27.2, 23.8, 22.3 (all CH2),
21.5 (Ar-Me), 21.1 (CH2) and 13.9 (Me).
2-Methyloct-4-enoic acid 34. To a stirred solution of hex-1-
en-3-ol (5.00 g, 50.0 mmol), triethylamine (6.05 ml, 50.0 mmol)
and 4-dimethylaminopyridine (10 mg) in dichloromethane at
0 ЊC was added dropwise propionyl chloride (4.77 ml, 55.0
mmol). The reaction mixture was heated to reflux for 2 h, then
cooled and washed with aqueous 2 M hydrochloric acid (2 × 30
ml). The organic solution was dried and evaporated to leave a
yellow oil which was purified by cc (dichloromethane) to afford
the propionate 33 (7.20 g, 85%) as a colourless oil: Rf 0.76
(dichloromethane): νmax/cmϪ1 2961 (s), 2940 (s), 2876 (w), 1739
(C᎐O), 1463 (s) and 1362 (s); δ (250) 5.76 (1H, ddd, J 16.0, 9.4
᎐
H
and 6.2, 2-H), 5.29–5.11 (3H, m, 1-CH2 and 3-H), 2.32 (2H, q,
J 7.6, 3Ј-CH2), 1.64–1.17 (4H, m, 4-CH2 and 5-CH2), 1.14 (3H,
t, J 7.6, 4-Me) and 0.91 (3H, t, J 7.3, 6-Me); δC (67.8) 173.7
(C᎐O), 136.7 (2-CH), 116.7 (1-CH ), 74.3 (3-CH), 36.3, 27.8,
᎐
2
18.3 (all CH2), 13.8 (4-Me) and 9.1 (6-Me).
To neat diisopropylamine (2.31 ml, 16.7 mmol), stirred at
Ϫ78 ЊC, was added dropwise butyllithium (1.6 M solution in
hexanes, 5.10 ml, 11.1 mmol) and the mixture warmed to ambi-
ent temperature during 1 h. The hexane was removed by a
stream of nitrogen to leave a cream paste which was dissolved
in THF (25 ml). The resulting solution of LDA was cooled to
Ϫ78 ЊC and unsaturated ester 33 (1.56 g, 10.0 mmol) was added
dropwise. The reaction mixture was maintained at Ϫ78 ЊC for
10 minutes, after which trimethylsilyl chloride (1.20 g, 11.1
mmol, freshly distilled from calcium hydride) was added drop-
wise. The reaction mixture was warmed to ambient temperature
during 0.5 h then refluxed for 1 h. The reaction mixture was
cooled to ambient temperature, poured into aqueous 2 M
sodium hydroxide (30 ml) and the mixture washed with diethyl
ether (3 × 20 ml). The aqueous layer was acidified with concen-
trated hydrochloric acid, then extracted with dichloromethane
(3 × 30 ml). The combined dichloromethane extracts were dried
and evaporated to give the acid 34 (1.03 g, 66%) as a clear oil:
Rf 0.47 (dichloromethane); νmax/cmϪ1 3112 (OH), 2959 (s), 2663
(E)-(1RS,2RS)-2-(Hex-1-en-1-yl)-1-(p-tolylsulfonylamino)-
cyclohexane 31. To a stirred solution of sulfonamide 30b (0.10
g, 0.30 mmol) in THF (10 ml) was added lithium aluminium
hydride (1 M solution in THF, 3.0 ml, 3.0 mmol) and the result-
ing solution refluxed for 48 h. The solution was then cooled and
excess reagent was quenched by the dropwise addition of water.
The resulting white solid was removed by filtration. The filtrate
was evaporated, and the residue dissolved in dichloromethane
(10 ml) and treated with triethylamine (50 µl, 0.30 mmol) and
toluene-p-sulfonyl chloride (78 mg, 0.30 mmol). The resulting
(s), 1706 (C᎐O), 1463 (s) and 1418 (s); δ (270) 5.56–5.33 (2H,
᎐
H
J. Chem. Soc., Perkin Trans. 1, 2001, 1182–1203
1193

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m, 4- and 5-H), 2.59–2.34 (2H, m, 3-CH2), 2.21–1.87 (3H, m,
2-H and 6-CH2), 1.46–1.26 (2H, m, 7-CH2), 1.18 (3H, d, J 7.0,
ambient temperature for 18 h. The reaction mixture was then
neutralised with 2 M hydrochloric acid and extracted with
dichloromethane (3 × 10 ml). The combined organic solutions
were dried and evaporated to afford the amide 35d (0.92 g, 70%)
as a pale yellow oil: Rf 0.52 (methanol–dichloromethane 1 : 9);
1Ј-Me) and 0.90 (3H, t, J 7.3, 8-Me); δC (67.8) 182.8 (C᎐O),
᎐
133.2, 126.5 (both ᎐CH), 67.8 (2-CH), 36.4, 34.6, 22.5 (all CH ),
᎐
2
16.1 (1-Me) and 13.5 (8-Me).53
νmax/cmϪ1 3454 (NH), 2956 (s), 2932 (s), 1682 (C᎐O), 1430 (s)
᎐
(E)-2-(tert-Butoxycarbonylamino)oct-4-ene 35a.
A
stirred
and 1351 (s); δH (270) 5.39 (1H, dt, J 15.5 and 6.6, 5-H), 5.23
(1H, dt, J 15.5 and 6.3, 4-H), 3.83–3.99 (1H, m, 2-H), 2.04 (2H,
dd, J 6.6 and 6.3, 3-CH2), 1.91 (2H, td, J 7.2 and 6.6, 6-CH2),
1.85 (3H, s, C(O)Me), 1.27 (2H, hex, J 7.2, 7-CH2), 1.03 (2H, d,
J 6.6, 1-Me) and 0.79 (3H, t, J 7.2, 8-Me); δC (67.8) 169.8
solution of the foregoing acid 34 (2.60 g, 17.0 mmol), diphenyl-
phosphoryl azide (3.59 ml, 17.0 ml, 17.0 mmol) and triethyl-
amine (2.44 ml, 17.0 mmol) in tert-butyl alcohol (50 ml) was
refluxed for 18 h. The reaction mixture was cooled, and the tert-
butyl alcohol removed under reduced pressure. The residue was
dissolved in benzene (50 ml) and the solution washed succes-
sively with water (30 ml), saturated aqueous sodium carbonate
(60 ml) and brine (30 ml). The organic solution was then dried
and evaporated to leave a clear oil which was purified by cc
(dichloromethane) to afford the N-Boc amine 35a (2.79 g, 72%)
as a clear oil: Rf 0.44 (dichloromethane); νmax/cmϪ1 3342 (NH),
(C(O)Me), 134.1, 125.5 (both ᎐CH), 44.9 (2-CH), 39.5, 34.7
᎐
(both CH2), 24.3 (C(O)Me), 22.6 (CH2), 20.2 (1-Me) and 13.6
(8-Me); m/z (FAB) 170 (Mϩ ϩ 1, 24%), 155 (30), 154 (100), 136
(70), 107 (25) and 77 (21).
(E)-2-Methoxycarbonylaminooct-4-ene 35e. A solution of
amine 35b (0.10 g, 0.78 mmol), methyl chloroformate (0.06 ml,
0.86 mmol, freshly distilled from calcium hydride) and triethyl-
amine (0.12 ml, 0.86 mmol) in dichloromethane (20 ml) was
stirred at ambient temperature for 5 h then neutralised with 2 M
hydrochloric acid and extracted with dichloromethane (3 × 20
ml). The combined organic solutions were dried and evaporated
to give a mixture of mono- and diacylated products which were
separated by cc (methanol–dichloromethane 5 : 95) to afford
the carbamate 35e (0.08 g, 53%) as a pale yellow oil: Rf 0.14
(dichloromethane); νmax/cmϪ1 3437 (NH), 2961 (s), 2931 (s),
2964 (s), 2872 (s), 1693 (C᎐O), 1523 (s) and 1248 (s); δ (250)
᎐
H
5.42 (1H, dt, J 15.5 and 6.6, 5-H), 5.37 (1H, dt, J 15.5 and 6.6,
4-H), 4.42–4.28 (1H, m, NH), 3.72–3.57 (1H, m, 2-H), 2.10 (1H,
dd, J 6.6 and 6.0, 3-H), 1.96 (2H, td, J 7.2 and 6.6, 6-CH2), 1.42
t
(9H, s, Bu), 1.36 (2H, qt, J 7.4 and 7.2, 7-CH2), 1.07 (3H, t,
J 6.6, 1-Me) and 0.86 (3H, t, J 7.4, 8-Me); δC (67.8) 133.8,
125.7 (both ᎐CH), 47.4 (2-CH), 40.0, 34.7, 22.5 (all CH ), 20.5
᎐
2
(1Ј-Me) and 13.6 (8-Me); m/z (FAB) 228 (Mϩ ϩ 1, 15%), 172
(100), 154 (10), 144 (29), 88 (33), 68 (27) and 56 (46) [Found:
Mϩ ϩ 1, 228.1959. C13H26NO2 requires M, 228.1963].
1713 (C᎐O), 1514 (s) and 1435 (s); δ (270) 5.55–5.31 (2H, m,
᎐
H
4- and 5-H), 3.92–3.79 (1H, m, 2-H), 3.62 (3H, s, OMe), 2.11
(2H, dd, J 6.5 and 6.2, 3-CH2), 1.95 (2H, td, J 7.3 and 6.6,
6-CH2), 1.35 (2H, hex, J 7.3, 7-CH2), 1.15 (3H, d, J 6.6, 1-Me)
and 0.89 (3H, t, J 7.3, 8-Me); δC (67.8) 156.2 (C(O)OMe), 134.6,
(E)-2-Aminooct-4-ene 35b. To a stirred solution of the
N-Boc-amine 35a (0.40 g, 1.80 mmol) in dichloromethane
(20 ml) was added trifluoroacetic acid (2.05 g, 18 mmol) and the
solution stirred at ambient temperature for 3h, then neutralised
with saturated aqueous sodium hydrogencarbonate, followed
by extraction with dichloromethane (3 × 30 ml). The combined
organic solutions were dried (sodium sulfate) and evaporated
to afford the amine 35b (0.19 g, 86%) as a yellow oil: Rf 0.18
(methanol–dichloromethane 1 : 9); νmax/cmϪ1 3370 (NH), 2945
(s), 2837 (s), 1460 (s) and 1342 (s); δH (270) 5.58 (1H, dt, J 15.3
124.9 (both ᎐CH), 54.6 (C(O)OMe), 47.0 (2-CH), 43.7, 34.6,
᎐
22.5 (all CH2), 20.1 (1-Me) and 13.6 (8-Me) [Found (ES):
Mϩ ϩ 1, 186.1491. C10H20NO2 requires M, 186.1494].
Iodocyclisations with sodium hydrogen carbonate as base:
general procedure
To a stirred mixture of the cyclisation precursor (1 mmol, 1 eq.)
and sodium hydrogen carbonate (0.25 g, 3 mmol, 3 eq.) in dry
acetonitrile (1 ml) was added portionwise iodine (0.76 g,
3 mmol, 3 eq.). The reaction mixture was stirred at ambient
temperature until no starting material remained according
to TLC analysis (typically 5–30 min). The reaction mixture
was then treated with saturated aqueous sodium thiosulfate
(1–2 ml) and the resulting pale yellow solution extracted with
dichloromethane (3 × 2 ml). The combined organic solutions
were dried, filtered and the solvent evaporated to yield the
crude product which was purified by column chromatography.
Any isomer ratios quoted were determined from 1H NMR
spectra for the mixtures; the peaks used for the determination
of the ratios are stated in each case.
and 6.7, ᎐CH), 5.44 (1H, dt, J 15.3 and 7.1, ᎐CH), 3.77–3.65
(1H, m, 2-H), 2.08–1.83 (4H, m, 3- and 6-CH2), 1.38–1.23 (2H,
m, 7-CH2), 1.05 (3H, d, J 6.4, 1-Me) and 0.81 (3H, t, J 7.3,
᎐
᎐
8-Me); δC (67.8) 138.2, 122.8 (both ᎐CH), 49.9 (2-CH), 38.3,
᎐
35.2, 22.7 (all CH2), 18.9 (1-Me) and 14.2 (8-Me); m/z (FAB)
128 (Mϩ ϩ 1, 23%), 73 (10), 69 (17) and 43 (100) [Found:
Mϩ ϩ 1, 128.1565. C8H18N requires M, 128.1557].
(E)-2-Trifluoroacetylaminooct-4-ene 35c.
A solution of
amine 35b (0.28 g, 2.20 mmol), trifluoroacetic anhydride (0.24
ml, 2.20 mmol) and triethylamine (0.34 ml, 2.20 mmol) in
dichloromethane (20 ml) was stirred at ambient temperature for
2 h. The reaction mixture was then neutralised with 2 M hydro-
chloric acid and extracted with dichloromethane (3 × 20 ml).
The combined organic solutions were dried and evaporated to
give a mixture of mono- and diacylated products which were
separated by cc (dichloromethane) to afford the title compound
35c (0.31 g, 63%) as a pale yellow oil: Rf 0.37 (dichlorometh-
Cyclisation of 4-(phenylsulfonylamino)pent-1-ene 24a. Homo-
allylic sulfonamide 24a (0.06 g, 0.25 mmol) was reacted under
the conditions described above for 1 h. The crude product was
purified by cc (dichloromethane) to afford an inseparable mix-
ture of isomers in the ratio 3 : 2 together with a trace of another
unidentified product (0.04 g, 42%). The isomer ratio was deter-
mined by measurement of the alkyl methyl peaks. Data for the
two predominant isomers: Rf 0.55 (hexane–ethyl acetate 1 : 1);
δH (250) 7.79–7.91 (4H, m, Ar-H, both isomers), 7.65–7.51 (6H,
m, Ar-H, both isomers), 3.93–3.84 (1H, m, minor isomer),
3.79–3.64 (3H, m, both isomers), 3.61–3.50 (2H, m, both
isomers), 3.46–3.38 (1H, m, minor isomer), 3.28–3.17 (2H, m,
major isomer), 2.62–2.50 (1H, m, minor isomer), 2.31–2.19
(1H, m, major isomer), 1.99–1.84 (1H, m, minor isomer), 1.61–
1.52 (1H, m, major isomer), 1.38 (3H, d, J 5.9, minor isomer)
and 1.32 (3H, d, J 6.3, major isomer); δC (100) 138.4 (Ar-C,
ane); νmax/cmϪ1 3621 (NH), 3021 (s), 2975 (s), 1723 (C᎐O), 1527
᎐
(s) and 1383 (s); δH (270) 5.49 (1H, dt, J 15.3 and 6.8, 5-H), 5.35
(1H, dt, J 15.3 and 7.1, 4-H), 4.12–4.01 (1H, m, 2-H), 2.21 (2H,
dd, J 7.1 and 6.9, 3-CH2), 1.97 (2H, td, J 7.2 and 6.8, 6-CH2),
1.40–1.28 (2H, m, 7-CH2), 1.20 (3H, d, J 6.6, 1-Me) and 0.87
(3H, t, J 7.2, 8-Me); m/z (FAB) 224 (Mϩ ϩ 1, 9%), 209 (12), 197
(34), 135 (100), 109 (59), 83 (29) and 69 (94) [Found: Mϩ ϩ 1,
224.1272. C10H17F3NO requires M, 224.1262].
(E)-2-Acetylaminooct-4-ene 35d. A solution of amine 35b
(0.10 g, 0.78 mmol), acetic anhydride (0.07 ml, 0.78 mmol),
triethylamine (0.11 ml, 0.78 mmol) and 4-dimethylamino-
pyridine (10 mg) in dichloromethane (10 ml) was stirred at
1194
J. Chem. Soc., Perkin Trans. 1, 2001, 1182–1203

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minor isomer), 135.8 (Ar-C, major isomer), 133.4 (Ar-CH,
minor isomer), 129.4 (Ar-CH, minor isomer), 129.3 (Ar-CH,
major isomer), 129.2 (Ar-CH, minor isomer), 128.3 (Ar-CH,
major isomer), 127.4 (Ar-CH, major isomer), 59.8 (CH, major
isomer), 58.6 (CH2, minor isomer), 56.8 (CH, minor isomer),
55.5 (CH, major isomer), 46.7 (CH2, minor isomer), 32.6 (CH2
major isomer), 22.6 (Me, minor isomer), 22.3 (Me, major
isomer) and 10.2 (CH2, major isomer); m/z (EI) 351 (Mϩ, 2%),
336 (Mϩ Ϫ Me, 30%), 224 (25), 210 (96), 141 (74) and 77 (100)
[C11H14INO2S requires M, 351].
allylic tosylamide 24j (0.04 g, 0.12 mmol) was subjected to the
iodocyclisation conditions described in the general procedure
and the reaction was complete after 40 min. The resulting crude
product was purified by cc (dichloromethane) to yield the title
compounds as a colourless solid (0.04 g, 76%) in an isomer ratio
of 2 : 1. The isomer ratio was measured by comparison of the
1
aryl-methyl peaks in the H NMR spectrum. Comparison of
the spectral data (see below) for the mixture with those for the
potassium carbonate and base-free reactions showed that the
major isomer was the 2,5-trans-pyrrolidine 36j and the minor
isomer was the corresponding 2,5-cis-pyrrolidine 37j.
(2SR,3RS)-2-Ethyl-3-iodo-1-(p-tolylsulfonyl)pyrrolidine
36b. (E)-Homoallylic tosylamide 24b (0.20 g, 0.79 mmol) was
cyclised under the general conditions above, and the reaction
was complete within 10 min. The crude product was obtained
as a colourless solid, which was recrystallised (hexane–ethyl
acetate 9 : 1) to give the iodopyrrolidine 36b (0.25 g, 84%) as a
colourless, crystalline solid, mp 109–110 ЊC: Rf 0.52 (dichloro-
methane); νmax/cmϪ1 (CHCl3) 2950 (s), 2923 (s), 2856 (w), 1592
(w), 1456 (w) and 1338 (s); δH (400) 7.75 (2H, d, J 8.3, Ar-H),
7.32 (2H, d, J 8.3, Ar-H), 4.14 (1H, ddd, J 5.1, 2.1 and 1.4,
3-H), 3.88 (1H, ddd, J 9.5, 3.9 and 1.4, 2-H), 3.55 (1H, ddd,
J 9.8, 7.2 and 2.5, 5-Hα), 3.42 (1H, ddd, J 9.8, 9.8 and 6.2, 5-Hβ),
2.41 (3H, s, Ar-Me), 2.25 (1H, dddd, J 14.0, 9.8, 5.1 and 2.5,
4-Hα), 1.95 (1H, dddd, 14.0, 7.2, 6.2 and 2.1, 4-Hβ), 1.83 (1H,
dqd, J 9.5, 7.5 and 3.9, 1Ј-Hα), 1.46 (1H, ddq, J 9.5, 9.5 and 7.5,
1Ј-Hβ) and 0.96 (3H, t, J 7.5, 2Ј-Me); δC (100) 143.1, 132.6 (both
Ar-C), 129.5, 127.8 (both Ar-CH), 72.9 (2-CH), 47.6 (5-CH2),
35.9 (4-CH2), 30.3 (1Ј-CH2), 23.8 (Ar- Me), 21.4 (3-CH) and
10.1 (2Ј-Me); m/z (ES) 380 (Mϩ ϩ 1, 100%), 329 (7), 279 (8),
254 (20), 83 (12) and 60 (23) [Found: Mϩ ϩ 1, 380.0181.
C13H19INO2S requires M, 380.0187].
Cyclisation of (Z)-1-(p-tolylsulfonylamino)hex-3-ene 26a.
(Z)-Homoallylic tosylamide 26a (0.20 g, 0.79 mmol) was
reacted under the general conditions described above and the
reaction appeared complete after 1 h. The crude product was
obtained as a yellow oil, which was purified by cc (dichloro-
methane) to give an inseparable mixture of isomers (0.12 g,
40%) in the ratio 2 : 1. The isomer ratio was determined by
measurement of the signals corresponding to the alkyl methyl
groups in the 1H NMR spectrum. Comparison of the 1H NMR
spectrum with that for iodocyclisation of the corresponding
(E)-tosylamide 24b revealed that the minor product was the
2,3-trans-iodopyrrolidine 36b (see above). Data for mixture: Rf
0.52 (dichloromethane); δH (270) 7.80–7.73 (4H, m, Ar-H, both
isomers), 7.45–7.30 (4H, m, Ar-H, both isomers), 4.20–4.04
(2H, m, both isomers), 3.89–3.70 (2H, m, both isomers), 3.55–
2.95 (4H, m, both isomers), 2.41 (3H, s, Ar-Me, minor isomer),
2.38 (3H, s, Ar-Me, major isomer), 2.27–1.39 (8H, m, both
isomers), 1.04 (3H, t, J 7.3, major isomer) and 0.96 (3H, t, J 7.5,
2Ј-Me, minor isomer).
Cyclisation of (Z)-1-(methylsulfonylamino)hex-3-ene 26b.
(Z)-Homoallylic mesylamide 26b (0.02 g, 0.07 mmol) in
acetonitrile (0.2 ml) was reacted as described in the general
procedure for 1 h. The crude product was purified by cc
(dichloromethane) to give an inseparable mixture of isomers in
the ratio 1 : 1 (0.06 g, 45%). The ratio of isomers was deter-
(2SR,3RS)-1-Phenylsulfonyl-2-ethyl-3-iodopyrrolidine
36c.
(E)-Homoallylic sulfonamide 24c (0.20 g, 0.84 mmol) was
cyclised under the general conditions described above and the
reaction was complete within 10 min. The crude product
was obtained as a colourless solid, which was recrystallised
(hexane–ethyl acetate 9 : 1) to afford the iodopyrrolidine 36c
(0.26 g, 84%) as a colourless crystalline solid, mp 101–102 ЊC:
Rf 0.56 (dichloromethane); νmax cmϪ1/(CHCl3) 2951 (s), 2920 (s),
2856 (w), 1592 (w), 1452 (s) and 1338 (s); δH (400) 7.93–7.53
(5H, m, Ph), 4.17 (1H, ddd, J 5.2, 2.1 and 1.4, 3-H), 3.90 (1H,
ddd, J 9.4, 3.8 and 1.4, 2-H), 3.62 (1H, ddd, J 9.8, 7.2 and 2.5,
5-Hα), 3.43 (1H, ddd, J 9.8, 9.8 and 6.2, 5-Hβ), 2.27 (1H, dddd,
J 14.0, 9.8, 7.2 and 5.2, 4-Hα), 1.96 (1H, dddd, 14.0, 6.2, 2.5 and
2.1, 4-Hβ), 1.83 (1H, dqd, J 14.0, 7.5 and 3.8, 1Ј-Hα), 1.46 (1H,
ddq, J 14.0, 9.4 and 7.5, 1Ј-Hβ) and 0.98 (3H, t, J 7.5, 2Ј-Me);
δC (100) 136.3 (Ar-C), 132.9, 129.5, 127.8 (all Ar-CH), 73.1
(2-CH), 47.7 (5-CH2), 35.9 (4-CH2), 30.8 (1Ј-CH2), 23.8 (3-CH)
and 10.2 (2Ј-Me); m/z (EI) 336 (Mϩ Ϫ C2H5, 28%), 208 (39),
141 (65), 128 (63), 86 (98) and 77 (100) [Found: C, 39.6; H, 4.5;
N, 3.8. C12H16INO2S requires C, 39.5; H, 4.4; N, 3.8%].
1
mined by integration of the –SO2Me peaks in the H NMR
spectrum. Data for the mixture: Rf 0.53 (dichloromethane);
δH (250) 4.79–4.68 (1H, m), 4.31–4.20 (1H, m), 4.08–3.96 (1H,
m), 3.62–3.15 (4H, m), 3.00 (3H, s, SO2Me), 2.98 (3H, s,
SO2Me), 2.11–1.34 (8H, m), 1.06 (3H, t, J 7.3, Me) and 0.97
(3H, t, J 7.3, Me).
Cyclisation of (Z)-3-(p-tolylsulfonylamino)dec-5-ene 26c.
(Z)-Homoallylic tosylamide 26c (0.10 g, 0.34 mmol) was
cyclised under the conditions described in the general pro-
cedure above for 1 h. The crude product was purified by cc
(dichloromethane) and gave an inseparable mixture of isomers
in the ratio 3 : 2 : 2 (0.09 g, 65%). The two minor isomers were
found (by comparison of 1H NMR data for the mixture) to be
identical to the products (36f and 37f) obtained from the
cyclisation of the corresponding (E)-homoallylic tosylamide
24f (see above). The major isomer was tentatively assigned the
all-cis-structure 44.
(2SR,3RS,5SR)- and (2RS,3SR,5SR)-2-Butyl-5-ethyl-3-iodo-
1-(p-tolylsulfonyl)pyrrolidine 36f and 37f. (E)-Homoallylic
sulfonamide 24f (0.05 g, 0.16 mmol) was cyclised under the
general conditions described above; the reaction was com-
plete after 25 min. The resulting crude oil was purified by cc
(dichloromethane) to yield the iodopyrrolidine as a yellow oil
(0.05 g, 76%) in a ratio of isomers of 3 : 1. The isomer ratio
was determined by measurement of the aryl-methyl peaks
Potassium carbonate as base: general procedure
A mixture of the cyclisation precursor (1.0 mmol, 1 eq.) and
potassium carbonate (0.41 g, 3 mmol, 3 eq.) in dry acetonitrile
(1 ml) and water (0.01 ml) was stirred for 0.5 h, after which time
iodine (0.76 g, 3 mmol, 3 eq.) was added portionwise. The reac-
tion was followed by TLC analysis, and once complete (typic-
ally 0.5–1 h), the mixture was quenched with saturated aqueous
sodium thiosulfate (1 ml). The resulting layers were separated
and the aqueous layer extracted with dichloromethane (3 × 2
ml). The combined organic solutions were dried and evaporated
to yield the crude product which was purified by column
chromatography.
1
in the H NMR spectrum. Comparison of the spectral data
for the mixture with those for the potassium carbonate and
base-free reactions (see later) revealed that the major isomer
was the 2,5-trans-pyrrolidine 36f while the minor product was
the 2,5-cis-pyrrolidine 37f.
(2SR,3RS,5SR)- and (2RS,3SR,5SR)-5-Ethyl-3-iodo-2-
phenyl-1-(p-tolylsulfonyl)pyrrolidine 36j and 37j. (E)-Homo-
J. Chem. Soc., Perkin Trans. 1, 2001, 1182–1203
1195

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(2SR,3RS)-2-Ethyl-3-iodo-1-(p-tolylsulfonyl)pyrrolidine 36b.
(E)-Homoallylic sulfonamide 24b (0.20 g, 0.79 mmol) was
cyclised under the conditions described above using potassium
carbonate as the base, and the reaction was complete after
20 min. The crude product was purified by recrystallisation
(hexane–ethyl acetate 9 : 1) to yield the iodopyrrolidine 36b (0.22
g, 73%) as a colourless crystalline solid, mp 108–110 ЊC; other
spectral and analytical data were identical to the sample pre-
pared using sodium hydrogen carbonate as the base (see above).
36g (0.01 g, 72%) as a pale yellow, viscous oil: Rf 0.59
(dichloromethane); νmax/cmϪ1 2952 (s), 2931 (s), 2875 (w), 1461
(w) and 1341 (s); δH (400) 4.29 (1H, ddd, J 6.3, 2.3 and 1.7,
3-H), 4.05 (1H, ddd, J 10.3, 3.3 and 1.7, 2-H), 3.88 (1H, dddd,
J 11.9, 9.0, 3.2 and 2.9, 5-H), 3.06 (3H, s, SO2Me), 2.41–2.29
(2H, m, 1Ј-CH2), 2.74 (1H, ddd, J 15.3, 9.0 and 6.3, 4-Hα), 2.32
(1H, ddd, J 15.3, 3.2 and 2.3, 4-Hβ), 2.09 (1H, ddq, J 15.0, 11.9
and 7.3, 1Љ-Hα), 1.43 (1H, dqd, J 15.0, 7.3 and 2.9, 1Љ-Hβ), 1.38–
1.24 (4H, m, 2Ј- and 3Ј-CH2), 0.95 (3H, t, J 7.3, 2Љ-Me) and 0.88
(3H, t, J 7.5, 4Ј-Me); δC (67.8) 73.9 (2-CH), 61.4 (5-CH), 42.4
(SO2Me), 38.5 (4-CH2), 35.2 (1Љ-CH2), 28.4, 26.2, 22.5 (all
CH2), 22.1 (3-CH), 13.9 (2Љ-Me) and 11.1 (4Ј-Me); m/z (ES)
360 (Mϩ ϩ 1, 38%), 254 (36), 234 (39), 193 (30), 83 (66) and 64
(100) [Found: Mϩ ϩ 1, 360.0494. C11H23INO2S requires M,
360.0499].
(2SR,3RS,5SR)-2-Butyl-3-iodo-5-methyl-1-(p-tolylsulfonyl)-
pyrrolidine 36d. (E)-Homoallylic tosylamide 24d (0.20 g, 0.68
mmol) was subjected to the cyclisation conditions described in
the general procedure (K2CO3), and the reaction was complete
after 25 min. The resulting crude product was purified by cc
(dichloromethane) then recrystallised (hexane–ethyl acetate
9 : 1) to afford the iodopyrrolidine 36d (0.24 g, 85%) as a colour-
less, crystalline solid, mp 84–85 ЊC: Rf 0.52 (dichloromethane);
νmax/cmϪ1 (CHCl3) 2957 (s), 2928 (s), 2856 (w), 1597 (w), 1458
(s) and 1335 (s); δH (250) 7.84 (2H, d, J 8.3, Ar-H), 7.30 (2H, d,
J 8.3, Ar-H), 4.29–4.20 (2H, m, 2- and 3-H), 4.15 (1H, dqd,
J 9.0, 6.6 and 3.0, 5-H), 2.89 (1H, ddd, J 15.2, 9.0 and 6.1,
4-Hα), 2.43 (3H, s, Ar-Me), 2.10 (1H, ddd, J 15.2, 3.0 and 3.0,
4-Hβ), 2.05–1.98 (2H, m, 1Ј-CH2), 1.42 (3H, d, J 6.6, 5-Me),
1.37–1.21 (4H, m, 2Ј- and 3Ј-CH2) and 0.91 (3H, t, J 6.9,
4Ј-Me); δC (67.8) 142.8, 139.6 (both Ar-C), 129.5, 126.9 (both
Ar-CH), 74.3 (2-CH), 55.2 (5-CH), 43.2 (4-CH2), 34.4 (1Ј-CH2),
28.2 (2Ј-CH2), 22.3 (3Ј-CH2), 22.0 (5-Me), 21.3 (3-CH), 21.2
(Ar-Me) and 13.8 (4Ј-Me); m/z (FAB) 422 (Mϩ ϩ 1, 68%), 391
(7), 364 (39), 294 (47), 198 (100), 155 (69), 136 (56), 91 (86) and
77 (30) [Found: C, 45.7; H, 6.0; N, 3.6; Mϩ ϩ 1, 422.0596.
C16H24INO2S requires C, 45.6; H, 5.7; N, 3.3%; C16H25INO2S
requires M, 422.0566].
(2SR,3RS,5SR)-5-Ethyl-3-iodo-2-pentyl-1-(p-tolylsulfonyl)-
pyrrolidine 36h. (E)-Homoallylic sulfonamide 24h (0.05 g, 0.16
mmol) in acetonitrile (0.3 ml) was cyclised under the conditions
described in the general procedure (K2CO3) and the reaction
was complete after 25 min. The resulting crude product was
purified by cc (dichloromethane) to yield the title compound 36h
(0.06 g, 79%) as a pale yellow, viscous oil: Rf 0.49 (dichloro-
methane); νmax/cmϪ1 2952 (s), 2931 (s), 2875 (w), 1461 (w) and
1342 (s); δH (400) 7.84 (2H, d, J 8.3, Ar-H), 7.28 (2H, d, J 8.3,
Ar-H), 4.29–4.21 (2H, m, 2- and 3-H), 3.85 (1H, dddd, J 11.3,
8.8, 3.2 and 3.1, 5-H), 2.71 (1H, ddd, J 15.2, 8.8 and 6.6, 4-Hα),
2.42 (3H, s, Ar-Me), 2.25 (1H, ddd, J 15.2, 3.2 and 2.2, 4-Hβ),
2.09–1.50 (4H, m, 1Ј- and 1Љ-CH2), 1.49–1.16 (6H, m, 2Ј-,
3Ј- and 4Ј-CH2), 0.94 (3H, t, J 6.9, 2Љ-Me) and 0.88 (3H, t, J 7.5,
5Ј-Me); δC (67.8) 142.9, 140.0 (both Ar-C), 129.3, 127.0 (both
Ar-CH), 74.2 (2-CH), 61.4 (5-CH), 39.3, 34.5, 31.5, 26.4, 25.9,
22.4 (all CH2), 21.5 (3-CH), 21.3 (Ar-Me), 13.9 (11-Me) and
11.0 (1-Me) [Found: C, 48.3; H, 6.3; N 3.1. C18H28INO2S
requires C, 48.1; H, 6.2; N, 3.1%].
(2SR,3RS,5SR)-2-Butyl-5-ethyl-3-iodo-1-(p-tolylsulfonyl)-
pyrrolidine 36f. (E)-Homoallylic tosylamide 24f (0.20 g, 0.64
mmol) was cyclised under the conditions described in the gen-
eral procedure (K2CO3) and the reaction was complete after 30
min. The crude product was purified by cc (dichloromethane)
then recrystallised (hexane–ethyl acetate 9 : 1) to yield the title
compound 36f (0.21 g, 74%) as a colourless, crystalline solid: mp
72–73 ЊC; Rf 0.52 (dichloromethane); νmax/cmϪ1 (CHCl3) 2950
(s), 2927 (s), 2872 (w), 1465 (w), 1337 (s); δH (400) 7.82 (2H, d,
J 8.3, Ar-H), 7.29 (2H, d, J 8.3, Ar-H), 4.27–4.19 (2H, m, 2- and
3-H), 3.86 (1H, dddd, J 11.2, 8.7, 3.3 and 3.2, 5-H), 2.73 (1H,
ddd, J 15.2, 8.7 and 6.6, 4-Hα), 2.41 (3H, s, Ar-Me), 2.25 (1H,
ddd, J 15.2, 3.2 and 2.2, 4-Hβ), 2.09–1.50 (4H, m, 1Ј- and
1Љ- CH2), 1.47–1.28 (4H, m, 2Ј- and 3Ј-CH2), 0.88 (3H, t, J 7.2,
2Љ-Me) and 0.79 (3H, t, J 7.4, 4Ј-Me); δH (d6-acetone, 400) 7.85
(2H, d, J 8.3, Ar-H), 7.37 (2H, d, J 8.3, Ar-H), 4.48 (1H, ddd,
J 6.6, 2.2 and 1.6, 3-H), 4.23 (1H, ddd, J 10.1, 3.2 and 1.6, 2-H),
3.89 (1H, dddd, J 11.2, 8.7, 3.3 and 3.2, 5-H), 2.88 (1H, ddd,
J 15.3, 8.7 and 6.6, 4-Hα), 2.59 (3H, s, Ar-Me), 2.23 (1H, ddd,
J 15.3, 3.2 and 2.2, 4-Hβ), 2.20–1.95 (2H, m, 1Ј-CH2), 1.72 (1H,
ddq, J 14.1, 11.2 and 7.3, 1Љ-Hα), 1.49 (1H, dqd, J 14.1, 7.3 and
3.3, 1Љ-Hβ), 1.47–1.15 (4H, m, 2Ј- and 3Ј-CH2), 0.92 (3H, t,
J 7.3, 2Љ-Me) and 0.86 (3H, t, J 7.5, 4Ј-Me); δC (67.8) 142.9,
139.6 (both Ar-C), 129.3, 127.0 (both Ar-CH), 74.2 (2-CH),
61.4 (5-CH), 39.3 (4-CH2), 34.5 (1Ј-CH2), 31.5 (1Љ-CH2), 26.4,
25.9 (both CH2), 21.4 (3-CH), 21.3 (Ar-Me), 13.9 (4Ј-Me) and
10.9 (2Љ-Me); m/z (ES) 436 (Mϩ ϩ 1), 391 (10), 102 (28), 83 (72)
and 60 (100) [Found C, 46.9; H, 6.15; N, 3.3. C17H26INO2S
requires C, 46.9; H, 6.0; N, 3.3%].
(2SR,3RS,5SR)-5-Butyl-3-iodo-2-pentyl-1-(p-tolylsulfonyl)-
pyrrolidine 36i. (E)-Homoallylic sulfonamide 24i (0.30 g, 0.85
mmol) was cyclised under the general conditions (K2CO3), and
the reaction was complete after 35 min. The resulting crude
product was purified by cc (dichloromethane) to yield the title
compound 36i (0.33 g, 78%) as a viscous, pale yellow oil: Rf 0.62
(dichloromethane); νmax/cmϪ1 2950 (s), 2935 (s), 2871 (w), 1461
(w), 1358 (s) and 1342 (s); δH (400) 7.82 (2H, d, J 8.3, Ar-H),
7.29 (2H, d, J 8.3, Ar-H), 4.24–4.19 (2H, m, 2- and 3-H), 3.94
(1H, dddd, J 11.2, 8.7, 3.4 and 3.2, 5-H), 3.71 (1H, ddd, J 15.2,
8.7 and 6.6, 4-Hα), 2.42 (3H, s, Ar-Me), 2.20 (1H, ddd, J 15.2,
3.4 and 2.3, 4-Hβ), 2.06–2.01 (2H, m, 1Ј-CH2), 1.71–1.61 (2H,
m, 1Љ-CH2), 1.61–1.11 (10H, m, 2Ј-, 2Љ-, 3Ј-, 3Љ- and 4Ј-CH2),
0.89 (3H, t, J 7.2, Me) and 0.83 (3H, t, J 7.1, Me); δC (67.8)
142.9, 139.9 (both Ar-C), 129.0, 127.0 (both Ar-CH), 73.9
(2-CH), 60.0 (5-CH), 39.8 (4-CH2), 34.4 (1Ј-CH2), 33.0
(1Љ-CH2), 31.6, 29.4, 26.8, 22.5, 22.4 (all CH2), 21.6 (3-CH),
21.4 (Ar-Me), 13.9 (Me) and 13.8 (Me); m/z (ES) 478 (Mϩ ϩ 1,
100%), 391 (5), 254 (96) and 60 (7) [Found: Mϩ ϩ 1, 478.1280.
C20H33INO2S requires M, 478.1279].
(2SR,3RS,5SR)-5-Ethyl-3-iodo-2-phenyl-1-(p-tolylsulfonyl)-
pyrrolidine 36j. (E)-Homoallylic tosylamide 24j (1.00 g, 3.04
mmol) was subjected to the iodocyclisation conditions
described in the general procedure (K2CO3), and the reaction
was complete after 45 min. The resulting orange solid was
purified by cc (dichloromethane) followed by recrystallisation
(hexane–ethyl acetate 9 : 1) to afford the 2-phenyliodopyrrol-
idine 36j (1.12 g, 83%) as a pale cream solid: mp 156–157 ЊC;
Rf 0.52 (dichloromethane); νmax/cmϪ1(CHCl3) 3286 (s), 3062 (s),
2966 (s), 2876 (w), 2251 (w), 1700 (w), 1676 (w) and 1446 (s);
δH (400) 7.59 (2H, d, J 8.3, Ar-H), 7.31–7.16 (7H, m, Ar-H),
5.32 (1H, d, J 2.3, 2-H), 4.28–4.18 (2H, m, 3- and 5-H), 2.74
(1H, ddd, J 15.0, 8.7 and 6.7, 4-Hα), 2.40 (3H, s, Ar-Me), 2.25
(2SR,3RS,5SR)-2-Butyl-5-ethyl-3-iodo-1-methylsulfonyl-
pyrrolidine 36g. (E)-Homoallylic sulfonamide 24g (0.01 g, 0.04
mmol) in acetonitrile (0.2 ml) was cyclised under the conditions
described in the general procedure (K2CO3) and the reaction
was complete after 25 min. The resulting crude product was
purified by cc (dichloromethane) to afford the iodopyrrolidine
1196
J. Chem. Soc., Perkin Trans. 1, 2001, 1182–1203

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(1H, ddd, J 15.0, 3.0 and 2.4, 4-Hβ), 1.98–1.84 (2H, m, 1Ј-CH2)
and 0.91 (3H, t, J 7.4, 2Ј-Me); δH (270, d6-benzene) 8.05–7.13
(9H, m, Ar-H), 5.70 (1H, d, J 2.3, 2-H), 4.28 (1H, dddd, J 11.2,
8.3, 3.3 and 3.2, 5-H), 3.98 (1H, ddd, J 6.6, 3.3 and 2.3, 3-H),
2.72 (1H, ddd, J 14.8, 11.2 and 6.6, 4-Hα), 2.62 (3H, s, Ar-Me),
2.31–2.19 (2H, m, 1Ј-CH2), 2.10 (1H, ddd, J 14.8, 3.3 and 3.3,
4-Hβ) and 0.93 (3H, t, J 7.3, 2Ј-Me); δC (100) 143.7, 140.4, 134.5
(all Ar-C), 129.6, 128.5, 128.0, 127.9, 126.6 (all Ar-CH), 74.8
(2-CH), 62.9 (5-CH), 41.8 (4-CH2), 28.7 (1Ј-CH2), 26.2 (3-CH),
21.6 (Ar-Me) and 10.7 (2Ј-Me); m/z (ES) 456 (Mϩ ϩ 1, 100%),
282 (10), 276 (47) and 104 (21) [Found: C, 50.2; H, 5.0; N, 3.1.
C19H22INO2S requires C, 50.1; H, 4.9; N, 3.1%].
(1H, m, minor isomer), 4.79–4.70 (1H, m, major isomer), 4.22–
4.15 (1H, m, major isomer), 3.98–3.89 (1H, m, minor isomer),
3.21–1.95 (4H, m, both isomers), 2.38 (3H, s, Ar-Me, minor
isomer), 2.36 (3H, s, Ar-Me, major isomer), 2.12–1.51 (8H, m,
both isomers), 1.06 (3H, t, J 7.3, minor isomer) and 0.94 (3H, t,
J 7.2, major isomer). These data indicate that the major isomer
was the 2,3-trans-iodopyrrolidine 36b.
Attempted cyclisation of (Z)-1-(methylsulfonylamino)hex-3-
ene 26b. (Z)-Homoallylic mesylamide 26b (0.02 g, 0.11 mmol)
in acetonitrile (0.2 ml) was reacted under the conditions
described above (K2CO3) for 1 h, but no reaction was observed.
The reaction was repeated and left stirring for 24 h at ambient
temperature but, again, no reaction was found to have
occurred.
(2SR,3RS,4SR,5RS)-4,5-Dimethyl-3-iodo-2-propyl-1-(p-
tolylsulfonyl)pyrrolidine 38. (E)-anti-Homoallylic tosylamide
27b (0.20 g, 0.7 mmol) was subjected to the iodocyclisation
conditions described above (K2CO3) and the reaction was com-
plete after 40 min. The resulting crude product was purified by
cc (dichloromethane) followed by recrystallisation (hexane–
ethyl acetate 9 : 1) to yield the iodopyrrolidine 38 (0.22 g, 76%)
as a colourless, crystalline solid, mp 102–103 ЊC: Rf 0.62
(dichloromethane); νmax/cmϪ1(CHCl3) 2950 (s), 2932 (s), 2873
(w), 1462 (w) and 1339 (s); δH (400) 7.72 (2H, d, J 8.2, Ar-H),
7.33 (2H, d, J 8.2, Ar-H), 3.87 (1H, ddd, J 8.7, 6.2 and 3.6,
2-H), 3.72 (1H, dq, J 7.2 and 6.9, 5-H), 3.61 (1H, dd, J 11.6 and
8.7, 3-H), 2.45 (3H, s, Ar-Me), 1.95–1.89 (2H, m, 1Ј-CH2), 1.60
(1H, ddq, 11.6, 7.2 and 6.8, 4-H), 1.48–1.36 (2H, m, 2Ј-CH2),
1.11 (3H, d, J 6.9, 5-Me), 0.97 (3H, t, J 7.2, 3Ј-Me) and 0.99
(3H, d, J 6.8, 4-Me); δC (67.8) 143.6, 134.6 (both Ar-C), 129.8,
127.4 (both Ar-CH), 69.4 (2-CH), 58.6 (5-CH), 46.5 (4-CH),
35.9 (1Ј-CH2), 30.5 (3-CH), 21.6 (Ar-Me), 17.67 (2Ј-CH2), 17.2
(5-Me), 14.2 (3Ј-Me) and 12.7 (4-Me); m/z (FAB) 422 (Mϩ ϩ 1,
36%), 378 (13), 294 (28), 251 (8), 198 (37), 155 (29), 123 (16),
109 (24), 91 (52) and 69 (90) [Found: C, 46.0; H, 5.7; N, 3.0;
Mϩ ϩ 1, 422.0618. C16H24INO2S requires C, 45.6; H, 5.8; N,
3.3%; C16H25INO2S requires M, 422.0650].
Cyclisation of (Z)-3-(p-tolylsulfonylamino)dec-5-ene 26c. (Z)-
Homoallylic tosylamide 26c (0.10 g, 0.33 mmol) was reacted
under the conditions described above (K2CO3) for 1 h. The
crude product was purified by cc (dichloromethane) to give an
inseparable mixture of isomers in the ratio of ca. 5 : 1 (0.09 g,
63%). The isomer ratio was determined by integration of the
1
aromatic methyl groups in the H NMR spectrum. The major
isomer was found, by comparison with spectral data from the
cyclisation of the corresponding (E)-precursor 24f, to be the
foregoing (2SR,3RS,5SR)-iodopyrrolidine 36f (see above).
Data for the mixture: Rf 0.53 (dichloromethane); the minor
isomer showed distinctive resonances at δH (250) 7.69 (2H, d,
J 8.3, Ar-H), 7.38 (2H, d, J 8.3, Ar-H), 4.65–4.57 (1H, m), 4.42–
4.32 (1H, m), 4.12–4.19 (1H, m) and 2.43 (3H, s, Ar-Me); com-
parisons with the spectral data displayed by the pyrrolidine 37f
suggested this was not the minor product which was hence
assigned the all-cis-structure 44.
Cyclisation of (E)-2-(tert-butoxycarbonylamino)oct-4-ene
35a. (E)-Homoallylic amide 35a (0.03 g, 0.13 mmol) was
reacted under the conditions described above (K2CO3) for 30
min. The crude product was purified by cc (methanol–
dichloromethane 5 : 95) to afford the carbamate as a mixture of
isomers 45 in the ratio 2 : 1 (0.04 g, 79%) as a viscous yellow
oil: Rf 0.78 (methanol–dichloromethane 5 : 95); νmax/cmϪ1 3433
(2RS,3SR,4RS,5RS)-4,5-Dimethyl-3-iodo-2-propyl-1-(p-
tolylsulfonyl)pyrrolidine 39. (E)-syn-Homoallylic tosylamide
28b (0.20 g, 0.7 mmol) was cyclised under the conditions
described in the general procedure (K2CO3), and the reaction
was complete after 45 min. The crude product was purified by
cc (dichloromethane) to yield the iodopyrrolidine 39 (0.23 g,
79%) as a colourless crystalline solid, mp 108–109 ЊC: Rf 0.64
(dichloromethane); νmax/cmϪ1 (CHCl3) 2953 (s), 2928 (s), 2879
(w), 1458 (w) and 1345 (s); δH (250) 7.75 (2H, d, J 8.3, Ar-H),
7.28 (2H, d, J 8.3, Ar-H), 4.31 (1H, ddd, J 7.6, 6.3 and 4.1,
2-H), 3.50 (1H, dd, J 9.2 and 6.3, 3-H), 3.20 (1H, dq, J 9.4 and
6.5, 5-H), 2.42 (3H, s, Ar-Me), 2.10–1.95 (2H, m, 1Ј-CH2), 1.71
(1H, ddq, J 9.4, 9.2 and 6.6, 4-H), 1.49–1.38 (2H, m, 2Ј-CH2),
1.31 (3H, d, J 6.5, 5-Me), 0.97 (3H, d, J 6.6, 4-Me) and 0.94
(3H, t, J 7.3, 3Ј-Me); δC (67.8) 143.0, 141.3 (both Ar-C),
129.6, 126.5 (both Ar-CH), 70.6 (2-CH), 61.8 (5-CH), 52.8
(4-CH), 36.8 (1Ј-CH2), 30.3 (3-CH), 21.5 (Ar-Me), 18.3 (2Ј-
CH2), 16.8 (5-Me), 15.2 (4-Me) and 14.1 (3Ј-Me); m/z (FAB)
422 (Mϩ ϩ 1, 1%), 421 (Mϩ, 39%), 378 (13), 294 (28), 279 (5),
251 (8), 198 (29), 155 (29), 91 (60), 71 (44) and 69 (100) [Found:
C, 45.7; H, 5.9; N, 3.0%; Mϩ, 421.0595. C16H24INO2 requires
M, 421.0574].
(NH), 3248 (NH), 2932 (w), 2874 (w), 1714 (C᎐O), 1459 (s) and
᎐
1342 (s); δH (250) 6.68 (1H, br s, NH, minor isomer), 6.52 (1H,
br s, NH, major isomer), 4.31–3.98 (4H, m, both isomers),
3.70–3.51 (2H, m, both isomers), 2.41–2.15 (2H, m, minor
isomer), 2.10–1.23 (10H, m, both isomers), 1.27 (3H, d, J 6.6,
Me, minor isomer), 1.25 (3H, d. J 6.7, Me, major isomer), 0.90
(3H, t, J 7.3, Me, minor isomer) and 0.89 (3H, t, J 7.3, major
isomer); δC (67.8) 154.3 (C᎐O, major isomer), 154.1 (C᎐O,
᎐
᎐
minor isomer), 79.6 (CH, major isomer), 76.9 (CH, minor
isomer), 46.3 (CH2, major isomer), 43.8 (CH2, minor isomer),
38.0 (CH, major isomer), 37.7 (CH2, minor isomer), 37.6 (CH2,
major isomer), 37.2 (CH, minor isomer), 35.5 (CH2, major
isomer), 32.9 (CH2, minor isomer), 29.1 (Me, minor isomer),
22.9 (CH2, both isomers), 22.0 (Me, major isomer), 13.5 (Me,
minor isomer) and 13.4 (Me, major isomer); m/z (FAB) 298
(Mϩ ϩ 1, 100%), 154 (48), 136 (54), 88 (67), 69 (56) and 55 (76)
[Found: Mϩ ϩ 1, 298.0298. C9H17INO2 requires M, 298.0304].
Cyclisation of (E)-2-trifluoroacetylaminooct-4-ene 35c. (E)-
Homoallylic amide 35c (0.05 g, 0.23 mmol) was reacted under
the conditions described in the general procedure (K2CO3) for
1 h. The crude product was purified by cc (dichloromethane) to
afford a mixture of isomers 46c in a ratio of 3 : 1 (0.05g, 57%),
as a yellow oil. The isomer ratio was determined by integration
Cyclisation of (Z)-1-(p-tolylsulfonylamino)hex-3-ene 26a.
(Z)-Homoallylic tosylamide 26a (0.02 g, 0.07 mmol) in
acetonitrile (0.2 ml) was reacted under the conditions described
in the general procedure (K2CO3) for 1 h. Purification of the
crude product by cc (dichloromethane) afforded a mixture of
isomers in a ratio 2 : 1 (0.01 g, 52%). The isomer ratio was
determined from measurement of the alkyl methyl peaks from
the H NMR spectrum. Data for mixture: Rf 0.58 (methanol–
dichloromethane 2 : 98); δH (250) 7.75–7.72 (4H, m, Ar-H, both
isomers), 7.32–7.29 (4H, m, Ar-H, both isomers), 5.01–4.85
1
of the alkyl-methyl peaks in the H NMR spectrum. Data for
mixture: Rf 0.47 (dichloromethane); νmax/cmϪ1 2980 (s), 2951 (s),
1730, 1504 (s) and 1346 (s); δH (250) 4.12–4.09 (2H, m, major
isomer), 4.01–3.97 (1H, m, major isomer), 3.62–3.60 (1H, m,
minor isomer), 3.58–3.49 (2H, m, minor isomer), 2.36 (1H, ddd,
1
J. Chem. Soc., Perkin Trans. 1, 2001, 1182–1203
1197

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J 13.8, 4.3 and 2.9, major isomer), 1.85–1.40 (11H, m, both
isomers), 1.32 (3H, d, J 6.7, Me, major isomer), 1.30 (3H, d,
J 6.6, Me, minor isomer) and 0.96 (6H, t, J 7.3, Me, both
isomers); δC (67.8) 118.3 (C, major isomer), 78.6 (CH, major
isomer), 75.7 (minor isomer), 48.8 (CH, major isomer), 46.3
(CH, minor isomer), 37.1 (CH, major isomer), 36.9 (CH2,
minor isomer), 36.8 (CH2, major isomer), 36.6 (CH, minor
isomer), 34.5 (CH2, major isomer), 33.1 (CH2, minor isomer),
32.2 (CH2, minor isomer), 22.5 (Me, major isomer), 22.3 (CH2,
major isomer), 21.9 (Me, minor isomer) and 13.1 (Me, both
isomers). The sample decomposed before a mass spectrum
could be obtained.
δC (67.8) 143.2, 134.2 (both Ar-C), 129.7, 128.1 (both Ar-CH),
72.9 (2-CH), 56.4 (5-CH), 45.0 (4-CH2), 37.5 (1Ј-CH2), 28.0
(2Ј-CH2), 22.6 (3Ј-CH2), 22.2 (Ar-Me), 22.1 (3-CH), 21.6
(5-Me) and 14.0 (4Ј-Me); m/z (FAB) 422 (Mϩ ϩ 1, 100%), 410
(11), 364 (52), 335 (20), 294 (55), 237 (23), 198 (81), 154 (74),
136 (64), 91 (75) and 77 (29) [Found: C, 45.7; H, 6.0; N, 3.5;
Mϩ ϩ 1, 422.0682. C16H24INO2S requires C, 45.6; H, 5.7; N,
3.3%, C16H25INO2S requires M, 422.0652].
(2S,3R,5R)-2-Butyl-3-iodo-5-methyl-1-(p-tolylsulfonyl)-
pyrrolidine 37e. (2R)-(E)-Homoallylic tosylamide 24e (20 mg,
0.07 mmol) in acetonitrile (0.2 ml) was cyclised under the con-
ditions described in the general procedure (no base) to give a
yellow oil which was purified by recrystallisation (hexane–ethyl
acetate 9 : 1) to afford the iodopyrrolidine 37e (25 mg, 85%) as
a colourless, crystalline solid, mp 112–114 ЊC: [α]D ϩ 14.0 (c
0.015 in CHCl3); other spectral and analytical data, except the
melting point, were identical to those obtained for the racemic
product 37d (see above).
Cyclisation of 2-methoxycarbonylaminooct-4-ene 35e. (E)-
Homoallylic carbamate 35e (0.05 g, 0.23 mmol) was reacted
under the conditions described in the general procedure
(K2CO3) for 1 h. The crude product was purified by cc
(methanol–dichloromethane 5 : 95) to afford a mixture of iso-
mers 46e in a ratio of 2 : 1 (0.03 g, 48%), as a yellow oil. The
isomer ratio was determined by integration of the –OMe peaks
in the 1H NMR spectrum of the mixture. Data for the mixture:
Rf 0.23 (methanol–dichloromethane 5 : 95); δH (250) 4.52–4.48
(1H, m, major isomer), 4.46–3.98 (4H, m, both isomers), 3.92–
3.86 (1H, m, minor isomer), 3.69 (3H, s, OMe, major isomer),
3.68 (3H, s, OMe, minor isomer), 2.80–2.71 (1H, m, major
isomer), 2.31–2.11 (2H, minor isomer), 2.03–1.20 (9H, m, both
isomers), 1.22 (3H, d, J 6.6, Me, minor isomer), 1.20 (3H, d,
J 6.6, Me, major isomer), 0.95 (3H, t, J 7.3, major isomer) and
0.93 (3H, t, J 7.3, minor isomer).
(2RS,3SR,5SR)-2-Butyl-5-ethyl-3-iodo-1-(p-tolylsulfonyl)-
pyrrolidine 37f. i) By iodocyclisation of sulfonamide 24f. (E)-
Homoallylic tosylamide 24f (0.20 g, 0.64 mmol) was cyclised
under the general conditions described above (no base); the
reaction was complete after 3 min. The crude product was puri-
fied by cc (dichloromethane) then recrystallised (ethyl acetate–
hexane 15 : 85) to give the iodopyrrolidine 37f (0.23 g, 78%) as a
pale orange, crystalline solid: mp 94–95 ЊC; Rf 0.56 (dichloro-
methane); νmax/cmϪ1(CHCl3) 2918 (s), 2930 (s), 2889 (s), 1597
(w), 1335 (s) and 1304 (s); δH (250) 7.77 (2H, d, J 8.2, Ar-H),
7.34 (2H, d, J 8.2, Ar-H), 4.07 (1H, ddd, J 5.6, 3.5 and 3.4,
3-H), 3.95 (1H, ddd, J 9.1, 3.6 and 3.4, 2-H), 3.72 (1H, dddd,
J 8.0, 7.5, 6.8 and 4.2, 5-H), 2.43 (3H, s, Ar-Me), 2.10 (1H, ddd,
J 14.2, 7.5 and 5.6, 4-Hα), 2.02 (1H, ddd, J 14.2, 6.8 and 3.5,
4-Hβ), 1.77 (1H, ddq, J 13.3, 8.0 and 7.2, 1Љ-Hα), 1.44 (1H, dqd,
J 13.3, 7.2 and 4.2, 1Љ-Hβ), 1.41–1.28 (6H, m, 1Ј- 2Ј- and
3Ј-CH2), 0.92 (3H, t. J 7.2, Me) and 0.90 (3H, t, J 7.2, Me);
δC (100) 141.4, 136.3 (both Ar-C), 129.4, 127.9, (both Ar-CH),
72.7 (2-CH), 61.9 (5-CH), 41.9 (4-CH2), 37.1 (1Ј-CH2), 28.4
(1Љ-CH2), 24.5, 22.5 (both CH2), 22.3 (Ar-Me), 21.9 (3-CH),
14.0 (4Ј-Me) and 9.9 (2Љ-Me); m/z (FAB) 435 (Mϩ, 1%), 406
(19), 378 (80), 326 (7), 251 (47), 212 (48), 187 (7) and 91 (100)
[Found: C, 47.3; H, 6.2; N, 3.2; Mϩ, 435.0745. C17H26INSO2
requires C, 46.9; H, 6.0; N, 3.3%; M, 435.0729].
Iodocyclisations with no base present: general procedure
To a stirred solution of the cyclisation precursor (1.0 mmol,
1 eq.) in acetonitrile (1 ml) was added portionwise iodine
(3.0 mmol, 3 eq.) and the reaction stirred at ambient temper-
ature until complete according to TLC analysis (typically 2–20
min). TLC samples were taken every 30 seconds. The aceto-
nitrile was removed under reduced pressure and the residue
partitioned between dichloromethane (1 ml) and saturated
aqueous sodium thiosulfate (1 ml). The resulting two layers
were separated, and the aqueous layer extracted with dichloro-
methane (3 × 2 ml). The combined organic solutions were dried
and evaporated to give crude products which were purified by
column chromatography.
ii) By acid-catalysed isomerisation of iodopyrrolidine 36f. The
(2SR,3RS,5SR)-iodopyrrolidine 36f (0.02 g, 0.05 mmol) in dry
acetonitrile (0.2 ml) was treated with 57% aqueous hydrogen
iodide (2 µl) and the mixture stirred at ambient temperature for
20 min. The standard sodium thiosulfate work-up described
above afforded the 2,5-cis-pyrrolidine 37f (0.02 g, 94%) as a
colourless solid, mp 95–97 ЊC (mixed mp 94–96 ЊC); other
spectral and analytical data were identical to those displayed
by the sample prepared by the iodocyclisation conditions
described immediately above.
(2SR,3RS)-2-Ethyl-3-iodo-1-(p-tolylsulfonyl)pyrrolidine
36b. Homoallylic tosylamide 24b (0.20 g, 0.80 mmol) was
cyclised under the general conditions with no base and the reac-
tion was complete within 2 min. The crude product was purified
by cc (dichloromethane) followed by recrystallisation (hexane–
ethyl acetate 9 : 1) to afford the title compound 36b (0.27 g, 88%)
as a colourless crystalline solid, mp 108–109 ЊC; other spectral
and analytical data were identical to those displayed by samples
prepared using either sodium hydrogen carbonate or potassium
carbonate as the base (see above).
(2SR,3RS,5SR)-2-Butyl-5-ethyl-3-iodo-1-methylsulfonyl-
pyrrolidine 36g. (E)-Homoallylic methanesulfonamide 24g
(0.01 g, 0.04 mmol) was cyclised under the conditions described
in the general procedure (no base) and the reaction was com-
plete after 3 min. The reaction was left for a further 30 min in an
attempt to effect isomerisation. The crude product was purified
by cc (dichloromethane) to afford the title compound 36g (0.01
g, 78%) as a viscous, pale yellow oil: spectral and analytical data
were identical to those obtained for the same substrate, cyclised
in the presence of potassium carbonate.
(2RS,3SR,5SR)-2-Butyl-3-iodo-5-methyl-1-(p-tolylsulfonyl)-
pyrrolidine 37d. (E)-Homoallylic tosylamide 24d (0.2 g, 0.7
mmol) was cyclised under the general conditions (no base), and
the reaction was complete after 3 min. The crude product was
purified by cc (dichloromethane) then recrystallised (hexane–
ethyl acetate 9 : 1) to afford the pyrrolidine 37d (0.25 g, 86%)
as a colourless, crystalline solid mp 102–103 ЊC: Rf 0.56
(dichloromethane): νmax/cmϪ1(CHCl3) 2959 (s), 2924 (s), 2875
(w) and 1342 (s); δH (270) 7.77 (2H, d, J 8.3, Ar-H), 7.33 (2H, d,
J 8.3, Ar-H), 4.09 (1H, ddd, J 5.7, 3.4 and 3.2, 3-H), 4.01–3.97
(1H, m, 2-H), 3.93 (1H, dqd, J 7.5, 6.6 and 6.2, 5-H), 2.43 (2H,
s, Ar-Me), 2.20 (1H, ddd, J 13.9, 7.5 and 5.7, 4-Hα), 2.15 (1H,
ddd, J 13.9, 6.2 and 3.4, 4-Hβ), 1.43 (3H, d, J 6.6, 5-Me), 2.08–
1.09 (6H, m, 1Ј-, 2Ј- and 3Ј-CH2) and 0.92 (3H, t, J 7.3, 4Ј-Me);
(2RS,3SR,5SR)-5-Ethyl-3-iodo-2-pentyl-1-(p-tolylsulfonyl)-
pyrrolidine 37h. (E)-Homoallylic tosylamide 24h (0.05 g, 0.16
mmol) was cyclised under the general conditions described
above (no base); the reaction was complete after 3 min. The
1198
J. Chem. Soc., Perkin Trans. 1, 2001, 1182–1203

View Article Online
crude product was purified by cc (dichloromethane) to afford
the title compound 37h (0.05 g, 74%) as a pale orange, viscous
oil: Rf 0.56 (dichloromethane); νmax/cmϪ1 2919 (s), 2930 (s), 2886
(s), 1711 (w), 1595 (w), 1337 (s) and 1301 (s); δH (250) 7.75 (2H,
d, J 8.2, Ar-H), 7.33 (2H, d, J 8.2, Ar-H), 4.05 (1H, ddd, J 5.7,
3.5 and 3.4, 3-H), 3.94 (1H, ddd, J 9.1, 3.6 and 3.4, 2-H), 3.72
(1H, dddd, J 8.0, 7.5, 6.8 and 4.2, 5-H), 2.44 (3H, s, Ar-Me),
2.10 (1H, ddd, J 14.2, 7.5 and 5.7, 4-Hα), 2.02 (1H, ddd, J 14.2,
6.8 and 3.5, 4-Hβ), 1.77 (1H, ddq, J 13.4, 8.0 and 7.1, 1Љ-Hα),
1.44 (1H, dqd, J 13.4, 7.1 and 4.2, 1Љ-Hβ), 1.43–1.20 (8H, m,
1Ј-, 2Ј-, 3Ј- and 4Ј-CH2), 0.92 (3H, t, J 7.3, Me) and 0.90 (3H, t,
J 7.1, Me); δC (100) 141.2, 136.2 (both Ar-C), 129.4, 127.9,
(both Ar-CH), 72.5 (2-CH), 61.9 (5-CH), 41.9 (4-CH2), 37.1
(1Ј-CH2), 28.4 (1Љ-CH2), 22.5 (CH2), 22.3 (Ar-Me), 22.1 (CH2),
21.8 (3-CH), 14.2 (5Ј-Me) and 9.93 (2Љ-Me) [Found: C, 48.6; H,
6.4; N, 3.0. C18H28INO2S requires C, 48.1; H, 6.2; N, 3.1%].
J 5.0, 2-H), 4.13 (1H, ddd, J 6.2, 6.2 and 5.0, 3-H), 3.94 (1H,
dddd, J 9.8, 6.2, 6.2 and 4.4, 5-H), 2.30 (1H, ddq, J 13.3, 9.8 and
7.5, 1Ј-Hα), 2.14–2.07 (2H, m, 4-CH2), 1.75 (1H, dqd, J 13.3, 7.3
and 4.4, 1Ј-Hβ) and 0.98 (3H, t, J 7.3, 2Ј-Me); δC 140.8, 137.8,
(both Ph-C), 132.9, 128.9, 128.5, 127.9, 126.5 (all Ph-CH), 74.8
(2-CH), 62.8 (5-CH), 41.7 (4-CH2), 28.7 (1Ј-CH2), 26.0 (3-CH)
and 10.7 (2Ј-Me); m/z (FAB) 442 (Mϩ ϩ 1, 19%), 410 (53), 380
(46), 252 (63), 184 (66), 133 (100) and 77 (49) [Found: C, 49.2;
H, 4.6; N, 3.2. C18H20INO2S requires C, 49.0; H, 4.6; N, 3.2%].
(2SR,3RS,4SR,5RS)-4,5-Dimethyl-3-iodo-2-propyl-1-(p-
tolylsulfonyl)pyrrolidine 38. (E)-Homoallylic tosylamide 27b
(0.10 g, 0.34 mmol) was cyclised under the general conditions
(no base), and the reaction was complete after 5 min. The reac-
tion was stirred at ambient temperature for a further 30 min to
effect possible isomerisation. The crude product was purified by
cc (dichloromethane) followed by recrystallisation (hexane–
ethyl acetate 9 : 1) to afford the title compound 38 (0.12 g, 82%)
as a colourless solid, mp 103–104 ЊC: the spectral and analytical
data were identical to those obtained for the same substrate
when cyclised in the presence of potassium carbonate.
(2RS,3SR,5SR)-5-Butyl-3-iodo-2-pentyl-1-(p-tolylsulfonyl)-
pyrrolidine 37i. (E)-Homoallylic tosylamide 24i (0.30 g, 0.85
mmol) was subjected to the general iodocyclisation conditions
(no base), and the reaction was complete after 15 min. The
crude product was purified by cc (dichloromethane) to yield the
iodopyrrolidine 37i (0.32 g, 76%) as a pale yellow, viscous oil:
Rf 0.64 (dichloromethane); νmax/cmϪ1 2955 (s), 2928 (s), 2858
(w), 1685 (w), 1598 (w), 1455 (s) and 1346 (s); δH (250) 7.75 (2H,
d, J 8.3, Ar-H), 7.33 (2H, d, J 8.3, Ar-H), 4.05 (1H, ddd, J 5.1,
3.4 and 3.3, 3-H), 3.94 (1H, ddd, J 8.7, 3.7 and 3.3, 2-H), 3.75
(1H, dddd, J 8.5, 7.8, 6.9 and 4.5, 5-H), 2.43 (3H, s, Ar-Me),
2.13–1.74 (4H, m, 1Ј- and 4-CH2), 1.53–1.20 (12H, m, 1Љ-, 2Ј-,
2Љ-, 3Ј-, 3Љ and 4Ј-CH2), 0.94 (3H, t, J 7.2, Me) and 0.88 (3H, t,
J 7.3, Me); δC (100) 143.5, 134.4 (both Ar-C), 129.6, 128.0 (both
Ar-CH), 72.2 (2-CH), 60.6 (5-CH), 42.7 (4-CH2), 37.1 (1Ј-CH2),
35.3, 31.6, 27.9, 25.4, 22.5, 22.4 (all CH2), 21.7 (3-CH), 21.5
(Ar-Me), 14.0 (Me) and 13.9 (Me); m/z (ES) 478 (Mϩ ϩ 1,
45%), 419 (100), 391 (24), 352 (33), 254 (56), 83 (28) and 60 (22)
[Found: Mϩ ϩ 1, 478.1277. C20H33INO2S requires M, 478.1279]
[Found: C, 50.3; H, 6.9; N, 3.1. C20H32INO2S requires C, 50.3;
H, 6.8; N, 2.9%].
(2SR,3RS,4SR,5SR)-4,5-Dimethyl-3-iodo-2-propyl-1-(p-
tolylsulfonyl)pyrrolidine 39. (E)-Homoallylic tosylamide 28b
(0.10 g, 0.34 mmol) was cyclised under the general conditions
(no base), and the reaction was complete after 4 min. The reac-
tion was stirred at ambient temperature for a further 30 min to
effect possible isomerisation. The crude product was purified
by cc (dichloromethane) followed by recrystallisation (hexane–
ethyl acetate 9 : 1) to yield the title compound 39 (0.11 g, 78%) as
a solid, mp 110–111 ЊC. The spectral and analytical data were
identical to those obtained from the potassium carbonate reac-
tion described previously.
Cyclisation of (Z)-3-(p-tolylsulfonylamino)dec-5-ene 26c. The
(Z)-homoallylic tosylamide 26c (0.05 g, 0.16 mmol) was reacted
under the conditions described in the general procedure (no
base) for 1 h. Purification by cc (dichloromethane) afforded
an unresolvable mixture of isomers in the ratio 4 : 1 : 1 (0.04 g,
57%). The two minor isomers were found (by comparison
of the 1H NMR spectrum of the mixture) to be the
(2SR,3RS,5SR)-pyrrolidine 36f and the (2RS,3SR,5SR)-
pyrrolidine 37f obtained from the cyclisation of the correspond-
ing (E)-precursor 24f under acidic and basic conditions,
respectively. The 1H and 13C NMR spectra were sufficiently well
resolved to assign the peaks for the major isomer: Rf 0.52
(dichloromethane); νmax/cmϪ1(CHCl3) 2948 (s), 2930 (s), 2868
(w), 1475 (w) and 1340 (s); δH (400) 7.69 (2H, d, J 8.3, Ar-H),
7.31 (2H, d, J 8.3, Ar-H), 3.80 (1H, ddd, J 9.8, 6.6 and 3.8,
3-H), 3.51–3.44 (1H, m, 5-H), 3.27 (1H, ddd, J 12.5, 7.0 and 6.6,
2-H), 2.45 (3H, s, Ar-Me), 2.12–1.92 (4H, m), 1.45–1.28 (6H,
m), 0.93 (3H, t, J 7.4, Me) and 0.90 (3H, t, J 7.3, Me); δC (67.8)
142.8, 135.6 (both Ar-C), 129.9, 127.5 (both Ar-CH), 63.6, 62.3
(both CH), 41.4, 33.6, 31.0, 28.4, 22.5 (all CH2), 21.5 (Ar-Me),
20.9 (3-CH), 14.0 (4Љ-Me) and 10.2 (2Љ-Me); m/z (FAB), 436
(Mϩ ϩ 1, 100%), 308 (95), 212 (84), 155 (69), 91 (86), 68 (49)
and 56 (52) [Found: Mϩ ϩ 1, 436.0770. C17H27INO2S requires
M, 436.0807], which was tentatively assigned the all-cis
structure 44.
(2RS,3SR,5SR)-5-Ethyl-3-iodo-2-phenyl-1-(p-tolylsulfonyl)-
pyrrolidine 37j. (E)-Homoallylic tosylamide 24j (0.50 g, 1.52
mmol) was cyclised under the foregoing general conditions
(no base), and the reaction was complete after 10 min. The
crude product was purified by cc (dichloromethane) followed
by recrystallisation (hexane–ethyl acetate 9 : 1) to yield the
iodopyrrolidine 37j (0.42 g, 76%) as a colourless, flaky solid: mp
110–112 ЊC; Rf 0.54 (dichloromethane); νmax/cmϪ1(CHCl3) 3061
(w), 2966 (s), 2993 (s), 2876 (w), 1446 (w) and 1349 (s); δH (400)
7.96 (2H, d, J 8.3, Ar-H), 7.42–7.25 (7H, m, Ar-H), 4.98 (1H, d,
J 4.9, 2-H), 4.11 (1H, ddd, J 6.2, 6.2 and 4.9, 3-H), 3.92 (1H,
dddd, J 9.6, 6.2, 6.2 and 4.5, 5-H), 2.43 (3H, s, Ar-Me), 2.28
(1H, ddq, J 13.5, 9.6 and 7.5, 1Ј-Hα), 2.12 (2H, app. dd, J 6.2 and
6.2, 4-CH2), 1.75 (1H, dqd, J 13.5, 7.5 and 4.5, 1Ј-Hβ) and 1.01
(3H, t, J 7.5, 2Ј-Me); δC (100) 142.8, 140.1, 139.3 (all Ar-C),
129.1, 128.5, 127.8, 127.1, 126.4 (all Ar-CH), 76.6 (2-CH), 63.6
(5-CH), 38.4 (4-CH2), 26.8 (1Ј-CH2), 24.7 (3-CH), 21.5 (Ar-Me)
and 11.1 (2Ј-Me); m/z (ES) 456 (Mϩ ϩ 1, 54%), 330 (6), 276
(15), 106 (100) and 74 (17) [Found: C, 50.4; H, 5.1; N, 3.2.
C19H22INO2S requires C, 50.1; H, 4.9; N, 3.1%].
(2RS,3SR,5SR)-1-Phenylsulfonyl-5-ethyl-3-iodo-2-phenyl-
pyrrolidine 37k. The (E)-homoallylic benzenesulfonamide 24k
(0.677 g, 2.15 mmol) was cyclised under the foregoing general
conditions (no base); the reaction was complete after 10 min.
The crude product was purified by cc (dichloromethane) fol-
lowed by recrystallisation from hexane–ethyl acetate (8 : 1) to
give the iodopyrrolidine 37k (0.768 g, 81%) as orange clusters:
mp 102–104 ЊC (see discussion); Rf 0.51 (dichloromethane);
νmax/cmϪ1 (CHCl3) 3061 (w), 2966 (s), 2930 (s), 2876 (w), 1446
(w) and 1349 (s); δH 7.85–7.31 (10H, m, 2 × Ph), 5.01 (1H, d,
(2SR,3RS,3aSR,7aRS)-2-Butyl-3-iodo-1-(p-tolylsulfonyl)-
octahydroindole 40. (E)-Tosylamide 31 (20 mg, 0.06 mmol) was
cyclised under the conditions described in the general pro-
cedure (no base), and the reaction was complete after 15 min.
The crude product was purified by cc (hexane–ether 4 : 1) to
afford the title compound 40 (20 mg, 75%) as a yellow oil: νmax
/
cmϪ1 2952 (s), 2935 (s), 2884 (s), 1342 (s) and 1294 (s); δH (400)
7.73 (2H, d, J 8.1, Ar-H), 7.33 (2H, d, J 8.1, Ar-H), 3.96 (1H,
dd, J 11.7 and 8.6, 3-H), 3.92–3.87 (1H, m, 2-H), 3.57 (1H, dt,
J 11.2 and 6.8, 7a-H), 2.45 (3H, s, Ar-Me), 2.02–0.98 (15H, m)
J. Chem. Soc., Perkin Trans. 1, 2001, 1182–1203
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and 0.95 (3H, t, J 7.2, Me); δC (100) 143.6, 134.8 (both Ar-C),
129.8, 127.4 (both Ar-CH), 69.6, 59.7 (both CH), 47.3 (3a-CH),
33.9, 30.8 (both CH2), 27.2 (CHI), 26.9, 24.6, 24.4, 22.8 (all
CH2), 21.6 (Ar-Me), 20.1 (CH2) and 14.0 (Me); m/z (ES) 462
(Mϩ ϩ 1, 5%), 336 (15), 124 (71) and 58 (100) [Found: Mϩ ϩ 1,
462.0964. C19H29INO2S requires M, 462.0967].
(typically 2–5 h). The reaction mixture was cooled and the
toluene evaporated. The remaining crude product was dissolved
in acetonitrile (10 ml) and extracted with hexane (3 × 10 ml) to
remove any organotin residues. The acetonitrile was evaporated
to yield the required product which was purified by column
chromatography.
(2SR,5SR)-2-Butyl-5-methyl-1-(p-tolylsulfonyl)pyrrolidine
49a. Iodopyrrolidine 36d (0.05 g, 0.12 mmol) was deiodinated
as described above to give the title compound 49a (0.03g, 88%)
(2RS,3RS,3aSR,7aRS)-2-Butyl-3-iodo-1-(p-tolylsulfonyl)-
octahydroindole 41. (Z)-Tosylamide 32 (12 mg, 0.03 mmol) was
cyclised under the conditions described in the general pro-
cedure (no base), and the reaction was complete after 3 h. The
crude product was purified by cc (hexane–ether 80 : 20) to
as a colourless, viscous oil: Rf 0.32 (dichloromethane); νmax
/
cmϪ1 2959 (s), 2938 (s), 2875 (w) and 1355 (s); δH (250) 7.73 (2H,
d, J 8.3, Ar-H), 7.25 (2H, d, J 8.3, Ar-H), 4.02 (1H, dqd, J 6.5,
6.3 and 1.2, 5-H), 3.84–3.77 (1H, m, 2-H), 2.41 (3H, s, Ar-Me),
2.08–1.09 (10H, m, 1-, 2-, 3Ј-, 3Ј- and 4Ј-CH2), 1.19 (3H, d,
J 6.3, 1Љ-Me) and 0.85 (3H, t, J 7.2, 4Ј-Me); δC (100) 142.4,
139.3 (both Ar-C), 129.3, 126.9 (both Ar-CH), 60.7 (5-CH),
56.3 (2-CH), 33.9 (1Ј-CH2), 31.5, 28.5, 27.7, 22.5 (all CH2), 21.4
(Ar-Me), 21.1 (1Љ-Me) and 14.0 (4Ј-Me); m/z (ES) 296 (Mϩ ϩ 1,
100%), 125 (3), 102 (4) and 60 (7) [Found: Mϩ ϩ 1, 296.1680.
C16H26NO2S requires M, 296.1684].
afford the title compound 41 (7 mg, 43%) as a yellow oil: νmax
/
cmϪ1 2950 (s), 2937 (s), 2879 (s), 1350 (s) and 1300 (s); δH (400)
7.74 (2H, d, J 8.3, Ar-H), 7.29 (2H, d, J 8.3, Ar-H), 4.45 (1H,
dd, J 12.7 and 7.8, 3-H), 3.90–3.83 (2H, m, 2- and 7a-H), 2.43
(3H, s, Ar-Me), 2.27–2.20 (1H, m), 2.01–1.87 (2H, m), 1.64–
1.08 (12H, m) and 0.83 (3H, t, J 7.2, Me); δC (100) 143.4, 133.2
(both Ar-C), 129.5, 127.2 (both Ar-CH), 60.4, 59.7 (both CH),
44.2 (3a-CH), 35.8 (CH2), 30.9 (CHI), 28.8, 28.0, 25.4, 23.8,
22.7 (all CH2), 21.4 (Ar-Me), 19.7 (CH2) and 14.0 (Me); m/z
(ES) 462 (Mϩ ϩ 1, 3%), 124 (42) and 58 (100) [Found: Mϩ ϩ 1,
462.0964].
(2SR,5SR)-2-Butyl-5-ethyl-1-(p-tolylsulfonyl)pyrrolidine 49b.
3-Iodopyrrolidine 36f (0.05 g, 0.12 mmol) was deiodinated as
described above to give the title compound 49b (0.03 g, 84%) as a
colourless, viscous oil: Rf 0.32 (dichloromethane); νmax/cmϪ1
2959 (s), 2940 (s), 2877 (s) and 1355 (s); δH (250) 7.71 (2H, d,
J 8.2, Ar-H), 7.23 (2H, d J 8.2, Ar-H), 3.84–3.70 (2H, m, 2- and
5-H), 2.40 (3H, s, Ar-Me), 2.03–1.05 (12H, m, 1-, 2-, 3Ј, 3Ј- and
4Ј-CH2), 0.93 (3H, t, J 7.3, Me) and 0.90 (3H, t, J 6.9, Me);
δC (100) 142.1, 139.8 (both Ar-C), 129.0, 126.6 (both Ar-CH),
62.4 (5-CH), 56.3 (2-CH), 33.8, 31.9, 28.3, 27.4, 26.4, 22.3 (all
CH2), 21.3 (Ar-Me), 13.9 (4Ј-Me) and 10.7 (2Љ-Me); m/z (ES)
310 (Mϩ ϩ 1, 100%), 281 (35) and 91 (20) [Found: Mϩ ϩ 1,
310.1837. C17H28NO2S requires M, 310.1841].
Cyclisation of (E)-2-(N-tert-butoxycarbonylamino)oct-4-ene
35a. (E)-Homoallylic amide 35a (0.03 g, 0.13 mmol) was
cyclised under the conditions described in the general pro-
cedure (no base) for 30 min. The crude product was purified by
cc (methanol–dichloromethane 5 : 95) to afford the homoallylic
amine 35b (0.002 g, 15%) as a yellow oil (spectral and analytical
data were identical to the sample prepared earlier), and the
carbamates as a mixture of isomers 45 in the ratio 2 : 1 (0.03 g,
67%) as a viscous yellow oil: spectral and analytical data were
identical to those from the product of the same substrate with
potassium carbonate as the base.
(2SR,5SR)-5-Ethyl-2-pentyl-1-(p-tolylsulfonyl)pyrrolidine
49c. 3-Iodopyrrolidine 36h (0.05 g, 0.11 mmol) was deiodinated
as described above to give the title compound 49c (0.03 g,
84%) as a colourless, viscous oil: Rf 0.34 (dichloromethane);
νmax/cmϪ1 2958 (s), 2940 (s), 2875 (s) and 1357 (s); δH (250) 7.72
(2H, d, J 8.2, Ar-H), 7.25 (2H, d, J 8.2, Ar-H), 3.87–3.71 (2H,
m, 2- and 5-H), 2.41 (3H, s, Ar-Me), 2.03–1.02 (14H, m, 1Ј-, 1Љ-,
2Ј-, 3-, 3Ј-, 4- and 4Ј-CH2), 0.92 (3H, t, J 7.3, Me) and 0.89 (3H,
t, J 6.9, Me); δC (100) 142.2, 139.7 (both Ar-C), 129.3, 126.8
(both Ar-CH), 62.2 (5-CH), 56.3 (2-CH), 33.8, 31.6, 27.9, 27.4,
26.7, 26.1, 22.5 (all CH2), 21.4 (Ar-Me), 14.0 (5Ј-Me) and 10.64
(2Љ-Me); m/z (FAB) 324 (Mϩ ϩ 1, 10%), 291 (19), 235 (44), 179
(100) and 91 (9) [Found: Mϩ ϩ 1, 324.1985. C18H30NO2S
requires M 324.1997].
Cyclisation of (E)-2-acetylaminooct-4-ene 35d. (E)-Homo-
allylic amide 35d (0.10 g, 0.4 mmol) in acetonitrile (2 ml) was
reacted under the conditions described in the general pro-
cedure (no base) for 1 h. The crude product was purified by cc
(dichloromethane) to afford a mixture of isomers 46d in the
ratio 2 : 1 (0.07 g, 67%) as a yellow oil. The isomer ratio was
determined by measurement of acetyl-methyl peaks from the
1H NMR spectrum. Data for the mixture: Rf 0.49 (dichloro-
methane); νmax/cmϪ1 2948 (s), 2929 (s), 1691, 1419 (s) and 1341
(s); δH (250) 4.59–4.41 (4H, m, both isomers), 4.25–4.12 (2H, m,
both isomers), 2.67 (3H, s, Me, minor isomer), 2.64 (3H, s, Me,
major isomer), 2.04–1.40 (12 H, m, both isomers), 1.68 (3H, d,
J 6.6, Me, minor isomer), 1.62 (3H, d, J 6.6, Me, major isomer),
1.02 (3H, t, J 7.3, Me, minor isomer) and 1.01 (3H, t, J 7.3,
major isomer); δC (100, major isomer only) 83.2, 48.1, 37.0,
34.6, 32.7, 23.0, 21.8, 19.6 and 13.4.
(2SR,5SR)-5-Butyl-2-pentyl-1-(p-tolylsulfonyl)pyrrolidine
49d. Iodopyrrolidine 36i (0.07 g, 0.15 mmol) was deiodinated as
described above to yield the title compound 49d (0.04 g, 82%) as
a colourless, viscous oil: Rf 0.48 (dichloromethane); νmax/cmϪ1
2959 (s), 2936 (s), 2872 (w), 1464 (w) and 1355 (s); δH (250) 7.72
(2H, d, J 8.3, Ar-H), 7.26 (2H, d, J 8.3, Ar-H), 3.81 (2H, m,
2- and 5-H), 2.42 (3H, s, Ar-Me), 1.92–1.13 (18H, 1Ј-, 1Љ-, 2Ј-,
2Љ-, 3Ј-, 3Љ-, 4- and 4Ј-CH2), 0.88 (3H, t, J 7.3, Me) and 0.85
(3H, t, J 7.1, Me); δC (100) 142.4, 140.1 (both Ar-C), 129.3,
126.9 (both Ar-CH), 60.9 (2-CH and 5-CH), 33.8, 33.6, 31.6,
31.1, 28.6, 28.0, 26.1, 22.6 (all CH2), 21.4 (Ar-Me) and 14.0
(4Љ- and 5Ј-Me); m/z (ES) 352 (Mϩ ϩ 1, 100%), 296 (13), 291
(18), 235 (20), 102 (14) and 83 (17) [Found: Mϩ ϩ 1, 352.2310.
C20H34NO2S requires 352.2312].
Cyclisation of (E)-2-methoxycarbonylaminooct-4-ene 35e.
(E)-Homoallylic sulfonamide 35e (0.05 g, 0.23 mmol) was
reacted under the conditions described in the general pro-
cedure (no base) for 1 h. The crude product was purified by cc
(dichloromethane) to afford a mixture of isomers in the ratio
2 : 1 (0.03 g, 42%) as a yellow oil. The ratio of isomers and 46e
was determined by measurement of the OME resonances in the
1H NMR spectrum. The two isomers were identical to those
obtained from the same substrate when potassium carbonate
was used as the base.
Deiodination of iodopyrrolidines: general procedure
To a stirred solution of a 3-iodopyrrolidine (1 mmol, 1 eq.) in
dry, degassed toluene (50 ml) under nitrogen was added tributyl-
tin hydride (2.91 g, 10 mmol) and the reaction mixture heated
at reflux until complete reduction according to TLC analysis
(2RS,5SR)-5-Ethyl-2-phenyl-1-(p-tolylsulfonyl)pyrrolidine
49e. Iodopyrrolidine 36j (0.20 g, 0.60 mmol) was deiodinated as
described above to yield the title compound 49e (0.16 g, 82%) as
a viscous, colourless oil; Rf 0.34 (dichloromethane); νmax/cmϪ1
1200
J. Chem. Soc., Perkin Trans. 1, 2001, 1182–1203

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2959 (s), 2945 (s), 2875 (w), 1461 (w) and 1349 (s); δH (250) 7.37
(2H, d, J 8.3, Ar-H), 7.17–7.00 (7H, m, Ar-H), 5.98 (1H, dd,
J 7.9 and 1.4, 2-H), 4.07–4.04 (1H, m, 5-H), 2.43–2.39 (1H, m,
3-Hα), 2.35 (3H, s, Ar-Me), 2.25–2.09 (2H, m, 4- and 1Ј-Hα),
1.82–1.67 (2H, m, 3- and 4-Hβ), 1.51 (1H, dqd, J 13.4, 7.4 and
2.9, 1Ј-Hβ) and 0.90 (3H, t, J 7.4, 2Ј-Me); δC (100) 142.5, 142.2,
138.9 (all Ar-C), 128.8, 127.9, 126.8, 126.8, 126.5 (all Ar-CH),
63.9 (2-CH), 63.0 (5-CH), 33.3 (1Ј-CH2), 27.4 (3-CH2), 27.2
(4-CH2), 21.3 (Ar-Me) and 10.6 (1Ј-Me); m/z (ES) 330 (Mϩ ϩ 1,
100%), 176 (27), 174 (38), 102 (8), 85 (8) and 60 (19) [Found:
Mϩ ϩ 1, 330.1529 C19H24NO2S requires 330.1532].
(2SR,5SR)-5-Ethyl-2-phenyl-1-(p-tolylsulfonyl)pyrrolidine
50e. Iodopyrrolidine 37j (0.10 g, 0.30 mmol) was deiodinated as
described above to yield the title compound 50e (0.08 g, 85%) as
a colourless, viscous oil: Rf 0.36 (dichloromethane); νmax/cmϪ1
2960 (s), 2942 (s), 2875 (w), 1461 (w) and 1349 (s); δH (250) 7.72
(2H, d, J 8.3, Ar-H), 7.41–7.21 (7H, m, Ar-H), 5.98 (1H, dd,
J 6.9 and J 6.9, 2-H), 3.72 (1H, dddd, J 11.4, 7.4, 6.9 and 4.7,
5-H), 2.44 (3H, s, Ar-Me), 2.09 (1H, dqd, J 13.1, 7.3 and 4.7,
1Ј-Hα), 1.97–1.82 (2H, m, 3-CH2), 1.66–1.53 (3H, m, 1Ј-Hβ and
4-CH2) and 0.99 (3H, t, J 7.4, 2Ј-Me); δC (100) 143.2, 142.8,
135.1 (all Ar-C), 129.5, 128.2, 127.6 (all Ar-CH), 126.9
(Ar-CH), 128.2 (Ar-CH), 64.6 (2-CH), 63.8 (5-CH), 34.2
(1Ј-CH2), 29.5 (3-CH2), 29.3 (4-CH2), 21.4 (Ar-Me) and 10.9
(2Ј-Me); m/z (ES) 330 (Mϩ ϩ 1, 100%), 176 (23), 174 (63), 83 (7)
and 60 (17) [Found: Mϩ ϩ 1, 330.1528. C19H24NO2S requires
330.1532].
(2RS,5SR)-2-Butyl-5-methyl-1-(p-tolylsulfonyl)pyrrolidine
50a. Iodopyrrolidine 37d (0.05 g, 0.12 mmol) was deiodinated
under the conditions described in the general procedure to
afford the title compound 50a (0.03 g, 86%) as a colourless,
viscous oil: Rf 0.32 (dichloromethane); νmax/cmϪ1 2960 (s), 2942
(s), 2875 (w) and 1357 (s); δH (400) 7.71 (2H, d, J 8.1, Ar-H),
7.29 (2H, d, J 8.1, Ar-H), 3.69–3.63 (1H, m, 5-H), 3.58–3.53
(1H, m, 2-H), 2.42 (3H, s, Ar-Me), 1.89–1.27 (10H, m, 1Ј-,
2Ј- 3-, 3Ј- and 4Ј-CH2), 1.32 (3H, d, J 6.3, 1Љ-Me) and 0.92 (3H,
t, J 7.2, 4Ј-Me); δC (100) 143.4, 143.2 (both Ar-C), 129.5, 127.4
(both Ar-CH), 61.9 (5-CH), 57.2 (2-CH), 36.9, 32.1, 29.5, 28.4
(all CH2), 23.5 (1Љ-Me), 22.6 (CH2), 21.4 (Ar-Me) and 14.0
(4Ј-Me); m/z (ES) 296 (Mϩ ϩ 1, 100%), 276 (6) and 221 (5)
[Found: Mϩ ϩ 1, 296.1677].
Elimination of hydrogen iodide from iodopyrrolidines:
general procedure
A solution of the 3-iodopyrrolidine (1.0 mmol, 1 eq.) and DBU
(0.18 g, 1.2 mmol, 1.2 eq.) in toluene (10 ml) was heated at reflux
until the reaction was complete according to the TLC analysis
(typically 2–5 h). The reaction mixture was cooled, quenched
with aqueous 2 M hydrochloric acid (5 ml) and the resulting
two layers separated. The aqueous layer was extracted with
ether (3 × 10 ml) and the combined organic solutions dried and
the solvent evaporated to yield the product.
(2RS,5SR)-2-Butyl-5-ethyl-1-(p-tolylsulfonyl)pyrrolidine 50b.
Iodopyrrolidine 37f (0.05 g, 0.12 mmol) was deiodinated under
the conditions described in the general procedure to afford the
title compound 50b (0.03 g, 81%) as a colourless, viscous oil: Rf
0.35 (dichloromethane); νmax/cmϪ1 2960 (s), 2943 (s), 2874 (w)
and 1355 (s); δH (400) 7.72 (2H, d, J 8.2, Ar-H), 7.32 (2H, d,
J 8.2, Ar-H), 3.55–3.45 (1H, m, 2- and 5-H), 2.42 (3H, s,
Ar-Me), 1.91–1.12 (12H, m, 1Ј-, 1Љ-, 2-, 3-, 3Ј- and 4Ј- CH2),
0.92 (3H, t, J 7.3, Me) and 0.87 (3H, t, J 7.2, Me); δC (67.8)
142.8, 135.7 (both Ar-C), 129.5, 127.3 (both Ar-CH), 62.7, 61.4
(both CH), 37.2, 32.0, 29.8, 29.6, 25.8, 22.4 (all CH2), 21.5
(Ar-Me), 13.8 (4Ј-Me) and 10.5 (2Љ-Me); m/z (ES) 310 (Mϩ ϩ 1,
100%), 281 (26), 125 (43), and 91 (23) [Found: Mϩ ϩ 1,
310.1836].
(2RS,5SR)-5-Ethyl-2-phenyl-1-(p-tolylsulfonyl)-3-pyrroline
51. Iodopyrrolidine 36j (0.05 g, 0.11 mmol) was reacted as
described above to give the 3-pyrroline 51 (0.03 g, 78%) as a
viscous, colourless oil: Rf 0.48 (dichloromethane); δH (270)
7.19–6.83 (9H, m, Ar-H), 5.69 (1H, ddd, J 6.3, 1.9 and 1.6,
3-H), 5.58 (1H, ddd, J 6.3, 2.0 and 1.8, 4-H), 5.50 (1H, ddd,
J 5.3, 2.0 and 1.9, 2-H), 4.69–4.57 (1H, m, 5-H), 2.23 (3H, s,
Ar-Me), 2.14–1.85 (2H, m, 1Ј-CH2) and 0.88 (3H, t, J 7.2,
2Ј-Me); δC (67.8) 141.8, 138.1, 137.7 (all Ar-C), 129.9 (Ar-CH),
129.0 (3-CH), 128.9 (4-CH), 128.7, 127.9, 127.8, 126.4 (all
Ar-CH), 71.6 (2-CH), 67.7 (5-CH), 28.4 (1Ј-CH2), 21.2 (Ar-Me)
and 8.0 (2Ј-Me); m/z (ES) 328 (Mϩ ϩ 1, 97%), 245 (7), 157 (8)
and 102 (8) [Found: Mϩ ϩ 1, 328.1371. C19H22NO2S requires
M, 328.1371].
(2RS,5SR)-5-Ethyl-2-pentyl-1-(p-tolylsulfonyl)pyrrolidine
50c. Iodopyrrolidine 37h (0.06 g, 0.11 mmol) was deiodinated
by the general procedure to afford the pyrrolidine 50c (0.03 g,
82%) as a colourless, viscous oil: Rf 0.34 (dichloromethane);
νmax/cmϪ1 2959 (s), 2943 (s), 2872 (w) and 1356 (s); δH (400) 7.71
(2H, d, J 8.2, Ar-H), 7.30 (2H, d, J 8.2, Ar-H), 3.56–3.47 (2H,
m, 2- and 5-H), 2.41 (3H, s, Ar-Me), 1.91–1.12 (14H, m, 1Ј-, 1Љ-,
2Ј-, 3-, 3Ј-, 4- and 4Ј-CH2), 0.92 (3H, t, J 7.3, Me) and 0.88 (3H,
t, J 7.2, Me); δC (67.8) 142.9, 135.4 (both Ar-C), 129.5, 127.4
(both Ar-CH), 62.9, 61.7 (both CH), 37.1, 31.7, 29.8, 29.5, 29.1,
25.9, 22.6 (all CH2), 21.5 (Ar-Me), 14.0 (5Ј-Me) and 10.5
(2Љ-Me); m/z (FAB) 324 (Mϩ ϩ 1, 7%), 297 (22), 235 (43), 179
(100) and 91 (10) [Found: Mϩ ϩ 1, 324.1996].
(2SR,5SR)-5-Ethyl-2-phenyl-1-(p-tolylsulfonyl)-3-pyrroline
52. Iodopyrrolidine 37j (0.05 g, 0.11 mmol) was reacted as
described in the general procedure above to yield the 3-pyrroline
52 (0.03 g, 72%) as a viscous, colourless oil: Rf 0.48 (dichloro-
methane); δH (270) 7.56 (2H, d, J 8.2, Ar-H), 7.32–7.15 (7H,
m, Ar-H), 5.68 (1H, ddd, J 6.3, 2.0 and 1.9, 3-H), 5.56 (1H, ddd,
J 6.3, 2.0 and 1.9, 4-H), 5.40 (1H, ddd, J 2.0, 2.0 and 2.0, 2-H),
4.46–4.38 (1H, m, 5-H), 2.33 (3H, s, Ar-Me), 1.99–1.53 (2H, m,
1Ј-CH2) and 0.90 (3H, t, J 7.6, 2Ј-Me); δC (270) 143.8, 141.3,
135.7 (all Ar-C), 130.0, 129.7, 129.1, 128.8, 128.3 (all Ar-CH),
128.0, 127.7 (both CH), 71.1 (2-CH), 69.8 (5-CH), 30.8
(1Ј-CH2), 21.9 (Ar-Me), and 10.6 (2Ј-Me); m/z (ES) 328
(Mϩ ϩ 1, 94%), 245 (5), 157 (7) and 102 (9) [Found: Mϩ ϩ 1,
328.1371].
(2RS,5SR)-5-Butyl-2-pentyl-1-(p-tolylsulfonyl)pyrrolidine
50d. Iodopyrrolidine 37i (0.05 g, 0.11 mmol) was deiodinated
as described in the general procedure to yield the title com-
pound 50d (0.03 g, 83%) as a colourless, viscous oil: Rf 0.50
(dichloromethane); νmax/cmϪ1 2959 (s), 2931 (s), 2861 (w), 1461
(w) and 1335 (s); δH (250) 7.71 (2H, d, J 8.3, Ar-H), 7.29 (2H, d,
J 8.3, Ar-H), 3.56–3.48 (2H, m, 2- and 5-H), 1.88–1.09 (18H,
m, 1Ј-, 1Љ-, 2Ј-, 2Љ-, 3-, 3Ј-, 3Љ-, 4- and 4Ј-CH2), 0.94 (3H, t,
J 7.2, Me) and 0.87 (3H, t, J 6.7, Me); δC (100) 142.8, 135.2
(both Ar-C), 129.5, 127.6 (both Ar-CH), 61.7 (2- and 5-CH),
37.2, 36.9, 31.7, 29.8, 29.6, 28.5, 25.9, 22.6, 22.6 (all CH2), 21.5
(Ar-Me) and 14.1 (4Љ- and 5Ј-Me); m/z (ES) 352 (Mϩ ϩ 1,
100%), 291 (17), 235 (20), 102 (14) and 83 (15). These data are
consistent with those in the literature.41
(2R)-(E)-2-(p-Tolylsulfonylamino)non-4-ene 24e. (2S,3R,
5R)-Iodopyrrolidine 37e (25 mg, 0.07 mmol) in a mixture of
ethanol (2.0 ml) and acetic acid (0.01 ml) was treated with zinc
dust (0.325 mesh, 10 mg, 0.07 mmol). The resulting reaction
mixture was stirred at ambient temperature for 6 h then filtered
over Kieselguhr and the solid washed with dichloromethane
(3 × 2 ml). The combined organic solutions were washed with
2 M aqueous sodium hydrogen carbonate (2 × 5 ml), then dried
and the solvent evaporated to afford the sulfonamide 24e (18.6
mg, 90%) as a viscous, yellow oil: [α]D = ϩ32.1 (c 0.008, CHCl3);
other spectral data were identical to those for the racemic
sulfonamide 24d (see above).
J. Chem. Soc., Perkin Trans. 1, 2001, 1182–1203
1201

View Article Online
X-Ray crystallography for 37f, 36j and 37k†
thank the EPSRC Mass Spectrometry Service, University
College, Swansea, for the provision of some of the high reso-
lution mass spectral data, Mr R. Fleming for his assistance in
obtaining much of the spectroscopic data and the Royal Society
for a Leverhulme Senior Research Fellowship (to D. W. K.).
Single crystals were obtained by vapour diffusion as described
in the text; X-ray data were collected on a CAD4 diffractometer
using monochromatized Mo-Kα radiation (λ = 0.710 73 Å).
(2RS,3SR,5SR)-2-Butyl-5-ethyl-3-iodo-1-p-tolylsulfonyl-
pyrrolidine 37f. C17H26INO2S = 435.35. Orthorhombic, Pba21
(No. 29), a = 15.481(2), b = 14.469(3), c = 16.866(2) Å,
V = 3778(2) Å3, Z = 8.00, Dc = 1.531 g cmϪ3, F(000) = 1760.
Crystal size 0.26 × 0.18 × 0.15 mm. 15269 reflections were
measured over the range 1.93 < θ < 24.99Њ with Ϫ1 р h р 18,
Ϫ15 р k р 16, Ϫ18 р l р 15 giving 5378 independent reflec-
tions [R(int) = 0.0761].
Full matrix least-squares refinement with all non-hydrogen
atoms anisotropic and hydrogens in calculated positions. The
maximum peak in the final ∆F map was 1.834 ÅϪ3 and the
minimum was Ϫ0.801 ÅϪ3. Final cycles of refinement gave
R = 0.0588 and Rw = 0.1252.
References
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(2RS,3SR,5RS)-5-Ethyl-3-iodo-2-phenyl-1-p-tolylsulfonyl-
pyrrolidine 36j. C H INO S ᎐ 455.34. Monoclinic, P2 /n,
᎐
19 22
2
1
a = 7.648, b = 13.629, c = 18.213 Å, β = 93.73(2)Њ, V = 1894.5
Å3, Z = 4.00, Dc = 1.596 g cmϪ3, F(000) = 912. Crystal size
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a = 12.577(4), b = 12.900(4), c = 13.006(6) Å, β = 119.06(2)Њ,
V = 1844.5(12) Å3, Z = 4.00, Dc = 1.589 g cmϪ3, F(000) = 880.
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a = 14.617(3), b = 14.417(3), c = 8.616(2) Å, β = 94.63(3)Њ, V =
1809.8(6) Å3, Z = 4.00, Dc = 1.620 g cmϪ3, F(000) = 880. Crystal
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Ϫ9 р l р 9. A semi-empirical absorption was applied (trans-
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Full matrix least-squares refinement with all non-hydrogen
atoms anisotropic and hydrogens in calculated positions. The
maximum peak in the final ∆F map was 0.767 ÅϪ3 and the
minimum was Ϫ0.722 ÅϪ3. Final cycles of refinement gave
R = 0.0410 and Rw = 0.1041.
Acknowledgements
We are very grateful to Miss Alma Kuijpers for experimental
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† CCDC reference numbers 158105–158108. See http://www.rsc.org/
suppdata/p1/b0/b008537p/ for crystallographic files in .cif or other
electronic format.
1202
J. Chem. Soc., Perkin Trans. 1, 2001, 1182–1203

View Article Online
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