A detailed investigation of the aza-prins reaction

Article abstract of DOI:10.1039/b915797b

The development of a Lewis acid-promoted aza-Prins reaction to form piperidines and pyrrolidines is described. Indium trichloride has been found to be a highly successful and mild Lewis acid for promoting this reaction. A thorough mechanistic investigation is described, including the factors that influence the formation of the 5- or 6-membered ring product(s). The Royal Society of Chemistry.

Full text of DOI:10.1039/b915797b

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A detailed investigation of the aza-Prins reaction†
Adrian P. Dobbs,*a,b Sebastien J. J. Guesne´,b Robert J. Parker,b John Skidmore,c Richard A. Stephensond and
Mike B. Hursthoused
Received 3rd August 2009, Accepted 31st October 2009
First published as an Advance Article on the web 5th January 2010
DOI: 10.1039/b915797b
The development of a Lewis acid-promoted aza-Prins reaction to form piperidines and pyrrolidines is
described. Indium trichloride has been found to be a highly successful and mild Lewis acid for
promoting this reaction. A thorough mechanistic investigation is described, including the factors that
influence the formation of the 5- or 6-membered ring product(s).
the endothelial cell proliferation inhibitor (+)-Cortistatin.24 In
2005, Armstrong et al. reported an aza-Prins-pinacol approach
1. Introduction
The Prins reaction1–3 has become one of the cornerstone reactions
of organic synthesis over the last 15 years, being employed in the
key stages of many natural product total syntheses. Its particular
strength is in the synthesis of heterocycles, and especially pyrans
and related compounds. Piperidines are even more widespread in
natural products and also pharmaceuticals.4 Despite the fact that
there are now many routes by which to prepare piperidines,4 it has
long been a target of many research groups to develop a viable
nitrogen-based version of the Prins reaction, in order to prepare
piperidines—the so-called aza-Prins reaction.
Moderate success has started to be achieved towards this
goal by various research groups. Historically, Overman has
performed pioneering work in the area of Brønsted acid-catalysed
iminium ion cyclisations,5–12 and this has been further studied by
Tanner;13 from this, we have developed the Lewis acid-promoted
aza-silyl-Prins reaction to form tetrahydropyridines.14–17 Padwa
has also performed related reactions involving N-acyliminium
ions.18–20 Several groups have used aza-Prins-type cyclisations
in total syntheses, without always making specific reference to
the key Prins-type step: Frank and Aube´21 reported a titanium
tetrachloride-promoted aza-Prins-type reaction in their synthesis
of the core tricycle of the martinellines; Hanessian et al.22 used
tin tetrabromide to promote the N-acyloxyiminium ion aza-Prins
cyclisation to form octahydroindoles; Hsung et al.23 employed a
formic acid-promoted aza-Prins reaction (followed by Wharton
rearrangement) in their synthesis of the (+)-cylindricines, and
Shair et al. used an aza-Prins bicyclisation in their approach to
to 7-azabicyclo[2.2.1]heptanes25,26 but it was not until 2006 that
Mart´ın et al.27,28 reported the first study devoted specifically to
developing an aza-Prins reaction, in the conventional sense of
a Prins reaction, and followed this with a catalytic version in
2009.29 More recently, Yadav et al. have also reported that BiCl3,30
GaI3/I2 and heteropoly acids32 (such as phosphomolybdic acid)
31
will also promote aza-Prins type reactions. In 2007, Shimizu
et al. reported that olefins and acetylenes, in the presence of
titanium tetraiodide and iodine, underwent an aza-Prins-type
reaction to yield 1,3-iodoamines.33 Finally, both Fuchigama et al.34
and ourselves35 have utilised fluorine in Prins-type reactions
to piperidines, Fuchigami by using hydrogen fluoride salts in
ionic liquids, and we incorporated fluorine in the cyclisation
precursors.
However, many of these methods have distinct drawbacks,
primarily either low yield or a lack of stereocontrol between sub-
stituents during the cyclisation. What is clear from the literature,
however, is a lack of a detailed survey and study of potential
conditions for a Lewis acid-promoted aza-Prins reaction, and a
detailed study on the effects of conditions and of substituents
on the outcome of any successful aza-Prins reaction. Herein, we
attempt to fill this void and report our findings on developing a
Lewis acid-promoted aza-Prins cyclisation reaction.
2. Results and discussion
2.1. Initial studies and Lewis acid screening
Initially, we simply wished to screen a variety of reaction condi-
tions for the formation of 1,2,4-tri- and 1,2,4,6-tetra-substituted
piperidines from appropriately substituted homoallylic amines
and an aldehyde. Two methods were employed for the preparation
of the corresponding amines: tosylation of but-3-en-1-ol followed
by displacement with an amine, or an iodine-catalysed one-pot
multi-component reaction between an aldehyde, benzyl carbamate
and allyltrimethylsilane (Scheme 1).36
Employing our previously optimised conditions for the related
silicon-modified aza-silyl-Prins reaction (N-protected silylated
homoallylic amine, aldehyde and Lewis acid in a 1 : 1 : 1 ratio in
acetonitrile at reflux for 3–36 h) as a starting point, we proceeded
to screen a range of conditions for the aza-Prins cyclisation
(Scheme 2). This was then extended to a wide variety of conditions
aSchool of Biological and Chemical Sciences, Joseph Priestley Building,
Queen Mary University of London, Mile End Road, London, United
Kingdom E1 4NS. E-mail: A.Dobbs@qmul.ac.uk
bSchool of Chemistry, University of Exeter, Stocker Road, Exeter, United
Kingdom EX4 4QD
cNeurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline,
New Frontiers Science Park, Third Avenue, Harlow, Essex, United Kingdom
CM19 5AW
dEPSRC National Crystallographic Service, Chemistry, University of
Southampton, Southampton, United Kingdom SO17 1BJ
† Electronic supplementary information (ESI) available: The preparation
of, and characterisation data for, the precursor alcohols, their tosyl
derivatives, and for the N-tosyl amines, and full details concerning the
unsuccessful Lewis acid screening conditions. CCDC reference numbers
748949–748951. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b915797b
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Scheme 1 Synthesis of homoallylic amines.
Scheme 2 Lewis acid screening.
and Lewis acids; however, all failed to give any piperidine 8, with
quantitative recovery of starting material in almost every case.
Even the use of the more reactive ethyl glyoxylate, which only
required much milder conditions in the aza-silyl-Prins reaction,
failed to yield any product. The full range of conditions and exact
variables explored is presented in the ESI.†
aldol product 10 in 45% yield. The most probable reason for the
lack of cyclised product being obtained is an instability of the cyclic
carbocation formed during this reaction, preferring to exist as an
open-form iminium ion, with the cyclic carbocation not being
sufficiently stable or long lived to allow trapping to the desired
piperidine.
Two reactions did not lead either to recovered starting material
or decomposition. The first involved the use of indium triflate,
which with any substrate or substituent gave the aza-Cope
hydrolysis product 9. It is thought that this arises from initial
iminium ion 11 formation, followed either by direct aza-Cope
rearrangement, or by cyclisation and subsequent ring opening,
to give a new iminium ion 12, which was then hydrolysed
under the reaction conditions to the secondary amine isolated
(Scheme 3). While not useful, this product does at least imply
that initial iminium ion formation was taking place under the
reaction conditions, even if not going on to give the desired
product. The second product, which was only observed on one
occasion when using indium trichloride with hexanal, was the
The use of the N-carbamate-protected amine similarly failed
to give any cyclised product; not unsurprising given the extent
of delocalisation of the lone pair of electrons on the nitrogen
atom.
Given the relative ease of cyclisation in the aza-silyl-Prins
reaction, compared with the lack of observed cyclisation in these
examples, the only difference between the two reactions was the
presence of a stabilising trimethylsilyl moiety in the aza-silyl-Prins
reaction, which stabilises the intermediate, cyclised carbocation
by the b-effect. Therefore, it was decided to try to impart some
extra stabilisation in the carbocation intermediate in the aza-Prins
reaction by the introduction of an electron donating methyl group
on the alkene in the homoallylic amine, as the corresponding
Scheme 3 Aza-Cope rearrangement leading to the hydrolysis product.
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Scheme 4 Unsuccessful aza-Prins reactions of N-benzyl-3-methylbut-3-enylamine.
Scheme 5 Preparation of (E)- and (Z)-alkenyl N-tosylamines.
alcohol was commercially available. The N-benzylamine 13 was
prepared as before, via tosylation and reaction with benzylamine.
After coupling of this amine with cyclohexanecarboxaldehyde in
the presence of either indium trichloride or TMSOTf, the only
product obtained was the isomerised amine 14 (Scheme 4). On
reaction with ethyl glyoxylate in the presence of indium trichloride
after 3 d at reflux, TLC showed complete consumption of the
amine substrate and GC-MS showed presence of the molecular
ion for the acetonitrile-trapped piperidine 15 (Scheme 4). However,
after flash chromatography, this product was only obtained pure
in a disappointing 5% yield, with no other identifiable products.
Concurrent with our research, Mart´ın et al. have reported the
use of iron(III) halides in an aza-Prins and an alkyne-aza-Prins
type reaction, and employing N-tosyl amines.27,29 Surprisingly,
iron(III) halides have been quite unsuccessful in our previous
work.14,15,17,37 Further, it is known that the nitrogen atom in a
sulfonamide is of similar nucleophilicity to that of the oxygen atom
in an alcohol moiety, which is perhaps why this demonstrated
success for Mart´ın, by enhancement of the electrophilicity of
the iminium ion and so aiding the cyclisation step. Therefore,
we decided to repeat our failed cyclisations with our preferred
Lewis acid, indium trichloride (owing to it being cheaper, easier to
use/manipulate and more moisture tolerant/resistant to moisture
in the atmosphere), with a N-tosylamine.
quantities of sodium iodide (Scheme 5). Additional homoallylic
amines 23, 24 and 25 were also prepared by this method.
2.2. Aza-Prins cyclisations: use of (Z)-alkenes
The use of the (Z)-alkenyl homoallylic tosylamine 21 in an aza-
Prins reaction promoted by indium trichloride was successful,
giving piperidines in reasonable yields. Scandium triflate was also
found to give piperidines, albeit in consistently 10–15% lower
yields, although having the advantage that the scandium triflate
was recyclable after an aqueous work up. A number of aldehydes
were successfully employed (Table 1), with the optimum reaction
conditions being amine : indium trichloride : aldehyde 1 : 1.5 : 1.5.
We were surprised to observe a second cyclised prod-
uct in these reactions, in addition to the piperidine: 3-(1-
chloroethyl)pyrrolidines. All the reactions showed complete con-
sumption of starting materials. GCMS also suggested traces of
minor diastereoisomers, which could have been formed in the
reaction, or more probably from the very low traces of the
inseparable minor (E)-geometric isomer (that had been formed
in the reduction step earlier in the synthesis of the N-tosyl amine).
However, these trace isomers could not be isolated nor their
relative stereochemistry determined. Particularly low yields of
4-chloropiperidines were observed with benzaldehyde and ethyl
glyoxylate (Table 1, entries 2 and 5) and without any pyrrolidine
or other product. This is not unsurprising with benzaldehyde,
which has consistently given low yields in indium trichloride-
mediated Prins-type reactions,14,37 but was unexpected for ethyl
Starting with pent-3-yn-1-ol, we first prepared both the E- and
Z-alkenyl tosylamines 21 and 22 via hydrogenation (Z, 17) or
LiAlH4 reduction (E, 18), tosylation (19 and 20) and reaction
with 4-methylbenzenesulfonamide in the presence of catalytic
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Fig. 1 NOE data and X-ray structure for 4-chloro-3-methyl-2-phenyl-1-tosylpiperidine (26b) and 3-(1-chloroethyl)-2-cyclohexyl-1-tosylpyrrolidine (27d)
Table 1 Aza-Prins reactions of (Z)-homoallyl tosylamine
principle, which dictates that the product ratio depends only on
the difference in the activation energy of the transition state going
to each product, and not on the equilibrium constant between
the intermediates, in this case between the E- and Z-iminium ion
intermediates.) Therefore, as the iminium ion then folds around
in order to cyclise, the (E)-iminium ion and methyl group from
the olefin repel on steric grounds. This forces both substituents to
adopt a pseudo-axial conformation, with the consequence that the
intermediate secondary carbocation is trapped by a chloride anion
from the least hindered opposite face to the ring C2 substituent
(Scheme 6a).
A similar argument can be applied to the formation of 3-(1-
chloroethyl)pyrrolidine (Scheme 6b): the (E)-iminium ion again
forces the C2 substituent axial. Based on a chair-like transition
state, the ethyl side chain becomes pseudo-equatorial as the 5-
membered ring is formed and the sp2–sp2 olefin character is lost.
It is not entirely clear, however, what controls the configuration of
the third stereocenter. Assuming the carbocation to be trigonal
planar, then chloride could trap from either face, yet only
one diastereoisomer was observed. It appears unlikely that the
neighbouring groups would hinder the approach of the chloride
from one direction. The only alternative would be a transition
state where the chloride ion attacks the sp2 alkene carbon at the
point of cyclisation and so the geometry of the olefin is important
(Scheme 6c).
Entry
R
Time/h
Yield 26 (%)
Yield 27 (%)
1a
2b
3c
4d
5e
n-C7H15
Ph
Ph(CH2)2
c-Hex
CO2Et
17
144
17
144
1
35
15
40
26
20
35
0
36
50
0
glyoxylate. High overall yields of cyclised material were obtained
for the three aliphatic aldehydes (Table 1, entries 1, 3 and 4).
The relative stereochemistry of both the 6- and 5-membered
heterocycles were determined both by NOESY experiments and
X-ray crystallography (Fig. 1).
The X-ray structure of 3-(1-chloroethyl)-2-cyclohexyl-1-
tosylpyrrolidine 27d clearly supported the NOE data: the cy-
clohexyl substituent adopts an axial conformation and the 1-
chloroethyl substituent also adopts an axial conformation on the
opposite face (assuming that there is no conformational averaging
on the NMR timescale). Perhaps surprisingly, in the solid state, the
N-tosyl group is endo over the pyrrolidine ring, orientated rather
like a “sunshade” over the molecule.
Li et al.38 have previously reported a mixture of tetrahydropyran
and tetrahydrofuran products when employing internal olefins
in oxa-Prins reactions, and it is believed that a similar system
is in operation here. We postulate that the formation of the
pyrrolidines is based upon unfavourable 1,3-diaxial interactions.
Ab initio calculations have shown the intermediate (E)-iminium
ions are more stable than the corresponding (Z)-iminium ions,27,39
and thus we assume that our system formed the (E)-iminium ion.
(However, the authors made no comment on the Curtin–Hammett
In order to investigate further if disfavoured 1,3-diaxial inter-
actions during the cyclisation process were responsible for the
formation of the pyrrolidine products, the chain length of the
olefin substituent was increased, by preparing (Z)-N-(hex-3-enyl)-
4-methylbenzenesulfonamide 23 from (Z)-hex-3-en-1-ol using the
identical tosylation/displacement with tosylamine route (53%
over 2 steps). The indium trichloride aza-Prins reaction was again
performed using three different aldehydes, and three different
products were now obtained (Table 2).
Each aliphatic aldehyde again gave a mixture of a 2-
substituted 4-chloropiperidine 28 and a 2-substituted 3-(1-chloro-
propyl)pyrrolidine 29, together with a previously unobserved
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Scheme 6 Effect of (E)-iminium geometry on stereochemistry in 3-(1-chloroethyl)pyrrolidine.
Table 2 Further aza-Prins reactions of (Z)-homoallyl tosylamines
Entry
R
Time/h
Yield 28 (%)
Yield 29 (%)
Yield 30 (%)
Ratio 6-ring : 5-ringa
Ratio 6-ring : 5-ring from Table 1b
InCl3:
1
2
3
n-C7H15
(CH2)2 Ph
c-Hex
17
17
72
34
31
14
43
49
62
7
10
10
17 : 25
31 : 59
7 : 36
1 : 1
10 : 9
13 : 25
FeCl3:
4
5
6
n-C7H15
(CH2)2 Ph
c-Hex
<1
10
5
28
0
9
47
0
63
5
0
11
35 : 65
N/A
11 : 89
40 : 60
34 : 66
16 : 84
a Ratio of 6-membered product to 5-membered products. b Previous example using (Z)-4-methyl-N-(pent-3-enyl)benzenesulfonamide.
side chain-eliminated pyrrolidine 30. The total yield of cy-
clised material increased in each case based on compari-
son to the reactions performed with (Z)-4-methyl-N-(pent-3-
enyl)benzenesulfonamide (21). The starting amine was completely
consumed in under 24 h for the reactions with octanal or hydro-
cinnamaldehyde (Table 2, entries 1 and 2) but again required longer
reaction times for cyclohexanecarboxaldehyde (Table 2, entry 3),
although all three were significantly shorter times compared to the
reactions with (Z)-4-methyl-N-(pent-3-enyl)benzenesulfonamide.
The major difference in these reactions was the appearance of an
unsaturated pyrrolidine, assumed to be formed either by E1-type
elimination from the intermediate carbocation after cyclisation or
by direct E2 elimination of chloride from the trapped product. The
eliminated product was always the minor reaction product, and
was the (E)-isomer, as judged by NOE experiment and confirmed
by the X-ray structure. If the sum of the two 5-membered ring
products is considered, the quantity of 5-membered product has
been enhanced compared to 6-membered product as a result of
chain elongation. It is assumed that increased disfavoured pseudo-
1,3-diaxial interactions in the chair transition state were more
prominent with the ethyl group and so the yield of 5-membered
product increased (Fig. 2c). The relative stereochemistry of the
substituents was again determined by a combination of NOESY
experiments (with each compound showing very similar enhance-
ments between corresponding protons) and X-ray crystallography
(Fig. 2a and b). Finally, we repeated these reactions with iron(III)
chloride following the conditions of Mart´ın, in order to see how
the results compared with those from indium trichloride (Table 2,
entries 4–6). The overall conversions to product were better with
indium trichloride, although with the iron trichloride perhaps
showing slightly better selectivity for the 5-ring over the 6-ring.
Interestingly, inthese piperidines the tosyl group is nolonger ori-
entated over the piperidine ring, but now points away, presumably
minimising interaction with the ethyl group (Fig. 2c). Particularly
pleasing was that X-ray structures could be obtained from the
adducts with cyclohexanecarboxaldehyde for both the eliminated
pyrrolidine product (confirming both its formation and existence
as the (E)-isomer) and the chlorine-containing pyrrolidine (Fig. 3).
2.3. Aza-Prins cyclisations: use of (E)-alkenes
The same studies were repeated, now employing the correspond-
ing (E)-alkene: the indium trichloride-promoted reaction of N-
(pent-3-(E)-enyl)-4-methylbenzenesulfonamide 22 with different
aldehydes (Table 3).
The results were quite different from those observed from
the (Z)-alkene. In all except one case, the 4-chloropiperidine
product was formed exclusively; in the other example, the
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Fig. 2 NOEs and X-ray structures of 2,3,4-trisubstituted piperidines.
Fig. 3 X-Ray structure of 3-(1-chloropropyl)-2-cyclohexyl-1-tosylpyrrolidine and 2-cyclohexyl-3-(E-prop-1¢-enyl)-1-tosylpyrrolidine.
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Table 3 Aza-Prins reactions of (E)-homoallyl tosylamine
2-phenethyl-3-methyl-1-tosylpiperidine and 3-(1-chloroethyl)-2-
cyclohexyl-1-tosylpyrrolidine by X-ray crystallography (Fig. 4).
A similar argument to before could be used to explain the
selectivity within the products. Once again, it was assumed that
the (E)-iminium ion was formed preferentially and that this sets
the axial conformation of the C2 substituent in all products. The
major difference is that the (E)-alkene allows the C3 methyl group
to adopt a pseudo-equatorial conformation, and then the chloride
adds to the carbocation from the least hindered face, also ending
up equatorial (Scheme 7).
The only difference for the pyrrolidine product is that the
third stereocenter is the opposite configuration to that observed
in examples taken from the (Z)-amine precursor. This could be
a result of the geometry of the olefin in the starting material,
although if the mechanism proceeds via a planar carbocation,
this is debatable. Alternatively, the difference may point to an
alternative mechanism that does not proceed through a planar
carbocation. As before, in both cases, the N-tosyl group is endo
over the ring.
Entry
R
Time/h
Yield 31 (%)
Yield 32 (%)
1a
2b
3c
4d
n-C7H15
(CH2)2Ph
c-Hex
17
17
240
1
66
64
0
0
0
70
0
CO2Et
21
3-(1-chloroethyl)pyrrolidine was formed exclusively. As before, the
aliphatic aldehydes produced good yields of piperidines in reason-
ably short reaction times (Table 3, entries 1 and 2) with a slight
depreciation in yield compared with the overall (combined) yield of
cyclised product from the (Z)-amine precursor. No other products
could be isolated or identified, and certainly no 2-substituted 3-
(1-chloroethyl)pyrrolidine product. The use of ethyl glyoxylate
(Table 3, entry 4) is highly comparable with the example involving
the (Z)-amine precursor, with a very short reaction time and con-
sumption of all the starting materials, but a disappointingly low
yield. The conformation of the products were again determined by
NOE experiments, with similar enhancements being observed for
each of the piperidine compounds and confirmed for 4-chloro-
2.4. Effects of additional substituents
Having investigated the effects of an (E)- or (Z)-alkene on
the outcome of the aza-Prins reaction, we now examined the
outcome when using either an alkene with an internal substituent,
4-methyl-N-(3-methylbut-3-enyl)benzenesulfonamide (24) or
a
trisubstituted alkene, 4-methyl-N-(4-methylpent-3-enyl)-
benzenesulfonamide (25). Both homoallylic amines were again
Fig. 4 NOE data and X-Ray structure of 4-chloro-2-phenethyl-3-methyl-1-tosylpiperidine (31b) and 3-(1-chloroethyl)-2-cyclohexyl-1-tosylpyrrolidine
(32c).
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Table 4 Aza-Prins reactions of 4-methyl-N-(3-methylbut-3-enyl)benzenesulfonamide (24)
Entry
R
Time/h
Total yield (%)
Ratioa
1
2
3
(CH2)2Ph
n-C7H15
CO2Et
2
2
1
90
73
0
53 : 47
53 : 47
N/A
a Inseparable by chromatography—ratio obtained by analysis of 1H NMR integration.
Scheme 7 Iminium ion and olefin geometry effects in 4-chloropiperidine formation.
prepared from the corresponding available alcohols via the same
2-step process used previously (Scheme 5).
there is an equal chance of elimination from either side of the
carbocation to give the two isomeric products.
The most surprising feature when using 4-methyl-N-(3-
methylbut-3-enyl)benzenesulfonamide under identical reaction
conditions to the previous studies was the rapidity of the
reaction, with the reaction complete in under 2 h (Table 4).
The most striking feature was the formation of two isomeric 4-
methyltetrahydropyridines, in a near 1 : 1 ratio, and no chlorine-
containing products nor pyrrolidine(s). The two isomers were
inseparable by chromatography (flash, GC or HPLC) and the
ratios were obtained by analysis of the 1H NMR integration values
of the olefinic proton signals, which were separate. It is believed
that both the rapidity and exclusivity of the 6-membered ring
can be explained by considering the carbocation that is formed
upon cyclisation. In forming the 6-membered ring, extra stability
is gained by forming a tertiary carbocation 35, compared with
a primary carbocation 36 in forming a 5-membered ring; then
Finally, as far as studying substituents around the
alkene,
a trisubstituted alkene, 4-methyl-N-(4-methylpent-3-
enyl)benzenesulfonamide (25), was employed and once again the
results were slightly different from any of the previous examples
(Table 5). In each of the successful reactions, only eliminated
pyrrolidine products were obtained, but this time as a mixture
of two different alkene regioisomers (which were inseparable by
chromatography). Once again, we believe that the explanation lies
with the driving force for forming a tertiary carbocation: this is
possible if the pyrrolidine carbocation 39 is formed, but not if
forming a piperidine. Furthermore, there is a much greater chance
of unfavourable 1,3-diaxial interactions between the two methyl
groups and the other substituents if a 6-membered ring is formed
(as in Sections 2.2 and 2.3), which cannot happen when forming
a pyrrolidine. It was slightly surprising that the two eliminated
Table 5 Further aza-Prins reactions involving trisubstituted olefin
Entry
R
Time/h
Total yield (%)
Ratio
1
2
3
(CH2)2Ph
n-C7H15
c-Hex
6
6
144
75
60
trace
52 : 48
58 : 42
50 : 50
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products were formed in equal amounts. Statistically, there are six
methyl Hb protons compared with one Ha proton. This suggests
that the loss of Hb to give 38 (the kinetic product) would be
sterically and statistically favoured. However, the loss of Ha to give
37 generates the more substituted (and presumably more stable)
double bond, and thus this would be the thermodynamic product.
Therefore, it is assumed that the transition state for forming the
internal double bond is lower in energy and that this balances out
the statistical effect.
Finally, we investigated the formation of tetrasubstituted
piperidines, and in particular the effect of using an a-substituted
sulfonamide to generate a tetrasubstituted piperidine. It has been
reported (Scheme 8) that in the Prins and silyl-Prins reactions with
alcohols, very high cis selectivity is observed across the oxygen
atom in the ring,14,35,37 and for the aza-silyl-Prins reaction that
this is reversed and a trans selectivity observed14–17 (presumably
through the presence of the extra substituent on the nitrogen atom
and A strain).
The target cyclisation material, 4-methyl-N-(pent-4-en-2-
yl)benzenesulfonamide 41, was prepared in two steps from the
commercially available pent-4-en-2-ol. On this occasion, the tosy-
lation/amination procedure was unsuccessful (failing at the sec-
ond amination step), and instead the Mitsunobu reaction was
employed between pent-4-en-2-ol and t-butyl tosylcarbamate to
form the homoallylic tertiary amine in 69% yield (Scheme 9).
The carbamate function was then cleaved with TFA in DCM to
give the required homoallylic tosylamine in quantitative yield.
In order to investigate the effects of a substituent on the alkene
Scheme 8 Selectivity in the (a) silyl-Prins and (b) aza-silyl-Prins reactions.
(as before), (E)-N-(hex-4-en-2-yl)-4-methylbenzenesulfonamide
43 was also prepared in four steps, using our more conven-
tional approach. Unfortunately, despite repeated efforts, we were
unable to prepare the corresponding (Z)-N-(hex-4-en-2-yl)-4-
methylbenzenesulfonamide, with the amination step repeatedly
proving unsuccessful.
Aza-Prins reactions were now attempted under a variety of
conditions (Scheme 10).
When the three aliphatic aldehydes that brought the most
success in previous examples were screened in the presence of
indium trichloride and DCM or acetonitrile under a variety of
conditions (full details in the ESI†), no reaction was observed
when using 41. Even when more forcing conditions were attempted
with DCM or acetonitrile at reflux, still only starting material
Scheme 9 Synthesis of C1-substituted N-tosylamines.
Scheme 10 Aza-Prins reactions involving C1-substituted tosylamines.
1072 | Org. Biomol. Chem., 2010, 8, 1064–1080 This journal is The Royal Society of Chemistry 2010
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remained. The same outcome was observed with TMSOTf. Finally
we decided to screen iron(III) chloride and after 70 h at room
temperature all the starting material was consumed by TLC.
However, only trace quantities (ca. 5%) of product were detected
on analysis by GCMS and could not be isolated; the rest of the
crude mass was unidentifiable. The desired product could not be
obtained by chromatography. A similar trend emerged when using
(E)-N-(hex-4-en-2-yl)-4-methylbenzenesulfonamide 43, with all
conditions giving, at best, only a trace of product.
deposited with the Cambridge Crystallographic Data Centre
(CCDC).
4.1 General procedure for alcohol tosylation
A round-bottomed flask was charged with a homoallylic alcohol
(69.73 mmol, 1.00 eq.) and dich◦loromethane (140 mL). The
resulting solution was cooled to 0 C before adding portionwise
and sequentially 4-dimethylaminopyridine (5.08 g, 41.84 mmol,
0.60 eq.), p-toluenesulfonyl chloride (15.96 g, 83.68 mmol, 1.20
eq.) and triethylamine (dropwise, 9.82 mL, 69.73 mmol, 1.00
eq.). The resulting solution was stirred at 0 ◦C until TLC
showed complete consumption of starting material. The resulting
suspension was diluted with diethyl ether (150 mL), stirred for
a further 30 min and the precipitate removed by filtration. The
solution was then washed sequentially with 10% aqueous copper
sulfate (2 ¥ 75 mL), 10% aqueous sodium hydrogen carbonate
(2 ¥ 75 mL) and a saturated aqueous sodium chloride solution
(60 mL). The combined organic layers were dried over magnesium
sulfate, filtered, and concentrated in vacuo.
3. Conclusions
In summary, we have demonstrated a general aza-Prins reaction of
N-tosylhomoallylic amines promoted by Lewis acids, and indium
trichloride in particular. Further, we have shown that this may
give rise to both piperidine and pyrrolidine products, and that
the stereochemistry of the products depends on the conformation
of the starting material alkene. We are currently looking at the
application of the reaction in the synthesis of various natural
products and will report our results in due course.
Characterisation data for compounds 2, 19, 20 and 42 is
presented in the ESI.†
4. Experimental details
4.2. General procedure for tosyl displacement by primary amine
4.1. General
A round-bottomed flask equipped with a condenser was charged
with ethanol (18 mL), followed by a primary amine (90 mmol,
5.00 eq.) and finally a tosylated alcohol (18 mmol, 1.00 eq.). The
resulting solution was heated to reflux temperature and stirred
at this temperature until TLC showed complete consumption of
starting material. The solution was cooled to room temperature,
the ethanol removed in vacuo and the excess of primary amine
carefully distilled under reduced pressure. The resulting residue
was partitioned between dichloromethane (60 mL) and 1.0 M
aqueous sodium hydroxide solution (40 mL). The organic layer
was separated, the aqueous layer extracted with dichloromethane
(3 ¥ 10 mL), and the combined organic layers dried over
magnesium sulfate, filtered and concentrated in vacuo.
Diethyl ether and tetrahydrofuran were predried over sodium wire
and distilled from sodium under nitrogen, with benzophenone
ketyl as indicator directly in the reaction vessel. Dichloromethane
was distilled over calcium hydride and kept under nitrogen.
All reactions were carried out under anhydrous conditions and
in an atmosphere of nitrogen unless otherwise stated, using
flame-dried glassware and standard vacuum/nitrogen manifold
techniques, with all transfers performed using plastic syringes
and needles. Reactions were mixed by internal magnetic fol-
lower. All chemicals were purified by distillation, recrystallisation
or chromatography where appropriate; commercially available
compounds were generally used without further purification.
All reactions were followed by TLC. Plates were visualised by
ultraviolet light (254 nm) and aqueous potassium permanganate
spray (KMnO4 : K2CO3 : water 6 : 1 : 100, w/w/v). Purification was
by flash column chromatography or the use of Mass-Directed-
Auto-Prep (MDAP), a form of preparative HPLC, performed
in the laboratories at GlaxoSmithKline, Harlow, UK. Infrared
spectra were recorded in the range 4000–600 cm-1 with internal
calibration. Spectra were recorded as thin films between NaCl
plates, as KBr disks or as Nujol pastes. Proton (1H) NMR spectra
were recorded at 270, 300 or 400 MHz and carbon (13C) NMR
spectra at 75.5 or 100.6 MHz, respectively, in deuterated solvents.
NMR chemical shift values (dH and dC) are quoted in parts per
million (ppm) relative to an internal standard (CDCl3), or from the
residual protic solvent peaks. Coupling constants, J, are quoted
as experimentally observed.
Characterisation data for compounds 3 and 13 is in the ESI.†
4.3. General procedure for the iodine-catalysed synthesis of
homoallylic amines
To a solution of an aldehyde (15.00 mmol, 1 eq.) in acetonitrile (15
ml) at room temperature was added sequentially iodine (0.38 g,
1.5 mmol, 0.10 eq., in one portion), benzyl carbamate (2.38 g,
15.75 mmol, 1.05 eq., portionwise), and allyltrimethylsilane
(2.38 mL, 15 mmol, 1.00 eq., dropwise). The resulting suspension
was stirred at room temperature until TLC showed complete
consumption of starting material. To the solution was added
sodium thiosulfate (0.90 g) and distilled water (10 mL), and the
reaction mixture stirred for a further 20 min. The biphasic solution
was diluted with diethyl ether (30 mL), the organic layer washed
with saturated aqueous sodium chloride (2 ¥ 25 mL) and the
combined aqueous layers extracted with diethyl ether (2 ¥ 25 mL).
The combined organic layers were dried over sodium thiosulfate,
filtered, and concentrated in vacuo.
The preparation of, and characterisation data for, the alcohol
precursors and their tosyl derivatives, for the N-tosyl amines,
and details concerning the unsuccessful Lewis acid screening
conditions are given in the ESI.† All X-ray structure determination
was performed at the EPSRC National Crystallographic Service
(University of Southampton). Crystallographic data has been
Data for compounds 6 and 7 is in the ESI.†
This journal is
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4.4. General procedure for tosyl displacement with
4-methylbenzenesulfonamide, catalysed by sodium iodide
(3H, d, J 6.9, H-C19), 0.87 (3H, t, J 6.8, H-C13); dC (75.5 MHz;
CDCl3) 143.1 (C17), 138.1 (C14), 129.5 (C16), 126.9 (C15), 60.1
(C2), 57.4 (C4), 40.6 (C6), 37.3 (C3), 31.7 (C11), 30.0 (C5), 29.4
(C9 and C10), 26.8 (C12), 22.6 (C8), 21.5 (C18), 14.1 (C13), 12.7
(C19); m/z (CI) 386 (MH+, 100), 350 (60), 286 (42); HRMS (ES)
found [M + H]+ 386.1910, C20H33ClNO2S requires 386.1915.
A round-bottomed flask fitted with a reflux condenser was charged
with dimethylsulfoxide (87 mL), 4-methylbenzenesulfonamide
(27.98 g, 160.38 mmol, 2.30 eq.) and finely powdered potassium
hydroxide (5.06 g, 90.65 mmol, 1.30 eq.). The resulting suspension
was heated to 50 ◦C and stirred for 2 h. The resulting solution
was cooled to room temperature and an alcohol-derived tosylate
derivative (69.73 mmol, 1.00 eq.) in dimethylsulfoxide (10 mL)
added dropwise, followed by sodium iodide (3.15 g, 20.92 mmol,
0.30 eq.) in one portion. The mixture was heated to 50 ◦C and
stirred until TLC showed full consumption of starting material.
The mixture was cooled to room temperature, ice cold water
(100 mL) added, the organic layer separated, and the aqueous
layer extracted with dichloromethane (3 ¥ 50 mL). The combined
organic layers were washed with a 15% aqueous solution of
potassium hydroxide (100 mL), water (100 mL) and a saturated
aqueous solution of sodium chloride (100 mL). The organic layer
was dried over magnesium sulfate, filtered and concentrated in
vacuo.
(2S,3R)-3-((S)-1-Chloroethyl)-2-heptyl-1-tosylpyrrolidine/
(2R,3S)-3-((R)-1-chloroethyl)-2-heptyl-1-tosylpyrrolidine 27a
(Table 1 Entry 1). Further elution (90% hexane, 10% ethyl
acetate) provided the other title compound (84 mg, 0.22 mmol,
35%) as a colourless oil. nmax(neat)/cm-1 2927, 1598; dH (300 MHz;
CDCl3) 7.75 (2H, d, J 8.3, H-C15), 7.32 (2H, d, J 8.3, H-C16),
3.80 (1H, ddd, J 7.6, 4.9, 2.9, H-C2), 3.36 (1H, ddd, J 10.7, 7.3,
5.7, H-C5), 3.25 (1H, td, J 10.7, 7.3, H-C5), 3.09 (1H, qd, J 8.8,
6.5, H-C6), 2.43 (3H, s, H-C18), 2.13-2.01 (1H, m, H-C3), 1.93
(1H, dt, J 14.6, 7.3, H-C4), 1.79-1.66 (1H, m, H-C7), 1.66-1.51
(1H, m, H-C7), 1.48-1.31 (1H, m, H-C4), 1.27 (3H, d, J 6.5,
H-C19), 1.33-1.19 (10H, m, H-C8 to H-C12), 0.88 (3H, t, J 6.6,
H-C13); dC (75.5 MHz; CDCl3) 143.4 (C17), 135.0 (C14), 129.6
(C16), 127.5 (C15), 63.7 (C1), 59.2 (C6), 52.5 (C3), 47.3 (C5), 37.0
(C7), 31.8 (C11), 29.4 (C9 and C10), 27.8 (C4), 25.8 (C8), 23.1
(C19), 22.6 (C12), 21.5 (C18), 14.1 (C13); m/z (CI) 386 (MH+,
100), 350 (25), 286 (27); HRMS (ES) found [M + NH4]+ 403.2185,
C20H36ClN2O2S requires 403.2181.
Data for compounds 21, 22, 24, 25, 40 and 41 is in the ESI.†
4.5. General procedure for the aza-Prins reaction
A round-bottomed flask was charged with indium trichloride
(642 mg, 2.96 mmol, 1.50 eq.) and dichloromethane (5 mL). To the
resulting suspension was added an aldehyde (2.96 mmol, 1.50 eq.)
in dichloromethane (1.5 mL). After stirring the mixture for 15 min
at room temperature, a N-tosyl homoallylicamine derivative
(1.97 mmol, 1.00 eq.) in dichloromethane (1.5 mL) was added
and the resulting mixture stirred until TLC showed complete
consumption of starting material. The mixture was diluted with
dichloromethane (10 mL) and water (10 mL), and stirred for
30 min. The organic layer was separated and the aqueous layer
was extracted with dichloromethane (3 ¥ 10 mL). The combined
organic layers were dried over magnesium sulfate, filtered and
concentrated in vacuo, and purified by chromatography.
(2S,3R,4S)-4-Chloro-3-methyl-2-phenyl-1-tosylpiperidine/(2R,
3S,4R)-4-chloro-3-methyl-2-phenyl-1-tosylpiperidine 26b (Table 1
Entry 2). Following the general procedure, (Z)-4-methyl-N-
(pent-3-enyl)benzenesulfonamide (150 mg, 0.62 mmol) in the
presence of benzaldehyde (99 mg, 0.94 mmol), was consumed
based on analysis by TLC after 144 h of stirring at room
temperature. The work up afforded a yellow oil, which was purified
by flash column chromatography (90% hexane, 10% ethyl acetate)
to give the title compound (34 mg, 0.09 mmol, 15%) as a white
◦
solid. M.p. 112–114 C; nmax(neat)/cm-1 3029, 2940, 2344, 1596;
dH (300 MHz; CDCl3) 7.70 (2H, d, J 7.8, H-C8), 7.45-7.27 (5H,
m, Ar–H), 7.21 (2H, d, J 7.8, H-C9), 5.19 (1H, s, H-C2), 4.09 (1H,
td, J 11.8, 4.1, H-C4), 3.97-3.80 (1H, m, H-C6), 3.27 (1H, ddd,
J 13.9, 11.8, 3.5, H-C6), 2.88-2.72 (1H, m, H-C3), 2.47 (3H, s,
H-C11), 2.07-1.91 (1H, m, H-C5) 1.85-1.78 (1H, m, H-C5), 1.16
(3H, d, J 6.9, H-C12); dC (75.5 MHz; CDCl3) 143.8 (C10), 137.8
(C7), 137.7 (ArC), 129.6 (ArC), 128.7 (ArC), 127.2 (ArC), 127.1
(C8), 126.8 (C9), 62.5 (C2), 57.5 (C4), 41.8 (C6), 39.3 (C3), 29.8
(C5), 21.5 (C11), 13.0 (C12); m/z (CI) 364 (MH+, 64), 328 (30),
210 (55); HRMS (ES) Found [M + H]+ 364.1135, C19H23ClNO2S
requires 364.1133.
4.5.1 (2R,3R,4S)-4-Chloro-2-heptyl-3-methyl-1-tosylpiperi-
dine/(2S,3S,4R)-4-chloro-2-heptyl-3-methyl-1-tosylpiperidine
and
(2S,3R)-3-((S)-1-chloroethyl)-2-heptyl-1-tosylpyrrolidine/
(2R,3S)-3-((R)-1-chloroethyl)-2-heptyl-1-tosylpyrrolidine. Follo-
wing the general procedure for the aza-Prins reaction, (Z)-4-
methyl-N-(pent-3-enyl)benzenesulfonamide (150 mg, 0.62 mmol),
and octanal (120 mg, 0.94 mmol), were consumed based on
analysis by TLC after 17 h of stirring at room temperature. The
work up afforded a yellow oil, which was purified by flash column
chromatography (90% hexane, 10% ethyl acetate) to give the two
title compounds.
(2R,3R,4S)-4-Chloro-3-methyl-2-phenethyl-1-tosylpiperidine,
(2S,3S,4R)-4-chloro-3-methyl-2-phenethyl-1-tosylpiperidine, (2S,
3R)-3-((S)-1-chloroethyl)-2-phenethyl-1-tosylpyrrolidine and (2R,
3S)-3-((R)-1-chloroethyl)-2-phenethyl-1-tosylpyrrolidine. Follo-
wing the general procedure, (Z)-4-methyl-N-(pent-3-enyl)-
benzenesulfonamide (150 mg, 0.62 mmol) in the presence of
3-phenylpropanal (126 mg, 0.94 mmol), was consumed based on
analysis by TLC after 17 h of stirring at room temperature. The
work up afforded a yellow oil, which was purified by flash column
chromatography (90% hexane, 10% ethyl acetate) to give the two
title compounds.
(2R,3R,4S)-4-Chloro-2-heptyl-3-methyl-1-tosylpiperidine/(2S,
3S,4R)-4-chloro-2-heptyl-3-methyl-1-tosylpiperidine 26a (Table 1
entry 1). 84 mg (0.22 mmol, 35%) as
n
a colourless oil.
max(neat)/cm-1 2928, 1729, 1598; dH (300 MHz, CDCl3) 7.67 (2H,
d, J 8.2, H-C15), 7.27 (2H, d, J 8.2, H-C16), 4.31 (1H, td, J
12.6, 4.6, H-C4), 3.96-3.88 (1H, m, H-C2), 3.78-3.69 (1H, m, H-
C6), 2.94 (1H, td, J 13.6, 3.2, H-C6), 2.41 (3H, s, H-C18) 2.16-2.05
(1H, m, H-C3), 2.01-1.84 (1H, m, H-C5), 1.84-1.74 (1H, m, H-C5),
1.66-1.33 (2H, m, H-C7), 1.32-1.11 (10H, m, H-C8 to H-C12), 1.08
1074 | Org. Biomol. Chem., 2010, 8, 1064–1080
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(2R,3R,4S)-4-Chloro-3-methyl-2-phenethyl-1-tosylpiperidine/
(2S,3S,4R)-4-chloro-3-methyl-2-phenethyl-1-tosylpiperidine 26c
(Table 1 Entry 3). (98 mg, 0.25 mmol, 40%) as a colourless oil.
286 (10); Anal. Calcd. for C19H28ClNO2S requires C, 61.68; H,
7.63; N, 3.79%. Found: C, 61.44; H, 7.72; N, 3.76%.
(2S,3R)-3-((S)-1-Chloroethyl)-2-cyclohexyl-1-tosylpyrroli-
dine/(2R,3S)-3-((R)-1-chloroethyl)-2-cyclohexyl-1-tosylpyrroli-
n
max(neat)/cm-1 3063, 2938, 1598; dH (300 MHz; CDCl3) 7.66
(2H, d, J 8.3, H-C10), 7.34-7.13 (5H, m, Ar–H), 7.08 (2H, d,
J 8.3, H-C11), 4.32 (1H, td, J 12.3, 4.6, H-C4), 4.01 (1H, m,
H-C2), 3.80 (1H, dd, J 13.3, 4.5, H-C6), 2.99 (1H, td, J 13.3, 3.3,
H-C6), 2.66-2.47 (2H, m, H-C8), 2.42 (3H, s, H-C13), 2.22-2.13
(1H, m, H-C3), 2.02-1.88 (1H, m, H-C5), 1.89-1.77 (1H, m,
H-C5), 1.78-1.52 (2H, m, H-C7), 1.07 (3H, d, J 6.9, H-C14); dC
(75.5 MHz; CDCl3) 143.2 (C12), 140.9 (ArC), 138.0 (C9), 129.7
(C11), 128.5 (ArC), 128.2 (ArC), 126.9 (C10), 126.1 (ArC), 59.6
(C2), 57.2 (C4), 40.7 (C6), 37.4 (C3), 33.1 (C8), 31.8 (C5 or C7),
30.0 (C5 or C7), 21.5 (C13), 12.7 (C14); m/z (CI) 392 (MH+,
100), 356 (18), 238 (48); HRMS (ES) found [M + NH4]+ 409.1716,
C21H30ClN2O2S requires 409.1711.
dine 27d (Table
1 Entry 4). Further elution (90% hex-
ane, 10% ethyl acetate) provided the other title compound
(115 mg, 0.31 mmol, 50%) as a white solid. M.p. 109–112 ◦C;
n
max(KBr)/cm-1 2918, 1670, 1597; dH (300 MHz; CDCl3) 7.74 (2H,
d, J 8.1, H-C12), 7.30 (2H, d, J 8.1, H-C13), 3.69 (1H, dd, J 4.3,
2.5, H-C2), 3.38-3.30 (1H, m, H-C5), 3.28-3.19 (1H, m, H-C5),
3.02 (1H, qd, J 8.8, 6.5, H-C6), 2.41 (3H, s, H-C15), 2.17-2.09
(1H, m, H-C3), 1.98-1.83 (1H, m, H-C4), 1.78-1.58 (5H, m, H-C7
and H-C8), 1.38 (1H, ddd, J 16.8, 8.1, 4.8, H-C4), 1.16 (3H, d, J
6.5, H-C16), 1.22-0.76 (6H, m, H-C9 and H-C10); dC (75.5 MHz;
CDCl3) 143.4 (C14), 134.8 (C11), 129.5 (C13), 127.6 (C12), 68.1
(C2), 59.5 (C6), 49.6 (C3), 48.0 (C5), 43.3 (C7), 29.8 (C8), 28.5
(C8), 27.9 (C4), 26.4 (C10), 26.3 (C9), 26.2 (C9), 22.7 (C16), 21.5
(C15); m/z (CI) 370 (MH+, 100), 334 (28), 286 (20); Anal. Calcd.
for C19H28ClNO2S requires C, 61.69; H, 7.63; N, 3.79%. Found: C,
61.65; H, 7.84; N, 3.66%; HRMS (ES) Found [M + H]+ 370.1602,
C19H29ClNO2S requires 370.1599.
(2S,3R)-3-((S)-1-Chloroethyl)-2-phenethyl-1-tosylpyrroli-
dine/(2R,3S)-3-((R)-1-chloroethyl)-2-phenethyl-1-tosylpyrroli-
dine 27c (Table 1 Entry 3). Further elution (90% hexane, 10%
ethylacetate) providedthe other title compound (88mg, 0.22mmol,
36%) as a white solid. M.p. 122–123 ◦C; nmax(KBr)/cm-1 3062,
2955, 1664, 1594; dH (300 MHz; CDCl3) 7.81 (2H, d, J 8.3, H-
C10), 7.39 (2H, d, J 8.3, H-C11), 7.36-7.24 (5H, m, Ar–H), 3.94
(1H, dt, J 6.7, 3.2, H-C2), 3.55-3.31 (2H, m, H-C5), 3.18 (1H, qd,
J 9.1, 6.6, H-C6), 2.82 (2H, t, J 8.3, H-C8), 2.50 (3H, s, H-C13),
2.25-2.17 (1H, m, H-C3), 2.18-2.08 (2H, m, H-C7), 2.19-1.95 (1H,
m, H-C4), 1.45 (1H, dt, J 13.0, 6.2, H-C4), 1.34 (3H, d, J 6.6, H-
C14); dC (75.5 MHz; CDCl3) 143.6 (C12), 141.6 (ArC), 134.8 (C9),
129.6 (C11), 128.4 (ArC), 128.3 (ArC), 127.5 (C10), 125.7 (ArC),
63.4 (C2), 59.2 (C6), 52.9 (C3), 47.6 (C5), 38.6 (C7), 32.1 (C8),
27.9 (C4), 23.1 (C14), 21.5 (C13); m/z (CI) 392 (MH+, 100), 356
(12), 238 (58); Anal. Calcd. for C21H26ClNO2S requires C, 64.35;
H, 6.69; N, 3.57%. Found: C, 64.47; H, 6.58; N, 3.54%.
Crystal data. C19H28ClNO2S; M = 369.93; Orthorhombic; space
˚
group P212121; a = 9.5924(3), b = 12.9905(3), c = 15.0218(4) A;
3
˚
volume 1871.87(9) A ; T = 120 K; Z 4; 16 779 reflections
measured, 4283 unique [Rint = 0.0484]. The final R values R1 =
0.0376, wR2 = 0.0826 (observed) and R1 = 0.0516, wR2 = 0.0886
(all).
(2S,3R,4S)-Ethyl-4-chloro-3-methyl-1-tosylpiperidine-2-carb-
oxylate/(2R,3S,4R)-ethyl-4-chloro-3-methyl-1-tosylpiperidine-2-
carboxylate 26e (Table 1 Entry 5). Following the general pro-
cedure, (Z)-4-methyl-N-(pent-3-enyl)benzenesulfonamide (40 mg,
0.17 mmol), in the presence of a pre-heated 33% solution of ethyl 2-
oxoacetate in toluene (76 mg, 0.25 mmol, 1.50 eq.), was consumed
based on analysis by TLC after 1 h of stirring at room temperature.
The work up afforded a yellow oil, which was purified by flash
column chromatography (90% hexane, 10% ethyl acetate) to give
the title compound (12 mg, 0.03 mmol, 20%) as a pale yellow oil.
(2R,3R,4S)-4-Chloro-2-cyclohexyl-3-methyl-1-tosylpiperidine/
(2S,3S,4R)-4-chloro-2-cyclohexyl-3-methyl-1-tosylpiperidine and
(2S,3R)-3-((S)-1-chloroethyl)-2-cyclohexyl-1-tosylpyrrolidine/
(2R,3S)-3-((R)-1-chloroethyl)-2-cyclohexyl-1-tosylpyrrolidine. Fo-
llowing the general procedure, (Z)-4-methyl-N-(pent-3-
enyl)benzenesulfonamide (150 mg, 0.62 mmol) in the presence of
cyclohexanecarbaldehyde (105 mg, 0.94 mmol), was consumed
based on analysis by TLC after 144 h of stirring at room
temperature. The work up afforded a yellow oil, which was
purified by flash column chromatography (90% hexane, 10% ethyl
acetate) to give the two title compounds.
n
max(neat)/cm-1 2927, 1736, 1598; dH (300 MHz; CDCl3) 7.66
(2H, d, J 8.3, H-C8), 7.29 (2H, d, J 8.3, H-C9), 4.54 (1H, d, J
1.2, H-C2), 4.13-4.02 (1H, m, H-C4), 4.04-3.94 (2H, m, H-C13),
3.79-3.70 (1H, m, H-C6), 3.31 (1H, td, J 12.4, 3.4, H-C6), 2.69-
2.58 (1H, m, H-C3), 2.42 (3H, s, H-C11), 2.13-1.97 (1H, m, H-C5),
1.94-1.82 (1H, m, H-C5), 1.25 (3H, d, J 6.9, H-C15), 1.16 (3H, t,
J 7.1, H-C14); dC (75.5 MHz; CDCl3) 169.9 (C12), 143.4 (C10),
136.3 (C7), 129.4 (C9), 127.2 (C8), 61.6 (C13), 61.0 (C2), 57.2 (C4),
42.3 (C6), 37.2 (C3), 29.3 (C5), 21.5 (C11), 13.9 (C14), 11.9 (C15);
m/z (CI) 360 (MH+, 90), 286 (45), 206 (100); HRMS (ES) found
[M + H]+ 360.1027, C16H23ClNO4S requires 360.1031.
(2R,3R,4S)-4-Chloro-2-cyclohexyl-3-methyl-1-tosylpiperidine/
(2S,3S,4R)-4-chloro-2-cyclohexyl-3-methyl-1-tosylpiperidine 26d
(Table 1 Entry 4). (60 mg, 0.16 mmol, 26%) as a white solid.
M.p. 89–91 ◦C; nmax(KBr)/cm-1 3044, 2923, 1597; dH (300 MHz;
CDCl3) 7.70 (2H, d, J 8.4, H-C12), 7.27 (2H, d, J 8.4, H-C13),
4.34-4.24 (1H, m, H-C4), 3.76-3.64 (2H, m, H-C2 and H-C6),
2.98-2.83 (1H, m, H-C6), 2.42 (3H, s, H-C15), 2.39-2.28 (1H, m,
H-C3), 1.85-1.71 (2H, m, H-C5), 1.77-1.53 (5H, m, H-C7 and
H-C8), 1.27-0.99 (6H, m, H-C9 and H-C10), 0.95 (3H, d, J 6.9,
H-C16); dC (75.5 MHz; CDCl3) 142.9 (C14), 138.3 (C11), 129.4
(C13), 127.1 (C12), 65.8 (C2), 57.6 (C4), 41.0 (C6), 36.1 (C3), 34.7
(C7), 31.0 (C8), 30.2 (C8), 29.5 (C5), 26.3 (C10), 26.2 (C9), 26.1
(C9), 21.5 (C15), 13.2 (C16); m/z (CI) 370 (MH+, 100), 334 (12),
(2R,3R,4S)-4-Chloro-3-ethyl-2-heptyl-1-tosylpiperidine/(2S,
3S,4R)-4-chloro-3-ethyl-2-heptyl-1-tosylpiperidine and (2S,3R)-3-
((S)-1-chloropropyl)-2-heptyl-1-tosylpyrrolidine/(2R,3S)-3-((R)-
1-chloropropyl)-2-heptyl-1-tosylpyrrolidine. Following the gen-
eral procedure, (Z)-N-(hex-3-enyl)-4-methylbenzenesulfonamide
(500 mg, 1.97 mmol), in the presence of octanal (379 mg,
2.96 mmol), was consumed based on analysis by TLC after 17 h of
stirring at room temperature. The work up afforded a yellow oil,
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©

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which was purified by flash column chromatography (90% hexane,
10% ethyl acetate) to give two title compounds.
(C11), 128.4 (ArC), 128.3 (ArC), 126.8 (C10), 126.1 (ArC), 57.9
(C4), 55.2 (C2), 44.8 (C3), 40.7 (C6), 33.0 (C8), 31.2 (C5 or C7),
30.9 (C7 or C5), 21.4 (C13), 17.4 (C14), 12.2 (C15); m/z (CI)
406 (MH+, 20), 216 (90), 111 (100); HRMS (ES) found [M + H]+
406.1606, C22H29ClNO2S requires 406.1602.
(2R,3R,4S)-4-Chloro-3-ethyl-2-heptyl-1-tosylpiperidine/(2S,
3S,4R)-4-chloro-3-ethyl-2-heptyl-1-tosylpiperidine 28a (Table 2
Entry 1). 323 mg, (0.81 mmol, 41%) as a colourless oil.
Crystal data. C22H28ClNO2S; M = 405.96; Monoclinic; a =
n
max(neat)/cm-1 2957, 1729, 1598; dH (300 MHz; CDCl3) 7.66 (2H,
3
˚
˚
8.9411(3), b = 11.0719(3), c = 10.9373(4) A; volume 1066.91(6) A ;
d, J 8.4, H-C15), 7.26 (2H, d, J 8.4, H-C16), 4.37-4.28 (1H, m,
H-C4), 4.11-4.03 (1H, m, H-C2), 3.79-3.69 (1H, m, H-C6), 3.01-
2.87 (1H, m, H-C6), 2.40 (3H, s, H-C18), 1.91-1.74 (2H, m, H-C5),
1.75-1.63 (1H, m, H-C3), 1.59-1.29 (2H, m, H-C7), 1.32-1.23 (8H,
m, H-C8 to H-C11), 1.23-1.16 (4H, m, H-C19 and H-C12), 0.94
(3H, t, J 7.3, H-C20), 0.87 (3H, t, J 6.8, H-C13); dC (75.5 MHz;
CDCl3) 143.0 (C17), 138.1 (C14), 129.5 (C16), 126.8 (C15), 58.1
(C4), 55.8 (C2), 44.7 (C3), 40.6 (C6), 31.7 (C11), 30.9 (C5), 29.1
(C9 and C10), 26.7 (C8), 22.6 (C12), 22.6 (C7), 21.4 (C18), 17.4
(C19), 14.0 (C13), 12.3 (C20); m/z (CI) 400 (MH+, 100), 364 (78),
300 (42); HRMS (ES) found [M + H]+ 400.2073, C21H35ClNO2S
requires 400.2072.
T = 120 K; Z 2, 13 213 reflections measured, 4663 unique [Rint
=
0.0367]. The final R values R1 = 0.0404, wR2 = 0.1043 (observed)
and R1 = 0.0470, wR2 = 0.1078 (all data). Flack parameter 0.44(6).
(2S,3R)-3-((S)-1-Chloropropyl)-2-phenethyl-1-tosylpyrroli-
dine and (2R,3S)-3-((R)-1-chloropropyl)-2-phenethyl-1-tosyl-
pyrrolidine 29b (Table 2 Entry 2). Further elution (90% hexane
10% ethyl acetate) provided the other title compound (392 mg,
0.97 mmol, 49%) as a white solid. M.p. 69–71 ◦C; nmax(neat)/cm-1
3088, 2936, 1598; dH (300 MHz; CDCl3) 7.75 (2H, d, J 8.3, H-
C10), 7.35-7.16 (5H, m, Ar–H), 7.23 (2H, d, J 8.3, H-C11), 3.89
(1H, dt, J 6.2, 3.1, H-C2), 3.45-3.30 (2H, m, H-C5), 2.84 (1H, dt,
J 9.1, 2.9, H-C6), 2.80-2.71 (2H, m, H-C8), 2.43 (3H, s, H-C13),
2.24-2.14 (1H, m, H-C3), 2.09-1.84 (2H, m, H-C7), 1.97-1.85 (1H,
m, H-C4), 1.59-1.44 (1H, m, H-C14), 1.44-1.29 (2H, m, H-C14
and H-C4), 0.85 (3H, t, J 7.2, H-C15); dC (75.5 MHz; CDCl3)
143.6 (C12), 141.7 (ArC), 135.0 (C9), 129.6 (C11), 128.4 (ArC),
128.3 (ArC), 127.6 (C10), 125.8 (ArC), 66.7 (C6), 63.6 (C2), 51.2
(C3), 47.7 (C5), 38.6 (C7), 32.2 (C8), 28.6 (C14), 28.0 (C4), 21.5
(C13), 10.6 (C15); m/z (CI) 406 (MH+, 92), 252 (52), 216 (100);
HRMS (ES) found [M + H]+ 406.1602, C22H29ClNO2S requires
406.1606.
(2S,3R)-3-((S)-1-Chloropropyl)-2-heptyl-1-tosylpyrrolidine/
(2R,3S)-3-((R)-1-chloropropyl)-2-heptyl-1-tosylpyrrolidine 29a
(Table 2 Entry 1). Further elution (90% hexane 10% ethyl acetate)
provided the other title compound (339 mg, 0.85 mmol, 43%) as a
colourless oil. nmax(neat)/cm-1 2954, 1597, dH (300 MHz; CDCl3)
7.73 (2H, d, J 8.3, H-C15), 7.30 (2H, d, J 8.3, H-C16), 3.83-3.77
(1H, m, H-C2), 3.39-3.20 (2H, m, H-C5), 2.78 (1H, td, J 9.1,
2.8, H-C6), 2.41 (3H, s, H-C18), 2.16-2.05 (1H, m, H-C3), 1.96-
1.82 (1H, m, H-C4), 1.73-1.54 (2H, m, H-C7), 1.60-1.39 (2H, m,
H-C19), 1.43-1.29 (1H, m, H-C4), 1.31-1.19 (10H, m, H-C8 to
H-C12), 0.86 (3H, t, J 6.5, H-C13), 0.83 (3H, t, J 7.2, H-C20); dC
(75.5 MHz; CDCl3) 143.4 (C17), 135.0 (C14), 129.5 (C16), 127.5
(C15), 66.7 (C6), 63.7 (C2), 50.7 (C3), 47.4 (C5), 36.9 (C7), 31.8
(C11), 29.3 (C9 and C10), 28.5 (C19), 27.8 (C4), 25.8 (C8), 22.6
(C12), 21.4 (C18), 14.0 (C20), 10.5 (C13); m/z (CI) 400 (MH+,
100), 364 (40), 300 (25); Anal. calcd. for C21H34ClNO2S requires
C, 63.05; H, 8.57; N, 3.50%. Found: C, 62.99; H, 8.83; N, 3.50%.
Crystal Data. C22H28ClNO2S; M = 405.96; Orthorhombic;
˚
a = 14.7643(7), b = 13.3490(6), c = 10.3953(3) A; volume
3
˚
2048.80(15) A ; space group Pna21; T = 120 K; Z 4, 16 800
reflections measured, 4515 unique [Rint = 0.0836]. The final R
values R1 = 0.0504, wR2 = 0.1017 (observed) and R1 = 0.0832,
wR2 = 0.1143 (all data). Flack parameter 0.10(8).
(2R,3R,4S)-4-Chloro-2-cyclohexyl-3-ethyl-1-tosylpiperidine/
(2S,3S,4R)-4-chloro-2-cyclohexyl-3-ethyl-1-tosylpiperidine, (2S,
3R)-3-((S)-1-chloropropyl)-2-cyclohexyl-1-tosylpyrrolidine/(2R,
(2R,3R,4S)-4-Chloro-3-ethyl-2-phenethyl-1-tosylpiperidine/
(2S,3S,4R)-4-chloro-3-ethyl-2-phenethyl-1-tosylpiperidine, (2S,
3R)-3-((S)-1-chloropropyl)-2-phenethyl-1-tosylpyrrolidine and (2R,
3S)-3-((R)-1-chloropropyl)-2-phenethyl-1-tosylpyrrolidine. Fo-
llowing the general procedure, (Z)-N-(hex-3-enyl)-4-methyl-
benzenesulfonamide (500 mg, 1.97 mmol), in the presence of
3-phenylpropanal (398 mg, 2.96 mmol), was consumed based on
analysis by TLC after 17 h of stirring at room temperature. The
work up afforded a pale yellow oil, which was purified by flash
column chromatography (90% hexane, 10% ethyl acetate) to give
the two title compounds.
3S)-3-((R)-1-chloropropyl)-2-cyclohexyl-1-tosylpyrrolidine
and
(2S,3S,E)-2-cyclohexyl-3-(prop-1-enyl)-1-tosylpyrrolidine/(2S,
3S,E)-2-cyclohexyl-3-(prop-1-enyl)-1-tosylpyrrolidine. Follow-
ing the general procedure, (Z)-N-(hex-3-enyl)-4-methyl-
benzenesulfonamide (500 mg, 1.97 mmol), in the presence
of cyclohexanecarbaldehyde (332 mg, 2.96 mmol), was consumed
based on analysis by TLC after 72 h of stirring at room
temperature. The work up afforded a yellow oil, which was
purified by flash column chromatography (90% hexane, 10% ethyl
acetate) to give the three title compounds.
(2R,3R,4S)-4-Chloro-3-ethyl-2-phenethyl-1-tosylpiperidine/
(2S,3S,4R)-4-chloro-3-ethyl-2-phenethyl-1-tosylpiperidine
28b
(2R,3R,4S)-4-Chloro-2-cyclohexyl-3-ethyl-1-tosylpiperidine/
(Table 2 En◦try 2). 328 mg (0.81 mmol, 41%) as a white solid.
M.p. 95–97 C; nmax(neat)/cm-1 3032, 1941, 1598; dH (300 MHz;
CDCl3) 7.58 (2H, d, J 8.3, H-C10), 7.29-7.11 (5H, m, Ar–H),
7.04 (2H, d, J 8.3, H-C11), 4.35-4.25 (1H, m, H-C4), 4.11-4.04
(1H, m, H-C2), 3.81-3.70 (1H, m, H-C6), 2.99-2.85 (1H, m,
H-C6), 2.64-2.39 (2H, m, H-C8), 2.37 (3H, s, H-C13), 1.88-1.73
(2H, m, H-C5), 1.73-1.62 (1H, m, H-C3), 1.73-1.50 (2H, m,
H-C7), 1.30-1.11 (1H, m, H-C14), 0.84 (3H, t, J 7.3, H-C15); dC
(75.5 MHz; CDCl3) 143.2 (C12), 140.6 (ArC), 137.9 (C9), 129.6
(2S,3S,4R)-4-chloro-2-cyclohexyl-3-ethyl-1-tosylpiperidine
28c
(Table 2 Entry 3). 182 mg (0.47 mmol, 24%) as a white solid.
M.p. 151–153 ◦C (mixture); nmax(neat)/cm-1 3035, 2928, 1815
(mixture); dH (300 MHz; CDCl3) 7.68 (2H, d, J 8.3, H-C12), 7.27
(2H, d, J 8.3, H-C13), 4.37-4.28 (1H, m, H-C4), 3.84 (1H, d, J
10.5, H-C2), 3.76-3.65 (1H, m, H-C6), 2.99-2.85 (1H, m, H-C6),
2.42 (3H, s, H-C15), 1.94-1.84 (1H, m, H-C3), 1.85-1.51 (5H, m,
H-C7 and H-C8), 1.75-1.54 (2H, m, H-C5), 1.29-0.88 (6H, m,
H-C9 and H-C10), 1.09-0.82 (2H, m, H-C16), 0.97-0.92 (3H, m,
1076 | Org. Biomol. Chem., 2010, 8, 1064–1080
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H-C17); dC (75.5 MHz; CDCl3) 142.9 (C14), 138.4 (C11), 129.4
(C13), 126.9 (C12), 61.4 (C2), 58.5 (C4), 43.8 (C3), 41.1 (C6), 35.9
(C7), 31.0 (C8), 30.4 (C8), 28.3 (C5), 26.5 (C10), 26.4 (C9), 26.2
(C9), 21.5 (C15), 17.2 (C16), 12.2 (C17); m/z (CI) 384 (MH+,
100), 348 (78), 300 (22); Anal. calcd. for C20H30ClNO2S requires
C, 62.56; H, 7.88; N, 3.65%. Found: C, 62.66; H, 8.01; N, 3.69%.
M.p. 56–57 ◦C; nmax(neat)/cm-1 2925, 1712, 1461; dH (300 MHz;
CDCl3) 7.69 (2H, d, J 8.4, H-C15), 7.27 (2H, d, J 8.4, H-C16),
3.98 (1H, td, J 9.7, 4.4, H-C2), 3.84-3.82 (1H, m, H-C4), 3.81-
3.75 (1H, m, H-C6), 2.99 (1H, td, J 15.1, 2.7, H-C6), 2.40 (3H, s,
H-C18), 2.03-1.93 (1H, m, H-C5), 1.83-1.69 (1H, m, H-C3), 1.67-
1.50 (1H, m, H-C5), 1.47-1.34 (2H, m, H-C7), 1.33-1.10 (10H, m,
H-C8 to H-C12), 1.01 (3H, d, J 6.9, H-C19), 0.86 (3H, t, J 6.8,
H-C13); dC (75.5 MHz; CDCl3) 143.1 (C17), 138.4 (C14), 129.7
(C16), 126.8 (C15), 60.6 (C4), 58.8 (C2), 42.1 (C3), 39.9 (C6), 35.9
(C5), 31.7 (C11), 29.2 (C9 and C10), 26.2 (C8), 24.4 (C7), 22.6
(C12), 21.4 (C18), 16.4 (C19), 14.0 (C13); m/z (CI) 386 (MH+,
100), 350 (42), 286 (40); HRMS (ES) Found [M+NH4]+ 403.2176,
C20H36ClN2O2S requires 403.2181.
(2S,3S,E)-2-Cyclohexyl-3-(prop-1-enyl)-1-tosylpyrrolidine/
(2S,3S,E)-2-cyclohexyl-3-(prop-1-enyl)-1-tosylpyrrolidine (only
partially separable from piperidine product) 30c (Table 2 Entry
3). dH (300 MHz; CDCl3) 7.73 (2H, d, J 8.2, H-C12), 7.31 (2H,
d, J 8.2, H-C13), 5.25-5.11 (1H, m, H-C16), 4.66-4.55 (1H, m, H-
C6), 3.40-3.30 (1H, m, H-C5), 3.31-3.25 (1H, m, H-C5), 3.27-3.21
(1H, m, H-C2), 2.62-2.51 (1H, m, H-C3), 2.43 (3H, s, H-C15),
1.84-1.68 (5H, m, H-C7 and H-C8), 1.69-1.56 (2H, m, H-C4), 1.41
(3H, dd, J 6.4, 1.3, H-C17), 1.29-1.03 (6H, m, H-C9 and H-C10);
dC (75.5 MHz; CDCl3) 143.2 (C14), 135.1 (C6), 133.0 (C11), 129.5
(C13), 127.7 (C12), 124.7 (C16), 70.7 (C2), 48.5 (C5), 43.4 (C3),
42.0 (C7), 31.7 (C8), 30.2 (C8), 26.6 (C4), 26.4 (C10), 26.3 (C10),
26.1 (C9), 21.5 (C15), 17.7 (C17); m/z (CI) 348 (MH+, 100), 264
(10), 194 (35).
(2R,3S,4S)-4-Chloro-3-methyl-2-phenethyl-1-tosylpiperidine/
(2S,3R,4R)-4-chloro-3-methyl-2-phenethyl-1-tosylpiperidine 31b
(Table 3 Entry 2). Following the general procedure, (E)-4-
methyl-N-(pent-3-enyl)benzenesulfonamide (150 mg, 0.62 mmol)
in the presence of 3-phenylpropanal (126 mg, 0.94 mmol), was
consumed based on analysis by TLC after 17 h of stirring at
room temperature. The work up afforded a yellow oil, which was
purified by flash column chromatography (90% hexane, 10% ethyl
acetate) to give the title compound (157 mg, 0.40 mmol, 64%) as a
white solid.
Crystal data. C20H29NO2S; M = 347.50; Monoclinic; a =
3
˚
˚
7.7257(2), b = 21.1223(7), c = 11.5315(2) A; volume 1869.09(9) A ;
space group P21/c; T = 120 K; Z 4; 20 906 reflections measured,
4239 unique [Rint = 0.0585]. The final R values R1 = 0.0678, wR2 =
0.1531 (observed) and R1 = 0.0950, wR2 = 0.1737 (all data).
M.p. 105–106 ◦C; nmax(KBr)/cm-1 3030, 2955, 1596; dH
(300 MHz; CDCl3) 7.83 (2H, d, J 8.1, H-C10), 7.39 (2H, d, J
8.1, H-C11), 7.36-7.18 (5H, m, Ar–H), 4.26-4.15 (1H, m, H-C2),
3.97 (1H, dd, J 15.0, 4.9, H-C6), 3.85 (1H, td, J 11.6, 4.5, H-C4),
3.25-3.11 (1H, m, H-C6), 2.79-2.66 (1H, m, H-C8), 2.65-2.52 (1H,
m, H-C8), 2.51 (3H, s, H-C13), 2.13-2.00 (1H, m, H-C5), 1.95-1.71
(1H, m, H-C3), 1.87-1.63 (2H, m, H-C7), 1.74-1.56 (1H, m, H-C5),
1.09 (3H, d, J 6.8, H-C14); dC (75.5 MHz; CDCl3) 143.4 (C12),
141.6 (ArC), 138.3 (C9), 129.9 (C11), 128.4 (ArC), 128.3 (ArC),
126.9 (C10), 125.9 (ArC), 60.4 (C4), 58.8 (C2), 41.9 (C3), 40.1 (C6),
35.7 (C5), 32.7 (C8), 26.9 (C7), 21.5 (C13), 16.4 (C14); m/z (CI)
392 (MH+, 40), 238 (20), 202 (74); Anal. calcd. for C21H26ClNO2S
requires C, 64.35; H, 7.08; N, 3.57%. Found: C, 64.15; H, 6.70;
N, 3.50%; HRMS (ES) found [M + H]+ 392.1446, C21H27ClNO2S
requires 392.1444.
(2S,3R)-3-((S)-1-Chloropropyl)-2-cyclohexyl-1-tosylpyrroli-
dine/(2R,3S)-3-((R)-1-chloropropyl)-2-cyclohexyl-1-tosylpyrro-
lidine 29c (Table 2 Entry 3). Further elution (90% hexane, 10%
ethyl acetate) provided the title compound (470 mg, 1.22 mmol,
62%) as a white solid. M.p. 102–103 ◦C; nmax(neat)/cm-1 3034,
2927, 1597; dH (300 MHz; CDCl3) 7.75 (2H, d, J 8.3, H-C12), 7.31
(2H, d, J 8.3, H-C13), 3.70 (1H, dd, J 4.8, 2.3, H-C2), 3.40-3.20
(2H, m, H-C5), 2.67 (1H, dt, J 9.2, 2.6, H-C6), 2.42 (3H, s, H-C15),
2.29-2.19 (1H, m, H-C3), 1.96-1.82 (1H, m, H-C4), 1.83-1.71 (4H,
m, H-C8), 1.71-1.60 (1H, m, H-C7), 1.54-1.37 (2H, m, H-C4 and
H-C16), 1.37-1.24 (1H, m, H-C16), 1.28-0.96 (6H, m, H-C9 and
H-C10), 0.81 (3H, t, J 7.2, H-C17); dC (75.5 MHz; CDCl3) 143.4
(C14), 135.0 (C11), 129.5 (C13), 127.6 (C12), 68.4 (C2), 67.1 (C6),
48.1 (C3), 48.0 (C5), 43.4 (C7), 29.7 (C8), 28.9 (C8), 28.2 (C16),
27.9 (C4), 26.4 (C10), 26.3 (C9), 26.3 (C9), 21.4 (C15), 10.7 (C17);
m/z (CI) 384 (MH+, 100), 348 (45), 300 (25); HRMS (ES) found
[M + NH4]+ 401.2021, C20H34ClN2O2S requires 401.2024.
Crystal data. C21H26ClNO2S; M = 391.94; Monoclinic; a =
3
˚
˚
24.2931(8), b = 11.7455(3), c = 14.3281(4) A; volume 3937.7(2) A ;
space group C12/c1; T = 120 K; Z 8; 22 425 reflections measured,
4514 unique [Rint = 0.0566]. The final R values R1 = 0.0494, wR2 =
0.1195 (observed) and R1 = 0.0830, wR2 = 0.1356 (all data).
Crystal data. C20H30ClNO2S; M = 383.96; Orthorhombic;
(2S,3R)-3-((S)-1-Chloroethyl)-2-cyclohexyl-1-tosylpyrrolidine/
(2R,3S)-3-((R)-1-chloroethyl)-2-cyclohexyl-1-tosylpyrrolidine 32c
(Table 3 Entry 3). Following the general procedure, (E)-4-
methyl-N-(pent-3-enyl)benzenesulfonamide (150 mg, 0.62 mmol)
in the presence of cyclohexanecarbaldehyde (105 mg, 0.94 mmol),
was consumed based on analysis by TLC after 240 h of stirring at
room temperature. The work up afforded a yellow oil, which was
purified by flash column chromatography (90% hexane, 10% ethyl
acetate) to give the title compound (162 mg, 0.44 mmol, 70%) as a
white solid.
˚
a = 13.0538(3), b = 15.5288(3), c = 19.1088(4) A; volume
3
˚
3873.54(14) A ; space group Pbca; T = 120 K; Z 8, 31 418
reflections measured, 4422 unique [Rint = 0.0516]. The final R
values R1 = 0.0406, wR2 = 0.1017 (observed) and R1 = 0.0550,
wR2 = 0.1096 (all data).
(2R,3S,4S)-4-Chloro-2-heptyl-3-methyl-1-tosylpiperidine/(2S,
3R,4R)-4-chloro-2-heptyl-3-methyl-1-tosylpiperidine 31a (Table 3
Entry 1). Following the general procedure, (E)-4-methyl-N-
(pent-3-enyl)benzenesulfonamide (150 mg, 0.62 mmol)), in the
presence of octanal (120 mg, 0.94 mmol), was consumed based
on analysis by TLC after 17 h of stirring at room temperature. The
work up afforded a yellow oil, which was purified by flash column
chromatography (90% hexane, 10% ethyl acetate) to give the title
compound (159 mg, 0.41 mmol, 66%) as a white solid.
M.p. 116–118 ◦C; nmax(neat)/cm-1 2927, 1669, 1599; dH
(300 MHz; CDCl3) 7.73 (2H, d, J 8.4, H-C12), 7.31 (2H, d, J
8.4, H-C13), 3.45-3.41 (1H, m, H-C2), 3.38-3.28 (3H, m, H-C6
and H-C5), 2.43 (3H, s, H-C15), 2.23-2.14 (1H, m, H-C3), 1.91-
1.63 (7H, m, H-C4, H-C7 and H-C8), 1.32 (3H, d, J 6.6, H-C16),
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1.28-0.81 (6H, m, H-C9 and H-C10); dC (75.5 MHz; CDCl3) 143.5
(C14), 134.9 (C11), 129.5 (C13), 127.7 (C12), 67.2 (C2), 59.4 (C6),
49.1 (C3), 48.1 (C5), 43.3 (C7), 30.1 (C8), 28.0 (C8), 27.3 (C4), 26.5
(C10), 26.3 (C9), 26.2 (C9), 23.9 (C16), 21.5 (C15); m/z (CI) 370
(MH+, 100), 334 (55), 286 (62); HRMS (ES) found [M + NH4]+
387.1871, C19H32ClN2O2S requires 387.1868.
370 (MH+, 100), 264 (18), 216 (35); HRMS (ES) found [M + H]+
(mixture) 370.1837, C22H28NO2S requires 370.1835.
( )-2-Phenethyl-3-(propan-2-ylidene)-1-tosylpyrrolidine (mi-
nor regioisomer) 37a. dH (300 MHz; CDCl3) 7.69-7.61 (2H, m,
H-C10), 7.30-7.24 (2H, m, H-C11), 7.30-7.24 (5H, m, Ar–H), 4.59-
4.56 (1H, m, H-C14), 4.41-4.39 (1H, m, H-C14), 3.51-3.41 (1H,
m, H-C2), 3.54-3.38 (2H, m, H-C5), 2.83-2.65 (2H, m, H-C8),
2.66-2.50 (1H, m, H-C3), 2.40 (3H, s, H-C13), 2.28-2.10 (1H, m,
H-C4), 2.09-1.94 (1H, m, H-C4), 1.87-1.70 (2H, m, H-C7), 1.51
(3H, s, H-C15); dC (75.5 MHz; CDCl3) 143.9 (C6), 143.3 (C12),
141.7 (ArC), 134.9 (C9), 129.5 (C11), 128.5 (ArC), 128.2 (ArC),
127.5 (C10), 125.7 (ArC), 111.9 (C14), 62.3 (C2), 51.7 (C3), 46.8
(C5), 31.4 (C8), 29.7 (C7), 28.2 (C4), 21.4 (C13), 20.9 (C15); m/z
(CI) 370 (MH+, 100), 264 (15), 216 (40).
Crystal data. C19H28ClNO2S; M = 369.93; Orthorhombic; a =
3
˚
˚
15.4076(3), b = 12.9924(4), c = 9.3800(3) A; volume 1877.70(9) A ;
space group Pna21; T = 120 K; Z 4; 10 624 reflections measured,
4506 unique [Rint = 0.0506]. The final R values R1 = 0.0699, wR2 =
0.1726 (observed) and R1 = 0.0743, wR2 = 0.1761 (all data). Flack
parameter 0.40(12).
(2S,3S,4S)-Ethyl-4-chloro-3-methyl-1-tosylpiperidine-2-carb-
oxylate/(2R,3R,4R)-ethyl-4-chloro-3-methyl-1-tosylpiperidine-2-
carboxylate 31d (Table 3 Entry 4). Following the general proce-
dure, (E)-4-methyl-N-(pent-3-enyl)benzenesulfonamide (150 mg,
0.62 mmol), in the presence of a pre-heated 33% solution of ethyl 2-
oxoacetate in toluene (287 mg, 0.94 mmol, 1.50 eq.), was consumed
based on analysis by TLC after 1 h of stirring at room temperature.
The work up afforded a yellow oil, which was purified by flash
column chromatography (90% hexane, 10% ethyl acetate) to give
the title compound (47 mg, 0.13 mmol, 21%) as a pale yellow oil.
(2S,3S)-2-Heptyl-3-(prop-1-en-2-yl)-1-tosylpyrrolidine/(2R,
3R)-2-Heptyl-3-(prop-1-en-2-yl)-1-tosylpyrrolidine and ( )-2-
heptyl-3-(propan-2-ylidene)-1-tosylpyrrolidine (Table 5 Entry 2).
Following the general procedure, 4-methyl-N-(4-methylpent-3-
enyl)benzenesulfonamide (100 mg, 0.39 mmol), in the presence
of octanal (76 mg, 0.59 mmol), was consumed based on analysis
by TLC after 6 h of stirring at room temperature. The work
up afforded a yellow oil, which was purified by flash column
chromatography (90% hexane, 10% ethyl acetate) to give the
two title compounds as a partially separable mixture (85 mg,
0.23 mmol, 60%) as a colourless oil.
n
max(neat)/cm-1 2980, 1733, 1598; dH (300 MHz; CDCl3) 7.62
(2H, d, J 8.4, H-C8), 7.27 (2H, d, J 8.4, H-C9), 4.59 (1H, d, J 5.8,
H-C2), 4.01 (1H, td, J 11.6, 4.4, H-C4), 3.93-3.81 (1H, m, H-C6),
3.81-3.66 (2H, m, H-C13), 3.49 (1H, td, J 12.8, 2.8, H-C6), 2.41
(3H, s, H-C10), 2.26 (1H, tdd, J 9.5, 5.1, 2.8, H-C5), 2.14-2.01 (1H,
m, H-C3), 2.01-1.85 (1H, m, H-C5), 1.14 (3H, t, J 7.2, H-C14),
1.08 (3H, d, J 6.9, H-C15); dC (75.5 MHz; CDCl3) 168.9 (C12),
143.7 (C10), 135.6 (C7), 129.5 (C9), 127.1 (C8), 60.8 (C13), 59.6
(C2), 59.2 (C4), 42.1 (C6), 41.0 (C3), 36.0 (C5), 21.5 (C11), 15.2
(C15), 13.9 (C14); m/z (CI) 360 (MH+, 100), 286 (65), 206 (87);
HRMS (ES) found [M + H]+ 360.1029, C16H23ClNO4S requires
360.1031.
(2S,3S)-2-Heptyl-3-(prop-1-en-2-yl)-1-tosylpyrrolidine/(2R,
3R)-2-heptyl-3-(prop-1-en-2-yl)-1-tosylpyrrolidine (major regio-
isomer) 38b. nmax(neat)/cm-1 2926, 1735, 1645, 1598 (mixture);
dH (300 MHz; CDCl3) 7.72 (2H, d, J 8.3, H-C15), 7.29 (2H, d, J
8.3, H-C16), 4.39-4.33 (1H, m, H-C2), 3.52-3.37 (2H, m, H-C5),
2.42 (3H, s, H-C18), 1.86-1.70 (2H, m, H-C4), 1.70-1.57 (2H, m,
H-C7), 1.43 (3H, s, H-C20), 1.39 (3H, s, H-C19), 1.37-1.17 (10H,
m, H-C8 to H-C12), 0.91-0.84 (3H, m, H-C13); dC (75.5 MHz;
CDCl3) 143.0 (C17), 135.5 (C14), 132.5 (C3), 129.2 (C16), 127.4
(C15), 123.3 (C6), 62.3 (C2), 46.6 (C5), 34.7 (C4), 31.8 (C11),
29.6 (C7), 29.4 (C9 and C10), 25.4 (C8), 22.6 (C12), 21.5 (C18),
21.0 (C20), 20.2 (C19), 14.1 (C13); m/z (CI) 364 (MH+, 100), 264
(40), 210 (38); HRMS (ES) found [M + NH4]+ (mixture) 381.2569,
C21H37N2O2S requires 381.2570.
(2S,3S)-2-Phenethyl-3-(prop-1-en-2-yl)-1-tosylpyrrolidine/
(2R,3R)-2-Phenethyl-3-(prop-1-en-2-yl)-1-tosylpyrrolidine and ( )-
2-phenethyl-3-(propan-2-ylidene)-1-tosylpyrrolidine (Table 5 Entry
1). Following the general procedure, 4-methyl-N-(4-methylpent-
3-enyl)benzenesulfonamide (100 mg, 0.39 mmol), in the presence
of 3-phenylpropanal (80 mg, 0.59 mmol), was consumed based on
analysis by TLC after 6 h of stirring at room temperature. The
work up afforded a yellow oil, which was purified by flash column
chromatography (90% hexane, 10% ethyl acetate) to give the two
regioisomer title compounds as only a partially separable mixture
(108 mg, 0.29 mmol, 75%) as a colourless oil.
( )-2-Heptyl-3-(propan-2-ylidene)-1-tosylpyrrolidine (minor
regioisomer) 37b. dH (300 MHz; CDCl3) 7.65 (2H, d, J 8.4,
H-C15), 7.24 (2H, d, J 8.4, H-C16), 4.56-4.52 (1H, m, H-C19),
4.43-4.37 (1H, m, H-C19), 3.52-3.39 (1H, m, H-C2), 3.40-3.25
(2H, m, H-C5), 2.49 (1H, dd, J 13.2, 6.8, H-C3), 2.40 (3H, s,
H-C18), 2.27-2.12 (1H, m, H-C4), 2.08-1.94 (1H, m, H-C4),
1.55 (3H, s, H-C20), 1.54-1.43 (2H, m, H-C7), 1.37-1.17 (10H,
m, H-C8 to H-C12), 0.91-0.84 (3H, m, H-C13); dC (75.5 MHz;
CDCl3) 144.2 (C6), 143.2 (C17), 135.4 (C14), 129.5 (C16), 127.5
(C15), 111.4 (C19), 63.2 (C2), 51.2 (C3), 48.5 (C5), 35.8 (C4), 31.8
(C11), 29.7 (C7), 29.3 (C9), 28.2 (C10), 25.1 (C8), 22.6 (C12), 21.5
(C18), 21.0 (C20), 14.1 (C13); m/z (CI) 364 (MH+, 100), 264 (30),
210 (44).
(2S,3S)-2-Phenethyl-3-(prop-1-en-2-yl)-1-tosylpyrrolidine/
(2R,3R)-2-phenethyl-3-(prop-1-en-2-yl)-1-tosylpyrrolidine (ma-
jor regioisomer) 38a. nmax(neat)/cm-1 3026, 2925, 1644, 1599
(mixture); dH (300 MHz; CDCl3) 7.69-7.61 (2H, m, H-C10), 7.30-
7.24 (2H, m, H-C11), 7.27-7.13 (5H, m, Ar–H), 4.46-4.40 (1H, m,
H-C2), 3.47-3.32 (2H, m, H-C5), 2.71-2.58 (2H, m, H-C8), 2.40
(3H, s, H-C13), 2.28-2.10 (1H, m, H-C4), 2.09-1.94 (1H, m, H-
C4), 1.95-1.81 (2H, m, H-C7), 1.39 (3H, s, H-C15), 1.37 (3H, s,
H-C14); dC (75.5 MHz; CDCl3) 143.2 (C12), 142.1 (ArC), 135.2
(C9), 132.2 (C3), 129.3 (C11), 128.4 (ArC), 128.2 (ArC), 127.4
(C10), 125.6 (ArC), 123.8 (C6), 62.0 (C2), 48.7 (C5), 37.2 (C4),
36.4 (C7), 31.7 (C8), 21.4 (C13), 21.0 (C15), 19.9 (C15); m/z (CI)
( )-4-Methyl-2-phenethyl-1-tosyl-1,2,3,6-tetrahydropyridine
and ( )-4-methyl-2-phenethyl-1-tosyl-1,2,5,6-tetrahydropyridine
(Table 4 Entry 1). Following the general procedure, 4-methyl-N-
(3-methylbut-3-enyl)benzenesulfonamide (250 mg, 1.04 mmol),
in the presence of 3-phenylpropanal (210 mg, 1.56 mmol), was
1078 | Org. Biomol. Chem., 2010, 8, 1064–1080
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consumed based on analysis by TLC after 2 h of stirring at
room temperature. The work up afforded a yellow oil, which was
purified by flash column chromatography (90% hexane, 10% ethyl
acetate) to give the title compounds as an inseparable mixture
(331 mg, 0.93 mmol, 90%) as a pale yellow oil.
H-C6), 2.40 (3H, s, H-C18), 2.16-1.98 (1H, m, H-C3), 1.58-1.47
(1H, m, H-C3), 1.49 (3H, s, H-C19), 1.55-1.41 (2H, m, H-C7),
1.38-1.11 (10H, m, H-C8 to H-C12), 0.91-0.84 (3H, m, H-C13);
dC (75.5 MHz; CDCl3) 142.8 (C17), 138.0 (C14), 131.1 (C4), 129.4
(C16), 126.9 (C15), 116.0 (C5), 50.9 (C2), 40.3 (C6), 35.2 (C3),
31.8 (C11), 31.2 (C7), 29.3 (C9), 29.2 (C10), 26.4 (C8), 23.5 (C19),
22.7 (C12), 21.5 (C18), 14.1 (C13).
( )-4-Methyl-2-phenethyl-1-tosyl-1,2,3,6-tetrahydropyridine.
n
max(neat)/cm-1 3026, 2929, 1736, 1598 (mixture); dH (300 MHz;
CDCl3) 7.82-7.79 (2H, m, H-C10), 7.44-7.39 (2H, m, H-C11),
7.39-7.23 (5H, m, Ar–H), 5.48-5.42 (1H, m, H-C3), 4.50-4.37
(1H, m, H-C2), 3.98 (1H, dd, J 14.6, 6.1, H-C6), 3.28 (1H, ddd, J
14.6, 11.8, 4.8, H-C6), 3.07 (1H, t, J 7.5, H-C8), 2.95-2.86 (1H, m,
H-C8), 2.51 (3H, s, H-C13), 2.00-1.89 (2H, m, H-C7), 1.87-1.72
(2H, m, H-C5), 1.64 (3H, s, H-C14); dC (75.5 MHz; CDCl3) 142.9
(C12), 141.9 (ArC), 138.4 (C9), 132.7 (C4), 129.4 (C11), 128.3
(ArC), 128.3 (ArC), 127.0 (C10), 125.7 (ArC), 121.5 (C3), 53.6
(C2), 40.4 (C6), 36.8 (C5), 32.8 (C8), 28.1 (C7), 23.2 (C14), 21.5
(C13); m/z (CI) (mixture) 356 (MH+, 100), 250 (25), 202 (37);
HRMS (ES) found [M + H]+ (mixture) 356.1682, C21H26NO2S
requires 356.1679.
Acknowledgements
We are grateful to GlaxoSmithKline (CASE award to RJP) and
the EPSRC (Studentship to SJJG and DTA award to RJP) for
funding and the EPSRC National Mass Spectrometry Service
(Swansea) for some mass spectral data. We are also grateful to
the EPSRC National Crystallographic Service (Southampton) for
X-ray crystallography and also Dr Stephen Simpson for help with
structure determination. All X-ray structures have been deposited
in the Cambridge Crystallographic Data Centre (CCDC).
( )-4-Methyl-2-phenethyl-1-tosyl-1,2,5,6-tetrahydropyridine.
dH (300 MHz; CDCl3) 7.79-7.75 (2H, m, H-C10), 7.38-7.34 (2H,
m, H-C11), 7.39-7.23 (5H, m, Ar–H), 5.40-5.35 (1H, m, H-C5),
4.31-4.23 (1H, m, H-C2), 4.26-4.18 (1H, m, H-C6), 3.77-3.62
(1H, m, H-C6), 2.88-2.70 (2H, m, H-C8), 2.51 (3H, s, H-C13),
2.24-2.12 (1H, m, H-C3), 1.87-1.71 (2H, m, H-C7), 1.77-1.65
(1H, m, H-C3), 1.60 (3H, s, H-C14); dC (75.5 MHz; CDCl3) 142.9
(C12), 141.7 (ArC), 137.9 (C9), 131.0 (C4), 129.5 (C11), 128.4
(ArC), 128.3 (ArC), 126.9 (C10), 125.9 (ArC), 116.0 (C5), 50.7
(C2), 45.3 (C6), 38.5 (C3), 32.7 (C8), 27.5 (C7), 23.4 (C14), 21.5
(C13).
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the presence of octanal (200 mg, 1.56 mmol), was consumed based
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( )-2-Heptyl-4-methyl-1-tosyl-1,2,3,6-tetrahydropyridine (ma-
jor regioisomer). nmax(neat)/cm-1 2927, 1598 (mixture); dH
(300 MHz; CDCl3) 7.73-7.68 (2H, m, H-C15), 7.27-7.23 (2H, m,
H-C16), 5.36-5.30 (1H, m, H-C3), 4.31-4.16 (1H, m, H-C2), 3.82
(1H, dd, J 14.6, 6.2, H-C6), 3.11 (1H, ddd, J 14.6, 11.9, 4.7, H-
C6), 2.40 (3H, s, H-C18), 1.77-1.58 (1H, m, H-C5), 1.58-1.44 (1H,
m, H-C5), 1.55 (3H, s, H-C19), 1.46-1.34 (2H, m, H-C7), 1.38-
1.11 (10H, m, H-C8 to H-C12), 0.91-0.84 (3H, m, H-C13); dC
(75.5 MHz; CDCl3) 142.8 (C17), 138.6 (C14), 132.1 (C4), 129.3
(C16), 127.0 (C15), 121.9 (C3), 53.8 (C2), 38.4 (C6), 32.7 (C5),
31.8 (C11), 31.6 (C7), 29.5 (C9), 29.2 (C10), 26.2 (C8), 23.2 (C19),
22.6 (C12), 21.5 (C18), 14.1 (C13); m/z (CI) (mixture) 350 (MH+,
100), 250 (12), 196 (40); HRMS (ES) found [M + H]+ (mixture)
350.2148, C20H32NO2S requires 350.2149.
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C15), 7.23-7.19 (2H, m, H-C16), 5.29-5.22 (1H, m, H-C5), 4.14-
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