Stereoselective synthesis of 3,4-disubstituted and 3,4,5-trisubstituted piperidines by Lewis acid-catalysed ene cyclisation of 4-aza-1,7-dienes

Article abstract of DOI:10.1039/b708139a

The thermal or Lewis acid-catalysed ene cyclisation of a variety of 4-aza-1,7-dienes afforded 3,4-disubstituted or 3,4,5-trisubstituted piperidines. Activation of the enophile with a single ester facilitated a thermal ene cyclisation, although the reaction was not amenable to Lewis acid catalysis. With other activating groups on the enophile it was found that Lewis acid catalysis was facile, although there was a fine balance between the desired ene cyclisation and the competing hetero-Diels-Alder reaction, with the product distribution being influenced by the activating group on the enophile, the nature of the ene component, and the Lewis acid used. Activation of the enophile with an oxazolidinone function facilitated Lewis acid-catalysed cyclisation to afford mixtures of ene and hetero-Diels-Alder products. Activating the enophile with two ester groups gave a substrate that underwent a very facile ene cyclisation catalysed by MeAlCl₂ to give the corresponding trans 3,4-disubstituted piperidines with diastereomeric ratios of >200: 1. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b708139a

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Stereoselective synthesis of 3,4-disubstituted and 3,4,5-trisubstituted
piperidines by Lewis acid-catalysed ene cyclisation of 4-aza-1,7-dienes†
Stephen M. Walker, Jodi T. Williams, Alexander G. Russell, Benson M. Kariuki and John S. Snaith*
Received 5th June 2007, Accepted 19th July 2007
First published as an Advance Article on the web 3rd August 2007
DOI: 10.1039/b708139a
The thermal or Lewis acid-catalysed ene cyclisation of a variety of 4-aza-1,7-dienes afforded
3,4-disubstituted or 3,4,5-trisubstituted piperidines. Activation of the enophile with a single ester
facilitated a thermal ene cyclisation, although the reaction was not amenable to Lewis acid catalysis.
With other activating groups on the enophile it was found that Lewis acid catalysis was facile, although
there was a fine balance between the desired ene cyclisation and the competing hetero-Diels–Alder
reaction, with the product distribution being influenced by the activating group on the enophile, the
nature of the ene component, and the Lewis acid used. Activation of the enophile with an
oxazolidinone function facilitated Lewis acid-catalysed cyclisation to afford mixtures of ene and
hetero-Diels–Alder products. Activating the enophile with two ester groups gave a substrate that
underwent a very facile ene cyclisation catalysed by MeAlCl2 to give the corresponding trans
3,4-disubstituted piperidines with diastereomeric ratios of >200 : 1.
Introduction
Results and discussion
Piperidines occupy a central position in the pharmaceutical and
agrochemical sectors, a fact that can be attributed to their often
potent biological properties.1 This role is mirrored in Nature, with
the piperidine ring system occurring as a key structural element in
a vast array of natural products.2 Numerous stereoselective routes
to variously substituted piperidines have been developed,3 but the
demand for piperidines incorporating a range of functionality and
substitution patterns continues to drive the development of new
routes to these compounds.4
Continuing our interest in the synthesis of N-heterocycles by
pericyclic processes,5,6 we wished to explore the possibility of
synthesising 3,4-disubstituted piperidines via the ene cyclisation
of 4-aza-1,7-dienes.7 The ene reaction is a valuable tool in ring
synthesis, generating two contiguous stereocentres with an often
high degree of stereocontrol.8 In particular, Lewis acid catalysis
has been shown to lead to very impressive levels of stereoselectivity
in the formation of 6-membered rings.9–11 Despite this, there have
been few piperidine syntheses in which the ring is formed by
ene chemistry.12 Oppolzer studied the thermal ene reaction of
simple 4-aza-1,7-dienes to afford 3,4-disubstituted piperidines.13
Cyclisation was achieved on prolonged heating at 290 ◦C, to
afford a 26% yield of the two stereoisomeric products in an
undetermined ratio. Takacs and co-workers have reported the
transition metal-catalysed cross-coupling of a diene with an allylic
ether or another diene to afford piperidines.14 Formally, these
processes can be regarded as [4 + 4]- or [4 + 6]-ene reactions,
although mechanistically they are far removed from the classical
ene reaction.
Since ene reactions proceed most readily when the enophile is
electron-deficient, we envisaged that attachment of an electron-
withdrawing group such as an ester to the enophile would activate
the system towards thermal cyclisation. Moreover, we reasoned
that the Lewis basicity of the ester would open up the possibility
of Lewis acid catalysis of the reaction.
Thus, our first cyclisation precursor was 2, in which the enophile
is activated with an ester. This was readily prepared by a Wittig
reaction between the previously reported15 aldehyde 1 and methyl
(triphenylphosphoranylidene)acetate, affording ester 2, exclusively
as the E diastereomer, in 65% yield after chromatography
(Scheme 1). Surprisingly, the energy barrier for the uncatalysed
ene reaction of 2 was high, with ◦cyclisation occurring on heating
in refluxing diphenyl ether (259 C) for 7 hours. Removal of the
solvent by distillation, followed by chromatography, afforded the
piperidine products 3 and 4 in a combined yield of 62% as an
inseparable mixture, with a trans : cis ratio determined as 3 : 2 by
integration of the 1H NMR spectrum.‡
=
Scheme 1 Reagents and conditions: (i) Ph3P CHCO2Me, CH2Cl2, 65%;
(ii) Ph2O, reflux, 62%.
We were hopeful that Lewis acid catalysis would decrease
the activation barrier substantially and hence allow us to effect
cyclisation at a lower temperature. With this goal in mind, we
School of Chemistry, The University of Birmingham, Edgbaston,
Birmingham, B15 2TT, UK. E-mail: j.s.snaith@bham.ac.uk
† Electronic supplementary information (ESI) available: Additional ex-
perimental procedures and ORTEP plots; crystal structure data. See DOI:
10.1039/b708139a
‡ The major product was confirmed as the trans diastereomer by compar-
ison of the 1H NMR spectrum with that of 28 (vide infra).
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 2925–2931 | 2925
©

View Article Online
Table 1 Cyclisation of 7 with a variety of Lewis acids
screened the Lewis acids FeCl3, ZnBr2, MeAlCl2 and Sc(OTf)3 for
their ability to catalyse the cyclisation, at temperatures ranging
from −78 ◦C to 180 ◦C. The results were disappointing, and
in most cases unreacted starting material was recovered. In the
reactions employing ferric chloride and scandium triflate at room
temperature, cleavage of the ene moiety was observed, yielding 5.
Presumably this results from coordination of the Lewis acid to the
sulfonamide, facilitating the dissociation of an allylic cation which
then loses a proton to afford 5 and 2-methylbutadiene (Fig. 1).
Lewis acida
8 : 9 : 10b
Trans : cis ratio of ene product
Me2AlCl
MeAlCl2
AlCl3
FeCl3
Sc(OTf)3
ZnBr2
42 : 36 : 22
59 : 27 : 14
65 : 20 : 15
32 : 11 : 57
50 : 11 : 39
28 : 5 : 67
49 : 6 : 45
1.2 : 1
2.2 : 1
3.3 : 1
2.9 : 1
4.5 : 1
5.6 : 1
8.2 : 1
TiCl4
a All reactions were performed with 1 equivalent of Lewis acid at room
temperature in dichloromethane. b Ratios determined by integration of 1H
NMR spectra of crude cyclisation products.
Fig. 1 Cleavage of 2 on treatment with Lewis acids.
a chair-like transition state in which both the ene and enophile
adopt pseudo-equatorial positions.
This result suggested that we needed to modify our cyclisation
precursor to enhance coordination of the Lewis acid to the
enophile. Accordingly, we designed the cyclisation precursor 7,
in which the enophile is activated by an oxazolidinone group; it
was expected that the two carbonyl groups would be able to chelate
a Lewis acid, overcoming the Lewis basicity of the sulfonamide.
Oxazolidinone 7 was prepared in 76% yield as a 25 : 1 E : Z
mixture by a Wittig reaction between 1 and the known16 ylide 6
(Scheme 2).
Although crude yields were high, in all cases bicyclic lactone
10 was present as a side product, and with some Lewis acids the
lactone was the major product. We propose that this compound
arises from hydrolysis of 11, implying that 7 was undergoing a
competing hetero-Diels–Alder reaction.16 X-Ray crystallography
confirmed that lactone 10 was obtained as the trans stereoisomer
(Fig. S2†), a stereochemical outcome that is in agreement with lit-
erature precedent for closely related systems11 and consistent with
the geometrical constraints inherent in such an intramolecular
Diels–Alder reaction.
Competition between ene and Diels–Alder pathways has been
observed by others, with the balance between the two processes
being dependent on the choice of Lewis acid, the reaction
temperature and the activating group on the enophile.10,11,16,17
It has previously been shown in intermolecular ene reactions18
and in intramolecular ene reactions leading to 5-membered rings13
and 6-membered rings19 that the configuration of the double bond
of the ene component influences the stereochemical outcome of
the reaction, in agreement with the proposal that these reactions
proceed through largely concerted transition states. On this basis,
and assuming cyclisation through chair-like transition states, one
might expect E-crotyl compound 11 to exhibit a preference for the
trans piperidine 12, whereas Z-crotyl compound 13 would cyclise
to the cis piperidine 14 via a higher activation barrier (Fig. 2).
We hoped that this would allow us to tune the product outcome,
as well as affording piperidines with a synthetically versatile vinyl
substituent at the 4-position.
Scheme 2 Reagents and conditions: (i) CH2Cl2, 76%.
Pleasingly, a range of Lewis acids were found to catalyse the
cyclisation of 7 at room temperature, affording the two piperidines
8 and 9 as an inseparable mixture (Table 1), without competitive
cleavage of the ene moiety.
Diastereomeric ratios were generally moderate, with titanium
tetrachloride affording an 8.2 : 1 trans : cis ratio of piperidines 8
and 9 in the best case. It proved possible to grow single crystals
from chloroform, which allowed us to confirm the identity of
the major isomer 8 (Fig. S1†). Preferential formation of the trans
diastereomer may be explained by the reaction proceeding through
Fig. 2 Expected transition states for cyclisation of 11 and 13.
2926 | Org. Biomol. Chem., 2007, 5, 2925–2931 This journal is
The Royal Society of Chemistry 2007
©

View Article Online
To probe this effect we prepared the two cyclisation precursors
11 and 13 by Wittig reaction between the previously reported15
aldehydes 15 and 16, as 5 : 1 and 1 : 6 E : Z mixtures respectively,
and ylide 6 (Scheme 3). After chromatographic purification, 11
was obtained in 62% yield as a 3 : 1 E : Z mixture about the ene
double bond, while 13 was produced in 72% yield as a 1 : 7 E :
Z mixture; in both cases the a,b-unsaturated double bond was
E-configured.
ene product 14, with only a trace reacting through the Diels–Alder
pathway.
Transition state diagrams consistent with the observed products
are shown in Fig. 3. It would appear that in the case of the Z-crotyl
precursor 13, a steric clash between the methyl group and the Lewis
acid disfavours the transition state leading to 18, and hence 13 is
preferentially converted into 14. The steric clash is absent in the
transition state leading from E-crotyl precursor 11 to the IMDA
cycloadduct 17.
Fig. 3 Left: TS for IMDA of 11 leading to 17. Right: TS for IMDA of 13
leading to 18.
In an effort to provide a more highly activated enophile, while
retaining the ability to chelate the Lewis acid, we turned our
attention to diester 19. The simplest route to 19 appeared to be
via a Knoevenagel reaction between aldehyde 1 and a malonate
ester (Scheme 5). Surprisingly, all attempts to prepare 19 by
these means were unsuccessful. Under the standard conditions
employing dimethyl malonate in the presence of piperidine and
acetic acid, only trace amounts of the desired diester 19 were
produced, inseparable from a complex mixture of compounds.
Mass spectrometric evidence suggested side-products had resulted
from the addition of a second equivalent of malonate into the a,b-
unsaturated diester to give 20, as well as a molecule consistent with
21 and higher molecular weight species likely to have resulted from
base-mediated oligomerisation processes. The reportedly milder
conditions employing ammonium acetate and acetic acid were
similarly unsuccessful,20 as was switching to malononitrile as the
nucleophile.
Scheme 3 Reagents and conditions: (i) CH2Cl2, 62–72%.
Loss of a methyl group from the ene made the system much less
reactive, and reaction was only achieved on heating at 60 ◦C in
the presence of 1 equiv. of MeAlCl2. Under these conditions 11
gave a mixture of products from which it was possible to isolate
piperidines 12 and 14 as an inseparable 2 : 1 cis : trans mixture in
15% yield, and the lactones 17 and 18 as a 10 : 1 mixture in 13%
yield (Scheme 4).
Scheme 4 Reagents and conditions: (i) MeAlCl2, CH2Cl2, 60 ◦C.
The stereochemistry of 12 and 14 were assigned on the basis
of spectral similarities with related compounds prepared within
our research group, while a crystalline sample of the lactones
allowed us to secure the structure of the major epimer 17 by X-ray
diffraction (Fig. S3†); spectral similarities indicated that the minor
lactone stereoisomer was 18, differing in the configuration of the
carbon bearing the methyl group. Cyclisation of the Z-isomer 13
was low-yielding, with only around 10% of the material being
recovered after chromatography, although this low yield partly
reflected difficulties in removing uncharacterisable decomposition
products which necessitated repeated chromatography. The puri-
fied product mixture comprised piperidines 12 and 14 in a 4 : 1
cis : trans ratio, along with a trace of lactones 17 and 18 in an
undetermined ratio.
Clearly one must exercise caution in drawing any conclusions
from low-yielding reactions. However, assuming that the reactions
follow a concerted pathway, the stereochemistry of the major
Diels–Alder adduct 17 would suggest that this product is derived
from the E-crotyl precursor 11, with a smaller amount going on to
afford the trans ene product 12. The same analysis would suggest
that the Z-crotyl precursor 13 is chiefly transformed into the cis
Scheme 5 Reagents and conditions: (i) dimethyl malonate, piperidine–
acetic acid or ammonium acetate–acetic acid, CH2Cl2, 0 → 20 ◦C.
A Wittig approach to 19 leads back to aldehyde 1 and dimethyl
(triphenylphosphoranylidene)malonate, or the ylide derived from
phosphonium salt 24 and dimethyl ketomalonate. Since dimethyl
(triphenylphosphoranylidene)malonate has been reported to be
too stable to participate in Wittig reactions,21 the latter approach
was explored.
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 2925–2931 | 2927
©

View Article Online
◦
=
Scheme 6 Reagents and conditions: (i) PPh3, CBr4, CH2Cl2, 95%; (ii) PPh3, MeCN, reflux, 87%; (iii) NaHMDS, THF, −78 → 0 C, 2 h, then (EtO2C)2C O,
−78 → 20 ◦C.
Treatment of the previously reported15 alcohol 22 with CBr4 and
PPh3 to give the bromide 23, followed by reaction with PPh3 in
refluxing acetonitrile, gave phosphonium salt 24 in excellent yield
(Scheme 6). Generation of the ylide by deprotonation of 24 with
NaHMDS, followed by reaction with diethyl ketomalonate§ gave
the a,b-unsaturated ester 25 and also a side product identified as
alcohol 26. The reaction was capricious; in the best case, 25 was
isolated in 39% yield, accompanied by 20% of 26, resulting from
deprotonation of 25 in the c-position and reaction with another
Scheme 8 Reagents and conditions: (i) o-dichlorobenzene, reflux, 74%;
(ii) MeAlCl2, CH2Cl2, −78 ◦C, 72%.
molecule of diethyl ketomalonate. Often the yield of 25 was much
lower, with evidence of higher molecular weight products being
formed. Variation of the base and reaction conditions, including
inverse addition of the ylide to diethyl ketomalonate, did nothing
to make the reaction more reliable.
that the diastereomeric purity of both products was >200 : 1 in
favour of the trans stereoisomer. The stereochemical assignment
was confirmed by X-ray analysis of single crystals of the diethyl
ester product grown from petrol and ethyl acetate (Fig. 4).
It appeared that many of the problems arose from the highly
acidic c-protons in 25, and so we adopted an approach in
which the a,b-unsaturated system was revealed at a late stage,
under essentially neutral conditions (Scheme 7). Alkylation of
dimethyl malonate with bromide 23 proceeded in good yield, and
deprotonation by LDA with trapping of the resultant anion by
phenylselenyl chloride gave phenylselenide 27 in 94% yield after
chromatography. Purification of the phenylselenide allowed us to
remove traces of the unreacted saturated diester, which proved
inseparable from the final a,b-unsaturated product. Oxidation of
27 with hydrogen peroxide resulted in spontaneous elimination to
afford diester 19 in 73% yield.
Fig. 4 ORTEP plot of diethyl ester; ellipsoids drawn at 30% probability.
Scheme 7 Reagents and conditions: (i) (MeO2C)2CH2, NaHMDS, THF,
78%; (ii) LDA, THF, −78 → 20 ◦C, 30 min, then PhSeCl, THF,
−78 → 20 ◦C, 94%; (iii) H2O2, THF, 73%.
Since we had also isolated, albeit in low yield, the alcohol
26 which contained an a,b-unsaturated diester functionality, we
decided to attempt the Lewis acid-catalysed cyclisation of this
substrate (Scheme 9).
Cyclisation of 19 was achieved on heating in refluxing o-
dichlorobenzene (180 ◦C) for 7 h to afford an inseparable 5 : 1
mixture of 28 and 29 in 70% yield, with the thermodynamically
more favourable trans diastereomer predominating as expected
(Scheme 8). Moreover, we were delighted to find that, on◦ addition
of MeAlCl2, the diester 19 cyclised in CH2Cl2 at −78 C to give
essentially a single stereoisomeric piperidine, compound 28, in
72% yield after chromatography. In a similar fashion, 25 gave
the diethyl analogue of 28 in 67% yield. HPLC analysis revealed
◦
On treatment with two equivalents of MeAlCl2 at −78 C, 26
showed no reaction, but at room temperature, consumption of
the starting material was observed to be complete after 25 h.
Chromatographic purification afforded lactone 30 as the major
product in approximately 70% yield, inseparable from a trace
side product which mass spectrometry suggested was the alcohol
31. Single crystals of the major product 30 were grown from
petrol and ethyl acetate, and X-ray analysis confirmed the relative
stereochemistry of the substituents (Fig. S4†).
Encouraged by these results, we decided to attempt the cyclisa-
tion of the E- and Z-crotyl analogues of 19, compounds 34 and
§ Diethyl ketomalonate was used because dimethyl ketomalonate is not
commercially available.
2928 | Org. Biomol. Chem., 2007, 5, 2925–2931
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
Scheme 9 Reagents and conditions: (i) MeAlCl2, CH2Cl2.
Scheme 10 Reagents and conditions: (i) PPh3, CBr4, CH2Cl2, 97%; (ii) (MeO2C)2CH2, NaHMDS, THF, 63–71%; (iii) LDA, THF, −78 → 20 ◦C, 30 min,
then PhSeCl, THF, −78 → 20 ◦C, 83–90%; (iv) H2O2, THF, 77–80%; (v) MeAlCl2, CH2Cl2.
35. These were prepared in good yield from alcohols 32 and 33,
using the selenium route (Scheme 10).
zophenone ketyl. Toluene was distilled from sodium. CH2Cl2
and acetonitrile were distilled from CaH2. Anhydrous DMF was
purchased from Aldrich. Triethylamine was distilled from KOH
and stored over KOH pellets. Diisopropylamine was distilled
Both substrates were sluggish to react on treatment with
MeAlCl2, with starting material recovered after 24 h at −78 ◦C. In
both cases complete consumption of the starting material occurred
on warming to ambient temperature. Disappointingly, Z-substrate
35 (5 : 1 Z : E mixture) afforded a complex mixture of products
from which a small amount of the trans piperidine 36 could be
isolated by semi-preparative HPLC. Much more pleasingly, the
E-substrate 34 (5 : 1 E : Z mixture) gave a 20 : 1 mixture of trans
and cis piperidines 36 and 37 in 60% yield. The amino alkene
38 was isolated in 28% yield, accounting for almost all of the
remaining starting material.
˚
over NaOH and stored over 4 A molecular sieves. Solutions
of n-BuLi were titrated against N-pivaloyl-o-toluidine following
Suffert’s method.22 Flash column chromatography was performed
using laboratory-grade solvents on Fluorochem 60A (43–63 lm
mesh) silica gel. Thin layer chromatography was carried out using
Merck 60 F254 0.25 mm precoated glass-backed silica gel plates and
visualised using UV light (254 nm) and basic KMnO4 solution. All
Rf values refer to the eluent used in purification unless otherwise
stated.
In conclusion, we have shown that a number of acyclic
precursors will undergo ene cyclisation on heating or under Lewis
acid catalysis, to afford 3,4-disubstituted or 3,4,5-trisubstituted
piperidines. The balance between the desired ene cyclisation and
the competing hetero-Diels–Alder reaction is a delicate one, and
the product distribution is influenced by the activating group on
the enophile, the nature of the ene component, and the Lewis
acid used. Oxazolidinones 7, 11 and 13 underwent Lewis acid-
catalysed cyclisation to afford mixtures of ene and hetero-Diels–
Alder products, while diesters 19 and 25 underwent a highly
diastereoselective ene cyclisation catalysed by MeAlCl2 at −78 ◦C
to afford almost exclusively the corresponding trans piperidines
in good yield (diastereomeric ratio >200 : 1). The E-crotyl
diester 34 with the slightly less nucleophilic ene moiety gave
the corresponding trans piperidine in 60% yield with a 20 : 1
diastereomeric ratio, along with products derived from Lewis
acid-catalysed decomposition. This stereoselective approach to
piperidines should find application in the synthesis of more
complex targets.
Melting points were measured in open glass capillaries using a
Stuart Scientific SMP1 apparatus and are uncorrected.
Elemental analyses were recorded on a Carlo Erba EA1110
simultaneous CHNS analyser.
Infrared spectra were recorded between NaCl plates as neat
films, as CHCl3 films or as KBr discs on a Perkin Elmer 1600
series FTIR or a Perkin Elmer FT-IR Paragon 1000 spectrometer.
1H, 13C, 19F and 31P NMR spectra (300, 75, 282 and 121 MHz
respectively) were recorded on Bruker AC-300 and Bruker AV-
300 spectrometers. HSQC, HMBC, COSY 90, 1H and 13C NMR
spectra were recorded on a Bruker DRX500 (500 MHz and
1
125 MHz for H and 13C) or a Bruker AMX400 spectrometer
(400 MHz and 100 MHz for 1H and 13C). 1H and 13C NMR spectra
were recorded using deuterated solvent as the lock and were
referenced downfield from tetramethylsilane. 13C spectra NMR
were recorded using the PENDANT pulse sequence. J values are
reported in Hz. The multiplicities of the spectroscopic signals are
represented in the following manner; s = singlet, d = doublet, t =
triplet, q = quartet, p = pentet, m = multiplet, br s = broad singlet
and env = overlapping signals.
Chemical ionisation (CI) and electron impact (EI) mass spectra
were recorded on a VG Zabspec mass spectrometer or a VG
Prospec mass spectrometer. Chemical ionisation (CI) methods
used ammonia as the carrier gas. Liquid secondary ion mass
spectra (LSIMS) were recorded using a VG Zabspec instrument.
A Micromass LCT mass spectrometer was used for both low-
resolution electrospray time of flight (ES-TOF) mass spectrometry
Experimental
General chemical procedures
All chemicals and reagents were obtained from commercial
sources and used without further purification unless otherwise
stated. THF and diethyl ether were distilled from sodium ben-
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 2925–2931 | 2929
©

View Article Online
(using a methanol mobile phase) and accurate mass measurement
(using a lock mass incorporated into the mobile phase).
organic extracts washed with brine (100 mL), dried over MgSO4
and concentrated in vacuo before purification by flash column
chromatography (silica; eluent 3 : 1 hexane–ethyl acetate) afforded
the title compound as a colourless oil (1.83 g, 78%); Rf = 0.27;
Found: C 58.22, H 7.28, N 3.49; Required for C20H29NO6S: C
HPLC was carried out using Dionex Summit HPLC systems
and monitored using Chromeleon 6.11 software. The analytical
and semi-preparative systems both incorporated a Summit P580
Quaternary Low Pressure Gradient Pump with built-in vacuum
degasser and a Summit UVD 170 s UV/Vis Multi-Channel De-
tector with analytical flow cell. Analytical HPLC was performed
using a Phenomenex Luna 10 l C18 (250 mm × 4.6 mm) column
using either water–acetonitrile or water–methanol methods at a
flow rate of 1.0 mL min−1. Semi-preparative HPLC was carried
out on a Phenomenex Luna 10 l C18 (250 mm × 10 mm) column
using either water–acetonitrile or water–methanol methods at a
flow rate of 5.0 mL min−1.
Single-crystal data were recorded at room temperature on a
Bruker Smart 6000 diffractometer equipped with a CCD detector
and a copper tube source. Structures were solved and refined using
SHELX97.23 Non-hydrogen atoms were refined anisotropically
and a riding model was used for C-H hydrogen atoms.
58.37, H 7.10, N 3.40; mmax (film)/cm−1 2955 (CH), 1739 (C O),
=
=
=
=
1736 (C O), 1598 (Ar C C), 1437 (Ar C C), 1340 (SO2), 1159
(SO2); dH (300 MHz) 1.45–1.63 (8 H, env, including 1.56 (3 H, s,
CH3), 1.60 (3 H, s, CH3) and CH2), 1.79–1.90 (2 H, m, CH2), 2.37
(3 H, s, CH3), 3.04 (3 H, t, J 7.4, CH2CH2N), 3.32 (1 H, t, J 7.4,
CH(CO2CH3)2), 3.68 (6 H, s, 2 × CO2CH3), 3.72 (2 H, d, J 7.0,
NCH2CH), 4.86–4.96 (1 H, t, J 7.1, NCH2CH), 7.25 (2 H, d, J 8.1,
Ar CH), 7.62 (2 H, d, J 8.1, Ar CH); dC (75 MHz) 18.0 (CH3), 21.7
(CH3), 26.0 (CH3), 26.1 (CH2), 26.4 (CH2), 45.7 (CH2), 46.8 (CH2),
51.3 (CH(CO2CH3)2), 52.7 (2 × CO2CH3), 119.1 (NCH2CH),
127.4 (CH, Ar), 129.8 (CH, Ar), 137.1 (C4), 137.2 (C4), 143.3
4
+
+
=
(C ), 169.8 (C O); m/z (ES ) 434.1 (100% [M + Na] ); HRMS
(ES+) Found: 434.1624, required for C20H29NO6SNa: 434.1613.
2-[4-Aza-7-methyl-4-(p-toluenesulfonyl)oct-6-enylidine]malonic
N-(3-Bromopropyl)-4-methyl-N-(3-methylbut-2-enyl)-
acid dimethyl ester (19)
benzenesulfonamide (23)
n-BuLi (2.1 M solution in hexanes, 1.30 mL, 2.73 mmol) was
added to a stirred solution of diisopropylamine (0.50 mL, 0.36 g,
3.55 mmol) in THF (20 mL) at −78 ◦C. The mixture was stirred
at −78 ◦C for 15 min before warming to ambient temperature
and stirring for a further 15 min. The resulting solution of LDA
was returned to −78 ◦C and a solution of 2-[4-aza-7-methyl-4-
(p-toluenesulfonyl)oct-6-enyl]malonic acid dimethyl ester (1.00 g,
2.43 mmol) in THF (20 mL) was added dropwise. The mixture was
allowed to warm to ambient temperature and stirred for 1 h before
cooling to −78 ◦C. A solution of PhSeCl (0.70 g, 3.64 mmol)
in THF (20 mL) was added dropwise and the reaction stirred
for 18 h. The resulting bright yellow solution was poured into
water (100 mL) and the aqueous phase extracted with ethyl acetate
(4 × 100 mL). The organic extracts were washed with saturated
NaHCO3 solution (100 mL), brine (100 mL), dried over MgSO4
and concentrated in vacuo to afford a yellow oil, which was purified
by column chromatography (silica; eluent 15 : 1 toluene–diethyl
ether) to afford the selenide 27 as a yellow oil (1.29 g, 94%) which
was used immediately; Rf = 0.53; mmax (film)/cm−1 2983 (CH), 1739
Triphenylphosphine (2.29 g, 8.74 mmol) was added to a solution
of alcohol 22 (2.0 g, 6.72 mmol) in CH2Cl2 (10 cm3) at ambient
temperature. The reaction mixture was stirred for 5 min before
carbon tetrabromide (2.90 g, 8.74 mmol) was added and the
reaction mixture was stirred for a further 2 h. Removal of the
CH2Cl2 in vacuo followed by flash column chromatography (silica;
eluent 8 : 1 hexane–ethyl acetate) gave bromide 23 as a white
crystalline solid (2.28 g, 94%); Rf = 0.30; mp = 62–65 ◦C
(from hexane–ethyl acetate); Found: C, 50.23; H, 6.03; N, 3.85.
C15H22BrNO2S requires C, 50.00; H, 6.15; N, 3.89%; mmax(KBr
disc)/cm−1 2979 (CH), 2930 (CH), 1676 (C C), 1673 (C C), 1596
=
=
=
(ArC C), 1340 (SO2), 1161 (SO2); dH (300 MHz) 1.63 (3 H, s,
CH3), 1.67 (3 H, s, CH3), 2.07–2.16 (2 H, m, CH2CH2N), 2.43
(3 H, s, CH3), 3.18 (2 H, t, J 7.0, CH2CH2N), 3.42 (2 H, t, J
6.4, CH2Br), 3.77 (2 H, d, J 7.0, CHCH2N), 4.97–5.03 (1 H, m,
CHCH2N), 7.30 (2 H, d, J 8.3, Ar CH), 7.69 (2 H, d, J 8.3,
Ar CH); dC (75 MHz) 17.9 (CH3), 21.6 (CH3), 25.9 (CH3), 30.7
(CH2CH2Br), 32.3 (CH2Br), 46.1 (CHCH2N), 46.5 (CH2CH2N),
118.8 (CHCH2N), 127.3 (CH, Ar), 129.7 (CH, Ar), 136.6 (C4),
137.4 (C4), 143.3 (C4); m/z (ES+) 384 ([M(81Br) + Na]+, 90%), 382
([M(79Br) + Na]+, 100); HRMS (ES+) Found: 382.0446, required
for C15H2279BrNO2SNa: 382.0452.
=
=
=
(C O), 1598 (Ar C C), 1439 (Ar C C), 1374 (SO2), 1162 (SO2);
dH (300 MHz) 1.60–1.74 (9 H env, including 1.60 (3 H, s, CH3),
1.64 (3 H, s, CH3), and CH2CH2CH2N or CH2CH2N)), 1.76–1.88
(2 H, m, CH2CH2CH2N or CH2CH2N), 2.41 (3 H, s, CH3), 3.02
(2 H, t, J 7.2, CH2CH2N), 3.70 (6 H, s, 2 × CO2CH3), 3.76 (2 H, d,
J 7.2, NCH2CH), 4.90–4.99 (1 H, t, J 7.2, NCH2CH), 7.23–7.36
(4 H, Ar CH), 7.37–7.45 (1 H, Ar CH), 7.53 (2 H, d, J 8.1, Ar
CH), 7.66 (2 H, d, J 8.1, Ar CH); dC (75 MHz) 18.1 (CH3), 21.8
(CH3), 24.9 (CH2), 26.1 (CH3), 31.3 (CH2), 45.8 (CH2), 46.9 (CH2),
53.3 (2 × CO2CH3), 59.7 (C4), 119.3 (NCH2CH), 126.6 (C4), 127.5
(CH, Ar), 129.3 (CH, Ar), 129.9 (CH, Ar), 130.2 (CH, Ar), 137.3
2-[4-Aza-7-methyl-4-(p-toluenesulfonyl)oct-6-enyl]malonic acid
dimethyl ester
NaHMDS (5.55 mL, 11.10 mmol, 2 M solution in THF) was added
dropwise to a solution of dimethyl malonate (1.27 mL, 1.47 g,
11.11 mmol) in THF (20 mL) at 0 ◦C. The mixture was stirred
for 30 min and allowed to warm to ambient temperature before
cooling to 0 ◦C. A solution of bromide 23 (2.06 g, 5.72 mmol) in
THF (20 mL) was added dropwise and the reaction allowed to
warm to ambient temperature. After stirring for 18 h the solvent
was removed in vacuo and the residue dissolved in ethyl acetate
(100 mL) and poured into water (100 mL). The aqueous phase
was extracted with ethyl acetate (4 × 100 mL) and the combined
4
4
4
=
(C ), 137.4 (C ), 138.3 (CH, Ar), 143.3 (C ), 169.6 (C O); m/z
(ES+) 590 (100% [M + Na]+).
H2O2 (0.47 mL, 30% aqueous solution, 4.15 mmol) was added
to a solution of selenide 27 (1.17 g, 2.07 mmol) in THF (30 mL)
at ambient temperature and stirred for 16 h. The mixture was
poured into water (100 mL) and the aqueous phase extracted with
ethyl acetate (4 × 100 mL). The organic extracts were washed
2930 | Org. Biomol. Chem., 2007, 5, 2925–2931
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
with saturated Na2CO3 solution (100 mL), dried over MgSO4 and
concentrated in vacuo to give a pale yellow oil. Purification by
flash column chromatography (silica; eluent 15 : 1 toluene–diethyl
ether) afforded the a,b-unsaturated diester 19 as a colourless oil
(0.62 g, 73%); Rf = 0.45; mmax (film)/cm−1 2955 (CH), 2941 (CH),
References
1 J. A. Findlay, in The Alkaloids, ed. A. Brossi, Academic Press, London,
1985, vol. 26, pp. 89–183.
2 A. R. Pinder, Nat. Prod. Rep., 1986, 3, 171–180; A. R. Pinder, Nat.
Prod. Rep., 1987, 4, 527–537; A. R. Pinder, Nat. Prod. Rep., 1989, 6,
67–78; A. R. Pinder, Nat. Prod. Rep., 1990, 7, 447–455; A. R. Pinder,
Nat. Prod. Rep., 1992, 9, 491–504; A. O. Plunkett, Nat. Prod. Rep.,
1994, 11, 581–590; D. O’Hagan, Nat. Prod. Rep., 1997, 14, 637–651; D.
O’Hagan, Nat. Prod. Rep., 2000, 17, 435–446.
3 For reviews, see: S. Laschat and T. Dickner, Synthesis, 2000, 1781–
1813; P. M. Weintraub, J. S. Sabol, J. M. Kane and D. R. Borcherding,
Tetrahedron, 2003, 59, 2953–2989; M. G. P. Buffat, Tetrahedron, 2004,
60, 1701–1729.
4 C. Escolano, M. Amat and J. Bosch, Chem. Eur. J., 2006, 12, 8199–
8207; L. V. Adriaenssens, C. A. Austin, M. Gibson, D. Smith and
R. C. Hartley, Eur. J. Org. Chem., 2006, 4998–5001; B. I. Mobele, T.
Kinahan, L. G. Ulysse, S. V. Gagnier, M. D. Ironside, G. S. Knox and F.
Mohammadi, Org. Process Res. Dev., 2006, 10, 914–920; Y. Matsumura,
D. Minato and O. Onomura, J. Organomet. Chem., 2007, 692, 654–663;
J. M. Harris and A. Padwa, J. Org. Chem., 2003, 68, 4371–4381; C.
Legault and A. B. Charette, J. Am. Chem. Soc., 2003, 125, 6360–6361;
S. J. Hedley, W. J. Moran, D. A. Price and J. P. A. Harrity, J. Org. Chem.,
2003, 68, 4286–4292; E. Poupon, D. Francois, N. Kunesch and H. P.
Husson, J. Org. Chem., 2004, 69, 3836–3841; B. B. Toure and D. G.
Hall, Angew. Chem., Int. Ed., 2004, 43, 2001–2004; J. T. Kuethe and
D. L. Comins, J. Org. Chem., 2004, 69, 2863–2866; C. Y. Legault and
A. B. Charette, J. Am. Chem. Soc., 2005, 127, 8966–8967; R. P. Wurz
and G. C. Fu, J. Am. Chem. Soc., 2005, 127, 12234–12235.
5 R. C. F. Jones, K. J. Howard and J. S. Snaith, Tetrahedron Lett., 1996, 37,
1707–1710; R. C. F. Jones, K. J. Howard and J. S. Snaith, Tetrahedron
Lett., 1997, 38, 1647–1650; C. A. M. Cariou and J. S. Snaith, Org.
Biomol. Chem., 2006, 4, 51–53.
=
=
=
=
1752 (C O), 1731 (C O), 1649 (C C), 1598 (Ar C C), 1494 (Ar
=
=
C C), 1438 (Ar C C), 1339 (SO2), 1160 (SO2); dH (300 MHz)
1.60 (3 H, s, CH3), 1.65 (3 H, s, CH3), 2.41 (3 H, s, CH3),
2.58 (2 H, apparent q, J 7.4, CH2CH2N), 3.17 (2 H, t, J 7.4,
CH2CH2N), 3.70–3.81 (8 H, env, including 3.77 (3 H, s, CO2CH3),
3.80 (3 H, s, CO2CH3) and NCH2CH)), 4.91–5.02 (1 H, t, J 7.1,
NCH2CH), 6.98 (1 H, t, J 7.4, CHCH2CH2N), 7.28 (2 H, d, J 8.1,
Ar CH), 7.67 (2 H, d, J 8.1, Ar CH); dC (75 MHz) 18.1 (CH3),
21.8 (CH3), 26.1 (CH3), 30.1 (CH2), 45.9 (CH2), 46.4 (CH2), 52.7
(CO2CH3), 52.8 (CO2CH3), 119.0 (NCH2CH) 127.6 (CH, Ar),
129.8 (C4), 130.0 (CH, Ar), 136.9 (C4), 137.9 (C4), 143.6 (C4),
+
=
=
146.6 (CHCH2CH2N), 164.4 (C O), 165.7 (C O); m/z (ES )
432.1 (100% [M + Na]+); HRMS (ES+) Found: 432.1463, required
for C20H27NO6SNa: 432.1457.
(3S*,4S*)-4-[Bis(carbomethoxy)methyl]-3-isopropenyl-1-
(p-toluenesulfonyl)piperidine (28)
MeAlCl2 (1 M solution in hexanes, 488 lL, 0.488 mmol) was
added dropwise to a solution of diester 19 (200 mg, 0.488 mmol),
in CH2Cl2 (10 mL) under argon at −78 ◦C. The reaction was stirred
for 5 h before being quenched by addition of water (10 mL). The
aqueous phase was extracted with CH2Cl2 (4 × 10 mL) and the
organic extracts washed with brine (10 mL), dried over MgSO4 and
concentrated in vacuo to give a colourless oil which was purified
by flash column chromatography (silica; eluent 3 : 1 hexane–
ethyl acetate) to afford exclusively the trans piperidine 28 as a
colourless oil (143 mg, 72%); Rf = 0.36; mp 97–100 ◦C (from
hexane–ethyl acetate); Found: C 58.67, H 6.89, N 3.31; Required
for C20H27NO6S: C 58.66, H 6.65, N 3.42; mmax (film)/cm−1 2953
6 J. T. Williams, P. S. Bahia and J. S. Snaith, Org. Lett., 2002, 4, 3727–
3730.
7 For a preliminary account of this work, see: S. M. Walker, J. T. Williams,
A. G. Russell and J. S. Snaith, Tetrahedron Lett., 2005, 46, 6611–6615.
8 For a review, see: B. B. Snider, in Comprehensive Organic Synthesis, ed.
B. M. Trost and I. Fleming, Pergamon, Oxford, 1991, vol. 5, pp. 1–27.
9 L. F. Tietze and U. Beifus, Angew. Chem., Int. Ed. Engl., 1985, 24, 1042–
1044; L. F. Tietze and U. Beifus, Liebigs Ann. Chem., 1988, 321–329.
10 L. F. Tietze and U. Beifus, Synthesis, 1988, 359–361.
11 L. F. Tietze, U. Beifus and M. Ruther, J. Org. Chem., 1989, 54, 3120–
3129.
12 For examples of piperidine synthesis by imino ene reactions, see: S.
Laschat and M. Grehl, Angew. Chem., Int. Ed. Engl., 1994, 33, 458–
461; S. Laschat and M. Grehl, Chem. Ber., 1994, 127, 2023–2034.
For examples of piperidine synthesis by carbonyl ene reactions, see
ref. 6 as well as: S. Laschat and T. Fox, Synthesis, 1997, 475–479; A.
Monsees, S. Laschat, S. Kotila, T. Fox and E.-U. Wurthwein, Liebigs
Ann., 1997, 533–540; A. Monsees, S. Laschat, S. Kotila, T. Fox and
E.-U. Wurthwein, Liebigs Ann., 1997, 1041; L. E. Overman and D.
Lesuisse, Tetrahedron Lett., 1985, 26, 4167–4170.
13 W. Oppolzer, E. Pfenninger and K. Keller, Helv. Chim. Acta, 1973, 56,
1807–1812.
14 B. E. Takacs and J. M. Takacs, Tetrahedron Lett., 1990, 31, 2865–2868.
15 J. T. Williams, P. S. Bahia, B. M. Kariuki, N. Spencer, D. Philp and J. S.
Snaith, J. Org. Chem., 2006, 71, 2460–2471.
16 K. Narasaka, Y. Hayashi, S. Shimada and J. Yamada, Isr. J. Chem.,
1991, 31, 261–271.
17 L. F. Tietze and U. Beifuss, Tetrahedron Lett., 1986, 27, 1767–1770.
18 J. A. Berson, R. G. Wall and H. D. Perlmutter, J. Am. Chem. Soc., 1966,
88, 187–188.
19 B. E. Thomas, R. J. Loncharich and K. N. Houk, J. Org. Chem., 1992,
57, 1354–1362.
=
=
=
(CH), 2848 (CH), 1733 (C O), 1645 (C C), 1598 (Ar C C), 1437
=
(Ar C C), 1342 (SO2), 1165 (SO2); dH (300 MHz) 1.58–1.74 (4 H,
env, including 1.65 (3 H, s, CH3) and CHHCH2N), 1.84–2.14 (3 H,
env, including 2.08 (1 H, t, J 11.3, NCHHCH), CHHCH2N and
CHCH2CH2N), 2.25 (1 H, dt, J 12.0, 2.5, CH2CHHN), 2.36 (1 H,
dt, J 11.3, 3.8, NCH2CH) 2.43 (3 H, s, CH3), 3.56 (1 H, d, J
3.3, CH(CO2CH3)2), 3.67 (3 H, s, CO2CH3), 3.69–3.87 (5 H, env,
including 3.71 (3 H, s, CO2CH3), NCHHCH and CH2CHHN),
4.77 (1 H, s, C CHH), 4.93 (1 H, s, C CHH), 7.32 (2 H, d, J 8.1,
Ar CH), 7.62 (2 H, d, J 8.1, Ar CH); dC (100 MHz) 20.7 (CH3), 21.5
(CH3), 26.8 (CH2CH2N), 38.4 (CHCH2CH2N), 46.5 (NCH2CH),
46.6 (CH2CH2N), 51.1 (NCH2CH), 52.1 (CH(CO2CH3)2), 52.4
=
=
=
(CO2CH3), 52.6 (CO2CH3), 115.2 (C CH2), 128.3 (CH, Ar), 130.3
(CH, Ar), 133.8 (C ), 144.0 (C ), 144.3 (C ), 169.2 (C O), 170.2
(C O); m/z (ES ) 432.0 (100% [M + Na] ); HRMS (ES ) Found:
432.1466, required for C20H27NO6SNa: 432.1457.
4
4
4
=
+
+
+
=
20 J. Mirek, M. Adamczyk and M. Mokrosz, Synthesis, 1980, 296–299.
21 D. A. Phipps and G. A. Taylor, Chem. Ind., 1968, 1279.
22 J. Suffert, J. Org. Chem., 1989, 54, 509–510.
Acknowledgements
23 G. M. Sheldrick, SHELXS-97, Program for solution of crystal struc-
tures, University of Go¨ttingen, Germany, 1997; G. M. Sheldrick,
SHELXL-97, Program for refinement of crystal structures, University
of Go¨ttingen, Germany, 1997.
We thank the Engineering and Physical Sciences Research Council
and the University of Birmingham for financial support, and
Mr Graham Burns for help with HPLC analysis.
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 2925–2931 | 2931
©