Synthesis of 3,4-disubstituted piperidines by ene cyclisation of 4-aza-1,7-dienes

Article abstract of DOI:10.1016/j.tetlet.2005.08.002

Ene cyclisation of a variety of 4-aza-1,7-dienes affords 3,4-disubstituted piperidines. In particular, cyclisation of diesters 14 and 20 catalysed by MeAlCl₂ gives the corresponding trans 3,4-disubstituted piperidines with diastereomeric ratios

Full text of DOI:10.1016/j.tetlet.2005.08.002

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6611–6615
Synthesis of 3,4-disubstituted piperidines by ene cyclisation
of 4-aza-1,7-dienes
Stephen M. Walker, Jodi T. Williams, Alexander G. Russell and John S. Snaith*
School of Chemistry, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Received 29 June 2005; revised 29 July 2005; accepted 1 August 2005
Abstract—Ene cyclisation of a variety of 4-aza-1,7-dienes affords 3,4-disubstituted piperidines. In particular, cyclisation of diesters
14 and 20 catalysed by MeAlCl2 gives the corresponding trans 3,4-disubstituted piperidines with diastereomeric ratios of >200:1.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
One of the few examples of a type I ene reaction leading to
a piperidine is from the work of Oppolzer, who
explored the thermal ene reaction of a simple 4-aza-1,7-
diene to produce a 3,4-disubstituted piperidine.7 Intra-
molecular cyclisation was achieved at a high temperature
(290 ꢁC for 27 h) to give the 3,4-disubstituted diastereo-
meric piperidines in a combined 26% yield. The
diastereomeric ratio was undetermined, but under the
high-temperature conditions it is likely to have been poor.
Nitrogen heterocycles have always played a major role
in the pharmaceutical and agrochemical industries due
to their often potent physiological properties, which
have resulted in numerous applications.1 In particular,
substituted piperidines occur as key components in an
enormous array of biologically active natural and syn-
thetic products, and as a consequence there is a drive
towards the synthesis of diastereomerically and
enantiomerically enriched piperidines. Whilst a variety
of stereocontrolled approaches have been developed,2
the range of functionality and substitution patterns
encountered in piperidine targets continues to inspire
new chemistry.3
We reasoned that activating the enophile with an elec-
tron-withdrawing group, such as an ester, should lower
the thermal barrier to the ene reaction, potentially giving
improved stereoselectivity. Moreover, the activating
group could serve as a coordination site for a Lewis
acid, thus opening up the possibility of Lewis acid cataly-
sis of the reaction. Much elegant work on the Lewis
acid-catalysed ene reaction leading to six-membered
rings has been carried out by Tietze, and levels of stereo-
control can be impressive.8
The intramolecular ene reaction is a powerful ring-form-
ing reaction, generating two contiguous stereocentres,
often with a high degree of stereocontrol.4 However,
while the imino ene and carbonyl ene reactions have
received considerable attention,5 there have been few
piperidine syntheses employing an ene reaction with an
alkene as the enophile. Takacs and co-workers have
published transition-metal-mediated piperidine synthe-
ses involving the cross-coupling of a diene with either
an allylic ether or another diene.6 Although formally
these processes can be regarded as [4+4]- or [4+6]-ene
reactions, mechanistically they are far removed from
the classical ene reaction.
2. Results and discussion
The cyclisation precursor 4 was readily prepared from 3-
aminopropanol 1 (Scheme 1). N-Tosylation followed by
N-alkylation with prenyl bromide gave 2. Subsequent
PCC oxidation cleanly afforded aldehyde 3, which
underwent a Wittig reaction with methyltriphenylphos-
phoranylidene acetate to give ester 4, exclusively as the
E diastereomer, in 65% yield after chromatography.
Keywords: Piperidine; Ene; Cyclisation.
*
Surprisingly, addition of an ester group to the enophile
did not significantly lower the barrier for thermal
Corresponding author. Tel.: +44 1214144363; fax: +44
1214144403; e-mail: j.s.snaith@bham.ac.uk
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.002

6612
S. M. Walker et al. / Tetrahedron Letters 46 (2005) 6611–6615
Ts
N
Ts
N
Ts
N
NH
2
iii
i, ii
iv
OH
OH
O
CO Me
2
1
2
3
4
Scheme 1. Reagents and conditions: (i) TsCl, 2 equiv Et3N, CH2Cl2, 0–25 ꢁC, 1 h, 68%; (ii) Cs2CO3, MeCN, BrCH2CH@C(CH3)2, 25 ꢁC, 18 h, 93%;
(iii) PCC, Celite, CH2Cl2, 25 ꢁC, 2 h, 67%; (iv) Ph3P@CHCO2Me, CH2Cl2, 25 ꢁC, 18 h, 65%.
the sulfonamide suggested that we needed to modify our
enophile to make this the preferred site of coordination.
Ts
N
Ts
N
i
+
This prompted us to examine the cyclisation precursor 8,
in which the enophile is activated by an oxazolidinone
group. We hoped that the two carbonyl groups would
chelate a Lewis acid, overcoming the Lewis basicity of
the sulfonamide.
4
CO Me
CO Me
2
2
5
6
Scheme 2. Reagents and conditions: (i) Ph2O, 259 ꢁC, 7 h, 62%.
Oxazolidinone 8 (E:Z 25:1) was readily prepared in 76%
yield by a Wittig reaction between 3 and the known ylide
9 (Scheme 3).9
cyclisation compared with the system studied by Oppol-
zer. Thus, cyclisation of 4 could only be effected by heat-
ing in refluxing diphenyl ether (259 ꢁC) for 7 h (Scheme
2). Removal of the solvent by distillation, followed by
chromatography, afforded the piperidine products 5
and 6 in a combined yield of 62% as an inseparable mix-
ture, with a trans:cis ratio determined as 3:2 by integra-
A number of Lewis acids were screened for their ability
to catalyse the cyclisation (Table 1).
The inclusion of an oxazolidinone group sufficiently
lowered the activation barrier so that the Lewis acid-
catalysed cyclisation now occurred at ambient tempera-
ture. Fragmentation of the starting material was not ob-
served, indicating that the Lewis acid was preferentially
coordinating to the N-acyloxazolidinone rather than to
the sulfonamide. Diastereomeric ratios were generally
moderate, with titanium tetrachloride affording an
8.2:1 trans:cis inseparable mixture of piperidines 10
1
tion of the H NMR spectrum.
Although substitution of the enophile with an electron-
withdrawing group had only led to a small lowering of
the thermal reaction barrier, we envisaged that coordi-
nation of a Lewis acid to the carbonyl group would fur-
ther lower the activation barrier. The Lewis acids, ferric
chloride, zinc bromide, methyl aluminium dichloride
and scandium triflate, were screened for their ability to
catalyse the cyclisation, at temperatures ranging from
À78 to 180 ꢁC.
O
O
Ts
N
Ph3P
9
O
N
The results were disappointing, and in most cases unre-
acted starting material was recovered. In the reactions
employing ferric chloride and scandium triflate at room
temperature, smooth cleavage of the prenyl side chain
was observed. It is likely that this is due to the coordina-
tion of the Lewis acid to the sulfonamide, facilitating the
dissociation of a stabilised allylic cation which then loses
a proton to afford 7 and 2-methylbutadiene (Fig. 1). The
apparent preference for the Lewis acid to coordinate to
3
i
O
N
O
O
8
Scheme 3. Reagents and conditions: (i) CH2Cl2, 25 ꢁC, 72 h, 76%.
LA
LA
O
S
N
O
O
S O
N
O
S
NH
O
+
H
CO2Me
CO2Me
CO2Me
7
Figure 1.

S. M. Walker et al. / Tetrahedron Letters 46 (2005) 6611–6615
6613
Table 1. Results of Lewis acid screening for catalysis of cyclisation of 8
Ts Ts
Ts
N
Ts
N
N
N
Lewis acid
8
O
O
O
+
+
O
N
N
N
O
O
O
O
O
O
O
12
10
11
13
Lewis acida
10:11:12
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
1.2:1
2.2:1
3.3:1
2.9:1
4.5:1
5.6:1
8.2:1
1
TiCl4
49:6:45
a All reactions were performed with 1 equiv of Lewis acid at room temperature in dichloromethane. Ratios determined by integration of H NMR
spectra of crude cyclisation products.
and 11 in the best case. Crude reaction yields were high,
but in all cases significant amounts of a side product,
identified as lactone 12, were present. It is reasonable
to assume that this compound arises from hydrolysis
of 13, implying that 8 was undergoing a competing
hetero Diels–Alder reaction.10 In some cases, the yield
of 12 was greater than the combined yields of the trans
and cis piperidines. Lactone 12 was obtained as a single
stereoisomer, most likely the trans isomer based upon
the literature precedent for closely related systems11
and the geometrical constraints inherent in such an
intramolecular Diels–Alder reaction.
Ts
N
Ts
N
MeO C
2
i
3
MeO C
2
MeO C
CO Me
MeO C
CO Me
2
2
2
2
15
14
Scheme 4. Reagents and conditions: (i) dimethyl malonate, piperidine/
acetic acid or ammonium acetate/acetic acid, CH2Cl2, 0–25 ꢁC, 1 h.
tion of a second equivalent of malonate into the a,b-
unsaturated diester to give 15, as well as other products
from base-mediated oligomerisation processes. The
reportedly milder conditions employing ammonium ace-
tate and acetic acid were similarly unsuccessful,12 as was
switching to malononitrile as the nucleophile.
Although the lowering of the activation barrier by Lewis
acid coordination to the oxazolidinone was encourag-
ing, the competing Diels–Alder cyclisation pathway
was disappointing, and so we turned our attention to
the diester 14. This cyclisation precursor has the advan-
tage of two electron-withdrawing substituents on the
enophile as well as the ability to chelate a Lewis acid.
With aldehyde 3 in hand, the simplest route to our target
appeared to be via a Knoevenagel condensation with
dimethyl malonate (Scheme 4).
The significant base sensitivity of 14 led us to adopt an
approach in which the a,b-unsaturated system was
introduced under essentially neutral conditions by selen-
oxide elimination (Scheme 5).
Alkylation of dimethylmalonate by bromide 16 pro-
ceeded smoothly to afford the saturated diester 17 in
78% yield. Phenylselenation followed by oxidation to
the corresponding selenoxide led to spontaneous elimi-
nation at room temperature to afford 14 in 69% overall
yield.
Surprisingly, under the standard conditions of piper-
idine and acetic acid, only trace amounts of the desired
diester 14 were produced, inseparable from a complex
mixture of compounds. Mass spectrometric evidence
suggested that side-products had resulted from the addi-
Ts
N
Ts
N
Ts
N
ii
i
iii, iv
2
Br
MeO C
CO Me
2
MeO C
CO Me
2
2
2
16
17
14
Scheme 5. Reagents and conditions; (i) PPh3, CBr4, CH2Cl2, 25 ꢁC, 2 h, 94%; (ii) (MeO2C)2CH2, NaHMDS, THF, 25 ꢁC, 18 h, 78%; (iii) LDA,
THF, À78 to 25 ꢁC, 30 min then PhSeCl, THF, À78 to 25 ꢁC, 18 h, 94%; (iv) H2O2, THF, 25 ꢁC, 18 h, 73%.

6614
S. M. Walker et al. / Tetrahedron Letters 46 (2005) 6611–6615
Ts
N
Ts
N
i or ii
14
MeO2C
CO2Me MeO2C
CO2Me
18
19
Scheme 6. Reagents and conditions: (i) o-dichlorobenzene, 180 ꢁC, 7 h,
74%; (ii) MeAlCl2, CH2Cl2, À78 ꢁC, 5 h, 72%.
The diester was subjected to thermal cyclisation, and as
anticipated, showed a lower activation barrier than the
monoester, with cyclisation being complete within 7 h
in refluxing o-dichlorobenzene (180 ꢁC). Removal of the
solvent by distillation, followed by flash chromato-
graphy, afforded an inseparable 4:1 mixture of piperi-
dines 18 and 19 in 74% yield, with the thermodynamically
more stable trans isomer in excess as expected (Scheme 6).
Figure 2. ORTEP14 representation of 21; ellipsoids drawn at 30%
probability level.
with an oxazolidinone function, compound 8, did allow
the ene cyclisation to be catalysed by Lewis acids, yield-
ing the corresponding piperidines in a trans:cis ratio of
up to 8.2:1, but varying amounts of an intramolecular
Diels–Alder cycloadduct were also formed under these
conditions. Diesters 14 and 20 were found to undergo
ene cyclisations catalysed by MeAlCl2 at À78 ꢁC to
give the trans piperidines 18 and 21, with diastereomeric
ratios of >200:1. The methodology should find applica-
tion in the synthesis of more complex targets.
Encouraged by this result, we went on to examine cataly-
sis of the cyclisation by methylaluminium dichloride.
The alkyl aluminium halides have the advantage of
being commercially available as anhydrous solutions
and are able to scavenge small amounts of water, there-
by minimising side reactions that could be promoted by
the presence of traces of Brønsted acids.13 Furthermore,
the observation that MeAlCl2 did not induce prenyl
fragmentation in our attempts to cyclise monoester 4
suggested that it had a relatively low affinity for the sul-
fonamide, thereby minimising competitive binding of
the catalyst to this site.
2.1. Cyclisation procedure: Preparation of (3R*,4S*)-
4-[bis(carboethoxy)methyl]-3-isopropenyl-1-(toluene-
4-sulfonyl)piperidine (21)
We were delighted to find that diester 14 cyclised at
À78 ꢁC in the presence of MeAlCl2 to afford a 72% yield
of the trans piperidine 18 after chromatography, with a
diastereomeric ratio of >200:1, as determined by HPLC.
Repeating the cyclisation with the diethyl analogue 20
afforded trans piperidine 21 in 67% yield, with equally
high diastereoselectivity (Scheme 7).
Methyl aluminium dichloride (1 M soln. in hexanes,
0.12 cm3, 0.12 mmol) was added to a solution of diester
20 (53 mg, 0.12 mmol) in CH2Cl2 (10 cm3) at À78 ꢁC.
The resulting mixture was stirred at À78 ꢁC for 5 h, after
which it was quenched by the addition of water (10 cm3).
The aqueous phase was extracted with CH2Cl2 (4 · 10
cm3) and the combined organic phases were washed with
brine (10 cm3), dried over Na2SO4 and evaporated in
vacuo to leave a colourless oil, which was purified by
flash column chromatography (silica; eluent 3:1 petrol/
ethyl acetate) to give piperidine 21 as a white crystalline
solid (35 mg, 67%); (Rf = 0.39); mp = 84–86 ꢁC (from
petrol/ethyl acetate); (found: C, 60.41; H, 7.31; N,
3.09; S, 7.33. C22H31NO6S requires C, 60.39; H, 7.14;
N, 3.20; S, 7.33); mmax(neat)/cmÀ1 2982 (CH), 2928
(CH), 1724 (C@O), 1643 (C@C), 1597 (C@C aromatic),
1342 (SO2), 1157 (SO2); dH (400 MHz, CDCl3) 1.21 (3H,
t, J 7.1, CH2CH3), 1.26 (3H, t, J 7.1, CH2CH3), 1.62–
1.73 (4H, envelope, CH3 and CHHCH2N), 1.92–2.01
(2H, envelope, CHHCH2N and CHCH2CH2N), 2.09
Single crystals of 21 were grown from petrol and ethyl
acetate, and the relative stereochemistry was confirmed
by X-ray analysis (Fig. 2).
In conclusion, we have synthesised a number of precur-
sors and investigated their conversion to 3,4-disubsti-
tuted piperidines by ene cyclisation. Monoester 4 was
found to have a high barrier to thermal cyclisation, giv-
ing the corresponding cis and trans piperidines in a poor
diastereomeric ratio; the cyclisation of 4 was not amena-
ble to Lewis acid catalysis. Activation of the enophile
(1H, t,
J 11.2, CHCHHN), 2.22–2.28 (1H, m,
CH2CHHN), 2.37 (1H, dt, J 4.1 and 11.2, CHCH2N),
2.43 (3H, s, ArCH3), 3.52 (1H, d, J 2.9, CH(CO2Et)2),
3.71–3.76 (1H, m, CHCHHN), 3.79–3.85 (1H, m,
CH2CHHN), 4.08–4.19 (4H, m, 2 · CH2CH3), 4.78
(1H, br s, C@CHH), 4.93 (1H, t, J 1.5, C@CHH),
7.31 (2H, d, J 8.1, Ar CH), 7.62 (2H, d, J 8.1, Ar
CH); dC (100 MHz, CDCl3) 14.0 (CH3), 14.1 (CH3),
20.7 (CH3), 21.5 (CH3), 26.8 (CH2, CH2CH2N),
38.3 (CH, CHCH2CH2N), 46.4 (CH, CHCH2N), 46.5
Ts
N
Ts
N
i
EtO2C
CO2Et
EtO2C
CO2Et
20
21
Scheme 7. Reagents and conditions: (i) MeAlCl2, CH2Cl2, À78 ꢁC,
5 h, 67%.

S. M. Walker et al. / Tetrahedron Letters 46 (2005) 6611–6615
6615
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Acknowledgements
We are grateful to the EPSRC for funding, to Dr. Ben-
son Kariuki for X-ray analysis and to Mr. Graham
Burns for help with HPLC purification.
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