Diastereoselective preparation of 2,4,6-trisubstituted-2'-cyanopiperidines: application to the construction of the carbon framework of perhydrohistrionicotoxin.

Article abstract of DOI:10.1039/b209387a

The anodic cyanation of methanolic solutions of the 2-alkyl-N-phenylpiperidines 6b-d was performed in a flow cell equipped with a graphite felt anode. The reaction led to the formation of the 2-cyano-6-alkyl-N-phenylpiperidines 2b-d and proceeded with a high degree of regioselectivity. The 1H NMR spectra of the aminonitriles 2b-d showed an epimeric mixture at C-6. The major isomer has a trans configuration in which the cyano group is axial and the alkyl substituent is equatorial. Conversely, electrochemical oxidation of the 4-methyl-6-pentyl-N-phenylpiperidine 6e afforded the trisubstituted aminonitrile 2e as a single diastereomer (> 98% de). The 4-cyanobutyl side chain was incorporated in a two-step procedure to yield dinitrile 4e. This latter compound was directly converted into spiropiperidine 5e by using the Thorpe-Ziegler annulation procedure. The overall sequence (4 steps, 43%) allows the construction of the basic carbon framework of perhydrohistrionicotoxin.

Full text of DOI:10.1039/b209387a

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Diastereoselective preparation of 2,4,6-trisubstituted-2Ј-cyano-
piperidines: application to the construction of the carbon
framework of perhydrohistrionicotoxin
Richard Malassene,a Enguerran Vanquelef,a Loic Toupet,b Jean-Pierre Hurvois*a and
Claude Moineta
a Laboratoire d’Electrochimie, UMR 6509, Institut de Chimie, Université de Rennes I,
Campus de Beaulieu, F-35042 Rennes Cedex, France.
E-mail: Jean-Pierre.Hurvois@univ-rennes1.fr; Fax: ϩ 33( 0) 2 23 23 59 67
b Groupe Matière Condensée et Matériaux, Université de Rennes I, Campus de Beaulieu,
F-35042 Rennes Cedex, France
Received 26th September 2002, Accepted 25th November 2002
First published as an Advance Article on the web 8th January 2003
The anodic cyanation of methanolic solutions of the 2-alkyl-N-phenylpiperidines 6b–d was performed in a flow cell
equipped with a graphite felt anode. The reaction led to the formation of the 2-cyano-6-alkyl-N-phenylpiperidines
2b–d and proceeded with a high degree of regioselectivity. The 1H NMR spectra of the aminonitriles 2b–d showed an
epimeric mixture at C-6. The major isomer has a trans configuration in which the cyano group is axial and the alkyl
substituent is equatorial. Conversely, electrochemical oxidation of the 4-methyl-6-pentyl-N-phenylpiperidine 6e
afforded the trisubstituted aminonitrile 2e as a single diastereomer (>98% de). The 4-cyanobutyl side chain was
incorporated in a two-step procedure to yield dinitrile 4e. This latter compound was directly converted into
spiropiperidine 5e by using the Thorpe–Ziegler annulation procedure. The overall sequence (4 steps, 43%) allows
the construction of the basic carbon framework of perhydrohistrionicotoxin.
Introduction
The histrionicotoxin family encompasses a large number of
alkaloids isolated from skin extracts of the Colombian ‘poison-
arrow’ frog Dendrobates histrionicus. First isolated by Witkop1
and co-workers in 1971, histrionicotoxin (HTX) 1 or its satur-
ated congener, perhydrohistrionicotoxin (PHTX) 1a, are
illustrative of this family (Fig. 1). These compounds act as
non-competitive blocking agents of the acetylcholine-sensitive
conductance system in neuromuscular preparations.2
Their unique biological properties coupled with their intrig-
uing molecular frame, the 1-azaspiroundecane ring system,
have made these alkaloids popular targets on which to study
new synthetic compounds. Indeed, during the last decade,
several elegant well-designed total or formal syntheses of
(Ϫ)-HTX3 and ( )-PHTX4 have been completed. Despite these
numerous approaches, there is interest in developing new syn-
thetic tools for the construction of the heterocyclic framework
of these alkaloids. In a recent report,5 we have shown that lithi-
ation of the 2-cyano-4-methyl-N-phenylpiperidine 2a (lithium
diisopropylamide, tetrahydrofuran, Ϫ30 ЊC) followed by the
introduction 1-bromo-4-chlorobutane allowed the diastereo-
selective synthesis of the bifunctional α-aminonitrile 3a (R1 =
H, R2 = CH3). On further treatment with NaCN in DMSO,
substitution of the terminal chlorine atom readily occurred, to
afford the dinitrile 4a. The latter was submitted to a Thorpe–
Ziegler condensation6 (involving the cyano group at C-2 and
the terminal nitrile-stabilized carbanion) which allows the con-
struction of the spirocyclic piperidine 5a through formation of
the C-7,8 bond.7
Yet, anodic cyanation and alkylation of metallated α-amino-
nitriles, seemed to be a quite general approach for the form-
ation of new carbon–carbon bonds in the position α relative to
the nitrogen atom. Thus, to construct 4d (R1 = C5H11), condi-
tions were needed for the stereoselective preparation of trans-
2d. For the application of this strategy, one should be able to
introduce the C-8,11 carbon unit through metallation of 2d,
with retention of configuration at C-2.
Fig. 1
For this, we foccussed on the anodic cyanation8 of substi-
tuted piperidines 6b–d (Scheme 1), (a) to evaluate the regio-
chemical course of the oxidation procedure performed on
these amines, (b) as an instrument to study the stereochemical
course of addition of nucleophiles (HϪ or CNϪ) onto the
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 5 4 7 – 5 5 1
547

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Scheme 1 (i) NaBH4 (4 equiv.), MeOH, 65 ЊC, 1.5 h.
carbon–nitrogen double bond of 3,4,5,6-tetrahydropyridinium
species, and (c) to demonstrate that application of the Thorpe–
Ziegler annulation procedure could correctly orient the
cyanoenamine moiety with respect to the side chain borne at
the C-2 position of the piperidine ring. Details concerning the
chemical manipulations performed on the resulting amino-
nitriles 2b–e as well as the influence of a C-4 methyl substituent
on the stereochemical outcome of these transformations are
reported in the present paper.
Results and discussion
To demonstrate the generality of our synthetic plan, a series
of 2-alkyl-N-phenylpiperidines 6b–d were first synthesized
(Scheme 1) by sodium borohydride reduction of gem-disubsti-
tuted aminonitriles 7b–d. After extractive work-up and rapid
filtration over silica gel, the expected amines were obtained as
slightly yellow oils (78–93%).
In the 1H NMR spectra of these amines, characteristic
resonance multiplets signals attributed to H-2 were found at
δ = 3.8–3.9. We next directly prepared the 2-cyano-6-alkyl-N-
phenylpiperidines 2b–d.9 The electrochemical oxidation of
amines 6b–d (up to 3 g) was effected in a flow cell apparatus
(cf. experimental section) equipped with graphite felt anode,
and a stainless steel cathode. After electrolysis and usual work-
up, the expected aminonitriles 2b–d were obtained as single
Scheme 2
1
regioisomers in all cases. On the other hand, the H NMR
radical cation A (Scheme 2) and the vicinal methylene protons
at C-6.11 Note that no detectable amount of the alternative
regioisomers (7b–d), which could result from a proton loss at
C-2 has ever been encountered.
spectra of these aminonitriles revealed two sets of signals, indi-
cating that epimeric mixtures were obtained. The 1H NMR
spectra of these mixtures, well resolved, serve to determine the
1
structure of each epimer. For example, in the H NMR spec-
To improve the trans selectivity of the reaction we believe
that the iminium system 8e (R2 = CH3) should be locked into
conformation I, in which both the alkyl chains R1 and R2 were
maintained in a pseudo equatorial position (in the presence of
substituents at the C-2 and C-4 ring carbon atoms, conformer
II should be strongly destabilized by transannular inter-
actions).12 Note that the all cis derivative 2e should suffer from
severe 1,3-diaxial interactions. To apply this strategy, the 2,6-
dialkyl-N-phenylpiperidine 6e was prepared from reductive
decyanation of 7e13 (Scheme 3).
trum of trans-2b, the H-2 signal appeared as a triplet system
(J = 4.5 Hz) at δ = 4.15, whereas H-6 afforded a multiplet signal
at δ = 3.30. Also, selective irradiation at δ = 0.91 (6-CH3)
removed a geminal coupling constant (6.0 Hz) from the
H-6 signal, which appeared as a doublet of doublet system
(J = 10.5 Hz and 4.0 Hz). Collectively, these results indicate that
in the major epimer, the cyano group was axial and the methyl
group was equatorial. The spectra of aminonitriles 2c and 2d
closely resemble the spectrum of 2b, it then appears that
epimeric mixtures were also produced during the oxidation
of amines 6b–d. This observation agrees with the prediction
that, of the two possible isomers that could be formed from the
oxidation of 6b, the unhindered trans adduct 2b should be the
more stable isomer. It was also shown that the cis/trans stereo-
selectivity varies with the size of the C-2 substituent. Whereas
6b gave a 44% de, poor results were obtained with 6c (26% de)
or 6d (4% de). These results are consistent with the formation
of the iminium species 8b–c in which the phenyl and C-2 sub-
stituent are in close proximity causing the so-called A(1,2) allylic
effect.10
After extractive work-up, the 1H NMR spectrum of the
resultant crude reaction mixture revealed 6e as a single
As the C-2 methyl group in 8b is replaced by larger propyl
and pentyl substituents in 8c and 8d, respectively, the A(1,2)
strain increases significantly in 8b–d (R2 = H), shifting the equi-
librium from I (in which the substituent is in a pseudo equa-
torial disposition) to the more energetically favoured conformer
II. Axial attack of the cyanide anion (under a stereoelectronic
mode) on each of these two conformers adequately accounts
for the formation of either the cis and trans adducts. The pres-
ence of single adducts cyanated at the ring also revealed that
favourable interactions should be taken into account between
the partially occupied orbital on the nitrogen atom of the
Scheme 3 (i) NaBH4 (4 equiv.), MeOH, 65 ЊC, 1.5 h; (ii) Ϫ2 e, ϪHϩ,
NaCN (4 equiv.), AcOLi (20 g lϪ1), 2.2 F molϪ1, MeOH; (iii), LDA,
THF (2 M), Ϫ80 ЊC, Br(CH2)4Cl (1.1 equiv.); (iv) NaCN (2 equiv.),
DMSO, n-Bu4NI (5 mol%), rt, 48 h; (v) LDA, THF, Ϫ80 ЊC to rt, 17 h.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 5 4 7 – 5 5 1
548

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diastereomer (>98% de). The relative stereochemistry of 6e was
not determined at this stage but was presumably the one drawn
in Scheme 3. The possibility now exists to create a third stereo-
genic center at the piperidine ring employing anodic cyanation
as the key step. The electrolysis14 of a methanolic solution of
6e, performed under conditions similar to those for amines 6b–
d, led predominantly to the expected adduct 2e (85 : 15 mixture
with its regioisomer 7e). This product distribution reflects dif-
ferences in the regioselectivity of oxidation between 6b–d and
6e and is consistent with a competitive proton loss at both sites
α to the nitrogen atom of the ring.
the diastereoselective synthesis of the trisubstituted amino-
nitrile 4e, an advanced intermediate in the synthesis of new
spirocyclic piperidines. The utilization of a removable stereo-
directing group is currently under investigation.
Experimental
General
Purification by column chromatography was performed using
70–230 mesh silica gel (Merck). TLC analyses were carried out
on alumina sheets precoated with silica gel 60F254. IR spectra
were recorded with a Perkin–Elmer FT-IR 16PC (KBr powder
or methylene chloride). NMR spectra were recorded with a
Bruker AH 300 FT spectrometer [300 MHz (1H) and 75 MHz
(13C)] or a Bruker DPI 200 FT [200 MHz (1H) and 50 MHz
(13C)]. Chemical shifts are expressed in ppm downfield from
TMS where s, d, dd, t, q, m, designate singlet, doublet, doublet
of doublets, triplet, quartet and multiplet, respectively, and
coupling constants J are given in Hz. High resolution mass
spectra were obtained with a Mat 311 double focusing instru-
ment at the CRMPO with a source temperature of 170 ЊC.
An ion accelerating potential of 3 kV and ionizing electrons of
70 eV were used.
However, the expected trisubstituted aminonitrile 2e formed
during this reaction was obtained as a single stereoisomer as
1
determined from the H NMR spectrum of the reaction mix-
ture. Characteristic was the H-2 proton signal of the amino-
nitrile system which appeared as a doublet of doublet system
(J = 4.50 Hz and 2.34 Hz) at δ = 4.24. Since no large coupling
constant was observed with its neighbours it was concluded
that H-2 was equatorial, hence the cyanide substituent adopted
anaxialdisposition.Subsequentalkylation15 of2ewith1-bromo-
4-chlorobutane led to the formation of 3e as a single dia-
stereomer. The terminal chlorine atom was further displaced by
cyanide under standard conditions, this yielded the polar di-
nitrile 4e as pure material after chromatographic purification.
The 13C NMR spectrum of 4e contained one set of signals
indicating the formation of one geometric isomer. Twenty
carbon resonance lines were observed, two of which were due to
the C-2 and C-6 carbon atoms found at δ = 62.5 and 58.6,
respectively. Also interesting were the two quaternary CN sig-
nals found at δ = 119.72 and 121.33. We sought to construct the
C-8,7 bond of the azaspiroundecane ring system. To construct
new rings in polycyclic systems, the Thorpe–Ziegler annu-
lation16 is a versatile key reaction for the synthesis of natural
products. Accordingly, upon the exposure of a THF solution of
4e to a stoichiometric amount of LDA at Ϫ78 ЊC and warming
the reaction mixture to room temperature over a 17 hour
period, the spirocyclic derivative 5e was obtained (70%) as a
slightly brown solid after rapid chromatographic purification.
The spectral data of 5e (1H, 13C NMR and m/z) was consistent
with the proposed structure and revealed the formation of the
cyanoenamine moiety. On the other hand, the relative orien-
tation of the side chain substituent could not be determined
from the 1H NMR spectrum. Fortunately, from slow crystalliz-
ation of a solution of 5e single crystals were obtained. A fur-
ther X-ray study17 performed on one of these crystals indicated
that both the pentyl side chain and the C-8,11 carbon unit were
in a cis configuration (Fig. 2).
Materials
All glassware were oven dried (120 ЊC) over a 24 h period and
cooled under a stream of argon. All reagents were obtained
from a commercial source and were distilled prior to use. THF
was distilled from sodium benzophenone ketyl and stored
under an argon atmosphere. A solution of LDA (2 M) was
purchased from Acros and was used without titration.
General procedure for the electrochemical oxidation
Amines 6b–e (10 mmol), were dissolved in methanol (Carlo
Erba RE 99.6%), containing lithium acetate dihydrate (20 g lϪ1
,
Aldrich 98%) as the supporting electrolyte and sodium cyanide
(4 equiv. per mol of substrate) as the cyanating agent. The solu-
tion was filtered over a Millipore (5 µm) system and electrolyzed
in a flow cell18 fitted with a graphite felt anode (diameter = 50
mm, thickness = 12 mm). The flow rate ( f) of the solution was
regulated by a peristaltic pump at f = 5 mL minϪ1, and the
current (i1 ϩ i2) calculated according to a bielectronic process
(2) is given by the expression : i (ampere) = 2 × f × 96500 × 10Ϫ3
M/60 where M represents the molar concentration of the sub-
strate. The outlet solution was evaporated under reduced pres-
sure, the crude material was taken up in water (100 mL gϪ1 of
the starting compound) and extracted with methylene chloride
(2 × 100 mL gϪ1 of the starting compound). The organic layer
was dried over MgSO4 and concentrated. The α-cyanoamines
2b–e, were purified by column chromatography on silica gel
(eluent: diethyl ether and petroleum ether).
General procedure for the preparation of amines 6b–e
Solutions of cyanoamines 7b–e5 (10.0 mmol) in methanol
(50 ml), were treated with NaBH4 (40.0 mmol) and stirred at
room temperature for 5 min. Then, the solution was warmed to
65 ЊC for 90 min. After cooling, a solution (30 ml) of ammonia
(15%) was added and the solvent was removed under reduced
pressure. The crude reaction mixture was extracted (30 ml × 3)
with ether. The combined organic phases were dried over
MgSO4, and concentrated to give a crude material which was
purified by silica gel chromatography using diethyl ether–
petroleum ether as the eluent.
Fig. 2 ORTEP drawing of spiropiperidine 5e.
2-Methyl-1-phenylpiperidine 6b
Conclusion
In summary, a short and stereoselective route from simple
piperidine systems to the heterocyclic core of PHTX has been
developed. The presence of a stereodirecting group at C-4 allow
Rf = 0.70, diethyl ether–petroleum ether = 1 : 2, colourless oil
(1.36 g, 78%). δH(200 MHz, CDCl3) 1.01 (3 H, d, J 6.6 Hz),
1.52–1.95 (6 H, m), 2.98 (1 H, td, J = 11.0 and 3.0 Hz), 3.21
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 5 4 7 – 5 5 1
549

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(1 H, dm, J 12.0 Hz), 3.90 (1 H, m), 6.82 (1 H, t, J 7.2 Hz), 6.94
(2 H, d, J 8.1 Hz), 7.24 (2 H, m). HRMS calcd. for C12H17N
(Mϩ) 175.1361, found 175.1369.
4-Methyl-6-pentyl-1-phenylpiperidine-2-carbonitrile 2e
Rf = 0.55, diethyl ether–petroleum ether = 1 : 2, yellow oil (1.99
g, 75%). δH(200 MHz, CDCl3) 0.76 (3 H, t, J 7.1 Hz), 0.98 (3 H,
d, J 6.2 Hz), 1.05–1.70 (12 H, m), 1.90 (1 H, dm, J 11.9 Hz),
3.12–3.28 (1 H, m), 4.14 (1 H, dd, J 4.6 and 2.6 Hz), 7.08–7.28
(5 H, m). δC(50 MHz, CDCl3) 14.4, 22.1, 23.0, 24.9, 27.8, 32.4,
34.1, 37.8, 40.1, 54.6, 58.2, 118.5, 126.2, 126.6, 129.7, 149.3.
HRMS calcd. for C18H26N2 (Mϩ) 270.2096, found 270.2066. IR
(neat): ν = 2223 cmϪ1 (CN).
1-Phenyl-2-propylpiperidine 6c
Rf = 0.75, diethyl ether–petroleum ether = 1 : 2, colourless oil
(1.84 g, 91%). Found: C, 83.28; H, 10.35; N, 6.68. Calcd. for
C14H21N: C, 82.70; H, 10.41; N, 6.89%. δH(300 MHz, CDCl3)
0.86 (3 H, t, J 7.1 Hz), 1.12–1.79 (10 H, m), 2.98 (1 H, td,
J = 11.0 and 3.0 Hz), 3.33 (1 H, dm, J 12.0 Hz), 3.78 (1 H, m),
6.74 (1 H, tm, J 7.3 Hz), 6.87 (2 H, d, J 7.8 Hz), 7.21 (2 H, m).
δC(75 MHz, CDCl3) 14.2, 19.4, 20.2, 25.6, 27.8, 29.6, 43.7, 55.6,
116.3, 118.1, 129.0, 151.30. HRMS calcd. for C14H21N (Mϩ)
203.1674, found 203.1684.
2-(4-Chlorobutyl)-4-methyl-6-pentyl-1-phenylpiperidine-2-car-
bonitrile 3e
A solution (40 ml, THF) of 2e (1.89 g, 7.00 mmol) was cooled
to Ϫ80 ЊC, and treated dropwise with a 2.0 M solution of LDA
in THF–n-hexane (3.85 ml, 7.70 mmol). The reaction was
allowed to warm to Ϫ50ЊC and was maintained at that temper-
ature for 1 h and treated with 1-bromo-4-chlorobutane (0.89 ml,
1.31 g, 7.65 mmol). The solution was warmed to room temper-
ature before being stirred for 3 hours. The reaction mixture was
diluted by addition of water (50 ml) and extracted (30 ml × 3)
with diethyl ether (50 ml). The combined organic layers were
dried over MgSO4 and concentrated. The crude material was
purified by silica gel chromatography using diethyl ether–
petroleum ether (1 : 2) as the eluent to give 3e as a colourless oil
(2.14 g, 85%). Rf = 0.55. δH(200 MHz, CDCl3) 0.85 (3 H, t,
J 7.3 Hz), 0.95–2.15 (25 H, m), 3.20–3.40 (1 H, m), 3.48 (2 H, t,
J 6.0 Hz), 7.25–7.40 (5 H, m). HRMS calcd. for C22H33ClN2
(Mϩ) 360.9636, found 360.9640. IR (neat) ν = 2216 cmϪ1 (CN),
1491 cmϪ1 (Cl).
2-Pentyl-1-phenylpiperidine 6d
Rf = 0.75, diethyl ether–petroleum ether = 1 : 2, colourless oil
(2.14 g, 93%). Found: C, 83.00; H, 10.85; N, 6.03. Calcd. for
C16H25N: C, 83.06; H, 10.89; H, 6.05%. δH(200 MHz, CDCl3)
0.90 (3 H, t, J 7.3 Hz), 1.20–1.90 (14 H, m), 2.97 (1 H, td, J 12.6
Hz and 4.2 Hz), 3.32 (1 H, dm, J 12.5 Hz), 3.60–3.66 (1 H, m),
6.75 (1 H, t, J 7.3 Hz), 6.89 (2 H, d, J 7.9 Hz), 7.22 (2 H, m).
HRMS calcd. for C16H25N (Mϩ) 231.1987, found 231.1988.
4-Methyl-2-pentyl-1-phenylpiperidine 6e
Rf = 0.65, diethyl ether–petroleum ether = 1 : 2, colourless oil
(1.71 g, 70%). δH(300 MHz, CDCl3) 0.87 (3 H, t, J 6.4 Hz), 1.03
(3 H, d, J 6.1 Hz), 1.1–1.65 (11 H, m), 1.75 (1 H, dm, J 10.3 Hz),
1.90 (1 H, dq, J 10.2 and 2.9 Hz), 2.77 (1 H, dt, J 13.0 and
3.7 Hz), 2.8 (1 H, m), 3.19 (1 H, dt, J 13.0 and 4.4 Hz), 7.00–
7.11 (3 H, m), 7.20–7.30 (2 H, m). HRMS calcd. for C17H27N
(Mϩ) 245.2143, found 245.2138.
Cyanoamines 2b–d were obtained as inseparable mixtures of
cis and trans diastereoisomers. The following spectroscopic
data refer to these mixtures obtained after chromatographic
purification.
2-(4-Cyanobutyl)-4-methyl-6-pentyl-1-phenylpiperidine-2-
carbonitrile 4e
Chloroamine 3e (2.0 g, 5.55 mmol) and NaCN (0.55 g, 11.22
mmol) were dissolved in DMSO (10 ml) in the presence of
tetrabutylammonium iodide (10 mg). The reaction mixture was
stirred for 48 hours then quenched by addition of water (40 ml).
The product was extracted by CH2Cl2 (20 ml × 3). The com-
bined organic layers were dried over MgSO4 and concentrated.
The crude product was purified by silica gel chromatography
using diethyl ether–petroleum ether (1 : 2) as the eluent to
give 4e (1.87 g, 96%) as a viscous and colourless oil. Rf = 0.27.
δH(200 MHz, CDCl3) 0.85 (3 H, t, J 7.3 Hz), 0.95–2.15 (25 H,
m), 2.28 (2 H, t, J 6.3 Hz), 3.20–3.35 (1 H, m), 7.25–7.40 (5 H,
m). δC(50 MHz, CDCl3) 14.4, 17.3, 22.2, 22.8, 23.2, 24.9, 25.7,
28.2, 32.3, 34.9, 39.0, 40.1, 43.8, 58.6, 62.5, 119.7, 121.3, 127.5,
129.3 (2 carbons), 146.3. IR (neat) ν = 2216 cmϪ1 (CN), 2247
cmϪ1 (CN). HRMS calcd. for C23H33N3 (Mϩ) 351.2674, found
351.2670.
6-Methyl-1-phenylpiperidine-2-carbonitrile 2b
Rf = 0.70, diethyl ether–petroleum ether = 1 : 2, slightly amber-
coloured oil (1.50 g, 75%). δH(200 MHz, CDCl3) 0.90 (d, J 6.0
Hz, CH3, trans), 1.15 (d, J 6.8 Hz, CH3, cis), 1.25–2.15 (m),
3.22–3.45 (m, H-6, trans), 3.90–4.02 (m, H-6, cis), 4.15 (t, J 3.8
Hz, H-2, trans), 4.30 (t, J 4.1 Hz, H-2, cis), 6.87–7.08 (m), 7.10–
7.37 (m). HRMS calcd. for C13H16N2 (Mϩ) 200.1314, found
200.1316. IR (neat): ν = 2221 cmϪ1 (CN).
6-Propyl-1-phenylpiperidine-2-carbonitrile 2c
7-Amino-4-methyl-2-pentyl-1-phenyl-1-azaspiro[5.5]undec-7-
Rf = 0.60, diethyl ether–petroleum ether = 1 : 2, slightly amber-
coloured oil (1.73 g, 77%). δH(300 MHz, CDCl3) 0.75 (t, J 7.10
Hz, CH3, trans), 0.85 (t, J 7.30 Hz, CH3, cis), 1.05–1.45 (m),
1.50–2.10 (m), 3.19–3.27 (m, H-6, trans), 3.85–3.92 (m, H-6,
cis), 4.15 (t, J 3.6 Hz, H-2, trans), 4.42 (t, J 3.60 Hz, H-2, cis),
6.87–7.35 (m). δC(75 MHz, CDCl3) 13.9, 14.2, 16.5, 18.1, 20.7,
26.9, 27.3, 29.7, 29.9, 30.8, 31.1, 35.9, 45.5, 54.4, 55.2, 57.5,
116.7, 117.9, 120.5, 120.8, 125.6, 126.0, 129.2, 129.5, 148.3,
149.2. HRMS calcd. for C15H20N2 (Mϩ) 228.1626, found
228.1626. IR (neat): ν = 2224 cmϪ1 (CN).
ene-8-carbonitrile 5e
A solution (40 ml, THF) of 4e (0.520 g, 1.47 mmol) was cooled
to Ϫ80 ЊC, and treated dropwise with a 2.0 M solution of LDA
in THF–n-hexane (0.81 ml, 1.62 mmol). The reaction was
allowed to warm to room temperature before being stirred for
17 hours. The reaction mixture was diluted by addition of water
(50 ml) and extracted (30 ml × 3) with diethyl ether (50 ml). The
combined organic layers were dried over MgSO4 and concen-
trated. The crude material was purified by silica gel chromato-
graphy using diethyl ether–petroleum ether (1 : 2) as the eluent
to give 5e as slightly brown crystals (0.362 g, 70%). Rf = 0.36.
δH(300 MHz, CDCl3) 0.88 (3 H, t, J 6.8 Hz), 1.08 (3 H, d, J 6.1
Hz), 1.20–2.40 (19 H, m), 3.75–3.90 (1 H, m), 4.85 (2 H, broad),
6.80–6.90 (3 H, m), 7.25–7.39 (3 H, m). δC(75 MHz, CDCl3)
14.0, 19.0, 22.6, 23.6, 23.8, 24.0, 26.6, 31.9, 35.6, 35.8, 37.0,
46.8, 55.9, 58.9, 72.7, 119.9, 121.1, 128.9 (2 carbons), 146.9,
163.8. HRMS calcd. for C23H33N3 (Mϩ) 351.2675, found
351.2671. IR (neat) ν = 2182 cmϪ1 (CN), 3364 and 3472 cmϪ1
(NH2). Mp 116 ЊC.
6-Pentyl-1-phenylpiperidine-2-carbonitrile 2d
Rf = 0.75, diethyl ether–petroleum ether = 1 : 2, slightly amber-
coloured oil (2.15 g, 80%). δH(200 MHz, CDCl3) 0.83 (t, J 7.4
Hz), 1.05–1.45 (m), 1.50–2.05 (m), 3.19–3.27 (m, H-6, trans),
3.75–3.90 (m, H-6, cis), 4.14 (t, J 3.8 Hz, H-2, trans), 4.40
(t, J 4.1 Hz, H-2 cis), 6.83–6.95 (m), 7.12–7.38 (m). HRMS
calcd. for C17H24N2 (Mϩ) 256.1939, found 256.1944. IR (neat):
ν = 2222 cmϪ1 (CN).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 5 4 7 – 5 5 1
550

View Article Online
6 B. R. Davis and P. J. Garrat, in Comprehensive Organic Synthesis,
Crystal data, X-ray data collection, and refinement results of 5e
Vol. 2, ed. C. H. Heathcock, Pergamon, Oxford, 1991, 848.
7 For a general survey of strategies aimed at the construction of the
azaspiroundecane ring system see: M. Kotera, Bull. Soc. Chim. Fr.,
1989, 370.
C23H33N3, M = 351.52, triclinic, space group P-1, a = 9.413(3),
b = 9.609(6), c = 12.855(4) Å, α = 100.19(4), β = 95.29(3),
γ = 109.46(5)Њ, V = 1064.6(8) ÅϪ3, Z = 2, Dx = 1.097 Mg mϪ3
,
µ = 0.65 cmϪ1, λ(MoKα) = 0.71073 Å, µ = 0.65 cmϪ1, F(000) =
384, T = 293 K. The sample (0.38 × 0.26 × 0.24 mm) is studied
on an automatic diffractometer CAD4 NONIUS with graphite
monochromatized MoKα radiation.19 The cell parameters are
obtained by fitting a set of 25 high-theta reflections. The data
collection (2θmax = 54Њ, scan ω/2θ = 1, tmax = 60 s, range HKL : H
0.12, K Ϫ12.12, L Ϫ16.16) gives 4625 unique reflections from
which 2601 with I > 2.0σ(I ). After Lorenz and polarization
corrections20 the structure was solved with SIR-9721 which
reveals the non hydrogen atoms of the compound. After aniso-
tropic refinement a Fourier Difference reveals all the hydrogens.
The whole structure was refined with SHELX9722 by the full
matrix least-square techniques (use of F square magnitude; x,
y, r, βij for C and N carbons, x, y, z in riding mode for H atoms,
236 variables and 1084 observations; calc w = 1/[σ2(Fo2) ϩ
(0.116P)2] where P = (Fo2 ϩ 2Fc2)/3 with the resulting R =
0.061, Rw = 0.191, Sw = 1.095 (residual ∆ρ ≤ 0.46 eÅϪ3)). Atomic
scattering factors are available from International tables for
X-ray Crystallography.23 Ortep views were realized with
PLATON9824 and Ortep-3 for windows.25
8 E. Le Gall, J.-P. Hurvois, T. Renaud, C. Moinet, A. Tallec, P. Uriac,
S. Sinbandhit and L. Toupet, Liebigs Ann. Recl, 1997, 2089.
9 For a different approach to the 6-alkyl-2-cyanopiperidine system
see: (a) M. Bonin, J. R. Romero, D. S. Grierson and H.-P. Husson,
J. Org. Chem., 1984, 49, 2392; (b) M. Bonin, R. Besselièvre,
D. S. Grierson and H.-P. Husson, Tetrahedron Lett., 1983, 24, 1493;
(c) M. Bonin, J. R. Romero, D. S. Grierson and H.-P. Husson,
Tetrahedron Lett., 1982, 23, 3369.
10 For synthetic applications of A(1,2) allylic strain on related systems
see: H-.P. Husson and J. Royer, J. Chem. Soc. Rev., 1999, 28, 383.
11 (a) E. Steckhan, in Organic Electrochemistry, 3rd edn., eds.H. Lund,
M. Baizer, Dekker, New York, 1991, 583; (b) E. Le Gall,
J.-P. Hurvois and S. Sinbandhit, Eur. J. Org. Chem., 1999, 2645.
12 E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds,
Wiley, New York, 1994, p. 665.
13 For the synthesis and structural determination of compound 7e see
ref. 5.
14 It was anticipated that in view of the previous results, cyanation of
6e should take place at the unsubstituted C-6 position.
15 It seems likely that deprotonation of 2e yielded an intermediate
lithiated species which was attacked from the equatorial direction by
the electrophile to produce 3e with the stereochemistry indicated
in the Fig. 1. For leading references concerning the reactivity of
nitrile-stabilized carbanions see: F. F. Fleming and B. C. Shook,
Tetrahedron, 2002, 58, 1 and references cited therein.
16 (a) A. Toro, P. Nowak and P. Deslongchamps, J. Am. Chem. Soc.,
2000, 122, 4526; (b) B. Dansou, C. Pichon, R. Dhal, E. Brown and
S. Mille, Eur. J. Org. Chem., 2000, 1527; (c) J. T. M Linders,
J. L. Flippen-Anderson, C. F. George and K. C. Rice, Tetrahedron
Lett., 1999, 40, 3905; (d ) M. Luyten and R. Keese, Tetrahedron,
1986, 42, 1687; (e) E. Piers, B. F. Abeysekara, D. J. Herbert and
I. D. Suckling, J. Chem. Soc., Chem. Commun., 1982, 404.
17 CCDC reference number 195340. See http://www.rsc.org/suppdata/
ob/b2/b209387a/ for crystallographic files in .cif or other electronic
format.
18 C. Moinet and E. Raoult, Bull. Soc. Chim. Fr., 1991, 214.
19 C. K. Fair, MolEN, An Interactive Intelligent System for Crystal
Structure Analysis, User manual, Enraf-Nonius, Delft, The
Netherlands, 1990.
20 A. L. Spek, HELENA, Program for the handling of CAD4-
Diffractometer output SHELX(S/L), Utrecht University, Utrecht,
The Netherlands, 1997.
21 A. Altomare, M. C. Burla, M. Camalli, G. Cascarano,
C. Giacovazzo, A. Guargliardi, A. G. G. Moliterni, G. Polidori and
R. Spagna, J. Appl. Crystallogr., 1999, 32, 115.
Acknowledgements
R. M. thanks the MENRT for a grant.
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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 5 4 7 – 5 5 1
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