Anodic cyanation of (S)-(-)-1-1(1-phenylethyl)piperidine: An expeditious synthesis of (S)-(+)-coniine

Article abstract of DOI:10.1055/s-2006-944214

A short and efficient asymmetric synthesis of enantiopure (S)-(+)-coniine is reported. Anodic cyanation of (-)-1-[(1S)-1-phenylethyl]piperidine, derived from [(1S)-1-phenylethyl]amine, results in regioselective formation of the corresponding α-amino-nitrile, which was alkylated with propyl iodide to give a bifunctional derivative. The latter underwent a stereoselective reductive decyanation (80% de), the product of which was hydrogenolyzed to afforded (S)-(+)-coniine (99% ee) with an overall 35% yield from (-)-1 -[(1S)-1-phenylethyl]piperidine. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-944214

LETTER
1679
Anodic Cyanation of (S)-(–)-1-(1-Phenylethyl)piperidine: an Expeditious
Synthesis of (S)-(+)-Coniine
Synthesis of
(
S
)-(+
i
)
-Coni
c
Laboratoire d’Electrochimie et Catalyse, UMR 6226, Université de Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France
Fax +33(2)23235967; E-mail: Jean-Pierre.Hurvois@univ-rennes1.fr
Received 28 March 2006
ethyl]piperidine (1, Scheme 2, R1 = C6H5, R2 = CH3). The
objectives were twofold. Firstly, to widen the scope of our
electrochemical approach to the regioselective synthesis
of aminonitriles II; secondly, to evaluate if the electro-
Abstract: A short and efficient asymmetric synthesis of enan-
tiopure (S)-(+)-coniine is reported. Anodic cyanation of (–)-1-[(1S)-
1-phenylethyl]piperidine, derived from [(1S)-1-phenylethyl]amine,
results in regioselective formation of the corresponding a-amino-
nitrile, which was alkylated with propyl iodide to give a bifunc- chemical approach could be efficient for the synthesis of
tional derivative. The latter underwent a stereoselective reductive
enantiomerically pure 2-alkyl piperidines.
decyanation (80% de), the product of which was hydrogenolyzed to
afforded (S)-(+)-coniine (99% ee) with an overall 35% yield from
(–)-1-[(1S)-1-phenylethyl]piperidine.
–2e–, –H+, CN–
Key words: alkaloids, anodic cyanation, alkylation, metallation,
stereoselective synthesis
N
CN
+
N
N
R1
R2
R1
R2
R1
R2
CN
II
I
III
Chiral piperidines constitute the framework of numerous
natural products and synthetic substances with important
biological activities.1 Accordingly, the discovery of new
synthetic schemes2 aimed at the elaboration of a new
chiral center adjacent to the nitrogen atom is an area of
active research. In the last decade, several methods based
on the utilization of chiral catalysts3 have led to the asym-
metric synthesis of alkaloids with ee greater than 99%.
Despite these successful approaches, synthetic strategies
involving the use of auxiliaries derived from the chiral
pool play a prominent role. Their success is mainly due to
established synthetic methods including diastereoselec-
tive addition of organolithium and Grignard reagents to
the C=N bond of preformed building blocks,4 or stereose-
lective alkylation of chiral dipole-stabilized anions.5 In
this context, a-aminonitriles occupy an interesting
position.6 These synthetic intermediates can serve both as
an imine or iminium ion precursor, or on contact with a
base can generate a nitrile-stabilized carbanion which can
be alkylated with an electrophile. Photochemical7 or
electrochemical8 oxidation of tertiary amines of the type
of I is performed under mild conditions and the expected
aminonitriles II and III are obtained in high yields. As
shown in Scheme 1 the general absence of regioselectivity
in many electrochemical methods9 has limited its syn-
thetic utility, but sometimes a single ring-cyanated
product II (R1 = C6H5, R2 = H)10 is detected. A ‘retro-
Strecker’ decomposition of quaternary aminonitriles (III)
should be taken into account to explain abnormal regio-
selectivities. These considerations prompted us to investi-
gate the anodic cyanation of (–)-1-[(1S)-1-phenyl-
Scheme 1 General oxidation pathway for the anodic cyanation of
tertiary amines.
The requisite amine 1 (>99.0% ee) was prepared accord-
ing to Eguchi’s procedure11 by heating (–)-[(1S)-1-phen-
ylethyl]amine with 1,5-dibromopentane in DMSO in the
presence of solid K2CO3 for 2 hours. (–)-1-[(1S)-1-phen-
ylethyl]piperidine (1) was obtained in 87% yield after
vacuum distillation {[a]D22, –26.55, (c 1.45, CHCl3)}.
Prior to macroscale electrolyses, an electrochemical
investigation was undertaken. Cyclic voltammetry (CV)
was performed at a glassy carbon electrode, peak poten-
tials were expressed in V/SCE; 1 was dissolved (20 mmol/
L) in a solution of LiClO4 (15 g/L) in the presence of 6
equivalents of NaCN. A first irreversible oxidation peak
H2N
CH3
1)
2)
N
Ph
Ph
CH3
(–)-1 (87%)
3)
2
+
N
CN
CH3
+
N
N
Ph
CH3
Ph
Ph
CH3
CN
3 (6%)
2 (85%)
Scheme 2 Synthesis of a-aminonitrile 2 from (–)-[(1S)-1-phenyl-
ethyl]amine. Reagents and conditions: 1) 1,5-dibromopentane (1.2
equiv), DMSO, K2CO3 (3 equiv) 100 °C, 2 h; 2) –2e–, –H+, NaCN (6
equiv), MeOH/LiClO4 (15 g/L), MeONa (6 equiv); 3) 50 °C, 45 min.
SYNLETT 2006, No. 11, pp 1679–1682
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-944214; Art ID: G07906ST
© Georg Thieme Verlag Stuttgart · New York
1
2
.0
7
.2
0
0
6

1680
N. Girard et al.
LETTER
was recorded at Epa1 = +1.0 V/SCE, while a second ill-
defined wave was found at Epa2 = +1.45 V/SCE. These
observations suggest that a selective transformation could
be performed at the first oxidation peak. Electrolyses were
conducted at controlled potential (E = +1.0 V/SCE) in a
C3H7
1)
N
CN
CH3
N
CN
CH3
Ph
2)
Ph
non-divided cell at
a vitreous carbon electrode
2
4 (72%)
(diameter = 100 mm, Carbone Lorraine®) as anode and a
carbon rod as cathode. For the synthesis of a-aminonitrile
2 a set of conditions was investigated. First trials were
made in the presence of 6 equivalents of NaCN and in the
absence of added base. The electrolysis was monitored by
CV and by gas chromatography. GC analysis of the crude
reaction mixture indicated the formation of a-aminonitrile
2 together with its regioisomer 3, in a (93:7) ratio. In con-
nection with the amount of electricity that was consumed
during the electrolysis (up to 4 F/mol) it was assumed that
a redox reaction between the nitrogen-centered radical
cation and cyanide anions took place.12 To overcome this
drawback, 6 equivalents of sodium methylate (formed in
situ by the addition of Na) were added in the electrolysis
medium. Under these more basic conditions the inter-
mediate radical cation was readily deprotonated and the
electrolysis consumed 2.1 F/mol of amine and the current
efficiency was 85%. In this way, a-aminonitriles 2 and 3
were obtained in a satisfactorily 91% yield after filtration
over a silica column. a-Aminonitrile 3 eluted first, fol-
lowed by the ring-cyanated adduct 2, which was obtained
as a mixture of diastereomers (1:1). The 13C NMR spec-
trum of 2 contains a set of four independent resonance
lines between d = 46.07 and 52.12 ppm which were attrib-
uted to the N–CH and N–CH2 carbon atoms. After several
experiments, optimized reaction conditions were founded.
Heating (55 °C, 45 min) the electrolysis medium, in
which an equal amount of water has been added, led to the
unexpected disappearance of the unwanted a-aminonitrile
3. As shown in Scheme 2, it seemed likely that 3 is more
prone to the ‘retro-Strecker’ decomposition than its en-
docyclic conterpart.13 In this way, compound 2 was ob-
tained cleanly and reproducibly on a 15 g scale in a 85%
yield. To further illustrate the advantages of our synthetic
approach, we turned to coniine14 (the toxic hemlock
alkaloid) whose simple structure is an attractive target to
test asymmetric methodologies.15 Alkylation of the anion
of 2 [LDA (1.1 equiv); THF, –80 °C, then 0 °C] with pro-
pyl iodide provided the substitution product 4 (72% yield,
9:1 mixture of diastereomers). Reductive decyanation was
made in the presence of an excess of NaBH4 (4 equiv) in
EtOH at 0 °C, to produce amines (+)-5 and (–)-6 which
were obtained in a 72% and 8% yield, respectively
(Scheme 3). Interestingly, these two diastereomers could
be easily separated over a silica column using a mixture of
diethyl ether and petroleum ether (9:1) as eluent. Major
N
C3H7
N
C3H7
+
Ph
CH3
Ph
CH3
(+)-5 (72%, 99% ee)
(–)-6 (8%, 99% ee)
4)
3)
5
N
C3H7
N
C3H7
H
Boc
(+)-8 (80%)
(+)-7 (90%)
Scheme 3 Synthesis of (S)-(+)-Boc-coniine (8) from a-aminonitrile
2. Reagents and conditions: 1) LDA, (1.15 equiv), THF, –80 °C to
0 °C, C3H7I, –80 °C to 0 °C; 2) NaBH4, (4.0 equiv), EtOH, 0 °C; 3)
H2, Pd/C (10%), MeOH, 48 h; 4) (Boc)2O (1.1 equiv),
[(CH3)2CH]2NC2H5, (3 equiv), MeCN, 80 °C, 2 h.
ate IV (Scheme 4) in which steric interactions between
the propyl chain and the chiral appendage are minimized.
The subsequent hydride delivery from the least hindered
ul face produced the major 2S-diastereomer.
Interestingly, this result (80% de) is in keeping with that
reported by Shipman et al.16 In their approach, 1-[(1S)-1-
phenylethyl]-2-methylaziridine was utilized as substrate
to introduce chirality for the synthesis of (S)-(+)-coniine.
In the final reductive step, the same chiral iminium system
IV was postulated to explain the high level of diastereo-
control (97% de) for the formation of (+)-5.
ul
H
H
N
N
CH3
CH3
IV
V
lk
ul attack of H–
lk attack of H–
(S,S)-5
(S,R)-6
Scheme 4 Mechanistical rationales for the diastereoselectivity.
22
2S-diastereomer {[a]D +10.4, (c 2.83, CHCl3); lit.16
26
[a]D +14.0, (c 0.86, CHCl3)} eluted first, followed by
22
Hydrogenolysis of the chiral appendage afforded optical-
ly pure (S)-(+)-coniine (7) in 90% yield after chromato-
graphic purification over a silica column (Et2O saturated
with gaseous NH3). The optical rotation of the hydrochlo-
ric salt of our synthetic coniine was dextrorotatory and
the more polar 2R-diastereomer {[a]D –60.8, (c 1.08,
CHCl3). Optical purity of (+)-5 was checked by GC on a
CP-Chirasil-Dex CB column and showed to be greater
than 99%. The formation of (+)-5 can be understood when
considering the prior formation of the iminium intermedi-
Synlett 2006, No. 11, 1679–1682 © Thieme Stuttgart · New York

LETTER
Synthesis of (S)-(+)-Coniine
1681
3
2.52 (m, 2 H), 4.47 (q, J = 6.8 Hz, 1 H), 7.25–7.46 (m, 5 H). 13
C
was consistent with those reported in the literature {(S)-
22
20
(+)-coniine·HCl, [a]D +7.5, (c 1.46, EtOH); lit.16 [a]D
NMR (75 MHz, CDCl3): d = 11.16, 14.37, 16.78, 22.29, 25.46,
36.26, 40.23, 42.74, 53.46, 59.76, 122.06, 126.50, 127.05, 128.11,
144.27. HRMS (EI): m/z calcd for C17H24N2 [M+]: 256.1939; found:
229.18305 [M – HCN+]. GC: tR = 4.33 min (200 °C). Anal. Calcd
for C17H24N2: C, 79.64; H, 9.44; N, 10.93. Found: C, 79.74; H, 9.39;
N, 10.94.
+8.1, (c 1.0, EtOH)}. In a similar fashion, the N-Boc-pro-
tected (S)-(+)-coniine (8) {[a]D22 +30.0, (c 1.34, CHCl3);
lit.3a [a]D26 +29.8, (c 1.45, CHCl3)} matched in all aspects
with the spectral data reported in the literature.
In conclusion, an efficient process (5 steps, 35% overall
yield) to (S)-(+)-coniine starting from commercially
available [(1S)-1-phenylethyl]amine is described. A clean
and scalable electrochemical process was effective for the
preparation of a chiral non-racemic aminonitrile deriva-
tive in high yield. The latter has been used in a classical
alkylation–reduction process, to synthesize optically pure
unnatural (S)-(+)-coniine. Further developments of this
methodology will be reported on due course.
Acknowledgment
N.G. wishes to thank the MENRT for a grant.
References and Notes
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Typical Procedures
1-[(1S)-1-phenylethyl]piperidine-2-carbonitrile (2)
Compound (+)-1 (3.0 g, 15.9 mmol) was dissolved in MeOH (150
mL) in the presence of LiClO4 (1.5 g) and 4.66 g (6 equiv) of NaCN.
Then, 2.19 g (6 equiv) of Na (cut into small cubes) were dissolved
in the electrolysis medium. When all the Na had reacted, the result-
ing solution was transferred in a non-divided cell equipped with a
vitreous carbon electrode (diameter 100 mm, Carbone Lorraine®) as
anode and a carbon rod as cathode. The working potential was ad-
justed to +1.0 V/SCE. After the consumption of 3200 C, the elec-
trolysis was stopped and 150 mL of H2O (Caution: LiClO4 may
lead to severe explosions when evaporated to dryness) were added
to the solution, which was evaporated under reduced pressure at
+50 °C. The resulting aqueous phase was extracted with Et2O
(2 × 100 mL). The combined organic layers were dried over
MgSO4, concentrated under reduced pressure and purified by silica
gel chromatography (PE–Et2O, 9:1) to give aminonitrile 2 (2.72 g,
85% yield, yellow oil) as a mixture (1:1) of diastereomers: Rf = 0.35
(PE–Et2O, 9:1). 1H NMR (300 MHz, CDCl3): d = 1.31 (d, 3J = 6.65
Hz, 3 H), 1.36 (3J = 6.50 Hz, 3 H), 1.40–2.00 (m, 12 H), 2.14 (td,
2J = 3J = 12.00 Hz, 3J = 2.80 Hz, 1 H), 2.33 (td, 2J = 3J = 11.60 Hz,
3J = 2.7 Hz, 1 H), 2.60 (dm, 2J = 11.50 Hz, 1 H), 3.19 (dm, 2J = 12.3
3
3
Hz, 1 H), 3.46 (q, J = 6.60 Hz, 1 H), 3.51 (q, J = 6.60 Hz, 1 H),
3.56–3.59 (m, 1 H), 4.21–4.24 (m, 1 H), 7.21–7.35 (m, 10 H). 13
C
NMR (75 MHz, CDCl3): d = 20.47, 20.66, 21.01, 21.47, 25.06,
25.27, 28.79, 29.11, 45.58, 48.10, 49.55, 51.62, 62.98, 63.11,
116.87, 117.04, 127.05, 127.10, 127.17, 127.49, 128.49, 128.74,
143.82, 144.70. HRMS (EI): m/z calcd for C14H18N2 [M+]:
214.1470; found: 214.14802. GC: tR = 3.04 min (200 °C).
1-[(1S)-1-phenylethyl]-2-propylpiperidine-2-carbonitrile (4)
To a THF solution (20 mL) containing 2.25 mL (1.62 g, 1.5 equiv)
of diisopropylamine at –80 °C were added (by syringe) 6.10 mL
(12.20 mmol) of n-BuLi (2 M). The solution was stirred at that tem-
perature for 30 min and was warmed up to 0 °C for 30 min. The re-
sulting LDA solution was transferred (by syringe) to a THF solution
(20 mL) cooled at –80 °C containing the aminonitrile 2 (2.30 g,
10.70 mmol). The solution was allowed to warm up to –15 °C for
90 min to afford a yellow anion solution. The solution was cooled
at –80 °C and n-iodopropane (1.25 mL, 12.80 mmol) was added.
The reaction mixture was stirred at that temperature for 90 min and
at 0 °C overnight. THF was evaporated in vacuo and the residue was
purified by silica gel chromatography (PE–Et2O, 8:2) to give ami-
nonitrile 4 (1.95 g, 72% yield, yellow oil) as a mixture (9:1) of
diastereomers. Rf = 0.8 (PE–Et2O, 8:2).17 1H NMR (300 MHz,
CDCl3): d = 0.99 (t, 3J = 7.3 Hz, 3 H), 1.20–2.05 (m, 13 H), 2.50–
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N. Girard et al.
LETTER
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Am. Chem. Soc. 1983, 105, 7754. For recent
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S.; Sacchetti, A.; Silvani, A.; Danieli, B. Tetrahedron:
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(17) Aminonitrile 3 readily decomposed on TLC plate, Rf value is
given for guidance.
Synlett 2006, No. 11, 1679–1682 © Thieme Stuttgart · New York