Construction of functionalized/substituted bipyridines by means of Negishi cross-coupling reactions. Formal synthesis of (±)-cytisine

Article abstract of DOI:10.1016/S0040-4039(01)01664-1

The use of Negishi cross-coupling reaction allows the construction of various substituted and functionalized bipyridines. The efficiency of the method permits to obtain in high yield a direct precursor of racemic cytisine.

Full text of DOI:10.1016/S0040-4039(01)01664-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7787–7790
Construction of functionalized/substituted bipyridines by means
of Negishi cross-coupling reactions.
Formal synthesis of ( )-cytisine
Prosper Nshimyumukiza,a Dominique Cahard,a Jacques Rouden,b Marie-Claire Lasneb and
Jean-Christophe Plaqueventa,*
aLaboratoire des Fonctions Azote´es et Oxyge´ne´es Complexes de l’IRCOF, UMR 6014, Universite´ de Rouen,
Faculte´ des Sciences, Rue Tesnie`re, F-76821 Mont-Saint-Aignan Cedex, France
bLaboratoire de Chimie Mole´culaire et Thio-Organique, UMR 6507, ISMRA, Universite´ de Caen, 6 Bd du Mare´chal Juin,
F-14050 Caen, France
Received 3 September 2001; accepted 4 September 2001
Abstract—The use of Negishi cross-coupling reaction allows the construction of various substituted and functionalized bipyridi-
nes. The efficiency of the method permits to obtain in high yield a direct precursor of racemic cytisine. © 2001 Elsevier Science
Ltd. All rights reserved.
Recently, attention has been directed to the potential
role of neuronal nicotinic acetylcholine receptors. They
are involved in the various pharmacological effects of
nicotine such as addiction, cognition enhancement,
analgesia, neuroprotection and are altered in various
pathologies such as Parkinson’s disease and
Alzheimer’s disease. The use of nicotinic agonists have
thus been envisaged for the prevention of neurodegen-
eration (Fig. 1).1 With the aim of synthesizing new
potential drugs and new ligands for the in vivo visual-
ization of nicotinic receptors, we have previously syn-
thesized new 2,2-disubstituted pyrrolidines2 and
derivatives of (−)-cytisine.3
as a reference in the study of new nAChRs. In order to
compare the biological profile of the (+) and (−) enan-
tiomers and to have a general access to substituted
derivatives we focused part of our work on the enan-
tioselective synthesis of cytisine.
The initially envisioned retrosynthesis is represented in
Scheme 1. Total syntheses of racemic cytisine were
reported 40 years ago6–8 and new interest in this com-
pound emerged recently with the publication of two
new different approaches from the Pfizer group.9
One of these involved the pyridinium 6, which led after
reduction then cyclization to racemic cytisine in high
yield. The key step in the preparation of compound 6
was either a Stille coupling (direct or in situ) or a
Suzuki reaction.9a,10 These papers prompt us to report
(−)-Cytisine 1, an alkaloid extracted from many Legu-
minosae, exhibits a high affinity (0.4–1 nmol) for nico-
4,5
tinic receptors of subtype a4b2 and is commonly used
Figure 1. High affinity a4b2 nAChRs ligands.
Keywords: alkaloid; bipyridine; cross-coupling reaction.
* Corresponding author. Fax: 0235522971; e-mail: jean-christophe.plaquevent@univ-rouen.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01664-1

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P. Nshimyumukiza et al. / Tetrahedron Letters 42 (2001) 7787–7790
Scheme 1.
the halogen–metal exchange reaction gave a higher
yield than THF (80% versus 20–30%), as sometimes
observed in this series.12
herein our own preliminary work on the synthesis of
the cytisine skeleton. Our approach is based on the
Negishi cross-coupling reaction11 of pyridine 4 (Scheme
2).
Table 2. Synthesis of aldehyde 9
The first step consisted of preparing the bipyridine 7
(Scheme 2).
Entry
RLi
Solvent
Electrophile
Yield 9 (%)
1a
2b
3b
4b
5c
6c
7c
8c
n-BuLi
n-BuLi
t-Buli
THF
THF
THF
THF
Ether
Ether
Ether
Ether
DMF
31
28
23
24
48
25
80
74
As shown in Scheme 2 and Table 1 the Negishi cross-
coupling yielded a mixture of the expected bipyridine 7
in an efficient manner (79%, corrected yield: 84%),
along with a small amount of the terpyridine 8 (11%).
The reaction mixture was easily separated by flash
chromatography on silica gel. In order to minimize the
amount of terpyridine, other reaction conditions were
tested by varying experimental conditions (duration
time, reactant ratio), but all of them gave a lower yield
in the required bipyridine 7 (Table 1). Since both the
yield and the purification procedure were satisfactory,
we continued the synthetic sequence en route to
cytisine.
N-Formylpiperidined
N-Formylpiperidined
N-Formylpiperidined
DMF/THF
PhLi
t-BuLi
n-BuLi
n-BuLi
n-BuLi
DMF/POCl3/THF
DMF/THF
HCOOEt/THF
a The electrophilic reagent was added at −78°C, then the reaction
mixture was allowed to warm up to rt. After cooling again to
−78°C, the reaction was quenched by a mixture THF/concentrated
HCl (10/1), then by water. After neutralization with solid potassium
carbonate, the reaction mixture was worked up as usual.
b The electrophilic reagent was added at −78°C, then the reaction
mixture was allowed to stand for 2 h at −40°C. After cooling again
to −78°C, the reaction was quenched by a mixture THF/water (1/1),
then worked up as usual.
The following step consisted in the formylation of the
bipyridine unit, in order to obtain the precursor of the
alcohol function. Several methods were tried, using
different organolithium reagents and formylating
agents (Table 2). The best result is reported in Scheme
3, and involved n-BuLi and DMF as reagents. Worthy
of note is that the use of diethylether as a solvent for
c The electrophilic reagent was added at −78°C, then the reaction
mixture was allowed to stand for 2 h at this temperature. The
reaction was then slowly warmed up to rt, in about 16 h. After
cooling again to −78°C, the reaction mixture was poured into a
sodium hydrogenocarbonate solution (5%).
d See Ref. 15.
Scheme 2.
Table 1. Negishi cross-coupling conditions
Entry
Time (h)
5 (equiv.)
Conversion (%)
Yield 7 (%)
Yield 8 (%)
1
2
3
4
24
48
24
24
1
1
1.5
2
75
79
88
93
51
55
70
79
Undetermined
19
12
11

P. Nshimyumukiza et al. / Tetrahedron Letters 42 (2001) 7787–7790
7789
Scheme 3. Reagents and conditions: n-BuLi, Et2O, −78°C, 1 h, then DMF (5 equiv.), THF, −78°C to rt; (ii) NaBH4, EtOH, rt;
(iii) Jones oxidation; (iv) BnCl, DMF, 100°C; (v) NaH, DMF, BnBr, rt; (vi) MCPBA, CHCl3, rt; (vii) BnBr (3 equiv.), MeOH;
(viii) BnBr, MeOH, reflux.
Reduction of the carbonyl moiety by means of sodium
borohydride yielded the alcohol 3 in almost quantita-
tive yield. In some experiments, a small amount of the
corresponding amine–borane was detected in addition
to the reduced compound; a simple reaction of the
amine–borane derivative with a water/THF solution of
potassium carbonate transformed quantitatively the
complex into the wanted carbinolbipyridine compound
3. Finally, benzylation with an excess of benzyl bro-
mide led to the bipyridinium salt 6 with a 92% yield.
Benzylation was completely regioselective, in the sense
that only the nitrogen in the 3%-pyridyl unit was alkyl-
ated. Such behavior has previously been described by
us,13 and others,14 and is generally assumed to be due to
the more crowded position of the nitrogen atom of the
2-pyridyl unit. A series of derivatives was obtained by
means of standard procedures (Scheme 3): each of these
compounds could be an interesting starting material for
the construction of cytisine analogs and will be used in
our further studies regarding the possibility of enan-
tioselective reduction possibly giving access to chiral
precursors of cytisine.
simple methods a set of derivatives in the bipyridine
and bipyridinium series, which will be used in further
studies.
Acknowledgements
The research was supported by the ‘Re´seau RINCOF’.
The authors thank Dr. Florence Mongin for helpful
discussions on heteroaromatic cross-coupling reactions.
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Negishi cross-coupling reaction for the construction of
various substituted and functionalized bipyridines. The
high efficiency of this method permits to elaborate a
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