of (S)-R-methylbenzylamine-derived aminopentadienals or
of an optically active menthyl carbamate did not induce any
significant diastereomeric excess (see Supporting Informa-
tion).
area rely on the construction of the pyrrolidine or piperidine
ring starting from a pyridine derivative. Here, we report a
method in which the aromatic heterocycle is built onto a
five- or six-membered nitrogen compound.
The procedure depicted in Table 1 was not efficient with
aminopentadienal 2d (R′ ) Bn, X ) Br), chosen in order to
avoid double addition, and the hydroxylactam 8,10 derived
from N-methylsuccinimide (Figure 1), even in the presence
The N-benzylpyridinium salts 6b and 6f were subjected
to hydrogenolysis of both the C-N+ and C-Br bonds, in
the presence of triethylamine for 6f,16 to yield the corre-
sponding pyridines. By reduction of the carbamate moiety
or acidic treatment, in the case of the Boc derivative, nicotine
11a, 5-methylnicotine 11b17 and 5-methylnornicotine 11c
were obtained (Scheme 3).
Scheme 3
.
Formation of (()-Nicotine 11a and Derivatives from
Pyridinium Salts 6b and 6fa
Figure 1. Structures of compounds 7 and 8.
of 1 equiv of Zn(OTf)2,11 since the desired product was
obtained in 7% yield only. This result could be attributed to
the lower stabilization and intrinsically poorer reactivity of
the N-methylpyrrolidone-derived N-acyliminium ion, com-
pared to its carbamate counterparts.12
a Significant hydrogenolysis of the benzylic pyrrolidine C-N bond was
observed in the case of 6f.
With 2d as the nucleophilic partner, the pyridinium salts
10 could be obtained, using the open-chain carbamates 9a13
and 9b14 as N-acyliminium ions precursors, through an
R-amidoalkylation-type reaction (Scheme 2).
Since the bromine substituent opens up avenues for the
introduction of other functionalities, a method for debenzyl-
ation of the pyridinium ion without hydrogenolysis of the
C-Br bond was developed. Taking advantage of the leaving
group properties of the PMB moiety, due to the stabilization
of the p-methoxybenzyl cation, a complete transfer of this
group onto pyridine was achieved by heating pyridinium salt
6g in this solvent (Scheme 4).18 Reduction of the carbamate
moiety with LiAlH4 led to 5-bromonicotine 12,19 a compound
which has previously been converted to the anti-Parkinson’s
drug SIB-1508Y.20
Scheme 2. Formation of Pyridinium Salts 10 via the Addition of
,
Open-Chain N-Acyliminium Ions onto Aminopentadienal 2da b
(15) For a recent review on the synthesis of nicotine and its derivatives,
see: (a) Wagner, F. F.; Comins, D. L. Tetrahedron 2007, 63, 8065–8082.
For selected syntheses of nicotine and anabasine, see: (b) Felpin, F.-X.;
Girard, S.; Vo-Thanh, G.; Robins, R. J.; Villie´ras, J.; Lebreton, J. J. Org.
Chem. 2001, 66, 6305–6312. (c) Spangenberg, T.; Breit, B.; Mann, A. Org.
Lett. 2009, 11, 261–264.
a Same conditions as for Table 1. b TFA (1 equiv) was added at rt, after
heating, and the mixture stirred for cyclization completion (20 mn).
(16) A base is added to trap HBr, released during hydrogenolysis of
the C-Br bond, which favors the ring-opening of the N-methoxycarbon-
ylpyrrolidine. This could be related to the racemization of nicotine
derivatives with chloroformates: Bleicher, L. S.; Cosford, N. D. P. J. Org.
Chem. 1999, 64, 5299–5300.
To illustrate the method, an application to the synthesis
of natural pyridine-containing alkaloids, such as nicotine and
anabasine, was envisaged. The simplicity of the molecular
architecture of these compounds and the important biological
profile of nicotine have attracted significant attention from
the synthetic chemistry community.15 Most syntheses in this
(17) Racemic compound: (a) Seeman, J. I.; Secor, H. V.; Chavdarian,
C. G.; Sanders, E. B.; Bassfield, R. L.; Whidby, J. F. J. Org. Chem. 1981,
46, 3040–3048. Enantiomerically enriched (S)-(-) compound: (b)
Chavdarian, C. G.; Sanders, E. B.; Bassfield, R. L. J. Org. Chem. 1982,
47, 1069–1073. (()-5-Methylnicotine has the same affinity than nicotine
for the R4ꢀ2 nicotinic cholinergic receptor: (c) Dukat, M.; Ramunno, A.;
Banzi, R.; Damaj, M. I.; Martin, B.; Glennon, R. A. Bioorg. Med. Chem.
Lett. 2005, 15, 4308–4312.
(10) Hubert, J. C.; Wijnberg, J. B.; , P. A.; Speckamp, W. N. Tetrahedron
1975, 31, 1437–1441.
(18) Wanner, M. J.; Koomen, G.-J. Eur. J. Org. Chem. 1998, 889–895.
(19) (a) Castonguay, A.; Van Vunakis, H. J. Org. Chem. 1979, 44, 4332–
4337. (b) Bleicher, L. S.; Cosford, N. D. P.; Herbaut, A.; McCallum, J. S.;
McDonald, I. A. J. Org. Chem. 1998, 63, 1109–1118. For biological
activities of (()-5-bromonicotine, see: (c) Cosford, N. D. P.; Bleicher, L.;
Vernier, J.-M.; Chavez-Noriega, L.; Rao, T. S.; Siegel, R. S.; Suto, C.;
Washburn, M.; Llyod, G. K.; McDonald, I. A. Pharm. Acta HelV. 2000,
74, 125–130. (d) Dukat, M.; Damaj, M. I.; Young, R.; Vann, R.; Collins,
A. C.; Marks, M. J.; Martin, B. R.; Glennon, R. A. Eur. J. Pharmacol.
2002, 435, 171–180.
(11) Zn(OTf)2 (1.2 equiv) was employed in the case of the reactions
mentioned in ref 8.
(12) D’Oca, M. G. M.; Moraes, L. A. B.; Pilli, R. A.; Eberlin, M. N. J.
Org. Chem. 2001, 66, 3854–3864.
(13) For the preparation of 6a, see Supporting Information.
(14) (a) Esch, P. M.; Hiemstra, H.; Speckamp, W. N. Tetrahedron 1992,
48, 3445–3462. (b) Lumbroso, A.; Chevallier, F.; Beaudet, I.; Quintard,
J.-P.; Besson, T.; Le Grognec, E. Tetrahedron 2009, 65, 9180–9187.
4762
Org. Lett., Vol. 12, No. 21, 2010