SCHEME 1. Biogenetic Scenario for the Formation of
Natural Pyridine Derivatives Extracted from Sponges in the
Order Haplosclerida (from ref 1)
Reaction of Aldimine Anions with Vinamidinium
Chloride: Three-Component Access to
3-Alkylpyridines and 3-Alkylpyridinium Salts and
Access to 2-Alkyl Glutaconaldehyde Derivatives
Jean-Charles Wypych, Tuan Minh Nguyen,
Michel Be´ne´chie, and Christian Marazano*
Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-YVette, France
SCHEME 2. Preparation of Vinamidinium Salt 6
ReceiVed October 25, 2007
In search for practical protocols based on the sequence
depicted in Scheme 1, we recently reported5 the successful
condensation of aldehyde imino derivatives with malonaldehyde
monoacetals or dimethylaminoacrolein, which gives analogues
of 4 and 5. These analogues cyclized in acidic medium to give
the corresponding pyridinium salts. This strategy was limited
by the low reactivity of imines in these conditions, requiring
the use of more reactive silyl derivatives, and the tendency of
2-alkyl-substituted glutaconaldehydes to dimerize in acidic
medium. We thus turned our attention to vinamidinium salts
(see 6, Scheme 2) as malonaldehyde equivalents. These reactive
intermediates were initially used by Nair6 for the preparation
of dienaminones from ketones and esters. More recently, a series
of paper by Davies and Marcoux7 described the synthesis of
2,3,5-trisubstituted pyridine derivatives from the reaction of
ketone enolates with vinamidinium hexafluorophosphates. This
last procedure was reported to be limited to vinamidinium
species possessing an electron-stabilizing substituent at position
2. In this paper, we now report an efficient procedure for the
preparation of 2-alkyl glutaconaldehyde derivatives and the
corresponding 3-alkylpyridine and 3-alkylpyridinium salts start-
ing from aldehydes and featuring, as a key step, condensation
of aldimine anions with vinamidinium chloride.
N-tert-Butylimino derivatives of aldehydes were deproto-
nated with LDA and reacted with vinamidinium chloride to
give 2-alkylaminopentadienimine derivatives, which were
isolated as their corresponding hydrochloride in 68-81%
yield. Reaction of these derivatives with ammonium acetate
or salts of primary amines, in n-butanol at 80 °C, afforded
the corresponding 3-alkylpyridines or 3-alkylpyridinium salts
in high yield. Alkaline hydrolysis of 2-alkylaminopentadi-
eneimine derivatives allowed a practical accesss to potassium
salts of 2-alkylglutaconaldehyde.
We have suggested1 that natural 3-alkylpyridine and 3-alky-
lpyridinium salts 1 (Scheme 1) extracted from sponges in the
order Haplosclerida can be biosynthesized by condensation of
an aldehyde 2 with a three-carbon unit, whose oxidation level
corresponds to malonaldehyde 3, and an amine (ammonia or a
primary amine). In this process glutaconaldehyde derivatives 4
and/or aminopentadienal species 5 were likely to be involved
as intermediates, while their dimerization could also be at the
biosynthetic origin of more complex alkaloids such as man-
zamines and halicyclamines.
This chemistry is of potential synthetic interest since it
constitutes a general three-component access to 3-alkylpyridines
(using ammonia as the amine component) or 3-alkylpyridinium
salts (using primary amines).2 In addition, we recently intro-
duced3 species 4 and 5, and related derivatives, as useful
intermediates in the arena of natural product synthesis.4
Vinaminidium chloride 6 was first prepared using a slight
modification of reported procedures6,8 (Scheme 2).
As a model, we first studied the reaction of salt 6 (Scheme
3) with the anion derived from propionaldehyde tert-butylimine
(3) (a) Jakubowicz, K.; Ben Abdeljelil, K.; Herdemann, M.; Martin, M.-
T.; Gateau-Olesker, A.; Almourabit, A.; Marazano, C.; Das, B. C. J. Org.
Chem. 1999, 64, 7381-7387. (b) Herdemann, M.; Al-Mourabit, A.; Martin,
M.-T.; Marazano, C. J. Org. Chem. 2002, 67, 1890-1897. (c) Sanchez-
Salvatori, M. d. R.; Marazano, C. J. Org. Chem. 2003, 68, 8883-8889.
(4) For a related recent example, see: Kearney, A. M.; Vanderwal, C.
D. Angew. Chem., Int. Ed. 2006, 45, 7803-7806.
(5) Sanchez-Salvatori, M.; Lopez-Giral, A.; Ben Abdeljelil, K.; Marazano,
C. Tetrahedron Lett. 2006, 47, 5503-5506.
(6) Nair, V.; Cooper, C. S. J. Org. Chem. 1981, 46, 4759-4765.
(7) (a) Marcoux, J.-F.; Corley, E. J.; Rossen, K.; Pye, P.; Wu, J.; Robbins,
M. A.; Davies, I. W.; Larsen, R. D.; Reider, P. J. Org. Lett. 2000, 2, 2339-
2341. (b) Davies, I. M.; Taylor, M.; Marcoux, J.-F.; Wu, J.; Dormer, P. G.;
Hughes, D.; Reider, P. J. J. Org. Chem. 2001, 66, 251-255. (c) Marcoux,
J. F.; Marcotte, F.-A.; Wu, J.; Dormer, P. G.; Davies, I. W.; Hughes, D.;
Reider, P. J. J. Org. Chem. 2001, 66, 4194-4199. (d) Davies, I. W.;
Marcoux, J.-F.; Reider, P. J. Org. Lett. 2001, 3, 209-211.
(1) Kaiser, A.; Billot, X.; Gateau-Olesker, A.; Marazano, C.; Das, B. C.
J. Am. Chem. Soc. 1998, 120, 8026-8034.
(2) For a recent review on pyridines and pyridinium salts syntheses,
see: Spitzner, D. In Science of Synthesis; Black, D. StC., Ed.; Georg Thieme
Verlag: Stuttgart, New York, 2005; Vol. 15, pp 11-284.
(8) Wei, X.-Y.; Zong, Z.-M.; Ji, Y.-F. Synth. Commun. 2003, 33, 367-
371.
10.1021/jo702311k CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/10/2008
J. Org. Chem. 2008, 73, 1169-1172
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