December 1998
SYNLETT
1359
Preparation of Highly Functionalized Pyridylmagnesium Reagents for the Synthesis of
Polyfunctional Pyridines
a
b
b
b
b,
c
a,*
Laurent Bérillon, Anne Leprêtre, Alain Turck, Nelly Plé, Guy Quéguiner, * Gérard Cahiez and Paul Knochel
a
Fachbereich Chemie der Philipps-Universität Marburg, 35032 Marburg, Germany
Fax: +49 6421/28-2189; e-mail: knochel@ps1515.chemie.uni-marburg.de
b
Laboratoire de Chimie Organique Fine et Hétérocyclique de l'IRCOF associé au CNRS, INSA de Rouen, BP 08,
76131 Mont-Saint-Aignan Cedex, France
c
Ecole Supérieure de Chimie Organique et Minérale, 13, Boulevard de l'Hautil, F-95092 Cergy-Pontoise, France
Received 28 August 1998
Abstract: Functionalized iodopyridines bearing either a chloride, ester
or nitrile function were converted to the corresponding
organomagnesium derivatives at -40 °C or -78 °C by treatment with i-
PrMgBr (1.1 equiv, 0.5 h, > 90% yield). The resulting functionalized
Grignard reagents react with aldehydes, TosCN directly or with allylic
bromides and benzoyl chloride after transmetalation with CuCN leading
to polyfunctional pyridines.
ester-functionalized Grignard reagent 2c gives the expected nitrile 3k in
moderate yield (55%; entry 11). The reaction of 2c with benzaldehyde
leads after lactonisation to the pyridine 3j in 56% yield. Allylation
reactions are best performed by adding CuCN (10 mol%) prior to the
addition of allyl bromide. These allylations are complete within 1 h at -
40 °C. A benzoylation of the ester-substituted pyridylmagnesium
reagent is realized by treating these organometallics with CuCN (1.0
equiv, -40 °C, 5 min) followed by the addition of PhCOCl leading to the
expected ketone 3i in 84% yield (entry 9).
Polyfunctional pyridines are important compounds and have found
many pharmaceutical applications. An important method for their
Interestingly, if 2-iodopyridines are used, the I-Mg exchange is
complicated by a competitive homo-coupling reaction due to the high
acceptor character of 2-iodopyridines (Scheme 2). Thus, in the case of
3-cyano-6-iodopyridine (1e), the Mg-I exchange followed by the
quenching with PhCHO affords under our standard conditions a mixture
of the desired product 3n and the homocoupling product 4 (major
product). This result can be greatly improved by performing the I-Mg
exchange at -78 °C by adding slowly the iodopyridine 1e to i-PrMgBr
(1.1 equiv) immediately followed by the addition of benzaldehyde,
leading to the product 3n (67%) with negligible amount of 4 (7%).
1
preparation uses metalated pyridines as intermediates. Especially
lithiated pyridines which display a high reactivity toward many
electrophilic functions proved to be very useful. However, the high
reactivity of the carbon-lithium bond precludes the presence of many
functional groups in the pyridines to be metalated. Since a carbon-
magnesium bond has a lower ionic character, a broader functional group
compatibility should be expected. Recently, we have shown that
polyfunctional aryl iodides are converted to the corresponding Grignard
reagents via a low temperature iodine-magnesium exchange using i-
PrMgBr or i-Pr Mg in THF allowing the preparation under mild
2
conditions of arylmagnesium compounds bearing an ester or nitrile
2
function. Herein, we wish to report an extension of this iodine-
3
magnesium exchange reaction for the preparation of functionalized
pyridylmagnesium reagents and their reaction with typical organic
electrophiles (Scheme 1 and Table 1).
Scheme 2
In summary, we have demonstrated that highly functionalized
pyridylmagnesium reagents can be prepared by an iodine-magnesium
exchange reaction. They react with various electrophiles in satisfactory
to excellent yields. Extension of this exchange to other heterocyclic
iodides is currently underway.
Scheme 1
Acknowledgment: We thank the Deutsche Forschungsgemeinschaft
(SFB 260, Leibniz program), BMBF (03D00562), BASF AG, Procope
program and CNRS for generous support.
Thus, the treatment of an iodopyridine 1 bearing as functional group a
chloride or ester with i-PrMgBr (1.1 equiv) at -40 °C for 0.5 h produces
the desired pyridylmagnesium derivative 2 in > 90% yield as estimated
by GC analysis of reaction aliquots. Remarkably, the presence of an
ester function is compatible with the formation of a pyridylmagnesium
functionality at -40 °C (entries 8-12). Aldehydes like benzaldehyde or
hexanal react well furnishing the corresponding alcohols 3a, 3b, 3e and
3f in 79-92% yields (entries 1, 2, 5 and 6 of Table 1). The reaction of the
References and Notes
(1) Quéguiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J. Adv.
Heterocycl. Chem. 1992, 52, 187. Trécourt, F.; Gervais, B.;
Mallet, M.; Quéguiner, G. J. Org. Chem. 1996, 61, 1673. Mongin,
F.; Mongin, O.; Trécourt, F.; Godard, A.; Quéguiner, G.
Tetrahedron Lett. 1996, 37, 6695. Cochennec, C.; Rocca, P.;
Marsais, F.; Godard, A.; Quéguiner, G. Synthesis 1995, 321.
4
pyridylmagnesium reagent 1b with tosyl cyanide provides 2-chloro-3-
cyanopyridine (3g; entry 7) in 81% yield. The same reaction with the