C O M M U N I C A T I O N S
Scheme 2. Competition between Acid and Ester
Scheme 3. Proposed Mechanism
by intramolecular Mg-Cl coordination (as intermediate 8 illustrated
in Scheme 3), butyric acid (1.5 equiv) was charged along with
additional equivalents of Mg(Ot-Bu)2 (Chart 1) to observe its effect
on the kinetic profile. The fact that in situ generated magnesium
butyrate slowed down the reaction compared to the control experiment
implies that the latter is a less likely scenario. The slower rate is likely
due to magnesium butyrate competitively binding the naphthyridinone
anion.
Acknowledgment. Dedicated to Professor Eric N. Jacobsen on his
50th birthday. We acknowledge Dr. Richard Staples for X-ray single
crystal structure determinations and Kelly Nadeau for early chiral HPLC
method development. We thank Professors Stephen Buchwald, David
MacMillan, Eric Jacobsen, and Paul Reider for valuable discussions.
Supporting Information Available: Complete ref 5b and 5e, additional
supporting data, complete experimental procedures, characterization data, X-ray
single crystal data, and chromatographic analyses of the products. This material
Chart 1. Kinetic Comparison between Added Butyric Acid and
Control
References
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Based on these experiments, a simplistic mechanism can be
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It is also likely that the congested magnesium metal center with
multiple ligands (typically six coordination) could exert an additional
Thorpe-Ingold effect to further enhance the reactivity.16 This Mg tethered
complex 9 is reminiscent of Stork’s Mg-templated intramolecular
Diels-Alder reaction.17 The oxaphilic nature of magnesium also explains
the exclusive selectivity of N-alkylation verses O-alkylation.18
In summary, we have found a highly efficient synthetic method for
the stereoselective N-alkylation of 2-pyridones, amides, and carbamates
with a nonracemic R-chloro- or R-bromocarboxylic acid using a
combination of a potassium and magnesium base. The reaction gives
inversion of stereochemistry with high fidelity to afford a variety of
highly valuable, enantiomerically enriched N-heterocyclic R-carboxylic
acids in one step. Experimental evidence suggests that the intramo-
lecular SN2 of an O-coordinated magnesium carboxylate amide is likely
responsible for the reactivity and selectivity.
(10) Product 2 completely racemizes with excess MOt-Bu (M ) Li, Na, K) in
THF at 60 °C.
(11) The crude all-in reaction mixture was assayed using Karl Fischer titrator.
An equivalent of <0.2 wt% H2O is necessary for this high reactivity.
(12) Boussac, H.; Crassous, J.; Dutasta, J.-P.; Grosvalet, L.; Thozet, A.
Tetrahedron: Asymmetry 2002, 13, 975.
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University Science Books: Sausalito, CA, 2004; pp 496-497.
(17) Stork, G.; Chan, T. Y. J. Am. Chem. Soc. 1995, 117, 6595.
(18) The O-coordination structure of 2-pyridone magnesium complexes has been well
characterized by X-ray single crystallography in the literature. (a) Blake, A. J.;
Gould, R. O.; Grant, C. M.; Milne, P. E. Y.; Reed, D.; Winpenny, R. E. P. Angew.
Chem., Int. Ed. Engl. 1994, 33, 195. (b) Nichol, G. S.; Clegg, W. Inorg.
Chim. Acta 2006, 359, 3474.
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