2-Formyl-4-pyrrolidino Pyridine1

[184304-16-3]  · C10H12N2O  · (MW 176.23)

(catalyst used for the selective methanolysis of a-hydroxy esters)

Physical Data: light-yellow crystalline solid; mp 98-99 °C.

Solubility: soluble in most common organic solvents. Not soluble in water.

Form Supplied in: not commercially available.

Analysis of Reagent Purity: 1H NMR, 13C NMR.

Preparative Methods: this catalyst has been prepared from the isopropyl amide of 2-picolinic acid by metalation with n-BuLi and trapping with iodine, followed by an halogen-dance reaction with LDA to provide the 4-iodo derivative. Nucleophilic aromatic substitution of the iodide for a pyrrolidine in refluxing pyrrolidine is followed by DIBAL reduction of the amide to provide the aldehyde in 34% overall yield for the four steps.1 Alternatively, it can be prepared from 4-pyrrolidino pyridine (PPY) by metalation of the BF3 complex and trapping with DMF.2

Purification: flash chromatography.

Handling, Storage, and Precautions: no special instructions for storage and handling are mentioned in the literature. Use in a fume hood.

Hydroxyl-Directed Methanolysis of Esters

2-Formyl-4-pyrrolidino pyridine (FPP, 1) has been used for the hydroxyl-directed methanolysis of a-hydroxy esters.1 The preference for the methanolysis of para-nitrophenyl glycolate over para-nitrophenyl methoxyacetate is 96:1 in competition reactions (1). The reaction requires active esters such as para-nitrophenyl, para-fluorophenyl, or phenyl esters, and fails with simple alkyl esters. Of these, the para-nitrophenyl esters react about eight times faster than the phenyl esters.

The reagent was designed as a nucleophilic catalyst with two sites, one a binding site (the aldehyde), the other a catalytic site (the pyridine nitrogen). Hydroxyl direction occurs by the formation of a hemiacetal between the hydroxyl group of the substrate and the aldehyde of the catalyst. An extensive examination of the mechanism of the reaction revealed that the pyridine nitrogen acts as a base. Its role is to deprotonate the hydroxyl oxygen of the hemiacetal which acts as a nucleophile, attacks the carbonyl of the substrate, and forms the unusual dioxolanone 3 (2).3 As such, modified catalysts in which the pyridine is more basic are more active, with silicon substitution at the six-position providing the most active catalyst (3, 1, compounds 4-6).

Within this class of catalysts, others are more selective, most notably, the ketone-derived catalysts 7-10.4 These compounds display comparable activity, but significantly greater selectivity for the methanolysis of para-nitrophenyl glycolate over para-nitrophenyl methoxyacetate than the aldehyde-derived catalysts (1700:1 or greater, 4, 2). This is thought to be because in the presence of methanol, the aldehyde-derived catalysts can form hemiacetals in which the hydroxyl group can be deprotonated by the pyridine nitrogen and is therefore capable of nucleophilic catalysis. The ketone-derived catalysts form hemiketals which contain non-nucleophilic tertiary hydroxyl groups and are, therefore, not catalytically active in the non-directed reaction. Thus the most effective catalysts studied to date are 7 and 8.

Related Reagents.

DMAP, 4-dimethylamino pyridine; PPY, 4-pyrrolidino pyridine.

1. Sammakia, T.; Hurley, T. B., J. Am. Chem. Soc. 1996, 118, 8967.
2. Hurley, T. B., The Development of Bifunctional Hydroxyl-Directed Acyl Transfer Catalysts. PhD Thesis, University of Colorado, Boulder, Colorado, 1999.
3. Sammakia, T.; Hurley, T. B., J. Org. Chem. 1999, 64, 4652.
4. Sammakia, T.; Hurley, T. B., J. Org. Chem. 2000, 65, 974.

Tarek Sammakia

University of Colorado, Boulder, Colorado, USA

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