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Synlett 2004(8): 1334-1338  
DOI: 10.1055/s-2004-825607
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of N,N-Dimethylpropanediamide and its Utility for the Preparation of 2-(Acetamidomethyl)-4-aryloxazoles

John A. Ragan*, Michael Burmaster, Paul D. Hill
Chemical Research & Development, Pfizer Global Research & Development, Groton, Connecticut, 06340, USA
Fax: +1(860)7159469; e-Mail: john_a_ragan@groton.pfizer.com;
Further Information

Publication History

Received 9 February 2004
Publication Date:
18 May 2004 (online)

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Abstract

A practical, readily scaleable synthesis of N,N-dimethylpropanediamide (1) is reported. The utility of this bis-amide is d­emonstrated in the preparation of several 2,4-disubstituted oxazoles from α-bromoketones.

Key words

oxazole - bromo-ketone - annulation - N,N-dimethylpropanediamide - heterocycle

    References

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  • 3b

    Interestingly, both Beilstein and Sci-Finder searches for bis-amide 1 gave the preceding reference for its synthesis. We suspect that this was a typographical error upon entry in these databases, as there is no description of compound 1 in the Gellman paper. The Beilstein reference gives a reaction time of 63 h and 81% yield, values which are identical to the first experimental procedure in the paper, in which the mono-N,N-dimethylamide of malonic acid (3) is prepared en route to N,N,N′-trimethylpropanediamide.
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  • 4 This effect has recently been noted in the esterification of carboxylic acids activated at the α-carbon with phosphonates, esters, sulfones, and nitriles. A mechanism proceeding through an acyl ketene was supported by trapping of the ketene with DCC in a [4+2] cycloaddition: Shelkov R. Nahmanh M. Melman A. J. Org. Chem.  2002,  67:  8975 
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5

Intermediacy of a ketene is also supported by the following experiment: exposure of ethyl benzoate to the same reaction conditions (2 N Me2NH in MeOH) for several days showed no detectable formation of N,N-dimethylbenzamide by 1H NMR or GC/MS.

6

Actually, the opposite enantiomer of the other diastereomer would be formed. For example, in the condensation of the R-acid chloride with racemic amine, the products are amide 10 and (ent)-11. This has no impact on the achiral HPLC and NMR analyses, however.