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Synthesis 2012(7): 1109-1118  
DOI: 10.1055/s-0031-1289744
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

SNAr Reactions of 2-Methylthio-4-pyrimidinones in Pivalic Acid: Access to Functionalized Pyrimidinones and Pyrimidines

Matthew L. Maddess*, Rhiannon Carter
Department of Discovery Process Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
Fax: +1(617)9922403; e-Mail: matthew_maddess@merck.com;
Further Information

Publication History

Received 19 December 2011
Publication Date:
15 March 2012 (online)

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Abstract

Pivalic acid is a useful medium to effect the direct SNAr displacement of 2-methylthio-4-pyrimidinones with a variety of anilines. Products are easily isolated in good to excellent yields, and following chlorination, provide an opportunity to rapidly query structure-activity relationships at the 4-position of functionalized pyrimidines.

Key words

heterocycles - nucleophilic aromatic - solvent effects - medicinal chemistry - regioselectivity

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26

Reactions performed on 1 mmol scale in sealed vials.

27

Three examples have been previously reported in which AcOH was used as a solvent for SNAr reactions of 2-methylthio-4-pyrimidinones (see ref. 1).

29

Methanethiol is generated during the course of the reaction; a nitrogen sweep is recommended especially on large scale with the outlet bubbled through a bleach scrubber.

30

Efficient stirring is recommended and should it become ineffective additional PivOH can be added.

34

Variable levels of pivalic acid (up to 1 molar equiv) were observed in the isolated 2-anilinopyrimidinones. This was not found to be problematic in subsequent halogenation at the 4- or 5-position.