Download PDF
Synlett 2002(11): 1901-1903
DOI: 10.1055/s-2002-34881
LETTER
© Georg Thieme Verlag Stuttgart · New York

Selective N1-Alkylation of 3,4-Dihydropyrimidin-2(1H)-ones Using Mitsunobu-Type Conditions

Doris Dallinger, C. Oliver Kappe*
Institute of Chemistry, Organic and Bioorganic Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, 8010 Graz, Austria
Fax: +43(316)3809840; e-Mail: oliver.kappe@uni-graz.at;
Further Information

Publication History

Received 18 August 2002
Publication Date:
21 October 2002 (online)

    Permissions and Reprints All articles of this category

Abstract

The regioselective N1-alkylation of 3,4-dihydropyrimidin-2(1H)-ones via Mitsunobu reaction is reported. Using the highly reactive Mitsunobu coupling reagent combination N,N,N′,N′-tetramethylazodicarboxamide/tributylphosphine (TMAD-TBP) and a set of primary alcohols a small library of N1-alkylated dihydropyrimidones is obtained in good to excellent yields.

Key words

Mitsunobu reaction - selective alkylations - amides - dihydropyrimidones - Biginelli condensation

5

Note that the successful use of N,N′-disubstituted and N-aryl-ureas in the Biginelli condensation is not well documented in the literature. In our own hands, these building blocks often produced mixtures of various unidentified products along with only small amounts of the desired dihydropyrimidones. See also: Kappe, C. O.; Stadler, A. Org. Synth. 2003, 63, in press.

14

Typical Experimental Procedure (Outlined for Entry 5): In a dry 5 mL reaction vial the appropriate DHPM (R1 = EtO, R2 = Ph, R3 = Me; 26 mg, 0.10 mmol) was dissolved in anhyd dioxane (0.5 mL) at 70 °C. After cooling to r.t. benzyl alcohol (54 mg, 0.50 mmol, 52 µL), TBP (51 mg, 0.25 mmol, 62 µL) and TMAD (43 mg, 0.25 mmol) were added. The vial was sealed, flushed with argon and the reaction mixture shaken for 15 h at r.t. The white precipitate that was formed was filtered off, and the crude reaction mixture separated by silica gel flash chromatography (DCM:EtOAc 1:1) providing 21.2 mg (61%) of N1-alkylated DHPM as colorless crystals, mp 155 °C (lit. [6] 155-156 °C). 1H NMR (DMSO-d 6): δ = 1.09 (t, J = 7.1 Hz, 3 H), 2.36 (s, 3 H), 4.02 (q, J = 7.1 Hz, 2 H), 4.84 and 5.09 (2 d, J = 16.6 Hz, 2 H), 5.24 (d, J = 3.2 Hz, 1 H), 7.06 (d, J = 7.0 Hz, 2 H), 7.22-7.35 (m, 8 H), 8.16 (d, J = 3.3 Hz, 1 H). MS (APCI): m/z (%) = 351(28) [M+].