Download PDF
Synlett 2010(11): 1657-1660  
DOI: 10.1055/s-0030-1258080
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of 2-Substituted Pyrimidines via Cross-Coupling Reaction of Pyrimidin-2-yl Sulfonates with Nucleophiles in Polyethylene Glycol 400

Xi-Cun Wang*a,b, Guo-Jun Yanga,b, Zheng-Jun Quana,b, Peng-Yan Jia,b, Jun-Ling Lianga,b, Rong-Guo Rena,b
a Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, China, Gansu 730070, P. R. of China
b Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Northwest Normal University, Anning East Road 967#, Lanzhou, Gansu 730070, P. R. of China
Fax: +86(931)7971971; e-Mail: wangxicun@nwnu.edu.cn;
Further Information

Publication History

Received 28 April 2010
Publication Date:
10 June 2010 (online)

    Permissions and Reprints All articles of this category

Abstract

A mild and rapid procedure to the synthesis of 2-substituted pyrimidines was developed via sequential functionalization of easily available Biginelli 3,4-dihydropyrimidine-2(1H)-ones via oxidation, esterification, followed by cross-coupling reaction of ­pyrimidin-2-yl sulfonates with N, S, and O nucleophiles in PEG-400 as a green reaction medium at room temperature.

Keywords

2-substituted pyrimidines - oxidation - esterification - cross-coupling reaction - PEG-400

15

General Procedure for the Preparation of 3
To a stirred mixture of compound 2 (1 mmol) and p-toluenesulfonyl chloride (1.5 mmol) in PEG-400 (2 g), K2CO3 (1.5 mmol) was added at 0 ˚C. The reaction mixture was taken slowly to r.t. and stirred for ca. 40 min. After complete conversion (TLC monitoring), the crude reaction mixture was poured into H2O to induce precipitation. The solid was filtered and washed with copious amounts H2O, then recrystallized from EtOH to give pure pyrimidin-2-yl sulfonates 3 as white solid. Selected Data for Compound 3a
Mp 106-108 ˚C. ¹H NMR (400 MHz, CDCl3): δ = 1.06 (t,
3 H, J = 7.2 Hz), 2.45 (s, 3 H), 2.57 (s, 3 H) 4.20 (q, 2 H, J = 7.2 Hz), 7.32-8.03 (m, 9 H). ¹³C NMR (100 MHz, CDCl3): δ = 13.6, 21.7, 22.5, 62.2, 123.8, 128.5, 128.5, 129.3, 129.4, 130.8, 133.8, 136.3, 145.5, 158.7, 166.7, 167.2, 169.6. ESI-MS: m/z = 413 [M + H+].


Table 3 Coupling of Pyrimidin-2-yl Sulfonates 3 with Phenol

Entry Sulfonate 3 R Product 7 Yield (%)c
1a 3a H 7a 88
2b 3a H 7a 90
3a 3a Cl 7b 80
a Reaction conditions A: 3 (1.0 mmol), phenol (1.5 mmol), K2CO3 (1.5 mmol), PEG-400 (2.0 g), r.t., 60 min.
b Reaction conditions B: 3 (1.0 mmol), phenol (1.5 mmol), NaOt-Bu (1.5 mmol), PEG-400 (2 g), r.t., 90 min.
c Isolated yield.
16

General Procedure for the Preparation of 4 and 5 To a stirred mixture of compound 3 (1 mmol) in PEG-400 (2 g) at r.t. were added nucleophiles (1.5 mmol) and K2CO3 (1.5 mmol). After the mixture was stirred at r.t. for 0.5-1 h (TLC monitoring), it was poured into H2O to induce precipitation. The solid was filtered and washed with copious amounts water, then recrystallized from EtOH and PE to give pure products 4 and 5 as white solid.
Selected Data for Compounds 4a
Mp 118-119 ˚C. ¹H NMR (400 MHz, CDCl3): δ = 0.95 (t, 3 H, J = 7.2 Hz), 2.50 (s, 3 H), 3.76 (t, 4, J = 4.8 Hz), 3.93 (m, 3 H), 4.04 (q, 2 H, J = 7.2 Hz), 7.40-7.58 (m, 5 H). ¹³C NMR (100 MHz, CDCl3): δ = 13.5, 23.1, 44.1, 60.9, 66.9, 114.5, 128.1, 128.2, 129.5, 139.3, 160.2, 165.7, 167.0, 168.9. ESI-MS: m/z 328 ([M+H+]).
Selected Data for Compounds 5a
Mp 65-66 ˚C. ¹H NMR (400 MHz, CDCl3): δ = 1.04 (t, 3 H, J = 7.2 Hz), 2.39 (s, 3 H), 2.50 (s, 3 H), 4.14 (q, 2 H, J = 7.2 Hz), 7.21-7.53 (m, 9 H). ¹³C NMR (100 MHz, CDCl3): δ = 13.6, 21.3, 22.6, 61.7, 121.4, 125.9, 128.3, 128.4, 129.7, 130.1, 135.1, 137.4, 139.2, 163.5, 165.8, 168.1, 172.4. ESI-MS: m/z = 365 [M + H+].

17

General Procedure for the Preparation of 6
To a stirred mixture of compound 3 (1 mmol) in PEG-400 (2 g) at r.t. were added nucleophiles (1.5 mmol) and NaOt-Bu (1.5 mmol). After the mixture was stirred at r.t. for 1.5 h (TLC monitoring), the reaction mixture was treated with H2O, and extracted with EtOAc, the organiclayers were dried over Na2SO4. The crude product was purified by flash chromatography (PE-EtOAc, 10:1) to give pure products 6 as colorless oil. Selected Data for Compound 6a
¹H NMR (400 MHz, CDCl3): δ = 0.92 (t, 3 H, J = 7.2 Hz), 1.34 (t, 3 H, J = 6.8 Hz), 2.47 (s, 3 H), 4.05 (m, 2 H), 4.40 (q, 2 H, J = 7.2 Hz), 7.30-7.56 (m, 5 H). ¹³C NMR (100 MHz, CDCl3): δ = 13.4, 14.2, 22.5, 61.3, 63.5, 119.5, 128.0, 128.1, 129.8, 137.7, 163.9, 166.2, 168.1, 168.4. ESI-MS: m/z = 287 [M + H+].