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

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.

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

References and Notes

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<A NAME="RW06810ST-15">15</A>

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

<TD VALIGN="TOP" COLSPAN="5">

</TD><TD VALIGN="TOP"> Entry </TD><TD VALIGN="TOP"> Sulfonate 3 </TD><TD VALIGN="TOP"> R </TD><TD VALIGN="TOP"> Product 7 </TD><TD VALIGN="TOP"> Yield (%)^c </TD><TD VALIGN="TOP"> 1^a </TD><TD VALIGN="TOP"> 3a </TD><TD VALIGN="TOP"> H </TD><TD VALIGN="TOP"> 7a </TD><TD VALIGN="TOP"> 88 </TD><TD VALIGN="TOP"> 2^b </TD><TD VALIGN="TOP"> 3a </TD><TD VALIGN="TOP"> H </TD><TD VALIGN="TOP"> 7a </TD><TD VALIGN="TOP"> 90 </TD><TD VALIGN="TOP"> 3^a </TD><TD VALIGN="TOP"> 3a </TD><TD VALIGN="TOP"> Cl </TD><TD VALIGN="TOP"> 7b </TD><TD VALIGN="TOP"> 80 </TD><TD COLSPAN="20">

---

</TD></TR><TR><TD VALIGN="TOP" COLSPAN="5"> ^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.
</TD><A NAME="RW06810ST-16">16</A>

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⁺].

<A NAME="RW06810ST-17">17</A>

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⁺].