Oxidation of Biginelli Reaction
Products: Synthesis of 2-Unsubstituted 1,4-Dihydropyrimidines,
Pyrimidines, and 2-Hydroxypyrimidines

Sam Sik Kim; Bo Seung Choi; Jae Hoon Lee; Ki Kon Lee; Tae Hee Lee; Young Ho Kim; Hyunik Shin

doi:10.1055/s-0028-1087920

LETTER

Oxidation of Biginelli Reaction Products: Synthesis of 2-Unsubstituted 1,4-Dihydropyrimidines, Pyrimidines, and 2-Hydroxypyrimidines

Sam Sik Kim^a, Bo Seung Choi^a, Jae Hoon Lee^a, Ki Kon Lee^a, Tae Hee Lee^a, Young Ho Kim^b, Hyunik Shin*^a
^a Chemical Development Division, LG Life Sciences, Ltd./R&D, 104-1, Moonji-dong, Yusong-gu, Daejon 305-380, Korea
Fax: +82(42)8665754; e-Mail: hisin@lgls.com;
^b Department of Fine Chemical Engineering & Applied Chemistry, BK21-E2M, Chungnam National University, Daejeon 305-764, Korea

Abstract

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Abstract

We have devised a new route toward 2-unsubstituted pyrimidine derivatives from the Biginelli product, dihydropyrimidin-2(1H)-thiones in two steps: Oxidation of dihydropyrimidin-2(1H)-thiones using oxone on wet alumina or hydrogen peroxide in the presence of catalytic amount of vanadyl sulfate provided 1,4-dihydropyrimidine, which was further oxidized to 2-unsubstituted pyrimidines by the treatment of KMnO₄. Oxidation of dihydropyrimidin-2(1H)-ones by KMnO₄ formed 2-hydroxypyrimidine in excellent yield, whereas attempted direct desulfurative aromatization of dihydropyrimidin-2(1H)-thiones by KMnO₄ resulted in the formation of 2-hydroxypyrimidines, the same products obtained in the oxidation of dihydropyrimidin-2(1H)-one.

Key words

Biginelli reaction - desulfurative oxidation - 2-unsubstituted pyrimidine - 1,4-dihydropyrimidine - 2-hydroxypyrimidine

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Referenzen

References and Notes

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23 Greenhalgh RP. Synlett 1992, 235

24

General Procedure for the Preparation of 1,4-Dihydro-pyrimidines 2a-e To a stirred mixture of 1a (1 g, 3.62 mmol) and a catalytic amount of vanadium sulfate (0.0072 g, 10 mol%) in EtOH (2.5 mL) and H₂O (2.5 mL) was added dropwise 30% H₂O₂ (1.52 g, 13.38 mmol) over 1 h maintaining the reaction temperature at about 50 ˚C. After 8-12 h, the mixture was cooled and volatiles were evaporated under vacuum. The mixture was diluted with CH₂Cl₂ (10 mL) and washed with H₂O (30 mL). The separated organic layer was dried with MgSO₄, filtered, and concentrated to afford crude 2a. Column chromatography with EtOAc-n-hexane gave 2a as a white solid (397 mg, 48%).
Spectroscopic Data
Compound 2a: ^¹H NMR (400 MHz, DMSO-d ₆): δ = 9.30 (s, 1 H), 7.30-7.16 (m, 5 H), 5.40 (s, 1 H), 3.97 (q, J = 4.0 Hz, 2 H), 2.22 (s, 3 H), 1.12 (t, J = 2.7 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 167.4, 145.6, 143.3, 128.9, 127.7, 127.6, 100.7, 60.2, 58.0, 19.3, 14.6. ESI-MS: m/z = 245.3 [M + 1].
Compound 2b: ^¹H NMR (400 MHz, CDCl₃): δ = 8.27 (br s, 1 H), 7.26-6.92 (m, 4 H), 5.48 (s, 1 H), 4.08 (q, J = 4.0 Hz, 2 H), 2.62 (q, J = 4.0 Hz, 2 H), 2.22 (s, 3 H), 1.26-1.15 (m, 6 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 167.3, 145.6, 144.4, 143.9, 142.8, 128.4, 127.5, 101.0, 60.2, 57.2, 28.9, 18.8, 15.8, 14.6. ESI-MS: m/z = 273.4 [M + 1].
Compound 2c: ^¹H NMR (400 MHz, CDCl₃): δ = 10.13 (s,
1 H), 9.91 (s, 1 H), 4.83 (t, J = 4.0 Hz, 1 H), 4.26 (m, 2 H), 2.48 (s, 3 H), 1.79-1.14 (m, 11 H), 0.87 (t, J = 2.7 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 164.3, 161.1, 142.7, 107.4, 61.7, 52.5, 51.7, 47.0, 36.9, 31.6, 23.3, 22.7, 17.9, 14.6, 14.3. ESI-MS: m/z = 239.3 [M + 1].
Compound 2d: ^¹H NMR (400 MHz, CDCl₃): δ = 7.43 (s,
1 H), 7.28-7.14 (m, 5 H), 4.63 (t, J = 4.0 Hz, 1 H), 4.18 (m, 2 H), 2.80-2.67 (m, 2 H), 2.28 (s, 3 H), 1.91-1.82 (m, 2 H), 1.26 (t, J = 3.3 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 175.9, 165.8, 165.7, 144.5, 141.1, 128.9, 128.7, 126.5, 103.2, 103.1, 60.8, 60.4, 52.3, 38.3, 30.9, 18.6, 14.7. ESI-MS: m/z = 271.4 [M + 1].
Compound 2e: ^¹H NMR (400 MHz, CDCl₃): δ = 7.34-6.99 (m, 4 H), 5.57 (s, 1 H), 5.40 (d, J = 4.0 Hz, 1 H), 4.09 (m,
2 H), 2.31 (s, 3 H), 1.20 (t, J = 2.7 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 167.1, 162.5 (d, J = 250.0 Hz), 145.1, 142.6, 141.4, 129.2 (d, J = 10.0 Hz), 115.6 (d, J = 20.0 Hz), 115.5, 101.2, 60.3, 57.4, 19.5, 14.6. ESI-MS: m/z = 263.3 [M + 1].

25a Girke WPK. Chem. Ber. 1979, 112: 1

25b de Bie DA. Nagel A. van der Plas HC. Koudijs A. Tetrahedron Lett. 1979, 649

26

General Procedure for the Preparation of 2-Unsubsti-tuted Pyrimidines 3a-e To a stirred solution of 2a (100 mg, 0.41 mmol) in acetone (2 mL) was added KMnO₄ (87 mg, 0.55 mmol). After the complete consumption of 2a, excess of KMnO₄ was decomposed by the addition of 2-PrOH. The reaction mixture was filtered through Celite and washed thoroughly with acetone (10 mL). Removal of solvent afforded product 3a (72mg, 73%) as a white solid.
Spectroscopic Data
Compound 3a: ^¹H NMR (400 MHz, CDCl₃): δ = 9.16 (s, 1 H), 7.68-7.43 (m, 5 H), 4.24 (q, J = 4.0 Hz, 2 H), 2.57 (s, 3 H), 1.10 (t, J = 2.7 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 167.4, 164.7, 162.9, 157.8, 137.2, 131.8, 131.5, 129.9, 128.3, 128.0, 125.7, 61.7, 22.3, 13.4. ESI-MS: m/z = 243.4 [M + 1].
Compound 3b: ^¹H NMR(400 MHz, CDCl₃): δ = 9.13 (s, 1 H), 7.60 (d, J = 4.0 Hz, 2 H), 7.37 (d, J = 4.0 Hz, 2 H), 4.26 (q, J = 4.0 Hz, 2 H), 2.73 (q, J = 4.0 Hz, 2 H), 2.62 (s, 3 H), 1.28 (t, J = 2.7 Hz, 3 H), 1.13 (t, J = 2.7 Hz, 3H). ^¹³C NMR (100 MHz, CDCl₃): δ = 168.3, 165.2, 163.6, 158.4, 147.2, 135.8, 128.8, 128.6, 126.2, 62.3, 29.1, 22.9, 15.8, 14.1. ESI-MS: m/z = 271.3 [M + 1].
Compound 3c: ^¹H NMR (400 MHz, CDCl₃): δ = 9.01 (s, 1 H), 4.48 (q, J = 4.0 Hz, 2 H), 2.79 (t, J = 4.0 Hz, 2 H), 2.54 (s, 3 H), 1.77-1.22 (m, 9 H), 0.92 (t, J = 2.7 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 167.8, 167.7, 164.2, 158.3, 62.2, 36.1, 31.9, 28.9, 22.9, 22.7, 14.4, 14.2. ESI-MS: m/z = 237.3 [M + 1].
Compound 3d: ^¹H NMR (400 MHz, CDCl₃): δ = 9.02 (s, 1 H), 7.40-7.00 (m, 5 H), 4.44 (q, J = 4.0 Hz, 2 H), 3.11-3.02 (m, 4 H), 2.54 (s, 3 H), 1.40 (t, J = 3.3 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 167.6, 166.8, 164.6, 158.5, 128.9, 128.8, 127.2, 126.7, 62.4, 38.2, 35.3, 23.2, 14.6. ESI-MS:
m/z = 271.4 [M + 1].
Compound 3e: ^¹H NMR (400 MHz, CDCl₃): δ = 9.14 (s, 1 H), 7.70-7.65 (m, 2 H), 7.21-7.11 (m, 2 H), 4.27 (q, J = 4.0 Hz, 2 H), 2.63 (s, 3 H), 1.18 (t, J = 2.7 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 168.1, 164.4 (d, d, J = 230.0 Hz), 164.0, 162.4, 158.5, 134.0, 131.0 (d, J = 10.0 Hz), 126.2, 116.2 (d, J = 20.0 Hz), 62.5, 23.0, 14.1. ESI-MS: m/z = 261.3 [M + 1].

27

General Procedure for the Preparation of 2-Hydroxy-pyrimidines 5a-e To a stirred solution of 4a (1.0 g, 3.84 mmol) in acetone (20 mL) was added KMnO₄ (1.52 g, 9.60 mmol). After the complete consumption of 4a, the excess KMnO₄ was decomposed by the addition of 2-PrOH. The reaction mixture was filtered through Celite and washed thoroughly with acetone (30 mL). Removal of solvent afforded product 5a (670mg, 81%) as a white solid.
Spectroscopic Data
Compound 5a: ^¹H NMR (400 MHz, CDCl₃): δ = 7.61-7.41 (m, 5 H), 4.05 (q, J = 4.0 Hz, 2 H), 2.62 (s, 3 H), 0.94 (t, J = 2.7 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 167.4, 164.7, 162.9, 157.8, 137.2, 131.8, 131.7, 131.5, 129.9, 128.3, 128.0, 125.7, 61.7, 22.3, 13.4. ESI-MS: m/z = 259.3 [M + 1].
Compound 5b: ^¹H NMR (400 MHz, CDCl₃): δ = 7.52-7.13 (m, 4 H), 4.80-4.26 (m, 2 H), 3.01 (q, J = 4.0 Hz, 2 H), 2.84 (s, 1 H), 2.69-2.45 (m, 2 H), 2.30 (s, 3 H), 1.26 (t, J = 2.7 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 165.8, 141.0, 140.4, 129.0, 128.8, 128.7, 126.9, 126.8, 62.2, 38.8, 31.8, 31.0, 30.7, 30.1, 25.5, 14.6. ESI-MS: m/z = 287.3 [M + 1].
Compound 5c: ^¹H NMR (400 MHz, CDCl₃): δ = 4.42 (q, J = 2.0 Hz, 2 H), 2.80 (t, J = 2.0 Hz, 2 H), 2.53 (s, 3 H), 1.73-1.26 (m, 9 H), 0.90 (t, J = 2.7 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 166.0, 158.7, 111.8, 62.1, 32.0, 31.8, 31.5, 22.8, 14.6, 14.29, 14.26. ESI-MS: m/z = 253.3 [M + 1].
Compound 5d: ^¹H NMR (400 MHz, CDCl₃): δ = 7.52-7.13 (m, 5 H), 4.80-4.26 (m, 2 H), 3.01 (q, J = 4.0 Hz, 2 H), 2.84 (s, 1 H), 2.69-2.45 (m, 2 H), 2.30 (s, 3 H), 1.26 (t, J = 2.7 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 175.9, 165.8, 165.7, 144.5, 141.1, 128.9, 128.7, 126.5, 103.2, 103.1, 60.8, 52.3, 38.3, 30.9, 18.6, 14.7. ESI-MS: m/z = 287.3 [M + 1].
Compound 5e: ^¹H NMR (400 MHz, CDCl₃): δ = 7.65-6.97 (m, 4 H), 4.11 (q, J = 4.0 Hz, 2 H), 2.62 (s, 3 H), 1.02 (t, J = 2.7 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 165.5, 162.4 (d, J = 250.0 Hz), 146.4, 139.7, 139.6, 128.4 (d, J = 10.0 Hz), 115.5 (d, J = 20.0 Hz), 101.4, 60.1, 55.0, 18.5, 14.2. ESI-MS: m/z = 277.3 [M + 1].