Efficient Access to Novel Mono- and Disubstituted Pyrido[3,2-d]pyrimidines

Abstract

New mono- and disubstituted pyrido[3,2-d]pyrimidines were synthesized starting from the corresponding 2,4-dichloro derivative through S_NAr and palladium-catalyzed reactions. S_NAr and palladium-catalyzed hydro-deshalogenation occurred selectively at position C-4. Further Suzuki cross-coupling led to C-2 and C-2,4 mono- and disubstituted compounds.

pyrimidines - palladium - Suzuki - S_NAr - selectivity

References and Notes

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12

Synthesis of 4.
A solution containing the 2,3-pyridine-carboxylic acid 2-methylester (2, 5 g, 27.62 mmol) and Et₃N (5.05 mL, 1.3 equiv, 35.90 mmol) in dry THF (100 mL) was cooled at
-10 °C. Ethyl chloroformate (3.96 ml, 1.5 equiv, 41.33 mmol) was added dropwise and the reaction mixture was stirred at this temperature for 1.5 h. A solution of NaN₃ (3.05 g, 1.7 equiv, 46.95 mmol) in H₂O (35 mL) was then added in one portion. After 1.5 h at 0 °C, the resulting heterogeous mixture was filtered, the organic solvent was removed under reduced pressure and the aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over MgSO₄, and concentrated in vacuo. The crude acyl azide was next dissolved in toluene (30 mL) and the solution was refluxed for 2 h. After cooling to r.t., a solution of 4-methoxybenzylamine (3.6 mL, 1 equiv, 27.62 mmol) in pyridine (30 mL) was added and the reaction mixture was refluxed for 24 h. The dark red solution was else evaporated to dryness and the residue was washed with EtOH (2 × 50 mL) and filtered to obtain compound 4 as a white solid (71% yield); mp 328-330 °C. IR (KBr): 3368, 3059, 2853, 1710, 1672, 1401, 1247, 809, 691 cm ^-1. ¹H NMR (250 MHz, DMSO-d ₆): δ = 3.70 (s, 3 H, OCH₃), 5.02 (s, 2 H, CH₂), 6.86 (d, 2 H, J = 8.5 Hz, H_Ar), 7.30 (d, 2 H, J = 8.5 Hz, H_Ar), 7.57-7.67 (m, 2 H, H_Py), 8.49 (dd, 1 H, J = 1.6, 4.1 Hz, H₆), 11.57 (s, 1 H, NH, exchangeable D₂O) ppm. ¹³C NMR (62.5 MHz, DMSO-d ₆) δ = 42.7 (CH₂), 54.7 (CH₃), 113.4 (2 CH), 123.4 (CH), 128.6 (CH), 128.9 (Cq), 129.0 (2 CH), 130.5 (Cq), 136.5 (Cq), 144.8 (CH), 149.4 (Cq), 158.1 (CO), 160.2 (CO) ppm. HRMS (EI-MS): m/z calcd for C₁₅H₁₃N₃O₃: 283.0956; found: 283.0967.

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15

Preparation of 6.
A mixture of 1H,3H-pyrido[3,2-d]pyrimidine-2,4-dione (5, 1 g, 5 mmol), POCl₃ (10 mL) and PCl₅ (5.41 g, 4 equiv) was refluxed for 4 h then cooled to r.t. Excess POCl₃ was evaporated and the residue neutralized with aq Na₂CO₃ and extracted with CH₂Cl₂. The combined organic layers were dried over MgSO₄, and concentrated in vacuo. The residue was purified by flash chromatography (PE-EtOAc, 8:2) to afford compound 6 as a pale yellow solid (58% yield); mp 168-169 °C. IR (KBr): 3068, 1537, 1462, 1443, 1369, 1186, 1107, 878, 831, 794 cm^-1. ¹H NMR (250 MHz, CDCl₃): d = 7.92 (dd, 1 H, J = 4.1, 8.5 Hz, H₇), 8,33 (dd, 1 H, J = 1.6, 8.5 Hz, H₈), 9.14 (dd, 1 H, J = 1.6, 4.1 Hz, H₆) ppm. ¹³C NMR (62.5 MHz, CDCl₃): d = 130.3 (CH), 136.3 (CH), 137.1 (Cq), 149.0 (Cq), 153.2 (CH), 155.8 (Cq), 166.2 (Cq) ppm. HRMS (EI-MS): m/z calcd for C₇H₃ ³⁵Cl₂N₃: 198.9704; found: 198.9715.

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23

Preparation of 9.
A solution containing the 2,4-dichloropyrido[3,2-d]pyrimi-dine (6, 500 mg, 2.5 mmol) in dry THF (25 mL) was cooled at 0 °C. Then, a prebuilt suspension of 2-propanethiol (0.232 mL, 1 equiv) and NaH (105 mg, 60% in oil, 1.05 equiv) in dry THF (15 mL) was dropwise added. The reaction mixture was allowed to r.t. and stirred overnight. Hydrolysis was realized with cold H₂O (30 mL) and the aqueous layers were extracted with EtOAc (3 × 20 mL). The combined organic layers were dried on MgSO_4, filtered and evaporated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE-EtOAc, 8:2) to afford compound 9 (88% yield); mp 93-94 °C. IR (KBr): 2963, 1555, 1518, 1458, 1426, 1334, 1169, 1110, 876, 853, 821, 720 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 1.48 (d, 6 H, J = 6.9 Hz, 2 CH₃), 4.18 (m, 1 H, J = 6.9 Hz, CH), 7.73 (dd, 1 H, J = 4.1, 8.5 Hz, H₇), 8.11 (dd, 1 H, J = 1.6, 8.5 Hz, H₈), 8.84 (dd, 1 H, J = 1.6, 4.1 Hz, H₆) ppm. ¹³C NMR ( 62.5 MHz, CDCl₃): δ = 22.6 (2 CH₃), 35.3 (CH), 129.1 (CH), 135.9 (CH), 137.9 (Cq), 145.1 (Cq), 150.3 (CH), 156.5 (Cq), 178.1 (Cq) ppm. HRMS (EI-MS): m/z calcd for C₁₀H₁₀ ³⁵ClN₃S: 239.02840; found: 239.0273.

24

Diffraction data were collected using a CAD4 Enraf-Nonius. Full crystallographic results have been deposited as Supplementary Materials at the Cambridge Crystallographic Data Centre, University Chemical Lab, 12 Union Road, Cambridge CB2 1EZ UK; e-mail: [e-mail].

25

Preparation of 21.
To a solution of 2-chloro-4-isopropylsulfanylpyrido[3,2-d]pyrimidine (9, 100 mg, 0.42 mmol) in DME (6 mL) were successively added 4-methoxyphenylboronic acid (76 mg, 1.2 equiv) and a solution of Na₂CO₃ (89 mg, 2 equiv) in H₂O (3 mL) and Pd(PPh₃)₄ (24 mg, 0.05 equiv). The reaction mixture was heated at 75 °C under vigorous stirring under argon atmosphere. After complete disappearance of 9, the solution was concentrated in vacuo and the residue diluted in H₂O (10 mL). After extraction with CH₂Cl₂ (3 × 20 mL), the dried organic layers were evaporated to dryness. The crude material was purified by flash column chromatography (PE-CH₂Cl₂, 3:7) to afford compound 21 as a white solid (85% yield); mp 125-126 °C. IR (KBr): 2954, 1600, 1587, 1536, 1458, 1435, 1376, 1165, 839, 821, 747, 696 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 1.58 (d, 6 H, J = 6.9 Hz, 2 CH₃), 3.86 (s, 3 H, OCH₃), 4.33 (m, 1 H, J = 6.9 Hz, CH), 7,00 (d, 2 H, J = 8.8 Hz, H_{3 ′}), 7.65 (dd, 1 H, J = 4.1, 8.5 Hz, H₇), 8.17 (dd, 1 H, J = 1.0, 8.5 Hz, H₈), 8.53 (d, 2 H, J = 8.8 Hz, H_{2 ′}), 8.78 (dd, 1 H, J = 1.0, 4.1 Hz, H₆) ppm. ¹³C NMR (62.5 MHz, CDCl₃): δ = 22.7 (2 CH₃), 34.6 (CH), 55.4 (CH₃), 113.9 (CH), 128.3 (CH), 130.2 (Cq), 130.5 (CH), 136.6 (CH), 138.0 (Cq), 144.4 (Cq), 149.0 (CH), 159.5 (Cq), 162.1 (Cq), 173.8 (Cq). HRMS (EI-MS): m/z calcd for C₁₇H₁₇N₃OS: 311.10923; found: 311.1116.

26 Aboul-Fadl T. Löber S. Gmeiner P. Synthesis  2000,  1727 

27

Synthesis of 25.
A solution of 2,4-dichloropyrido[3,2-d]pyrimidine (6, 1.0 g, 5 mmol), Bu₃SnH (1.48 mL, 1.1 equiv, 5.5 mmol) in toluene (60 mL) was degassed by argon bubbling during 30 min. Then, Pd(PPh₃)₄ (290 mg, 0.05 equiv, 0.25 mmol) was added in one portion and the reaction mixture was placed in a pre-heated oil 100 °C for 1 h. After cooling to r.t., the solvent was evaporated in vacuo and a sat. solution of KF (20 mL) was added. After filtration, the aqueous layers were extracted with EtOAc (3 × 25 mL). The combined organic layers were dried over MgSO₄, and concentrated in vacuo. The crude material was purified by flash chromatography (PE-EtOAc, 8:2) to afford compound 25 as a white solid (86% yield); mp 119-120 °C. IR (KBr): 3059, 1560, 1462, 1439, 1359, 1154, 1098, 873, 822, 696 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 7.89 (dd, 1 H, J = 4.1, 8.5 Hz, H₇), 8.32 (d, 1 H, J = 8.5 Hz, H₈), 9.11 (dd, 1 H, J = 1.6, 4.1 Hz, H₆), 9.54 (s, 1 H, H₄) ppm. ¹³C NMR (62.5 MHz, CDCl₃): δ = 129.5 (CH, C₇), 135.6 (CH, C₈), 139.2 (Cq, C_4a), 148.6 (Cq, C_8a), 153.0 (CH, C₆), 158.0 (Cq, C₂), 164.6 (CH, C₄) ppm. HRMS (EI-MS): m/z calcd for C₇H₄N₃ ³⁵Cl: 165.00937; found: 165.0104.