UV Light-mediated regioselective methylsulfanyl discrimination via Pd-catalyzed cross-coupling reactions of 2,4-dimethylsulfanylpyrido[2,3-d]pyrimidines

ABSTRACT

An effective and novel photochemical method for the preparation of 2,4-disubstituted pyrido[2,3-d]pyrimidines is reported from 2,4-dimethylsulfanyl-pyrido[2,3-d]pyrimidines through a Liebeskind-Sroglcoupling reaction involving an original selective methyl sulfanyl discrimination using UV light as a source of energy. Our strategies involve a two-step and a one-pot approach with reaction times of 11-18 h and yields ranging between 72 and 94%. The two strategies are compared.

GRAPHICAL ABSTRACT

KEYWORDS:

• Photochemical
• pyridopyrimidines
• Liebeskind-Srogl
• regioselective
• methylsulfanyl discrimination

Acknowledgment

The authors would like to thank the College of Pharmacy at Prince Sattam Bin Abdulaziz University for providing the necessary facilities to carry out this research work.

Disclosure statement

No potential conflict of interest was reported by the author.

Notes

1 General procedure for the synthesis of 4: A solution containing 2,4-dimethylsulfanylpyrido[2,3-d]pyrimidine 3 (0.35 mmol), the (het)aryl boronic acid (1.1 equiv), CuTC (2.2 equiv) and Pd(PPh₃)₄ (0.05 equiv) in dry DMF (5 mL) was flushed with argon for 15 min. The brown suspension was irradiated under argon for 8 h. After complete disappearance of starting material 3, a saturated aqueous solution of NaHCO₃ was added, and the mixture was extracted with dichloromethane (3 × 15 mL). The combined organic layers were washed with saturated NaHCO3 (2 × 10 mL). The solvent were evaporated under reduced pressure the residue was next purified by flash chromatography to give the attempted monoarylated products. General procedure for the synthesis of 4′ via Liebeskind-Srogl cross-coupling reaction:

2 A solution containing 4-heteroaryl-2-methylsulfanylpyrido[2,3-d]pyrimidine 4′ (0.35 mmol), the (het)aryl boronic acid (2.2 equiv), CuTC (2.2 equiv) and Pd(PPh₃)₄ (0.05 equiv) in dry DMF (5 mL) was flushed with argon for 15 min. The brown suspension was irradiated under argon for 8 h. After complete disappearance of starting material 4′, a saturated aqueous solution of NaHCO₃ was added, and the mixture was extracted with dichloromethane (3 × 15 mL). The combined organic layers were washed with saturated NaHCO₃ (2 × 10 mL). The solvent were evaporated under reduced pressure the residue was next purified by flash chromatography to give the attempted biarylated products types 4. 4-Phenyl-2-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine 4a: was isolated after flash chromatography (DCM) as a white solid. Mp 128-130°C; IR (ATR-Ge, cm⁻¹) ν 1592, 1456, 1314, 1262, 1078, 914, 856, 789; ¹H RMN (250 MHz, CDCl₃) δ 3.92 (s, 3H, OCH₃), 7.12 (d, J = 7.5 Hz, 2H, H_Ar), 7.50 (m, 4H, J = 2.5, 7.5 Hz, H_Ar, H₆), 7.86 (dd, 2H, J = 2.5, 7.5 Hz, H_Ar), 8.51 (d, 1H, J = 7.5 Hz, H₅), 8.80 (dd, 2H, J = 2.5, 7.5 Hz, H_Ar), 9.21 (d, 1H, J = 2.5 Hz, H₇); ¹³C RMN (62.5 MHz, CDCl₃) δ 55.66 (CH₃), 114.33 (2 × CH), 116.32 (Cq), 122.25 (CH), 128.55 (2 × CH), 129.20 (Cq), 129.28 (2 × CH), 131.28 (CH), 132.03 (2 × CH), 136.52 (CH), 137.48 (Cq), 157.44 (CH), 160.08 (Cq), 161.78 (Cq), 163.49 (Cq), 169.46 (Cq); HRMS (EIMS): m/z calcd for C₂₀H₁₅N₃O: 314.1287, found: 314.1289.

3 General procedure for the one-pot synthesis of 3 via Liebeskind-Srogl cross-coupling reaction: A solution containing 2,4-bimethylsulfanylpyrido[2,3-d]pyrimidine 3 (0.35 mmol), the (het)aryl boronic acid (1.1 equiv), CuTC (2.2 equiv) and Pd(PPh₃)₄ (0.05 equiv) in dry DMF (5 mL) was flushed with argon for 15 min. The brown suspension was irradiated under argon. After complete disappearance of starting material 3, the second (het)aryl boronic acid (1.5 equiv) dissolved in ethanol and added to the reaction. After complete of reaction, a saturated aqueous solution of NaHCO₃ was added, and the mixture was extracted with dichloromethane (3 × 15 mL). The combined organic layers were washed with saturated NaHCO₃ (2 × 10 mL). The solvent were evaporated under reduced pressure the residue was next purified by flash chromatography to give the attempted biarylated products types 4. 2-(4-Methoxyphenyl)-4-(3-thienyl)pyrido[2,3-d]pyrimidine 4c: was isolated after flash chromatography (DCM) as a white solid. Mp 182–184°C; IR (ATR-Ge, cm⁻¹) ν 1616, 1522, 1436, 1382, 1334, 1204, 944, 747 ; ¹H RMN (250 MHz, CDCl₃) δ 3.89 (s, 3H, OCH₃), 7.08 (d, 2H, J =  8.0 Hz, H_Ar), 7.37 (d, 1H, J = 8.0 Hz, H_Het), 7.42 (dd, 1H, J = 4.0, 8.0 Hz, H₆), 7.80 (d, 2H, J = 8.0 Hz, H_Ar), 8.16 (d, 1H, J = 4.0 Hz, H_Het), 8.44 (d, 1H, J = 8.0 Hz, H₅), 8.58 (dd, 1H, J = 4.0, 8.0 Hz, H_Het), 9.15 (d, 1H, J = 4.0 Hz, H₇); ¹³C RMN (62.5 MHz, CDCl₃) δ 55.50 (CH₃), 114.25 (2 × CH), 116.06 (Cq), 121.96 (CH), 125.90 (CH), 128.19 (CH), 128.96 (Cq), 129.94 (CH), 131.90 (2 × CH), 136.50 (CH), 141.81 (Cq), 157.30 (CH), 159.97 (Cq), 160.46 (Cq), 161.71 (Cq), 169.51 (Cq); HRMS (EIMS): m/z calcd for C₁₈H₁₃N₃OS: 320.0858, found: 320.0854.