Transition-Metal-Free N9-Amidoalkylation of Purines with N,N-Dialkylamides

Abstract

A novel method for the selective N9-amidoalkylation of purines using N,N-dialkylamides as alkylation reagents via activation of sp³ C–H bond adjacent to an amide nitrogen atom has been developed in the presence of KI and tert-butyl hydroperoxide (TBHP). This method was simple to operate and provided series of purine derivatives in moderate to excellent yield.

Key words

purines - amides - transition-metal-free - activation of sp³ C–H bond - amidoalkylation

• References and Notes

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• 10 Compound 3a: yield 40.4 mg, 86%; white solid; ¹H NMR (400 MHz, CDCl₃): δ = 8.55 (s, 1 H), 8.26 (s, 1 H), 5.73 (s, 2 H), 4.20 (s, 3 H), 3.24 (s, 3 H), 2.12 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.28, 161.12, 152.30, 152.25, 143.49, 120.78, 54.29, 36.64, 21.64. ESI-HRMS: m/z calcd for C₁₀H₁₃N₅NaO₂ [M + Na]⁺: 258.0961; found: 258.0965.
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• 12 Experimental Procedure Purine substrate 1 (0.2 mmol), KI (0.02 mmol, 3.32 mg), dried N,N-dialkylamides 2 (2 mmol, 0.2 mL) and TBHP (0.4 mmol, 70% in water) were successively added into a sealed tube. The resulting mixture was stirred at 80 °C for 10 h. After the reaction finished, the reaction mixture was cooled to r.t. and quenched by the addition of a sat. solution of NaHSO₃ (3 mL). The mixture was extracted with CH₂Cl₂ (3 × 6 mL), the combined organic phases were dried over anhydrous Na₂SO₄, and the solvent was evaporated under vacuum. Then the residue was purified by flash column chromatography on silica gel or preparative TLC on GF254 to afford the desired product 3.
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