Pyrazolo[4,3-d]pyrimidines. Regioselectivity of N-alkylation. Formation, rearrangement, and aldehyde coupling reactions of 3-lithio derivatives

Abstract

It has been previously shown by others7 that upon warming related diaza olefins noncharacterizable black materials are generated. Also upon treatment of either 6 or 7 with hydride ion (NaH, xylene, reflux) rapid deg-radation occurs to give a similar black, high-melting solid (H. C. R. Taylor, unpublished results). N-Alkylation reactions of 3-bromopyrazolo[4,3-d]pyrimidin-7-one and 3-bromo-7-chloro-and 3-bromo-7methoxypyrazolo[4,3-d]pyrimidineswere studied. Alkylations in aqueous base yielded predominately N -l alkyl products, as did trimethysilylation using hexamethyldisilazane. In contrast, alkylation with 2-chlorotetrahydropyran and sodiutn hydride in dimethylformamide or with dihydropyran and an acid catalyst in ethyl acetate yielded predominantly N-2 alkyl products. Formation of 3-lithio derivatives of N -l and N-2 alkylated 7-alkoxypyrazolo[4,3-d]pyrimidines from the corresponding 3-bromo compounds was accomplished by treatment with n-butyllithium at low temperatures. N-1 alkyl compounds yield complex mixtures of products, including those of N-dealkylation and rearrangement with rupture of the pyrazole ring. The N-2 alkylated compound, 3-lithio-7-methoxy-2-tetr~ihydropyran-2'-ylpyrazolo[4,3-d]pyrimidine, was stable and reacted with benzaldehyde in high yield.

Addition of Lithiated 9-Deazapurine Derivatives to a Carbohydrate Cyclic Imine: Convergent Synthesis of the Aza-C-nucleoside Immucillins

“…The lithiated compound derived from the pyrrolo[2,3- c ]pyridine 34 also added successfully to 6 under the same conditions to give the adduct 46 in 69% yield. However, the pyrazolopyrimidine 35 , on lithiation in THF or ether/anisole, failed to give any adduct with imine 6 , whereas it does add to benzaldehyde. The lithiated 35 does not survive warming to the temperature required for addition to 6 .…”

Synthesis of Second-Generation Transition State Analogues of Human Purine Nucleoside Phosphorylase

“…The reductive aminations of the hydrochloride salts of 1 or 9 with an appropriately formylated deazapurine were investigated, as the convergent nature of this reaction was attractive. Formylation of the previously reported bromodeazapurines compounds 11, 15 12, 29 and 13 30 was achieved via lithium-halogen exchange to afford the formyl derivatives 14, 15, and 16, respectively, in good yields (Scheme 3).…”

Imino-C-nucleoside Synthesis: Heteroaryl Lithium Carbanion Additions to a Carbohydrate Cyclic Imine and Nitrone

“…5-O- tert -Butyldimethylsilyl-1,4-dideoxy-1,4-imino-2,3- O -isopropylidene-1-β-(7-methoxy-2-tetrahydropyran-2-yl-1 H -pyrazolo[4,3- d ]pyrimidin-3-yl)- d -ribitol (13). A stirred solution of 3-bromo-7-methoxy-2-(tetrahydropyran-2-yl)-pyrazolo[4,3- d ]pyrimidine (1.0 g, 3.19 mmol) in dry THF at −78 °C was treated with n -butyllithium (2.2 mL, 1.5 M, 3.3 mmol) to give the lithiate 5 , and after 20 min a solution of the imine 3 (0.63 g, 2.21 mmol) in THF (1 mL) was added followed by SnCl 4 (0.51 mL, 4.4 mmol). The mixture was stirred at −70 °C for 2 h and then allowed to warm to 20 °C over 1 h, after which time the reaction was quenched by addition of NaOH (10 mL, 4 M).…”