Pyridine, alkyl subs

The Skraup reaction has been applied to the synthesis of pyrazolo[4,3-h]-pyridines (cf. Section II,A,8) but is limited, because of the vigorous conditions involved, to the preparation of alkyl- or phenyl-substituted derivatives. Thus under Skraup conditions 185 (R2 = H) furnished a moderate yield of 1-phenyl products (186, R1 = H,Me),4,89 which were assigned, using UV spectroscopy.4 Attempts to form the 2-substituted isomer from the 5-sub-stituted 4-aminopyrazole 185 (R1 = H R2 = Me) were unsuccessful.4... 

The solution to this synthesis problem goes back to the work of Reiner Sust-mann, who successfully carried out the formal, nickel(0)-mediated addition of alkyl or aryd halides to electron-deficient alkenes, like acrylate esters or acrylonitrile. [101] Sub-stoichiometric amounts of nickel(ll) chloride hexahydrate (15-20 mole %) are reduced with zinc in presence of pyridine to nickel(O), which forms together with pyridine a complex with the alkene. Oxidative addition of the alkyl halide leads to an alkyl-nickel species, the carbon-metal bond of which undergoes an alkene insertion. Hydrolysis gives ultimately the product. Heck reaction products are not observed. 

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