A Sequential Homologation of Alkynes and Aldehydes for Chain Elongation with Optional ¹³C-Labeling

Terminal alkynes (RCCH) are homologated by a sequence of ruthenium-catalyzed anti-Markovnikov hydration of alkyne to aldehyde (RCH₂CHO), followed by Bestmann-Ohira alkynylation of aldehyde to chain-elongated alkyne (RCH₂CCH). Inverting the sequence by starting from aldehyde brings about the reciprocal homologation of aldehydes instead. The use of ¹³C-labeled Bestmann-Ohira reagent (dimethyl ((1-¹³C)-1-diazo-2-oxopropyl)phosphonate) for alkynylation provides straightforward access to singly or, through additional homologation, multiply ¹³C-labeled alkynes. The labeled alkynes serve as synthetic platform for accessing a multitude of specifically ¹³C-labeled products. Terminal alkynes with one or two ¹³C-labels in the alkyne unit have been submitted to alkyne-azide click reactions; the copper-catalyzed version (CuAAC) was found to display a regioselectivity of >50 000:1 for the 1,4- over the 1,5-triazine isomer, as shown analytically by ¹³C NMR spectroscopy.