Palladium- and nickel-catalyzed cross-coupling reactions are at the top of the list for many chemists when it comes to functionalizing aromatic rings. But there are other ways. Exploring the options, a team led by Paul Knochel of Ludwig Maximilian University of Munich, in Germany, has developed a pair of transition-metal-free cross-couplings facilitated by the Lewis acid adduct BF3•O(CH2CH3)2 (Angew. Chem. Int. Ed. 2014, DOI: 10.1002/anie.201400750). In one case, Knochel, Quan Chen, and Thierry León carried out direct oxidative alkynylations of 4-substituted pyridines using alkynyllithium reagents to form 2,4-disubstituted pyridines. In the second case, they performed nonoxidative alkylations of 4-substituted pyridines using an alkylmagnesium reagent. The team realized they could combine the two approaches in tandem syntheses to prepare even more elaborately substituted pyridines (one example shown). Knochel’s group is now using the cross-coupling reactions to functionalize other nitrogen heterocycles and plans to apply the chemistry to natural product synthesis.