Catalytic Coupling of Arene C–H Bonds and Alkynes for the Synthesis of Coumarins: Substrate Scope and Application to the Development of Neuroimaging Agents

C–H bond functionalization offers strategically
novel approaches to complex organic compounds. However, many C–H
functionalization reactions suffer from poor compatibility with Lewis
basic functional groups, especially amines, which are often essential
for biological activity. This study describes a systematic examination
of the substrate scope of catalytic hydroarylation in the context
of complex amino coumarin synthesis. The choice of substrates was
guided by the design and development of the next generation of fluorescent
false neurotransmitters (FFNs), neuroimaging probes we recently introduced
for optical imaging of neurotransmission in the brain. Comparison
of two mild protocols using catalytic PtCl4 or Au­(PPh3)­Cl/AgSbF6 revealed that each method has a broad
and mutually complementary substrate scope. The relatively less active
platinum system out-performed the gold catalyst with indole substrates
lacking substitution at the C-3 position and provided higher regioselectivity
in the case of carbazole-based substrates. On the other hand, the
more active gold catalyst demonstrated excellent functional group
tolerance, and the ability to catalyze the formation of strained,
helical products. The development of these two protocols offers enhanced
substrate scope and provides versatile synthetic tools required for
the structure–activity examination of FFN neuroimaging probes
as well as for the synthesis of complex coumarins in general.