Regioselective Synthesis of Linear and Angular Pyridoquinazolones

Significance

Reported is the base-controlled regioselective synthesis of linear and angular pyridoquinazolones by a palladium-catalyzed carbonylation–S_NAr sequence of 2-bromofluorobenzenes 1 with 2-aminopyridines 2. The selectivity is attributed to the base strengths, as DBU is able to deprotonate 2 to generate 2-imino-2H-pyridin-1-ide B, which on reaction with A results in the formation of linear products 3. On the other hand, Et₃N is not able to generate B to a sufficient extent, and 5 is the major product. A variety of 1 and 2 were tested under these conditions, and generally the desired products were obtained in low to moderate yields. Under conditions A, dehalogenated products were observed when halogenated 2 were used, while the corresponding amides 4 were isolated with more sterically hindered substrates [R² = 6-Me, 5,6-(CH=CH-)₂]. In case of the formation of angular products 5, steric and electronic changes in the substrates did not significantly alter the outcome. Higher catalyst loadings were required for the preparation of 6 and 7.

Comment

Quinazolinones have shown unique pharmacological and biological activities (see Review below). Available methods for the synthesis of pyridoquinazolones are either multistep syntheses requiring high temperature (>200 °C) or are substrate specific. The current method provides selective formation of both linear and angular fused pyridoquinazolones at comparatively low temperature. The use of a COPdLBr species to induce S_NAr chemistry is interesting and leads to a wide variety of fluoro derivatives. However, conditions A are not tolerant to halogenated substrates (R² = F, Cl) and lead to poor yields in many cases. Despite these limitations, an advance has been made, and the method will be appreciated by medicinal and organic chemists.

Review

K. Nepali, S. Sharma, R. Ojha, K. L. Dhar Med. Chem. Res. 2013, 22, 1–15.