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Novel Route to Pyrido [2,3-d]pyrimidines

August 12, 2014

Hu and coworkers1 were recently able to apply microwave energy to a Heck-Sonogashira reaction to generate functionalized enyne substituted pyrimidines. The pyrimidines are then cyclized to form a various substituted pyrido[2,3-d]pyrimidines. Previous attempts to achieve similar functionalization involved condensation reactions of various pyridine or pyrimidines, a much more difficult route.


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Ideal conditions for the reaction include the use of microwave energy at 80 °C in DMF for 20 minutes with 2.5 equivalents of terminal alkyne, 4 equivalents of (n-Bu)3N, 0.05 equivalents of Pd(PPh3)4, and 0.01 equivalent of CuI. Commonly available Pd(PPh3)4 could be used as the catalyst, however, CuI was required as a co-catalyst for the reaction to proceed. A weak organic base generated the desired eyne while a strong organic base favored the formation of the Sonogashira alkyne product.

The Discover® LabMate microwave synthesizer was used to increase the yield while shortening the reaction time. Without microwave energy, the reaction proceeded overnight at 80 °C and generated 5% of the Sonogashira coupled byproduct. Microwave energy shortened the reaction time to only 20 minutes, as DiscLab.jpgdescribed above, and increased the yield from 67% to 71%, while reducing the byproduct formation to <5%. Once generated, the eyne products were cyclized using catalytic silver trifluoroacetate in TFA. With the exception of one, the eynes generated were able to cyclize to the desired substituted pyrido[2,3-d]pyrimidines in good to excellent yields.

The authors were able to demonstrate a quick and easy path to access a difficult product. The novel Heck-Sonogashira procedure to generate the functionalized eyne substituted pyrimidines, followed by cyclization to form substituted pyrido[2,3-d]pyrimidines. The same method could be applied to a variety of different substrates to access many of the biological molecules with the same structural motif.


1Liu, Y.; Jin, S.; Wang, Z.; Song, L.; Hu, Y.; Org. Lett., 2014, 16 (13), 3524.

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