Synthesis of Indolylpyrimidines via Cross-Coupling of Indolylboronic Acid with Chloropyrimidines: Facile Synthesis of Meridianin D

Palladium catalyzed cross-coupling reaction of 3-indolylboronic acid with 2,4-dichloropyrimidines proceeded regioselectively to yield indolylor bis(indolyl)pyrimidines in high yield, depending on the projection of 3indolylboronic acid.The marine indole alkaloid meridianin D and an analogue were synthesised via the palladium catalyzed cross-coupling reaction as a key step.Marine invertebrates are a very important source of antitumor secondary metabolites.Numerous biologically active indole alkaloids have been isolated from the marine environment over the past few years. [1]2][3][4] Interest in methodology for preparation of marine indole alkaloids has been stimulated both by their novel molecular structures and by their wide range of biological properties.The palladium catalyzed cross-coupling reaction of aryl bromides, aryl iodides, and triflates with arylboronic acids has emerged as an extremely powerful method employed for the formation of C-C bonds. 5Recently, nortopsentins A-D, antifungal marine 1,4-bis(indolyl)imidazole alkaloids, were synthesised through palladium catalyzed cross-coupling of halogenoimidazoles with 3-indolylboronic and 6-bromo-3-indolylboronic acids. 6 It was noted that the synthesis of bis(indolyl)pyrazine was achieved in low yield (10-15%) by palladium catalyzed reaction of dichloropyrazine with substituted indole. 7To the best of our knowledge there are few reports about cross-coupling reactions between indole derivatives and halogenopyrimidines.In this paper we report an efficient synthesis of indolylpyrimidines and bis(indolyl)pyrimidines via crosscoupling reaction of 3-indolylboronic acid with 2,4-dichloropyrimidines and its application to the synthesis of meridianin D. Phenylboronic acid (4) was initially chosen to examine its cross-coupling with 2,4-dichloropyrimidine catalyzed by tetrakis(triphenylphosphine)palladium (Scheme 1).The results are summarized in Table 1.