Multi cross-coupling reactions

The cross-coupling reactions can be combined with catalytic cyclization of 2-alkynylphenols in a one-pot, multi-component coupling procedure leading to 2,3-disubstituted benzofurans 39 as shown in Scheme 25 . 

The transition-metal catalyzed cross-coupling reaction of (hetero)aryl hahdes and triflates with primary and secondary amines or (hetero)aryl amines is know as the Buchwald-Hartwig reaction [144]. Mechanistically, this reaction is related to the crosscoupling reactions outlined thus far (Fig. 4.6). The modification arises at the point of transmetalation. This step in the process is substituted with the coordination of the amine reactant. Deprotonation of the amine nitrogen now precedes the reductive elimination step to generate the aryl amine product. This reaction has foimd utility in the academic setting, for use in natural product total synthesis, and in industry, for the preparation of materials up to the multi-hundred kilogram scale. 

The syntheses of benzyl derivatives from benzylic C—H are well developed. Traditionally, multi-step syntheses had to be used. Furthermore, a stoichiometric amount of base was used and toxic halides were produced. To avoid such problems, various catalytic methods have been developed recently via direct functionalization of benzylic C—H bonds. More recently, our group has reported the FeCl2-catalyzed oxidative activation of benzylic C—H bonds followed by a cross-coupling reaction to form C—C bonds (Equation 11.1) [7]. The reactions selectively cleave benzylic C—H bonds and avoid further oxidation. The present methodology opens a window for iron-catalyzed C—H bond oxidation and C—C bond formation. 

In 2010, Andreas Leitner and coworkers [174] at BASF reported the preparation of a very stable 2-pyridylzinc bromide (an sp organometallic nucleophile) on a multi-kilogram scale using Rieke technology and its application in the Negishi-Baba cross-coupling reaction. 

Practical and diversity-oriented synthesis of multi-substituted benzo[lr] furans was accomplished from simple phenols through a Pummerer annula-tion/cross-coupling sequence. Operationally simple and rapid reactions of phenols with ketene dithioacetal monoxides with the aid of trifluoroacetic anhydride provided the corresponding 2-methylsulfanylbenzo[ ]furans (14BCJ1349). 

Therefore, direct functionalization by iridium-catalyzed reactions involving C-H bond activation would provide an alternative protocol to the existing multi-step organic synthesis [116-130]. To date, iridium-catalyzed C-H activation of aromatic rings for reactions such as borylation [131 -136], alkylation/alkenylation [137-143] and silylation [144-146], and cross-coupling [147, 148] has been investigated. 

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