Ortho metallation protocol

A new synthetic protocol consisting of sequential directed ortho metallation, crosscoupling and a carbamoyl Baker-Venkataraman rearrangement has been applied to an efficient construction of coumarins (see Scheme 10). The formation of o-nitrosobenzaldehyde during the hydrolysis of o-nitrobenzyl tosylate in aqueous acetonitrile has been presented as a strong indication that the nitro group participates in the departure of the tosylate group as shown in Scheme 11. 

Most recently, Monteiro et al. have reported that cyclopalladated compounds derived from the ortho-metalation of benzylic tert-butyl thioethers are excellent catalyst precursors for the Suzuki cross-coupling reaction of aryl bromides and chlorides with phenylboronic acid under mild reaction conditions. A broad range of substrates and functional groups are tolerated in this protocol, and high catalytic activity is attained (Eq. (58)) [93]. 

A rational extension of ortho-tolyl benzamide metalation [68], part of the broadly encompassing lateral metalation protocol [69] that can be DoM-connected, is the DreM equivalent, 154 —> 155 (Scheme 41), which provides a general regioselective route to 9-phenanthrols (156, 157, 158) [70] and may be extended to diaryl nitriles, hydroxylamine ethers, and hy-drazones 160, which provide the corresponding 9-amino derivatives 161 of similar generality 162-165 (Scheme 42), as may also be applied in natural product synthesis [71]. Further opportunities for DoM-cross-coupling and reduction/oxidation chemistry (159) have also been demonstrated [70a]. 

The disclosure of a one-pot directed ortho metalation-boronation and Suzuki-Miyaura cross-coupling of derivatized pyridines 44 to give substituted azabiaryls 45 provided an excellent protocol for the in situ utilization of pyridyl boronic acids whose isolation is known to be difficult <07JOC1588>. The disclosed method relies on the in situ compatibility of LDA and B(Oz-Pr)3 and proceeds in good to excellent yields for the multi-step process. The report details a comprehensive survey of pyridyl boronates and is expected to be of considerable value in the synthesis of bioactive molecules. 

The log, lath-like molecular structure of most liquid crystalline compounds makes the cross-coupling protocol very important in syntheses [178,179]. The method based on arylboronic acids simplifies the procedure for liquid crystal materials of more complex substitution patterns [64,180,181] (Scheme 32). The synthesis of arylboronic acids via ortho-metalation of fiuoroarenes and the successive cross-coupling reaction readily extended the aryl units. The Pd/C-cat-alyzed reaction was also reported as an economical alternative [64]. Several liquid crystals having a biaryl unit are now an industrial process of Merck in Germany (ca. 3 tons/year) [182]. 

The ready availability of ort/io-functionalized arylboronic acids by a direct ortho-metallation-boronation sequence (Scheme 2-45) provides a very useful synthetic link to the cross-coupling protocol. Snieckus has amply demonstrated that the sequence has considerable scope for the synthesis of unsymmetrical biaryls, heterobiaryls, and terphenyls [120]. 

Applications in Retro-Mannich Reactions. Treatment of unprotected gramine with NIS results in smooth conversion to 3-iodoindole (eq 20). 3,4-Disubstituted indoles are obtained by combination of the retro-Mannich process with the directed ortho metalation reaction (DoM) or the Negishi cross-coupling protocol. ... 

A disadvantage of the von Pechmann synthesis is the lack of regioselectivity in coumarin formation with unsymmetrically substituted phenolic substrates. This is avoided by an alternative protocol [37], in which ortho-metalated phenolic ethers 16 are added to alkoxymethylene malonates as primary step ... 

The ready availability of ortAo-functionalized arylboronic acids by a metallation-boronation sequence provides a s)mthetic link to the crosscoupling protocol, which allows syntheses of various polycyclic heteroaromatics via cyclization between two ortho functionalities. The synthesis of arylboronic acids having an CONl 2 OCONEt2, NH Boc, or and their coupling with various... 

In a handful of cases, two CCXIH groups have been activated for the synthesis of biaryls. Larrosa and coworkers reported for the first time the decarboxylative homocoupling of aromatic acids mediated by Pd and Ag [62a]. The reaction makes use of Pd(TFA)j as a catalyst and Ag CO as an additive to afford the desired biaryls in 76-95% yields. The only by-products observed were due to the proto-decarboxylation of the aryl carboxylic acid. Both metals are essential for the reaction, and the role of the Ag salt is not only as the terminal oxidant but also as a mediator of the decarboxylation process. The method is subject to some limitations on the substituents on the benzoic acids. Thus, m- and p-nitrobenzoic acids as well as benzoic acids ortho substituted with F, Br, or MeO failed to give decarboxylative homocoupling products. In all cases, protodecarboxylations to the corresponding arenes were the main products observed. The same problem was reported in the protocol developed by Deng and coworkers, where the best results were obtained with PdCl and PPhj in the presence of Ag COj [62b]. 

In an effort to move away from precious metal catalysts, various reports in recent years have focused on the use of first-row metal catalysts for direct arylations [57-60]. As a representative example of these new developments, we illustrate in Scheme 23.15 the chelate-assisted ortho-C-H arylation of arenes with Fe catalysts [61]. With iron being cheap, nontoxic, and ubiquitous, this protocol is highly attractive for pharmaceutical syntheses. Using the catalyst precursor Fe(acac)j in conjunction with bidentate pyridine ligands, Zn-aryl reagents as aryl transfer reagents and 1,2-dichloroisobutane as the oxidant, excellent yields of the arylated product were obtained. An interesting feature of this reaction is the hydrolysis of the imine moiety after work-up. The reaction conditions tolerate additional functionalities such as cyanides, chlorides, triflates, tosylates, and thiophenes. 

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