Remote metalation

Directed remote metalation (DreM) of biaryl amides and O-carbamates, conceptually based on the complex-induced proximity effect (CIPE) [15] provides, especially in view of their link to transition metal-catalyzed cross coupling regimens [16], general and versatile routes to fluorenones (16 —> 15, Scheme 4) [5,17] and biaryl amides (16 —> 17) [18] whose features are overriding Friedel-Crafts reactivity and yield enhancement in comparison to Suzuki-Miyaura coupling routes for highly hindered biaryls, respectively. Additional features of the O-carbamate DreM result is potential further DoM of 17 with appropriate phenol protection and cyclization to dibenzopyranones [18]. 

Directed ortho and Remote Metalation (DoM and DreM) 106 Victor Snieckus and T. Macklin... 

The use of transition-metal arene complexes to facilitate nucleophilic aromatic substitution features in a route to derivatives of thiosalicylic acid and hence to thioxanthone. The cyclopentadienyl iron complex of 2-chlorobenzoic acid is converted into the benzamide prior to displacement of the chloride by thiophenoxide. Photolytic decom-plexation followed by directed remote metallation of the diaryl sulfide yielded the heterocycle (Scheme 207) <2000SL975>. 

Snieckus and Fu reported a new general and regiospecific synthesis of 9-phenanthrols involving direct ortho-metalation, Suzuki cross-coupling, and an LDA-mediated directed remote metalation sequence (Eq. (11)) [27]. 

Directed remote Metalation (DreM) in aromatics and heteroaromatics ... 

Beyond Do M The Directed Remote Metalation (DreM) of Biaryl Amides and O-Carbamates I 351... 

Scheme 43. Synthesis of fluorenones by tandem remote metalation-amide DMG translocation.

With metals in place of carbons, we might expect some similarities as well as differences, the latter due to the closer packing of energy levels and the availability of nonbonding (or nearly so) orbitals centered on the metals. One major difference between MeM bonds and CeC bonds is especially evident in nucleophilic addition. In eq. 4, displacement of the tr-bond by a nucleophile renders the remote carbon nucleophilic as a result of its nonbonding lone pair. However, displacement of the -bonds of MhM apparently renders the remote metal electrophilic as seen by electron counting arguments (eq. 5). Assume that both M and M1 have... 

A new approach to gilvocarcins features directed metallation and a Pd(0)-catalysed Suzuki cross coupling to produce the biaryl precursor. LDA remote metallation precipitates an anionic Fries rearrangement and generates the naphtho[ft,d]benzopyran system <97TL8149>. 

Remote metalation of biaryls and m-teraryls provides a general synthesis of substituted and condensed fluorenones (eq47). Similarly, biaryl 0-carbamates undergo remote metalation and anionic Fries rearrangement to 2-hydroxy-2 -carboxamidobiaryls, which are efficiently transformed into dibenzo[fc,i/]pyranones. ... 

For regioselective functionalizations of substituted arenes through directed ortho-metaUation reactions with stoichiometric amounts of organometaUic bases, see (a) Snieckus, V. and Macklin, T. (2005) Metallation of arenes. Directed ortho and remote metallation (DoM and DreM), in Handbook of C-H Transformations (ed. 

Synthetic Methodology Derived from the DoM-Cross-Coupling Nexus 11097 14.3.2.1 Directed Remote Metallation (DreM) Connections... 

Scheme 14.17 Directed remote metallation (DreM) strategies to condensed aromatics and heteroaromatics.

A most instructive demonstration of the power of the combined DoM-cross-coupHng-DreM strategy concerns the synthesis of MK-7285 143 (Scheme 14.29), a powerfiil anti-inflammatory agent In the large-scale synthesis of 143, a one-pot DoM-Suzuld-Miyaura cross-coupling, starting from benzamide 139 and bro-mobenzene 140, leads to the biaryl derivative 141 in excellent yields. Treatment with lithium diethylamide results in a lateral remote metallation of 141, subsequently inducing a cychzation to the phenanthrol derivative 142, which is converted in several steps to 143 [143]. 

James, C.A. (1998) The directed remote metalation - Carbamoyl migration reaction. Total syntheses of the defucogilvocarcins and amottin 1 and synthesis of heteroarylfused benzopy-ranones. Ph.D. Thesis. University of Waterloo, Canada. 

FIGURE 26.8 Directed remote metalation (DreM) categories. 

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