Directed ortho metalation, also

Amide-directed metallation-transmetallation enables allylation to be achieved in the 3-position of the naphthalene derivative 23, cyclisation of which yields the naphtho[2,3-c]pyran-l-one (Scheme 23). Application of similar methodology to benzothiophene afforded the [l]benzothieno[2,3-c]pyran system <01TL5955>. Directed ortho metallation also features in a synthesis of 4-arylisochroman-3-ols <01TL9293>. 

The synthesis of hippadine (44) and ungeremine (48) was performed by a combination of the directed ortho metallation and the modified Suzuki cross coupling reactions 134) (Scheme 15). (7-Bromo-5-mesyloxy)indoline reacted with (6-formyl-3,4-methylenedioxy)benzeneboronic acid under the modified Suzuki reaction conditions to give the pyrrolophenanthridone ring system 128, which was reduced with sodium bis(2-methoxyethoxy)alumi-num hydride (SMEAH) in boiling toluene to produce ungeremine (48) in 54% yield. Also, starting with 7-iodoindoline, a similar reaction sequence afforded anhydrolycorin-7-one (119), which was transformed to hippadine (44) in 90% yield by oxidation with DDQ. 

Metal hydroxides of first- and second-group elements can enhance ortho substitution, the degree of which depends on the strength of metal-chelating effects linking the phenolic oxygen with the formaldehyde as it approaches the ortho position. Transition metal ions of elements such as Fe, Cu, Cr, Ni, Co, Mn, and Zn as well as boric acid also direct ortho substitutions via chelating effects (Fig. 7.9). 

Ortho-directed metallations also allowed the synthesis of ferrocene-based hydroxamic acids such as 17 and 18 [23] as well as the preparation of planar-chiral carbenes 19 and 21 (which were trapped as chromium and rhodium complexes, 20 and 22, respectively) [24], In this context it is noteworthy that 19 was the first carbene with planar chirality ever reported. 

Other examples of intramolecularly coordinated (by 0 as well as by N groups) organolithium compounds can be found in Setzer and Schleyer (2) and Seebach (4). Two recent reviews are also pertinent. Klumpp (34) deals with 0- and N-assisted lithiation and carbolithiation of nonaromatic compounds, and Snieckus (34a) deals with directed (by amide and carbamate groups) ortho metalation in polysubstituted aromatics. 

Activation of aromatic compounds by transition-metal complexes was initially studied with Cr(CO)3 complexes. Nucleophilic addition of 2-lithio-l,3-dithianes to arene-chromium(O) complexes 185 followed usually by iodine-promoted decomplexation affords the corresponding 2-arylated 1,3-dithianes 186. The reaction of //-(toluene)- and (anisole)tricarbonylchromium (185) with compound 161 gave mixtures (52 46 and 10 90, respectively) of ortho and meta substituted derivatives (186) (Scheme 54)244. The meta directing effect was also observed (mainly better than 95%) with amino and fluoro substituted complexes245. 

A dye molecule that has found widespread attention in the synthetic metals community is phthalocyanine 186, which can be readily made from ortho-dicyanobenzene 187 in a metal-assisted cyclotetramerization that directly provides metal complex derivatives 188 (see scheme 44) [251]. A tuning of the electronic properties is possible via the central atom and, for example, by proceeding to the related tetranaphthalene compound 189 [252]. The importance of phthalocyanines 188 in both fundamental and industrial research comes from the great number of possible applications [253]. Also, 188 can be stacked into columnar arrays by using axial ligands at the metals or by linking silicon centers as central atoms by suitable spacers [254]. The introduction of long chain alkoxy... 

The pATa data listed in Table 1 note that tertiary amides are mote acidic than several other functional groups, suggesting thermodynamic acidity as an important component of the mechanistic rationale for their lithiation. Indeed tertiary amides are the strongest ortho directing group, taking preference over all other functional groups tested in both intra- and inter-molecular competition experiments. - N.. A -Tetramethylphosphonic diamides also promote efficient ortho metalation. The use of tertiary amides as ortho directors was reviewed in 1982, so this discussion will focus only on developments since then. 

Slocum and co-workers (18) recently examined the effect of TMEDA on directed metalation reactions. N,N-Dimethylbenzylamine, /3-phenyl-ethyldimethylamine, N,N-dimethylaniline, and anisole, all known to undergo ortho metalation with BuLi but at a relatively slow rate, were each lithiated under conditions similar to those previously reported, except that one equivalent of TMEDA was added to each metalation reaction. In three cases, the metalation rate was increased significantly with only a slight loss in overall yield. These workers also found that the site of ring metalation with p-methoxy-N,N-dimethylbenzylamine can be reversed by using TMEDA. 

We therefore wished to avoid the formation of the 4-lithio species, and examined the use of a non-exchangeable group at the 4- position in place of the iodide. We chose to study the 4-chloropyridine derivative 45 based on the fact that chlorine is known to direct ortho-lithiations at -78 °C and does not undergo halogen-metal exchange. Chloropyridines are also susceptible to nucleophilic aromatic substitution with alkoxides, and as such this compound contains a handle for the introduction of the methoxy group at the 4-position as required later in the synthesis. 

Ortho direction of metallation to C-3 by 2-bis(dimethylamino)phosphate and 2-oxazoline groups, and to C-2 by 3-hydroxymethyl have also been described. 5-Lithiation of furans with non-directing groups at C-2 provides a route to 2,5-disubstituted furans but choice of lithiating conditions can outweigh ortho directing effects as illustrated. ... 

Ortho direction of metallation to C-3 by 2-bisdimethylaminophosphate and 2-oxazolidine groups, and to C-2 by 3-hydroxymethyl,have also been described. 

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