Directed ortho Metalation synthesis

The Henegar modification of the Friedlander reaction has been recently reported. The A-Boc protected derivative of o-aminobenzaldehyde (25, in this case prepared via directed ortho metallation of 24) is a stable, crystalline compound that can be stored for extended periods (in contrast with 4, which typically is freshly prepared). Treatment of 25 with ketone 26 in acetic acid results in deprotection of the aniline in situ and subsequent formation of 27, an intermediate in the synthesis of mappicine. 

The formation of the chromene caibamate 21 from resorcinol dicarbamate involves directed ortho metallation and an intramolecular 0- 0 carbamoyl transfer. Further manipulation utilising directed metallation and transition metal catalysed reactions allows the synthesis of plicadin, a naturally occurring coumestan <99AG(E)1435>. 

The general synthesis of the Daniphos ligands starting from enantiomerically pure [(R)-l-(phenylethyl)dimethylamine]chromiumtricarbonyl 1, is depicted in Scheme 1.4.1 [15]. A directed ortho-metallation (DOM) and subsequent quench with a chlorophosphine leads to an enantiomerically pure planar-chiral complex, which after chlorination using ACE chloride (1-chloroethyl chloroformate) is transformed into the desired diphosphine by a nucleophilic substitution without any loss of optical purity (Scheme 1.4.1) [6, 10]. 

Snieckus, V. The directed ortho metalation— Ullmann connection. A new Cu(I (-catalyzed 231 variant for the synthesis of substituted diaryl ethers. J. Org. Chem. 1999, 64, 2986—2987. 

V Snieckus, Combined Directed Ortho Metalation-Cross Coupling Strategies. Design for Natural Product Synthesis, PureAppl. Chem. 1994, 66, 2155-2158. 

Victor Snieckus is well known for having developed powerful methodological tools for the synthesis of polysubstituted aromatics, in particular heteroaromatic directed ortho-metalation. Thus, in his chapter (No. 10), prepared with his co-author Christian Hartung, directed ortho-metalation is taken as a starting point for new synthetic aromatic chemistry. 

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]. 

Snieckus reported a combination directed ortho-metalation (DoM)-RCM strategy for the synthesis of benzazepine, benzazocine, and benzannulated sulfonamide heterocycles <00SL1294> (Scheme 60). For example, the Boc-protected aniline (75) was sequentially allylated to give 76 which underwent RCM in excellent yield to give benzazepine 77. Use of similar methodology led to 78 and 79 starting from Y-methylbenzamide and p-tolylsulfonamide, respectively. 

A more recent method for the synthesis of isatins is based upon the directed ortho-metalation (DoM) of A-pivaloyl- and 7V-(/-butoxycarbonyl (-anilines. The corresponding dianions are treated with diethyl oxalate and the isatins are obtained after deprotection and cyclisation of the intermediate a-ketoesters. This method has the advantage of being regioselective for the synthesis of 4-substituted isatins from me to-substituted anilines where the substituent is a metalation directing group (e.g. OMe) 49 (Scheme 12). 

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 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]. 

V. Snieckus and co-workers developed a new carbamoyl Baker-Venkataraman rearrangement, which allowed a general synthesis of substituted 4-hydroxycoumarins in moderate to good overall yields. The intermediate arylketones were efficiently prepared from arylcarbamates via directed ortho metallation and Negishi cross coupling. The overall sequence provided a regiospecific anionic Friedel-Crafts complement for the construction of ortho-acyl phenols and coumarins. 

Anctil, E. J. G., Snieckus, V. The directed ortho metalation-cross coupling symbiosis. Regioselective methodologies for biaryls and heterobiaryls. Deployment in aromatic and heteroaromatic natural product synthesis. J. Organomet. Chem. 2002, 653,150-160. 

Snieckus, V. Combined directed ortho metalation-cross coupling strategies. Design for natural product synthesis. PureAppl. Chem. 1994, 66,2155-2158. 

Gray, M., Chapell, B. J., Folding, J., Taylor, N. J., Snieckus, V. The di-tert-butylphosphinyl directed ortho metalation group. Synthesis of hindered dialkylarylphosphines. Synlett 1998, 422-424. 

Dipole moment interactions 955 Diquinocyclobutene, synthesis of 1292 Directed ortho metalation (DoM) reaction 781, 792... 

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. 

Snieckus, V. et al.. Directed ortho metalation-mediated F introduction. Regiospecific synthesis of fluorinated aromatics. Tetrahedron Lett., 35, 3465, 1994. 

There is a rather useful reaction with amides. Organolithium reagents react with DMF to give aldehydes.. An example is the reaction of 231 with s c-butyllithium to give the aryl-lithium reagent (see sec. 8.5.F for directed ortho metalation reactions). Subsequent reaction with DMF and hydrolysis gave a 91% yield of aldehyde 232 in Yamaguchi s synthesis of the radulanins. ... 

Kinsman AC, Snieckus V (1999) Directed ortho metalation-cross coupling route to indolo-4, 5-quinodimethanes. Synthesis of benz[e]indoles. Tetrahedron Lett 40 2453-2456... 

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>. 

Directed ortho Metalation (DoM). The synthesis of the alkaloid schumarmiophytine requires a silicon protection of the more reactive ortho 0-carbamate site to set the stage for the key step, a remote anionic Fries rearrangement that results in a pyridine ring carbamoyl translocation (eq 48). ... 

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