Ortho-metallation, amide-directed

The establishment of the stereocenter in efavirenz provides a challenging goal for the synthetic chemist (Pierce et al., 1998 Thompson et al., 1995). The synthesis starts by treating 4-chloroaniline with pivaloyl chloride under biphasic conditions to provide the desired amide 10 (Scheme 6.2). Ortho metallation as directed by the amide is accomplished with two equivalents of n-butyllithium (or w-hexyllithium) in tetramethylethylene diamine (TMEDA) and MTBE. The resulting dianion is quenched with ethyl trifluoroacetate to provide pivaloylamide ketone 11 (Euhrer and Gschwend, 1979). The amide is hydrolyzed in situ to provide the trifluoroketone hydrate hydrochloride 12, which crystallizes from the reaction mixture (>98% pure). 

Snieckus, V. Directed ortho Metalation—Tertiary Amide and o-Carbamate Directors in Synthetic Strategies for Polysubstituted Aromatics, Chem. Rev. 1990, 90, 879-933. 

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. 

The palladium-catalyzed formation of diarylamines has been used in several contexts to form molecules with biological relevance. The ability to prepare haloarenes selectively by an ortho-metallation halogenation sequence allows for the selective delivery of an amino group to a substituted aromatic structure. Snieckus has used directed metallation to form aryl halides that were subsequently reacted with anilines to prepare diarylamines (Eq. 34)) [156]. Frost and Mendon a have reported an iterative strategy to prepare (by palladium-catalyzed chemistry) amides and sulfonamides that may act as peptidomimetics. Diarylamine units are constructed using the DPPF-ligated palladium catalysts, and the products are then acylated or sulfo-nated with 4-bromo benzoyl or arylsulfonyl chlorides [157]. 

Lithium amides add to benzaldehydes to form a-aminoalkoxides that direct ortho metalation, as shown in Scheme In a related process, the a-aminoalkoxides may be metalated by lithium-halogen ex-change. ... 

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. 

Furans and thiophenes normally undergo a-lithiation, but when substituted at the 2-position by an activating group, a competition arises between metalation at the 3-position (ortho lithiation) and the S-posi-tion (a-lithiation). 2-Oxazolinylthiophenes may be lithiated selectively at either the 3- or 5-position by adjusting the reaction conditions tertiary amides give little or no ortho selectivity, but secondary amides direct ortho lithiation reasonably well, as seen in Scheme 23. Both thiophenes and furans that are substituted with an oxazoline or tertiary amide at the 2-position may be dilithiated at the 3- and S-po-sitions. 76 Although secondary amides are less successful at directing ortho lithiation of furans than thiophenes, A, Af,M,lV -tetramethyldiamido phosphates work quite well. Subsequent hydrolysis affords access to butenolides. A typical example is shown in Scheme 24. 

This process involves a straightforward directed ortho metallation (chapter 7) of the pyridine amide 206 and capture by the indole aldehyde 208. Without work-up, the product 209 is lithiated again and the ellipticine quinone 210 is formed in good yield.26... 

Snieckus, V. 1990. Directed ortho metalation. Tertiary amide and O-carbamate directors in synthetic strategies for polysubstituted aromatics. Chem. Rev. 90 879-933. 

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. ... 

Heteroatom-facilitated lithiations , Gschwend, H. W. and Rodriguez, H. R., Org. React., 1979, 26, 1 Directed metallation of 7r-deficient azaaromatics strategies of functionalisation of pyridines, quinolines, and diazines , Queguiner, G., Marsais, F., Snieckus, V., and Epsztajn, J., Adv. Heterocycl. Chem., 1991, 52, 187 Metallation and metal-assisted bond formation in 7r-electron deficient heterocycles , Undheim, K. and Benneche, T., Heterocycles, 1990, 30, 1155 Directed ortho metallation. Tertiary amide and O-carbamate directors in synthetic strategies for polysubstituted aromatics , Snieckus, V., Chem. Rev., 1990, 90, 879. 

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>. 

Clegg W, Dale SH, Hevia E et al (2006) Pre-Metalation structural insights into the use of alkali-metal-mediated zincation for directed ortho-metalation of a tertiary aromatic amide. Angew Chem Int Ed 45 2370-2374. doi 10.1002/anie.200503202... 

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