Some 25 years have elapsed since the topic of metalation reactions was reviewed by Gilman and Morton. The intervening years have been notable for intensive explorations in this area, in part because many organolithium reagents are now commercially available. Specifically, research efforts have been characterized by the discovery of new functional groups that promote metalation, elaboration of novel heterocyclic and olefinic substrates as metalatable species, recognition of new types of lithiating agents, and the continuation of efforts to define accurately the mechanism of metalation. Accordingly, heteroatom-facilitated lithiation has become recognized as an increasingly important tool, not only in the elaboration of carbocyclic aromatic and heteroaromatic systems, but also in synthetic aliphatic chemistry. A few recent reviews have covered the topic in a more limited or less specific sense. It is the purpose of this chapter to survey and classify the vast accumulation of heteroatom-facilitated lithiations recorded since the first coverage in Organic Reactions.



As outlined by Gilman and Morton, the terms “metalation” in general and “lithiation” in particular denote any replacement of a hydrogen atom by metal or lithium. In this review, however, lithiation is defined as the exchange of a hydrogen atom attached to an sp2-hybridized carbon atom by lithium to form a covalent lithium-carbon bond. More specifically, discussion is limited to those metalations that, through the influence of a heteroatom, are characterized by rate enhancement and regioselectivity. In fact, lithiation reactions of this type are noted for an extraordinarily high degree of regioselectivity, metalation generally occurring on the sp2-carbon atom closest to the heteroatom. Based on the relative position of the heteroatom, such lithiations are conveniently classified into two principal categories: alpha and beta (ortho) lithiations.



In alpha lithiations the metalating agent deprotonates the sp2-carbon atom alpha to the heteroatom to form a carbonlithium bond. This sp2-carbon atom may be part of an olefinic or heteroaromatic π system.



In beta lithiations the metalating agent is directed to deprotonate the sp2-carbon atom beta to the heteroatom-containing substituent. The sp2-carbon atom can be part of an aromatic or an olefinic π system. It should be noted that the designation “ortho metalation” is used specifically for the beta metalation of carbocyclic aromatic systems.



This chapter surveys all systems in which alpha and beta lithiations have been observed, with the exception of ferrocenes.


Keywords:

lithiations;
alpha lithiations;
beta lithiations;
scope;
limitations;
alpha activating atom;
oxygen;
sulfur;
nitrogen;
selenium;
tellurium;
halogens;
beta-directing atom;
substrates;
enamines;
vinyl isocyanides;
formamides;
pyrroles;
indoles;
pyrazoles;
imidazoles;
triazoles;
tetrazoles;
alkyl vinyl ethers;
pyrazoles;
pyridines;
pyrimidines;
furans;
oxazolines;
oxazoles;
sulfides;
sulfoxides;
thiophenes;
electron-withdrawing groups;
vinyl halogens;
amines;
ethers;
sulfones;
amides;
alcohols;
ketones;
experimental procedures

Heteroatom‐Facilitated Lithiations

Connection between metalation and cross-coupling strategies. A new convergent route to azacarbazoles.

Bestatin, valinoctin A, and microginin are naturally occurring small peptides containing a nonproteinogenic alpha-hydroxy-beta-amino acid at the N-terminus of the peptide chain. We report here our development of a general method for the synthesis of alpha-hydroxy-beta-amino acids and exemplify this with a synthesis of (-)-bestatin and analogues. Our synthesis utilizes an intramolecular acylnitrene-mediated aziridination to generate a key bicyclic aziridine in excellent yield and stereoselectivity. This bicyclic aziridine can be opened with a number of organometallic reagents to provide a series of substituted oxazolidinones. The oxazolidinones are readily converted to bestatin and a series of bestatin analogues. As part of this approach, we have developed a new method for the synthesis of azidoformates. We have also demonstrated that oxazolidinones can be selectively hydrolyzed in the presence of peptide bonds. This acylnitrene route to bestatin should prove useful for the synthesis of a variety of analogues of bestatin as well as other alpha-hydroxy-beta-amino acids and their corresponding peptides.

Acylnitrene Route to Vicinal Amino Alcohols. Application to the Synthesis of (-)-Bestatin and Analogues.

Review on the metallation of π -deficient heteroaromatic compounds

Reference LSCO-ARTICLE-2007-039doi:10.1002/(SICI)1521-3757(19980605)110:11 3.0.CO;2-B Record created on 2007-05-25, modified on 2016-08-08

John P. Hendrix

Papers

Product distribution in the metalation of some aromatic substrates with n-butyllithium

Steric effects in the metalation of some aromatic substrates with alkyllithium reagents