Remote lithiation

The lithiated propargyl carbamate is configurationally stable at -78 °C as long as a bulky substituent (R1) is present at the remote alkynyl position. 

The double lateral lithiation-sUylation of 579 allows the construction of remote stere-ogenic centres of 580 in a single step (Scheme 232) . 

In aromatic compounds, potent but frustrated (their ortho positions blocked) directing groups may lead to lithiations at positions other than ortho. For example, when the carbamate 610 is treated with LDA in refluxing THE, lithiation occurs at a remote position (not peri, note) and an anionic Fries rearrangement ensues to give 611 (see Section I.B.l.d). Lactonization gives 612 (Scheme 239). ... 

Carbamate 613 under the same conditions also undergoes remote lithiation and a remote anionic Fries rearrangement, and then the product amide 614 proceeds to direct a remote benzylic lithiation, even though it has a free ortho position. Finally, the benzylic organo-lithium 615 cyclizes onto the amide to form 616—all in one pot (Scheme 240) . 

Examples of the direct lithiation of sites more remote from heterocyclic 5/ 2-nitrogen are much less common, although evidence for direct 8-lithiation has been seen with 2-phenylthio-4,4-dimethyloxazoline, where migration of the oxazoline ring occurred as a result of nucleophilic attack by the initially formed 8-carbanion (Scheme 143) (83JOC2610). 

The lithiation of allylic positions directed by remote carbonyl groups is observable even when enolates are formed - labelling shows that only the cis methyl group of 140 is deprotonated during the formation of the extended enolate 141.46... 

The double lateral lithiation-silylation of 379 allows the construction of remote stereogenic centres of 380 in a single step.164... 

An important issue in fatty acid analysis is the stractural characterization, especially in terms of positions of double-bond, hydroxy, and other groups. Although results with low-energy negative-ion ESI-MS-MS was described [13], the MS-MS analysis of lithiated lithium salts [M-H+2Li] is the method of choice. Determination of the double-bond position relies on charge-remote fragmentation [2, 14]. 

With lithiated imidazoles, only bis(carbene) complexes are formed, although careful adjustment of the conditions can lead to a compound which contains carbene ligands resulting from both alkylation and protonation411. A similar methodology is applicable with isothiazolyl lithium. In the product the nitrogen atom occupies a position remote from the coordinated carbon (equation 93)412. 

Even a remote Boc-NH unit exerts a directing effect on the lithiation at a benzylic r< sition. Cyclic phosphonamidates form stabilized carbanions that react with elec-Tophiles stereoselectively. A bulky (e.g., f-Pr) group on the nitrogen atom impedes ne approach of the reagents from its side. ... 

Scheme 22 Directed remote C2-lithiation leading to fused indoles...

Snieckus reported a directed remote lithiation at C3 of the indole ring system [295]. Treatment of 2-arylindole 117 with LiTMP led to fused indole 119 via 3-lithioindole intermediate 118 (Scheme 25). 

Lateral LithiationP Laterally metalated o-toluic acids (eq 48), esters (eq 49), and amides (eq 50) are important intermediates for chain extension and carbo- and hetero-ring annulation. Remote lateral lithiation of 2-methyl-2 -carboxaminobiaryls constitutes a general regiospecific synthesis of 9-phenanthrols (eq 51). ... 

A Parham cyclization can be followed in the same pot by a second, remote halogen-lithium exchange and intermolecular reaction. Such a case is 33—>34. ° A related one-pot sequential lithiation process has... 

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