Directed lateral lithiation

The labile tertiary amide groups described in Section I.B.l.a are also applicable to lateral lithiations the piperazine-based amide 511 has been used to direct lateral lithiation before being methylated and cleaved to the acid 512 (Scheme 198). ... 

Sulphoxides direct lateral lithiation in a reaction which is also highly stereoselective. In common with other electrophiles, ClC02Et produces as a single diastereoisomer of 544... 

The usual directing groups such as secondary amides will also successfully direct lateral lithiation at the 2-methyl group of a pyrrole (Scheme 226/° . 

Ketones may direct lateral lithiation even if the ketone itself is enolised enolates appear to have moderate lateral-directing ability. Mesityl ketone 433, for example, yields 434 after silylation - BuLi is successful here because of the extreme steric hindrance around the carbonyl group.396 The lithium enolate can equally well be made from less hindered ketones by starting with a silyl enol ether.396... 

Sulfoxides direct lateral lithiation in a reaction which is also highly stereoselective.409 In common with other electrophiles, ClC02Et produces as a single diastereoisomer of 455 from 454, and Raney nickel can be used to remove the sulfinyl group from the product, making this a very versatile method for asymmetric functionalisation of a benzyl group. 

Comins used their aminoalkoxide methodology [323] to direct C2-lithiation with an indole-3-carboxaldehyde substrate [324]. Kitagaki and Mukai later used the Comins strategy to prepare a 2-iodoindole-3-carboxaldehyde, a precursor to a 2,3-bis(alkynyl)indole [325]. This strategy was also applied by Comins to direct lateral lithiation onto an A-methyl group from an aminoalkoxide generated at C2 [77]. 

Lateral lithiation is the lithiation of the benzylic position aUtyl groups which are themselves ortho to a directing group . A general scheme for a lateral lithiation directed by a group G is shown in Scheme 186. 

The directing effect of the amide group can then be used a second time in the lateral lithiation of 503 to give an organolithium 507 which adds to the imine 508 in a stereoselective manner, probably under thermodynamic control (imine additions of laterally lithiated amides appear to be reversible). Warming the reaction mixture to room temperature leads to a mixture of 509 and some of the (ultimately required) cyclized product... 

The greater acidity of lateral protons means that LDA is more than basic enough to remove them and hence many more electrophilic directing groups can be used for lateral lithiation than orthoUthiation. Methyl 2-methylbenzoate 516 is deprotonated at —78 °C by LDA, but as soon as the product organolithium forms it adds to unreacted starting material to give prodncts 517 (Scheme 202). ... 

Electron-rich heterocycles, snch as pyrrole and furan, bear more resemblance to car-bocyclic rings their side chains are mnch less acidic, and undergo lateral lithiation mnch less readily. Without a second directing group, methyl groups only at the 2-position of fnran, pyrrole or thiophene may be deprotonated. 

For cases where the regioselectivity of lithiation cannot be biased in the required direction, silylation can be used to block acidic sites while further lithiations are carried out. The blocking silyl group is later readily removed with fluoride . This method was used to avoid a competing lateral lithiation in the synthesis of the aldehyde 665 (Scheme 251... 

A number of reactions have close similarities to ortho- and lateral lithiation, even if they do not fall under the more rigid definition of the terms.233 For example, vinylic protons with nearby directing groups can frequently be lithiated readily. Some examples are shown - 479-483 are all lithiated as though the double bond were part of an aromatic ring.233 The importance of coordination in these reactions is shown by 483, which lithiates at the more acidic position a to S if HMPA is added to disrupt Li-0 interactions. Other similar lithiations are known in the cyclopropyl and cyclobutyl series.233... 

Treatment of the laterally lithiated amide generated from lactam 273 with LDA with /ra r-2-phenylsulfonyl-3-phenyloxaziridine 33 afforded hydroxyl product 274 in 85% yield as a single isomer <1999JOC8627>. Use of (+)-(camphorsulfonyl)oxaziridine 202 gave similar results. The /ra t-stereoselectivity is consistent with the earlier finding that the hydroxylation stereochemistry is controlled by nonbonded steric interactions in the transition state such that the oxygen of the oxaziridine is delivered from the sterically least hindered direction. Treatment of 275 with LDA followed by (+)-(camphorsulfonyl)oxaziridine 202 afforded hydroxyl product 276 in 47% yield and 60% ee <1997T8881>. 

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. 

We have tried to summarize in this chapter the basic tendencies and mechanisms of directed metalation. DoM in presence of DMG(s) allows for the regioexhaustive functionalization of aromatics. DreM, frequently combined with migration of the DMG or rearrangement, gives a powerful tool for the synthesis of natural products. Peri and lateral lithiations have shown to further enable functionalization for aromatic scaffolds, and last but not least, when coordinated to and thus activated by a metal complex, aromatic ring systems can be subjected to enantiose-lective metalation reactions. Although such a chapter cannot cover the topic in an exhaustive manner, we hope to have found a compromise between scholarly presentation and citation of relevant literature. 

The —CONHNR2 group of aromatic and heterocyclic 2,2-dialkyl hydrazides is a powerful director of ortho and lateral lithiation. Lithiation at C(7) of l-(2,2-diethylbutenoyl)indoles is directed kinetically by a complex-induced proximity effect of the nitrogen substituent which can be removed readily. ... 

Quinolones behave similarly, and unlike quinolines are not attacked by BuLi at the ring. A-Substituted pyridones and quinolones are lithiated, sometimes on the N-substituent, sometimes ortho to N and sometimes ortho to O . By way of example, the 4-pyridone 226 lithiates a to N in the ring, while in the 2-pyridone 227 the combined lateral directing effect of the O and the a-directing effect of N lead to lithiation on the side chain (Scheme 110). ... 

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