Ortholithiation amides

In aromatic compounds bearing two rotationally restricted amide groups, diastereoiso-meric atropisomers can arise because of the relative orientation of the amides. Ortholithi-ation can therefore lead to diastereoselectivity if the ortholithiation forms one of the two diastereoisomers selectively. A simple case is 169, whose double lithiation-ethylation leads only to the C2-symmetric diamide 170, indicating the probable preferred conformation of the starting material (Scheme 85) . 

Epoxides will also capture organolithiums formed by deprotonation, notably cyclopropyllithiums and ortholithiated tertiary amides. Ortholithiated amides cyclise regioselectively in a valuable route to benzofurans such as 142 and 143 and (less efficiently) benzopyrans 144.70... 

Af,A-Dimethyl amides are susceptible to attack at C=0, but can be successfully ortholithiated if kept cold. Keck and coworkers used successive ortholithiations of 23 in a route towards pancratistatin (Scheme 12) . (Park and Danishefsky s similar route using Af,A-diethylamides suffered from difficulties removing the amide group.)... 

In more heavily substituted amides, the amide group is forced to lie perpendicular to the aromatic ring —even in 21 the amide and the ring are not coplanar . Clearly this poses greater difficulties for ortholithiation, and Beak and coworkers have shown that the... 

Attachment to a solid support via a secondary amide linkage allows ortholithiations to be carried out in the sohd phase. After a reaction with an aldehyde or ketone, refluxing in toluene returns the amino-substituted polymer 41 (Scheme 21). ... 

To summarize the amides are most suitable for the formation, by ortholithiation, of condensed heterocycles and polycyclic aromatics (in which subsequent rings are formed by intramolecular attack on the amide group). In other cases the removal of the amide group may be problematic, though if carboxylic acids, aldehydes or hydroxymethyl-substituted compounds are required, alternative amide substituents may be used. 

Ortholithiated oxazoline 62 is best transmetallated to its magnesium analogue before reaction with aldehydes. As with the equivalent amide reaction, treatment with 4.5 M HCl then cyclizes the products to lactones (Scheme 31) °. ... 

The alkyl substituent meta to the methoxy substituent was easily introduced into the symmetrical diamide 72 by yet another ortholithiation. Allyl electrophiles react poorly with aryllithiums, so the ortholithiated amide 73 was first transmetallated to the Grignard reagent before allylation with allyl bromide to give 74. 

Even sulphonate esters 109 are powerful directing groups, competing well with tertiary amides. No substitution accompanies ortholithiation of ethyl or isopropyl benzene-sulphonate by BuLi. Hydrolysis and chlorination of the products 110 gives functionalized sulphonyl chlorides 111 (Scheme 48) °°. 

BuLi-TMEDA , are similarly powerful directors (Scheme 54). By contrast, the related amides, carbamates and ureas (125, R = COAr, CONR2, CO2R) usually undergo ben-zylic a-lithiation (see Section II.B). The bias can be shifted towards ortholithiation by additional electron-withdrawing substituents on the ring . 

Successful lithiation of aryl halides—carbocyclic or heterocyclic—with alkyUithiums is, however, the exception rather than the rule. The instability of ortholithiated carbocyclic aryl halides towards benzyne formation is always a limiting feature of their use, and aryl bromides and iodides undergo halogen-metal exchange in preference to deprotonation. Lithium amide bases avoid the second of these problems, but work well only with aryl halides benefitting from some additional acidifying feature. Chlorobenzene and bromobenzene can be lithiated with moderate yield and selectivity by LDA or LiTMP at -75 or -100 °C . 

The amide 504 may be made by ortholithiation of benzodioxolane 505, though a higher-yielding preparation starts from 1,2-dihydroxybenzoic acid 506. OrthoUthiation of 504, directed by the tertiary amide group, is straightforward, and gives the alkylated amide 503 (Scheme 196). 

Tertiary amides can direct vinylic lithiations in the manner of ortholithiations as shown by the example of 605 and 606. Even methyl groups can be lithiated given an appropriate director and base 607 forms the cyclopropane 609 on treatment with 608 in refluxing heptane (Scheme 238). ... 

Using deuterium labelling, we found that we could follow the detailed choreography of the deprotonation (Scheme 6).39 While some of the amide 11 was clearly deprotonated directly in the a (benzylic) position to give 21, a significant amount was ortholithiated first, to give 20 and the... 

These amides are a-lithiated because no other deprotonation can compete. With less hindered aromatic N,A-dimethylamides, a-lithiation still takes precedence over ortholithiation but the organolithium is immediately acylated by another molecule of amide. For example, LiTMP a-lithiates 46 even though ortholithiation could compete, but the product rapidly forms 47.7 With less readily lithiated groups on nitrogen (such as ethyl or isopropyl) ortholithiation (see section 2.3) takes over as the main reaction pathway. 

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