Amides lateral lithiation

In the case of 489, the product 490 cyclizes to the isoquinolone 491, and the amide substituent is a required part of the target molecule" . However, it frequently occurs that the amide substituent is not required in the final product, and the acid-sensitive alkenyl substituent of 492 has been used as a solution to the problem of cleaving a C—N bond in the product (Scheme 193) ° °. Weinreb-type amides 493 can also be laterally lithiated, and the methoxy group removed from 494 by TiCU" . Hydrazones similarly can be laterally lithiated and oxidatively deprotected. ... 

Laterally lithiated tertiary amides are more prone to self-condensation than the anions of secondary amides, so they are best lithiated at low temperature (—78 °C). N,N-Dimethyl, diethyl (495) and diisopropyl amides have all been laterally lithiated with aUcyllithiums or LDA, but, as discussed in Section I.B.l.a, these functional groups are resistant to manipulation other than by intramolecular attack" . Clark has used the addition of a laterally lithiated tertiary amide 496 to an imine to generate an amino-amide 497 product whose cyclization to lactams such as 498 is a useful (if rather low-yielding) way of building up isoquinoline portions of alkaloid structures (Scheme 194) ". The addition of laterally lithiated amines to imines needs careful control as it may be reversible at higher temperatures. ... 

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 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). ... 

Methylbenzoic acid 513 can be laterally lithiated with two equivalents of lithium amide base (LDA" or L1TMP °) or alkyllithium provided the temperature is kept low to avoid addition to the carbonyl group (Scheme 201). It is usually preferable to carry out the lithiation using aUcyllithiums", since with lithium amides the subsequent reaction of 514 with electrophiles is disrupted by the presence of the amine by-product (diisopropylamine, for example) . The dilithio species 514 is stable in THF even at room temperature, and (as with the amide 483) since LDA will also dilithiate 515 stabilization presumably comes principally from conjugation with the carboxylate. 

Temporary protection of an aldehyde by addition of a lithium amide can be used to facilitate lateral lithiation by n-BuLi. The best lithium amide for this purpose is 56 interestingly, lithium piperidide 53 promotes ortho-, rather than lateral, lithiation of 525 (Scheme 206) °, while 56 yields 526. 

Much more versatile than the simple anilines are their anilide derivatives. PivalaniUdes, benzanilides and other non"° (or scarcely ) enolizable amides 549 are laterally lithiated on treatment with two equivalents of BuLi, and may be quenched with electrophiles to give 551. In the absence of an electrophile, the organoUthiums 550 cyclize to indoles 552 (Scheme 218). 

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

Enantioselective reactions of laterally lithiated amides and anilides have been reported by Beak and coworkers but these are properly asymmetric transformations in which stereoselectivity arises subsequent to the lateral lithiation step they are not enantioselective lithiations. 

Better for the lateral lithiation of phenols are the N,N-dialkylcarbamate derivatives 444. These may be lithiated with LDA, allowing complete selectivity for the lateral position, presumably because this is the thermodynamic product.192 With s-BuLi ortholithiation is the predominant reaction pathway. If the lateral organolithium 445 is warmed to room temperature, an acyl transfer from O to C takes place, analogous to the anionic ortho-Fries (see section 2.3.2.1.4), giving amide 446.365... 

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>. 

A lateral lithiation occurs at a benzylic position29 (161 reacting to 162) rather than on the benzene ring itself. These reactions are quite common so we must discuss them briefly here as the same functional groups that behave as ortho-directors are also lateral lithiation directors as in the case of the amide 161 below. The lithiated species can be represented as a lithium enolate 163 or even with chelation 164. This is not possible with an ort/zo-lithiation where the charge is localised in a C-Li o-bond. 

Notice that orf/zo-lithiations frequently use BuLi or. vet-Bui.i but that the lateral lithiations frequently use lithium amide bases like LDA and LiTMP instead. This is not insignificant. 

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). ... 

After metalation of 2-ethyl-AfAf-diisopropyl benzamide 72 with t-BuLi in THF-toluene at -78°C, crystals can be obtained and identified as A(lV-diisopropyl-2-ethyl-6-lithiobenzamide-THF 73 by X-ray crystallography (Scheme 26.21). The solid-state structure showed that each metal center is stabilized by an amide O-center and one THF molecule. In contrast, in presence of PMDTA, lateral lithiation occnrs and leads to crystals that reveal by X-ray diffraction to be a-lithio-2-ethyl-A(Af-diisopropyl-l-benzamide-PMDTA74 [158, 159]. 

A nionic telomerizations of conjugated diolefins with hydrocarbon acids - are known but suffer from very low catalytic efficiencies. Morton et al. (I) and, later, Pappas et al. (2) used unchelated organosodium compounds to telomerize conjugated diolefins with weak hydrocarbon acids but obtained very low catalyst efficiencies (about 5 grams/gram catalyst). More recently, the anionic telomerization of butadiene and toluene by sodium on oxide supports (3) and sodium in tetrahydrofuran (4) was studied .also, a potassium amide/lithiated alumina catalyst was used to telomerize butadiene (5). 

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