Lithiation lateral

DMGs = CO2H, CONR, CONHR, CH2NR7, OCONR, NHCOR, NHCO R, NR, OR, etc. R =H, alkyl, aryl 

SCHEME 26.17 Competition between ortho and lateral metalation. 

SCHEME 26.18 Snieckus-Fries rearrangement. Atroposelective lithiation of A(Af-diisopropyl-l-naphthamide. 

---

Trifluoromethylbenzocyclobutenols yield isochroman-l-ols on treatment with aromatic aldehydes and LTMP and hence serve as laterally-lithiated 2-methyltrifluoromcthyl-acetophenone <96SL57>. 

The preparation of chiral isoquinoline derivatives continued to be investigated. Sulfanamide 59 was prepared by addition of a lateral lithiated o-toluonitrile with the corresponding sulfinimine. Treatment of 59 with MeLi followed by acidification afforded cyclic imine 60. Reduction of imine 60 with liAlHi/MejAl afforded the trans-1,3 derivative, and... 

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 organolithium deriving from a lateral lithiation is benzylic, and therefore often of significantly greater thermodynamic stability than the equivalent ortholithiated species. In general, ortho- and lateral lithiation strategies have developed in parallel with one another, and since the starting materials for a lateral lithiation may often be made by ortholithiation there are many links between the two classes of reaction. 

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. ... 

These reactions have been used in the synthesis of aikaioids such as corydalic acid methyi ester 502 (Scheme i95). Isoiated from Corydalis incisa, 502 is derived from a proposed biosynthetic intermediate in the route to the tetrahydroprotoberberine aikaioids. The 1,2,3,4-tetrasubstituted ring of 502 demands control by an ortholithiation strategy, and the synthetic route proposed by Clark and Jahangir employs a lateral lithiation of 503 and addition to an imine as the key disconnection at the centre of the molecule. 

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). ... 

Lateral lithiation of nitriles can be achieved—and self-condensation avoided—if LiTMP is used in THF at —78°C (Scheme 199/ . 

Oxazolines , imidazolines and tetrazoles can all be laterally lithiated. Oxazolines have been used in this regard rather less than for ortholithiation (Scheme 200). 

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. 

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). ... 

When the ketone cannot be enolized, lateral lithiation appears to be very easy 524 is lithiated by LDA at -78 °C (Scheme 205f >. 

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. 

Aldehydes can also be laterally lithiated if protected as imidazolidines (527) or as imines (528)". With imines, LUMP must be used to prevent nucleophilic addition to C=N (Scheme 207). 

Methylbenzyl alcohol 529 can just about be lithiated by treatment with BuLi in EtiO at room temperature, but the activation of the methyl group is very weak. Lateral lithiation of cresol 530 is even harder to achieve, and the superbase conditions required... 

The deactivating effect of a phenoxide oxyanion is removed in the ether series, but in cases such as 531 where ortholithiation can compete with lateral lithiation, mixtures of products are frequently obtained . The MOM acetal 532 is fully ortto-selective in its reaction with t-BuLi (Scheme 209/ . ... 

The prospects for lateral lithiation are slightly improved if ortholithiation is blocked, though even then yields are moderate at best (Scheme 210). 

Better for the lateral lithiation of phenols are the A(,A(-dialkylcarbamate derivatives 533. These may be lithiated with LDA, allowing complete selectivity for the lateral position, presumably because this is the thermodynamic product . With i-BuLi, ortholithiation is... 

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... 

By contrast, while the o-methyl sulphonamide 546 can be laterally lithiated, its p-methyl isomer undergoes ortholithiation rather than benzylic lithiation (Scheme 216)" " ". ... 

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 carbamates 549 (R = OBu-f) behave similarly, though they must be lithiated with i-BuLi to avoid addition to the carbonyl group °. It is possible simply to use a lithium carbamate to protect an amino group during a lateral lithiation an initial deprotonation and carbonation generates the lithium carbamate 556, which is then deprotonated twice more by t-BuLi (Scheme 220). After electrophilic quench, acid hydrolysis of the carbamic... 

The pffa of 3-methylpyridine, whose anion cannot be delocalized onto N, is closer to that of toluene, and deprotonation gives only low yields with most bases. However, with a combination of BuLi and lithiodimethylaminoethanol (LiDMAE) deprotonation is quantitative but yields products 561 arising from apparent lithiation a to N (Scheme 224) Trying to force lateral lithiation of pyridines is generally doomed to failure, as ring lithiation or nucleophilic addition nsnally takes place first . 

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. 

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

The reduced electrophUicity of indole-3-carboxylic esters (they are vinylogous carbamates) means that they are much more versatile directors of lateral lithiation than the comparable benzoates, as illustrated by the synthesis of 564 (Scheme 221... 

Pyrroles and indoles have one further unique mode of lateral lithiation—deprotonation of an Af-methyl group (also an a lithiation). The reaction works particularly weU with an aldehyde director, temporarily protected as the a-amino alkoxide 565 (Scheme 228)°° . 

Most benzylic organolithiums, unless they bear an a heteroatom, are configurationally unstable over a period of seconds or more" , so any stereoselectivity in lateral lithiation is rarely detectable. However, as implied above, the lateral lithiation of tertiary 1-naphthamides 570 is stereoselective, and yields a single diastereoisomeric atropiso-mer of the organolithium 571 Both diastereoisomers of 571 were characterized by... 

By carrying out a subsequent ortholithiation at low temperature, it was possible to show that tertiary benzamides also react atroposelectively in laterally lithiation-electrophilic quench sequences . Either atropisomer 575 or 578 could be made starting from 573 or 576 (Scheme 231). 

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

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. 

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 . For example, vinyhc... 

---