Lithiation Ortholithiation

In sulfoxides, sulfur s weak acidifying effect is enhanced, and the oxygen atom introduces a powerful coordination effect in contrast with sulfides, sulfoxides are very powerful directors of both ortholithiation and a-lithiation. Ortholithiation is possible with aryl sulfoxides lacking an a-proton, but since sulfoxides suffer from the disadvantage of being electrophilic at sulfur, diaryl sulfoxides must be lithiated with lithium amide bases rather than... 

To summarize, ortholithiation is a reaction with two steps (complex-formation and deprotonation) in which two features (rate and regioselectivity of lithiation) are controlled by two factors (coordination between organolithium and a heteroatom and acidity of the proton to be removed). In some cases, some of these points are less important (acidity, for example, or the coordination step). The best directing groups tend to have a mixture of the basic properties required for good coordination to lithium and the acidic properties required for rapid and efficient deprotonation. 

Double ortholithiation (to give a dUithiated ring) is usually feasible when two separate directing groups are involved, but using one group to direct simultaneously to both ortho positions usually fails . Simultaneous triple lithiation has never been achieved even with three separate groups . 

Addition of a lithiated secondary amine to an aldehyde both protects the aldehyde from attack by RLi and turns it into an ortholithiation directing group. The best lithioamines for this purpose are A-lithio-A-methylpiperazine 53, iV-lithio-iV,iV,iV -trimethylethylene-diamine 56 and Al-lithio-Al,0-dimethylhydroxylamine 58 , which optimize the opportunity for coordination of BuLi to the intermediate alkoxide (54) (Scheme 27) . ... 

Sulphides are weak orthodirectors (Scheme 42), and the lithiation of thioanisole 89 with BuLi leads to a mixture of a- and ortholithiated compounds 90 and 91 ". The ortholithiated compound forms about one third of the kinetic product mixture, but slow isomerization to the a-lithiated sulphide follows. The isomerization is much faster (and therefore the yield of a-lithiated sulphide much higher) if BuLi is used in the presence of DABCO". With two equivalents of BuLi, clean ortho - -a double lithiation occurs, giving 92 the SCH2Li group is itself an ortAo-director" , though a weaker one than... 

Sulphoxide removal using sulphoxide-lithium exchange is also effective. It was employed in tandem with a sulphoxide-directed stereoselective ortholithiation of the ferrocene 105 in the synthesis of the phosphine ligand 106 (Scheme 45). Ferrocene lithiation is discussed further in Section III. 

Sulphones are similar in some ways even more acidifying, and with a powerful ability to coordinate, but less likely to be attacked at S. As with sulphoxides, lithiation a to S competes, and ortholithiation is useful only with sulphones lacking a-protons. After lithiation, the removal of sulphones can sometimes be accomplished by transition metal-catalysed reduction or substitution (Scheme 47) °. 

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 . 

Chlorobenzene is lithiated more slowly and cannot be lithiated completely at temperatures where benzyne formation is slow. With 1,2,3,4-tetrachlorobenzene 165, MeLi leads to ortholithiation f-BuLi, on the other hand, leads to halogen-metal exchange (Scheme 83). ... 

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 . 

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) . 

With even more electrophilic heterocycles, addition of the lithiated species to the starting material can become a problem—for example, LDA will lithiate pyrimidine 181 at — 10°C, but the product, after work up, is the biaryl 182 resulting from ortholithiation and readdition (Scheme 91). By lithiating in the presence of benzaldehyde, a moderate yield of the alcohol 183 is obtainable . Strategies for the lithiation of pyrimidines and other very electrophilic heterocycles are discussed below . 

Ferrocene is best deprotonated by f-BuLi/f-BuOK in THF at 0 since BuLi alone will not lithiate ferrocene in the absence of TMEDA and leads to multiple lithiation in the presence of TMEDA. In the example in Scheme 134, a sulphur electrophile and a Kagan-Sharpless epoxidation lead to the enantiomerically pure sulphinyl ferrocene 278. The sulphinyl group directs stereoselective ortholithiation (see Section I.B.2), allowing the formation of products such as 279. Nucleophilic attack at sulphur is avoided by using triisopropylphenyllithium for this lithiation. 

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. 

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. 

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

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... 

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

Ai,Al-Dimethyl-o-toluidine 547 is reluctantly lithiated with n-BuLi—TMEDA at 25 °C ortholithiation occurs to some extent in the reaction but the yield of laterally functionalized product is maximized after 3 h (Scheme 217) ° . Without TMEDA, the extent of ortholidiiation is increased. 

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). 

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). ... 

There are a number of other reports of difficulties in ortholithiation when further coordination sites are present molecules containing more than one strong coordinating substituent frequently require numerous equivalents of alkyUithium for lithiation . 

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