Lithiation directed

Carbocyclic substitution can also be achieved by first introdueing a reactive organomelallic substituent. Preparation of organolithium reagents can be done by one of the conventional melhods. especially halogen-metal exchange or directed lithiation. Table 14.2 gives examples. 

The methodology of heteroatom-directed lithiation has been applied to the synthesis of a variety of organochalcogen compounds, including unstable, low-valent compounds (Section 15.6). ° The Se N interactions in the diselenide 15.4 activate the Se-Se bond toward insertion of a sulfur atom or a methylene group to give the derivatives 15.21a,... 

Recendy, Guiver et al. reported a number of derivatives of polysulfone and poly(aryl sulfone).172 188 Polysulfones were activated either on the ortho-sulfone sites or the ortho-ether sites by direct lithiation or bromination-lithiation. The lithiated intermediates were claimed to be quantitatively converted to azides by treatment with tosyl azides. Azides are thermally and photochemically labile groups capable of being transformed readily into a number of other useful derivatives. 

One group which could have utility in this context is the thiourea group (Fig. 17). Unfortunately, repeated attempts to generate the dianion via directed lithiation of A(,-dimethyl-Ar-phenylthiourea were unsuccessful. Again, bromo compounds came to the rescue. The 2-bromo derivative could be deprotonated (N-... 

Concerning the yldiide Ph3P=CH-Li, the question as to whether it could be obtained by direct lithiation of the ylides 23 (Y=H), for a long time in debate between Schlosser and Corey, could have found an answer. Effectively NMR studies seem to show that a directed ortho-metallation occurs on an aromatic ring when 23 is reacted with t-BuLi [65], leading thus to the formation of 24 whose evolution does not afford Ph3P=CH-Li (Scheme 13). 

Directed lithiation of aromatic compounds is a reaction of broad scope and considerable synthetic utility. The metalation of arenesulfonyl systems was first observed by Gilman and Webb and by Truce and Amos who reported that diphenyl sulfone is easily metalated at an orf/io-position by butyllithium. Subsequently, in 1958, Truce and coworkers discovered that metalation of mesityl phenyl sulfone (110) occurred entirely at an orf/io-methyl group and not at a ring carbon, as expected. Furthermore, refluxing an ether solution of the lithiated species resulted in a novel and unusual variation of the Smiles rearrangement and formation of 2-benzyl-4,6-dimethyl-benzenesulfinic acid (111) in almost quatitative yield (equation 78). Several other o-methyl diaryl sulfones have also been shown to rearrange to o-benzylbenzenesulfinic acids when heated in ether solution with... 

As with aromatic lithiation, the mechanism of directed lithiation in these systems appears to involve an association between the activating substituent and the lithiating agent.63... 

These efforts began with directed lithiation [53] of commercially available 4-methoxybenzaldehyde dimethyl acetal (117, Scheme 1.12), followed by quenching with amide 118 to produce chloro acetophenone 119 (52 %). Conversion... 

The ortfe-directed lithiation protocol allows selective functionalization of 3-arylsydnones in the aryl ring, the C4 position of the sydnone ring, or both simultaneously. The method allows access to fused ring structures (Sections 5.03.5.2.4 and 5.03.7.1.1). Reliable routes to otherwise unknown oxadiazolidines have been established (Section 5.03.9.4). Regiospecificity can now be achieved by judicious choice of substituents when propargylic esters react with sydnones to form pyrazoles (Section 5.03.5.2.6). 

Direct lithiation of N-(dimethylamino)pyrrole (80) and subsequent quenching with trimethylstannyl chloride affords 81 in excellent yield [67], The N-dimethylamino group can be removed with Cr2(0Ac)4 2H20. 

The advantage of this protocol over the direct lithiation method is that the lithiated glycal was produced under less demanding conditions. However, the first lithiation step is not avoided and thence the acidity related restrictions to protecting groups will still apply. In this context, Beau devised a route to 1-stannyl glycals based on a radical-mediated... 

DIRECTED ALDOL CONDENSATIONS threo-4-HYDROXY-3-PHENYL-2-HEPTANONE, 54, 49 DIRECTED LITHIATION OF AROMATIC COMPOUNDS (2-DIMETHYL-AMINO- 5-METHYLPHENYL) DI-PHENYLCARBINOL, 53, 56 DIRECT IODINATION OF POLYALKYL-BENZENES IODODURENE, 51, 94 Disiamylborane, 53, 79 Disodium hydroxylaminedisulfo-nate, 52, 83... 

Propargylic ethers undergo directed lithiation and subsequent transmetallation to afford oxygenated allenyl titanium reagents. Subsequent addition of aldehydes gives rise to various homopropargylic alcohol adducts as mixtures favoring the anti dia-stereomers (Tables 9.18 and 9.19) [29, 30]... 

Acidity is evidently the only factor directing lithiation when coordination to the heteroatom is electronically or geometrically impossible. For example, fluorobenzene is slowly lithiated by BuLi-TMEDA at —50°C, despite the unlikelihood of a strong F-Li complex forming (in contrast with anisole, no PhF-BuLi complex is discernible by NMR ). 

Amides of aminopyridines have also been widely used to direct lithiation, and are most effective when lithiated with BuLi in the absence of TMEDA (Scheme 38) . The lithiation of 80 can be used as a key step in the synthesis of naphthyridines and other condensed polycyclic heterocycles" . 

Hydrazones may also direct lithiation, and are particularly effective after deprotonation to an azaenolate 131 (Scheme 59). ... 

Nitriles will direct lithiation with non-nucleophilic bases such as LiTMP, particularly in conjuction with another nitrile group . The nitriles presumably act by an acidifying effect alone—no intramolecular N-Li coordination is possible in the intermediate (Scheme 60). 

No heterocycle containing a C=N bond is as powerful a director as the oxazolines or tetrazoles described above, but their imidazoline analogues 132 direct well if deprotonated to the amidine equivalent 133 of a secondary amide anion (Scheme 61). Pyrazoles 134 also direct lithiation, but need protecting with a bulky Af-substituent to prevent nucleophilic attack by the base (Scheme 62). ... 

Pyridines are yet more susceptible to nucleophilic attack, but may just about direct lithiation if ring addition can be avoided. Organolithium 135 is unstable and slowly isomerizes to 136 (Scheme 63). ... 

Particularly powerful synthetically is the ability of two meta-disposed methoxy groups jointly to direct lithiation to the position between them . Lithiation and carboxyla-tion of 1,3-dimethoxybenzene, for example, is a key step in the synthesis of methicillin (Scheme 65) . 

The enantioselective lithiation of anisolechromium tricarbonyl was used by Schmalz and Schellhaas in a route towards the natural product (+)-ptilocaulin . In situ hthi-ation and silylation of 410 with ent-h M gave ewf-411 in an optimized 91% ee (reaction carried ont at — 100°C over 10 min, see Scheme 169). A second, substrate-directed lithiation with BuLi alone, formation of the copper derivative and a quench with crotyl bromide gave 420. The planar chirality and reactivity of the chromium complex was then exploited in a nucleophilic addition of dithiane, which generated ptilocaulin precnrsor 421 (Scheme 172). The stereochemistry of componnd 421 has also been used to direct dearomatizing additions, yielding other classes of enones. ... 

Silicon protection is also commonly used to direct lithiation chemistry in five-membered heterocycles. For example, oxazoles , thiazoles and Ai-alkylimidazoles ° ° lithiate preferentially at C-2, where the inductive effect of the heteroatoms is greatest. If C-2 is blocked, lithiation occurs at C-5, where there is no adjacent lone pair to destabilize the organolithium. Functionalization of these heterocycles at C-5 can therefore be achieved by first silylating C-2, reacting at C-5 and then removing the silyl group. The synthesis of 666 illustrates this sort of sequence (Scheme 258) °. ... 

The most popular method for generation of a-thio-carbanion (migration terminus) is direct lithiation (deprotonation) with alkyllithium or lithium amide. These deprotonation methods are widely applicable to various substrates, not only benzyl or allyl sulfides , but also dithioacetals 142 which form 143 (equation 83), and a phosphonate substituted system 144 which gives 145 (equation 84). ... 

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