Ortholithiation

In 1994, the same authors reported the synthesis of corresponding oxazolines tethered to sulfoxides by ortholithiation of the parent 2-phenyl oxazoline with butyllithium followed by addition of either (5)- or (/ )-/ -tolylmenthyl-sulfinate. Applied as ligands in the test reaetion, these diastereomerie ligands gave very different results, as shown in Seheme 1.25, thus demonstrating the... 

A further investigation of the ortholithiation of anisole has taken advantage of previous spectroscopic evidence of the exclusive formation of disolvated dimers of n-BuLi in TMEDA, combined with rate studies which demonstrate that this combination promotes ortholithiation via [(n-BuLi)2((TMEDA)2(anisole)] in pentane. The substantial kinetic isotope effect fcbs(H)/ obs(D) = 20 3] found on comparison of anisole with anisole- fg is indicative of rate-determining proton transfer but the unusually high value has not been explained satisfactorily. 

The regiospeciflc ortholithiation of 3H-naphtho[2,l-fe]pyrans has also been used to advantage in methylteretifolione B synthesis. ... 

Attempts to use intermolecular and intramolecular kinetic isotope effects (KIE s) to identify a complexation step during ortholithiation have so far been inconclusive. Both intramolecular and intermolecular KIE s for the deprotonation of 2 and 3 by s-BuLi... 

Coordination to strongly orf/zo-directing groups is responsible for the regiochemistry of some other reactions which do not involve ortholithiation. For example, while the electron-withdrawing nature of the oxazoline would be expected to direct the addition of the organolithium nucleophile to benzyne 11 towards the meta position, the major product that arises is the result of addition at the ortho position to give 12 (Scheme 1). ... 

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. 

Directed metallation of aromatic compounds TABLE 2. piTa and ortholithiation ... 

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 . 

The ortholithiated products 19 and 22 will then react with a wide range of electrophiles the only reported important exceptions are enolisable aldehydes and allylic halides. Products requiring these electrophiles are best made by first transmetallating the organolithium to a Grignard reagent with MgCl2 or copper salts . 

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. 

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) . ... 

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) °. ... 

Af,Af-Dimethylcarbamates are unstable once ortholithiated, and rearrange rapidly by a carbamoyl transfer mechanism known as the anionic ortfio-Fries rearrangement . With Af,Af-diethylcarbamates, this rearrangement can be controlled the ortholithiated carbamate 64 is stable at —78°C but, on warming to room temperamre, rearranges to give a 2-hydroxybenzamide 65 (Scheme 33) °. ... 

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. 

Ortholithiation of thioanilides 81 has been used to construct benzothiazole rings 83 via the benzyne 82 (Scheme 39)". ... 

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) °. 

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) °°. 

The ortholithiation of benzenesulphinamides 119 is of use in the regioselective synthesis of mefa-substituted compounds 120 the sulphinamide group is used to set up two ortho relationships and then removed reductively (Scheme 52) . The same concept has been explored with other sulphur-containing orf/zo-directors °. 

Phosphine oxides are similar excellent orf/zo-directors which have seen only limited use so far. The iodide 123, for example—a precursor of a new class of bisphosphine ligands—can be made by cooperatively-directed ortholithiation of the phosphine oxide 122, itself derived by halogen-metal exchange from 121 (Scheme 53) . 

---