Lithiation, aromatic compounds

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... 

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... 

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) . 

In many ways, the electron-rich five-membered aromatic heterocycles behave very much like carbocyclic aromatic compounds when it comes to lithiation. Lithiation a to O or S of furan and thiophene is straightforward (Scheme 130) . The usual selection of orf/io-directing groups allows lithiation at other positions and some examples... 

In aromatic compounds, potent but frustrated (their ortho positions blocked) directing groups may lead to lithiations at positions other than ortho. For example, when the carbamate 610 is treated with LDA in refluxing THE, lithiation occurs at a remote position (not peri, note) and an anionic Fries rearrangement ensues to give 611 (see Section I.B.l.d). Lactonization gives 612 (Scheme 239). ... 

For conversion of functionalized diorganozincs into tertiary amines, aromatic compounds which contain a directed metallation group, such as Af,Af-dialkylbenzamides, methoxymethyl phenyl ether, phenyl oxazolines and phenyl Af,Af-dialkylcarbamates, were ortho-lithiated, transmetallated and then aminated with 2a in good yields, but with a slower reaction rate (Scheme 19). 

Sulfonic acids are prone to reduction with iodine [7553-56-2] in the presence of triphenylphosphine [603-35-0] to produce the corresponding iodides. This type of reduction is also facile with alkyl sulfonates (16). Aromatic sulfonic acids may also be reduced electrochemicaUy to give the parent arene. However, sulfonic acids, when reduced with iodine and phosphorus [7723-14-0]y produce thiols (qv). Amination of sulfonates has also been reported, in which the carbon—sulfur bond is cleaved (17). Ortho-lithiation of sulfonic acid lithium salts has proven to be a useful technique for organic syntheses, but has litde commercial importance. Optically active sulfonates have been used in asymmetric syntheses to selectively O-alkylate alcohols and phenols, typically on a laboratory scale. Aromatic sulfonates are cleaved, ie, desulfonated, by uv radiation to give the parent aromatic compound and a coupling product of the aromatic compound, as shown, where Ar represents an aryl group (18). 

DIRECTED LITHIATION OF AROMATIC COMPOUNDS (2-DIMETHYLAMINO-5-METHYLPHENYL)DIPHENYLCARBINOL... 

Methoxy-substituted aromatic compound 4 is lithiated metalation with Buli in THF, a step in which it proves useful to include lithium chloride. Because of the greater basicity of /t-butyllithium relative to 4. direct metallation is in fact possible thermodynamically, but /i-butyllithium is generally present in solution as a tetra-mer, and this reduces its reactivity. Addition of lithium chloride destroys these aggregates, and that eliminates the kinetic inhibition. Lithiated aromatic species 18 is further stabilized through chelate formation between lithium and the orr/icr-methoxy groups (ortho effect).8... 

Uemura, M. Tokuyama, S. Sakan, T. Selective nuclear lithiation of aromatic compounds facile synthesis of methoxyphthalide derivatives by carboxylation of the lithio compounds. Chem. Lett. 1975, 1195-1198. 

Certain derivatives of benzene and naphthalene can be lithiated with sec-butyllithium (sec-BuLi). This reaction is regioselective. It takes place exclusively in the ortho-position (Directed ortho Metalation, DoM) to a so-called Directed-Metalation Group (DMG), whose presence, accordingly, is a prerequisite for such a metalation. Figure 5.37 gives examples of DMGs that are bound through a C, an O, or an N atom to the aromatic compound. 

Any reaction Ar—H +. vec-BuLi — Ar—Li +. sec-BuH possesses a considerable driving force. In an DMG-controlled ortho-lithiation it is even greater than it would be normally. This is due to the stabilization of the orfho-lithiated aromatic compound A because of the intramolecular complexation of the Li atom by the donor oxygen of the neighboring DMG and, at least in some cases, to inductive stabilization provided by the DMG. The exclusive occurrence of orfho-lithiation is thus a consequence not only of the precoordination of sec-BuLi by the DMG but also of product development control. 

Fig. 5.30. ort/io-Selective electrophilic functionalization of aromatic compounds via a substituent-controlled lithiation. 

Fredericamycin is a curious aromatic compound extracted in 1981 from the soil bacterium Streptomyces griseus. It is a powerful antibiotic and antitumour agent, and its structure is shown below. The first time it was made in the laboratory, in 1988, the chemists in Boston started their synthesis with three consecutive lithiation reactions two are ortholithiations, and the third is slightly different. You needn t be concerned about the reagents that react with the organolithiums just look at the lithiation reactions... 

Formation of the antiaromatic enolate 11 from the low acidity ketone 10 " is evidently unfavourable compared with its acyclic variant 17. Attempts at isolating a stable enol derivative of 10, such as its silyl enol ether, have proved unsuccessful ". Treatment of benzocyclobutanone (10) with LiTMP in THE at —78°C, followed by the addition of trimethylsilyl chloride (MesSiCl), gave the corresponding C-silylated benzocyclobutanone 18 (equation 3) ". The non-aromatic C-lithiated ketone 20 appears to be more preferred than its related 0-lithiated enolate 11. Unlike traditional lithium enolates, this particular lithium enolate reacts in situwilh its parent compound, benzocyclobutanone (10), to give the diketone 19 (equation 3). In comparison, bridgehead enolates have also been shown to be similarly reactive ... 

Orr/io-lithiation of aromatic compounds has become a useful synthetic reaction It is... 

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