Allylic lithiation

Although allylic lithiation by deprotonation of non-heterosubstituted compounds is possible using superbases (see section 2.6), in most cases allylic lithiation requires a directing heteroatom. (Non-heterosubstituted allyllithiums are best produced by reductive lithiation of allyl ethers or allyl sulfides - see section 4.4.) One of the few cases where this heteroatom is not a to the new organolithium is shown below the p-lithiation of a homoallylic amide 137. The reaction is particularly remarkable because of the possibility of competing deprotonation... 

The first total synthesis of racemic indolizomycin was accomplished by S.J. Danishefsky et a. The natural product s trienyl side chain was elaborated using the classical J-L olefination. The macrocyclic a, 3-unsaturated aldehyde was treated with an ( )-allylic lithiated sulfone to give epimeric acetoxy sulfones upon acetylation. The mixture of epimers was exposed to excess sodium amalgam in methanol to afford the desired ( , , ) triene stereospecifically. 

The formation of asymmetric carbon-carbon and carbon-heteroatom bonds by lithiation-substitution at a carbon adjacent to nitrogen can be accomplished by deprotonations or des-tannylations, followed by reaction with electrophiles. Apphcations of these sequences for amine elaboration are summarized for reactions controlled by chiral hgands and chiral auxiliaries. Notable features include syntheses of alkaloids, the ability to make both enantiomers with a single chiral ligand and diastereoselective and enantioselective conjugate additions with benzylic and allylic lithiation intermediates. The sequences are classified, where information is available, in terms of stereocontrol in the lithiation or substitution step. 

Propargylic alcohol, after lithiation, reacts with CO2 to generate the lithium carbonate 243, which undergoes oxypalladation. The reaction of allyl chloride yields the cyclic carbonate 244 and PdC. By this reaction hydroxy and allyl groups are introduced into the triple bond to give the o-allyl ketone 245[129]. Also the formation of 248 from the keto alkyne 246 with CO2 via in situ formation of the carbonate 247 is catalyzed by Pd(0)[130]. 

Lithiated indoles can be alkylated with primary or allylic halides and they react with aldehydes and ketones by addition to give hydroxyalkyl derivatives. Table 10.1 gives some examples of such reactions. Entry 13 is an example of a reaction with ethylene oxide which introduces a 2-(2-hydroxyethyl) substituent. Entries 14 and 15 illustrate cases of addition to aromatic ketones in which dehydration occurs during the course of the reaction. It is likely that this process occurs through intramolecular transfer of the phenylsulfonyl group. 

Lithiation at C2 can also be the starting point for 2-arylatioii or vinylation. The lithiated indoles can be converted to stannanes or zinc reagents which can undergo Pd-catalysed coupling with aryl, vinyl, benzyl and allyl halides or sulfonates. The mechanism of the coupling reaction involves formation of a disubstituted palladium intermediate by a combination of ligand exchange and oxidative addition. Phosphine catalysts and salts are often important reaction components. 

Mixtures of anhydrous hydrogen fluoride and tetrahydrofuran are successfully used as fluorinating agents to convert 1,1,2-trifluoro-l-allcen-3-ols, easily prepared from bromotrifluoroethene via lithiation followed by the reaction with aldehydes or ketones, to 1,1,1,2-tetrafluoro-2-alkenes The yields are optimal with a 5 1 ratio of hydrogen fluoride to tetrahydrofuran The fluorination reaction involves a fluonde lon-induced rearrangement (Sf,j2 mechanism) of allylic alcohols [65] (equation 40)... 

A significant effect of Lewis acids on such transamiular C-H insertion reactions has been demonstrated. Treatment of 5,6-epoxycydooctene (31) with s-BuLi/ (-)-sparteine gave allylic alcohol 32, formally the product of P-elimination, in good yield (and ee) (Scheme 5.9). In the presence of BF3-Et20, however, alcohol 33 was produced as a result of a-lithiation, in 75% yield and 71 % ee [16]. 

Commonly employed anion-stabilizing groups are those containing silicon (Table 5.4, Entries 1-5). Magnus et al. reported that epoxysilane 147 could be deproto-nated with t-BuLi, and that the lithiated epoxide 148 thus generated could be trapped with allyl bromide to give epoxysilane 149 in a synthetically useful yield (Scheme 5.34) [55], Iodomethane (88%) and chlorotrimethylsilane (60%) could also be trapped. 

For the deprotonation of less acidic precursors, which do not lead to mesomerically stabilized anions, butyllithium/TMEDA in THF or diethyl ether, or the more reactive, but more expensive,. seobutyllithium under these conditions usually are the most promising bases. Het-eroatomic substitution on the allylic substrate, which docs not contribute to the mesomeric or inductive stabilization often facilitates lithiation dramatically 58. In lithiations, in contrast to most other metalations, the kinetic acidity, caused by complexing heteroatom substituents, may override the thermodynamic acidity, which is estimated from the stabilization of the competing anions. These directed lithiations59 should be performed in the least polar solvent possible, e.g.. diethyl ether, toluene, or even hexane. 

The best conditions for the a-regioselective coupling of a chiral, highly substituted, lithiated allyl sulfide to a chiral aldehyde were carefully worked out for the key step in an erythronolide B total synthesis108. 

Stannylation of lithiated allyl ethers gives (Z)-3-alkoxyallylstannanes (1)115,116, whereas mixtures of (Z)- and ( )-tributyl(3-methoxy-2-propenyl)stannanes (2) were obtained from free-radical addition of tributyltin hydride to l-methoxy-l,2-propadienel16. 

Z)-3-Alkoxyallylstannanes of high optical purity are available by stannylation of lithiated allyl carbamates derived from optically active allyl alcohols118. 

In contrast to allylic phosphine oxides, phosphonates, sulfones and sulfoxides, the chemistry of lithiated allylic sulfoximines has been less extensively developed25 27. The reaction of lithiated racemic A-phenyl-A -(4-rnethylphenyl)-S -(2-propenyl)sulfoximine with either 2-cy-clopentenone or 2-cyclohexenone gave a complicated mixture with 1,4-oc-ad ducts being slightly favored over the 1,4-7-adducts. The yields of these adducts were poor25. In contrast, lithiated racemic Ar-tert-butyldiphenylsilyl-5-phenyl-5,-(2-propenyl)sulfoximine gives mainly 1,4-y-ad-ducts on reaction with the same enones26. 

The oxidative dimerization of the anion of methyl phenyl sulfone (from a Grignard reagent) in ethereal solution in the presence of cupric chloride in 5% yield has been reported47. Despite the reported48 poor stability of the a-sulfonyl C-centered radicals, Julia and coworkers49 provoked the dimerization (in 13 to 56% yields) of the lithiated carbanion of alkyl phenyl sulfones using cupric salts as oxidants. The best results are obtained with cupric triflates in THF-isobutyronitrile medium (56% yield for R = H). For allyl phenyl sulfones the coupling in the 3-3 mode is predominant. 

Previous syntheses of terminal alkynes from aldehydes employed Wittig methodology with phosphonium ylides and phosphonates. 6 7 The DuPont procedure circumvents the use of phosphorus compounds by using lithiated dichloromethane as the source of the terminal carbon. The intermediate lithioalkyne 4 can be quenched with water to provide the terminal alkyne or with various electrophiles, as in the present case, to yield propargylic alcohols, alkynylsilanes, or internal alkynes. Enantioenriched terminal alkynylcarbinols can also be prepared from allylic alcohols by Sharpless epoxidation and subsequent basic elimination of the derived chloro- or bromomethyl epoxide (eq 5). A related method entails Sharpless asymmetric dihydroxylation of an allylic chloride and base treatment of the acetonide derivative.8 In these approaches the product and starting material contain the same number of carbons. 

Lithiated allylic carbamates (35) (prepared as shown) react with aldehydes or ketones (R C0R ), in a reaction accompanied by an allylic rearrangement, to give (after hydrolysis) y-hydroxy aldehydes or ketones. The reaction is called the homoaldol reaction, since the product is a homolog of the product... 

Thia-[2,3]-Wittig sigmatropic rearrangement of lithiated carbanions 47, obtained by deprotonation of the S-allylic sulfides 46, affords the thiols 48 or their alkylated derivatives 49. The corresponding sulfonium ylides 51, prepared by deprotonation of the sulfonium salts 50 also undergoes a [2,3]-sigmatropic shift leading to the same sulfides 49 [36,38] (Scheme 13). As far as stereochemistry is concerned, with crotyl (R R =H,R =Me) and cinnamyl (R, R =H,R =Ph) derivatives, it has been shown that the diastereoselectivity depends on the nature of the R substituent and on the use of a carbanion or an ylide as intermediate. 

In Entry 5, the carbanion-stabilizing ability of the sulfonyl group enables lithiation and is then reductively removed after alkylation. The reagent in Entry 6 is prepared by dilithiation of allyl hydrosulfide using n-bulyl lithium. After nucleophilic addition and S-alkylation, a masked aldehyde is present in the form of a vinyl thioether. Entry 7 uses the epoxidation of a vinyl silane to form a 7-hydroxy aldehyde masked as a cyclic acetal. Entries 8 and 9 use nucleophilic cuprate reagents to introduce alkyl groups containing aldehydes masked as acetals. 

As shown in Scheme 2.20, selective lithiation of substrate 2-87 by treatment with LDA in THF at -78 °C triggers an intramolecular Michael/intermolecular aldol addition process with benzaldehyde to give a mixture of diastereomers 2-90 and 2-91. 2-91 was afterwards transformed into 2-92, which is used as a chiral ligand for Pd-catalyzed asymmetric allylic substitution reactions [29]. 

Bailey s group has elaborated a fourfold anionic domino approach leading to a N-allyl-3,4-disubstituted indoline 2-582 from 2-580 (Scheme 2.131) [300]. The central step is the formation of an aryne by treatment of 2-fluoro-N,N-diallylaniline (2-580) with nBuLi followed by a regioselechve intermolecular addition of nBuLi to give 2-581. This then cyclizes to afford a new lithiated species which is intercepted by added TMSCI. 

---