Addition organolithiums

The mechanism of organolithium addition to naphthyl oxazolines is believed to occur via initial complexation of the alkyllithium reagent to the oxazoline nitrogen atom and the methyl ether to form chelated intermediate 17. Addition of the alkyl group to the arena 7t-system affords azaenolate 18, which undergoes reaction with an electrophile on the opposite face of the alkyl group to provide the observed product 4. The chelating methyl... 

Although lithium p-lithioalkoxides can also be generated from p halo alcohols by deprotonation and subsequent reductive lithiation of the carbon-halogen bond73 8 or from p-halo ketones by organolithium addition to the carbonyl group followed by reductive lithiation,8 the current method is more direct as well as more convenient, since epoxides are readily available either commercially or by a variety of procedures. 

Organolithium additions to 2-phenyl-3,3-dimethyl-3//-indole (37), followed by oxidation of indolines (38) with m-chloroperoxybenzoic acid, gave indolinic aminoxyls (39) in 20-30% yield. The organolithium addition does not occur when groups other than phenyl are present at C(2). Attempts to synthesize suitable precursors such as 1,2-dihydro-2-phenyl-2-alkylbenzothiazole, 1,2-dihydro-2-phenyl-2-alkylbenzoxazole, and l,2-dihydro-2-phenyl-2-alkyl-4//-3,l-benzoxazin-4-one for other new aminoxyls failed. 

The C2 symmetric chiral diether 28" and the naturally occurring chiral diamine, (—)-sparteine (29), have been the most successful external chiral ligands for asymmetric conjugate addition of organolithium reagents. The rest of this review highlights organolithium addition, which is mediated or sometimes catalyzed by 28 or 29. 

Mixed lanthanide-alkali chlorides, LnCl3.2LiCl (Ln = La, Ce, Nd) can be readily prepared as 0.5 mol dm-3 solutions in THF.235 They act as improved promoters of addition of organomagnesium reagents to ketones, and also to aldimines, and in addition have been found to promote organolithium addition. 

The addition of organolithiums to polarised C=X bonds is one of the most widely used ways of making C-C bonds, and (excepting some unusual intramolecular cases) will not be discussed in this book other than to say it is a reliable and successful reaction. With a few exceptions,1 3 stereoselectivity is not a general feature of organolithium addition reactions to C=0 n bonds. Much of this chapter will concern controlled addition of organolithiums to C=C 7i bonds after an overview of carbolithiation, we shall review the development of intramolecular carbolithiation, or anionic cyclisation. 

The reactions in this section cover the conjugate (Michael) addition of various lithiated nucleophiles to activated olefins such as enones and enoates. Lithium enolates are formed as intermediates during the addition process. They can be treated as such and trapped, for instance, by an electrophile to provide ketones or esters substituted both in the a and positions. We will focus only on the most important information relevant to the intermediate enolates, and those are rarely discussed in the literature on the Michael addition. The reader can advantageously consult Chapter 14 of the first part of this volume133, which is entirely dedicated to the organolithium additions to double bonds, for a more extensive coverage of the topic. 

Organolithium additions. Alkyl-, alkenyl-, and aryllithiums can react as potent nucleophiles in the presence of BF, etherate. Thus epoxides and oxetanes are rapidly alkylated by reaction with an organolithium and BF, etherate (2 equiv. of each) at —78°. Examples ... 

Organolithium additions to ketones appear to involve a single molecule of RLi [76], and do not require either added Lewis acids or solvents which can act as Lewis bases. The reacting complex is possibly of the type ... 

Diels-Alder cycloadditions occur on the endo face when the unsaturated bicyclic lactam is treated with 1,3-dienes such as Iso-prene (eq 10). Ester reduction followed by organolithium addition to the lactam carbonyl group and subsequent hydrolysis affords a variety of enantiopure functionalized cyclohexenes. ... 

A number of other examples have been reported which involve highly selective Grignard or organolithium additions to carbohydrates. Unfortunately, no general trends for these complex systems have been observed. Hie selectivities reported are often specific for one substrate under a particular set of reaction conditions. Reetz has reviewed the chelation and nonchelation control addition reactions (not confined to organolithium or organomagnesium reagents) of a- and 3-aUcoxycarbonyl compounds. ... 

Except for the a-dibenzylamino substrate cited, Grignard and organolithium additions to protected a-aminocarbonyls are not particularly well understood. Only modest stereoselectivities usually result, and... 

While examples of moderate to good stereoselectivities in remotely chiral molecules, such as those described above, are known, they are usually specific cases, and cannot be generalized to all systems. In general, stereoselective Grignard or organolithium additions which rely on remote or 3-chelation are not efficient. 

Threo diastereoselectivity is consistent with a chelation-controlled (Cram cyclic model) organolithium addition (Figure 8a). Since five-membered chelation of lithium is tenuous, an alternative six-membered chelate involving the dimethylamino nitrogen atom of the thermodynamically less stable (Z)-hydrazone (in equilibrium with the ( )-isomer) cannot be discounted. The trityl ether (entry 4, Table 9) eliminates the chelation effect of the oxygen atom such that the erythro diastereomer predominates (via normal Felkin-Ahn addition) (Figure 8b). 

In a synthetic effort directed toward a segment of erythronolide A, the addition of (2) to aldehyde (22) gave, after treatment with MeMgBr/CuI, an approximately 80 20 mixture of ring-opened products (23) and (24 equation ll). Interestingly, direct alkylation of this aldehyde (as a mixture of double bond isomers) with ethyllithium gave an 18 82 mixture of adducts. The factors responsible for the complementary face selectivity shown by (2) versus ethyllithium are unclear. Comparisons are particularly difficult due to the fact that most organolithium additions to carbonyl compounds are irreversible, kinetically controlled processes, whereas reactions of (2) can be reversible. 

The organolithium addition to pyridines or other nitrogen aromatic heterocycles is a well-established general synthetic method. It is usually used to achieve overall substitution on the ring, via lithium hydride elimination or oxidation of the dihydrointermediate [18]. 

The second report of catalytic enantioselective organolithium additions to the imine group came in 1991 from the laboratories of Itsuno and co-workers [23aj. These researchers studied the addition of -BuLi to AT-(trimethylsilyl)benzalde-hyde imine 5a in the presence of chiral modifiers such as alcohols, diols, and amino alcohols (<1 g of imine, ca. 0.13 M). The chiral ligands used were easily prepared according to literature procedures. The enantiomerically enriched primary amine 6 was obtained in 27-90% yield after appropriate workup, depending on the nature of the chiral ligand and the reaction solvent (Scheme 4). 

Organolithium additions to 2-phenyl-3,3-dimethyl-3//-indole (37), followed by oxidation of indolines (38) with m-chloroperoxybenzoic acid, gave indolinic aminoxyls... 

The chemistry is a development of earlier methodology. [17] The organolithium additions to A-aryl imines 18, are promoted by C2-symmetric bisoxazoline (BOX) ligands, [18] e.g. 20, or (-)-sparteine [19] 21 (Scheme 4) with high asymmetric induction. 

Organolithium addition to acid derivatives gives the disconnections ... 

The most prominent example of enantioselective organolithium additions to ketones is the development of the anti-AIDS drug efavirenz 23 (Scheme 3), a non-nucleoside reverse transcriptase inhibitor for a variety of HIV-1 mutant strains [88,89]. 

The key step in the synthesis of 23 is the enantioselective generation of its quaternary carbon center. This can be accomplished by adding to the protected ketoaniline precursor 24 the lithium acetylide 25 [Eq. (3)] [90]. Due to the high medical relevance of the final product efavirenz (23), this enantioselective organolithium addition has been intensively studied. These detailed investigations provide intriguing information on the nature of reactive intermediates and the origins of enantioselectivity. 

You will notice secondary alkyllithiums, an aryiiithium, and two vinyllithiums. The only organolithium addition... 

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