Selective Lithiation

Selective Lithiation.—In recent years chiral auxiliary groups have been used extensively as agents for the introduction of new or additional chiral centres 

The same authors have made use of a similar reaction sequence to prepare / ,/ -methylserine esters (3) from ketones (R R CO) and the lithio derivative of dihydropyrazine (4). Once again the dihydropyrazine is prepared from a chiral amino-acid (2 moles L-alanine). Alternatively, if alkyl halides are reacted with the lithio derivative of (4) then chiral homologues of L-valine are obtained. In a related application, the chiral amino-acid derivative L-AT-ethoxycarbonyl- 

Chiral amines, e.g. S-(6), can also be used as auxiliaries by conversion to the imine, e.g. (7). Once formed, these imines can then be converted to 5-2-alkylcyclohexanones (n = 1, 87—100% e.e.) and 2,6-dimethylcyclohexanone (rt = 1, 85% e.e.) by sequential lithiation, alkylation, and hydrolysis. Furthermore, for larger-ring analogues of (7 n = 5, 7 or 10) it has been shown that kinetic metallation followed by alkylation and hydrolysis gives 2-alkylcycloalk-anones of absolute configuration opposite to that formed under thermodynamic conditions. Thus, 5-(-)-2-methylcyclododecanone is formed in 60% e.e. with kinetic control, and i -(+)-2-methylcyclododecanone in 80% e.e. with thermodynamic control. 

The lithium enolate of R,R-tartrate acetonide (11) is another easily accessible chiral molecule and has been alkylated by reactive electrophiles (allyl and benzyl halides) with excellent stereospecificity ( 80%). This approach has been used in the synthesis of piscidic acid (12). Similarly, the dioxolanones (13) (from pivalaldehyde and 5-lactic acid) and (14) (from mandelic acid), and the 

Chiral sulphoxides have again been used, via their lithium salts, to induce chirality into a molecule. For instance, the chiral formyl anion equivalent (19) reacts with benzaldehyde and phenylacetaldehyde, and at the /S-position of cyclopentenones to give adducts with a high level of diastereoselective control. 

An early limitation in this area was the need for activated 

Other aspects of nitrogen-stabilised organolithiums have also been reported. Thus, deprotonations of aldehyde tert-butylhydrazones provides the anion (17) that functions effectively as an acyl anion 

Some mechanistic comment is made by the authors, who suggest a vinylbenzocyclobutane (27) as a possible intermediate based on the preferred conformation of the allyl anion (26). 13 17 20 21 22 23 Ultrasound has also found application in the selective ortho lithiation of the 

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Methylthiophene is metallated in the 5-position whereas 3-methoxy-, 3-methylthio-, 3-carboxy- and 3-bromo-thiophenes are metallated in the 2-position (80TL5051). Lithiation of tricarbonyl(i7 -N-protected indole)chromium complexes occurs initially at C-2. If this position is trimethylsilylated, subsequent lithiation is at C-7 with minor amounts at C-4 (81CC1260). Tricarbonyl(Tj -l-triisopropylsilylindole)chromium(0) is selectively lithiated at C-4 by n-butyllithium-TMEDA. This offers an attractive intermediate for the preparation of 4-substituted indoles by reaction with electrophiles and deprotection by irradiation (82CC467). 

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]. 

In continuation of his extraordinarily versatile and efficient directed-metalation technology, Snieckus employed indole 87 to selectively lithiate C-4 and to effect a Negishi coupling with 3-bromopyridine to give 88 in 90% yield [110]. In contrast, a Suzuki protocol gave 88 in only 19% yield (with loss of the TBS group). 

Imidazolylboronic acids are not well known. 5-Imidazolylboronic acid was prepared in situ by Ohta s group using selective lithiation at C(5) from 1,2-protected imidazole. However, the subsequent Suzuki coupling with 3-bromoindole gave the expected indolylimidazole in only 7% yield [18]. This observation indicated that more investigation into imidazolylboronic acids is necessary to better understand their synthesis and behavior. 

The deprotonation of A-Boc-piperidine (159), giving substituted piperidines such as 160, proceeds with much lower efficiency (equation 36)" " . The main side reaction is the attack of i-BuLi at the Boc-group. The observation of slower and less selective lithiation is supported by quantum-chemical studies. ... 

The tricarbonylchromium (0) complex of pyridine 94 has also recently been shown to undergo selective lithiation at the C-2 position with LDA, to give 95 [JCS(P1)501]. However, this result is not synthetically significant since the starting material 94 was actually prepared by desilylation of the... 

Relevant to the unveiling of the intrinsic electronic effects of various substituents is the selective lithiation of the fluoroanisole-Cr(CO)3 complexes [20]. The chelation control by the etheral oxygen atom which prevails in uncomplexes aromatic ethers becomes far less important. 

It has been shown that lithiation with lithium amides can also be regioselective (see 2-21).277 In the case of the cubane derivative 30, a saturated unactivated position was regio-selectively lithiated.278... 

Another effect of coordination is facilitated lithiation with -BuLi. Lithiation at the ortho position takes place with anisole, chlorobenzene and fluorobenzene 223, and reaction of the lithiation products 224 with electrophiles gives the ortho product 225 after decomplexation [58], This selective lithiation was applied to the synthesis of the... 

Regioselective lithiation.1 This complex undergoes selective lithiation at the orf/io-position, which can be trapped by methylation to give (2-methylpyridine)tri-carbonylchromium. The disilyl complex 2 undergoes selective lithiation at C4 because of steric effects. Reduction (DIBAH) of 1 provides (l,2-dihydro-pyridine)tri-carbonylchromium (3) after quenching (MeOH). Reaction of 1 with RLi followed by alkylation with CH3I provides the complex 4. 

Novel methods for site-selective lithiation of l-(chlorophenyl)-177-pyrroles and l-(methoxyphenyl)-177-pyrroles are described (Equations 179-181) <2001J(P1)1039>. 

The procedure described here offers a general route to 7-substituted indolines.3 The method is based on the directed ortho-lithiation of N-(tert-butoxycarbonyl)aniline derivatives.4 The teri-butoxycarbonyl group seems to be essential for C-7 selective lithiation, since other directing groups so far reported promote C-2 metalation on the Indoline ring.5 The C-7 selective lithiation of 1-(tert-butoxycarbonyl)indoline is in contrast to the C-2 selective lithiation of 1-(tert-butoxycarbonyl)indole.6... 

N-l-Protected 2,4,5-triiodoimidazole 243 was selectively lithiated at the 2-position via iodine-lithium exchange (Scheme 58) (2005S136>. The lithiated species was then quenched by a number of aryl aldehydes 244 to give unsymmetrical diarylmethyl alcohols 245 in high yields. The high yields of these reactions indicated that the iodine-lithium exchange of this triiodoimidazole is efficient and selective. 

Selective lithiation of alkyl- or aryl-pyridines is the key to the synthesis of a range of new phosphinopyridine ligands, e.g., (5), (6), and a fused phosphinomethylpyridinoferrocene. A similar approach has been used in the synthesis of chelating phosphino-oxazoline ligands, e.g.,... 

Another example is shown by the metallation of (IX), in which the relative reactivity of is at least 100 1 toward MeLi in THF at — 60°C. Other selective lithiations... 

Alkyl substitutents reduce the acidity of a protons. This results in selected lithiations, as in ... 

This transformation has been extended recently by the development of methods for the enantiotopos selective lithiation of a prochiral 2-butenylcarbamate and the subsequent formation of chiral 2-butenyltitanium reagents from these species (Scheme 10-94) [180]. The reaction of -2-butenylcarbamate 279 with a solution of 5ec -butyllithium and (-)-sparteine generates a crystalline lithium complex 280-sparteine. Upon addition of 4 equivalents of Ti(Oi-Pr)4, a homogeneous titanium complex 283 (see below) is formed. The titanium reagent is then allowed to react with aldehydes to produce diastereomerically pure homoallylic alcohols 282 with good to high enantioselectivity. The high enantioselectivity observed in the... 

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