Lithiated alkylation

Directed metallation continues to be developed as a convenient method for regiospecific substitution of pyridines. A mild and general procedure for the preparation of structurally diverse 4-alkyl-2-aminopyridines 37 involves the lithiation/alkylation of aminopyridine derivative 36 <96JOC(61)4810>. 

Transmetalation with Zn on a chiral lithiated alkyl carbamate had been reported by Taylor via addition of a solution of ZnCl2 to an in situ generated chiral organolithium (Scheme 8.10) [15]. 

Aminoisoxazoles 22 have been synthesized by nucleophilic addition of lithiated alkyl nitriles to a-chloroximes <06OL3679>. The cyclization of oxime dianions with diethyl oxalate afforded isoxazole-5-carboxylates 23 by acid-mediated dehydration of intermediate hydroxyisoxazolines <06S2515>. 

The tin-lithium exchange is of particular interest for the generation of configurationally stable, non-racemic a-lithiated alkyl ethers 19 (equation 10). The metal-metal exchange has been found to occur under retention of the configuration. Examples of this method... 

TABLE 4. Representative examples of a-lithiated alkyl ethers, generated by reductive lithiation of a-phenylthio and a-phenylsulfonyl ethers, and reactions with electrophiles... 

Whereas carbenoid character is definitely present in metalated alkyl vinyl ethers, lithiated alkyl and aryl vinyl sulfides and thioesters, which are easily available by hydrogen-lithium exchange, do not display carbenoid-typical reactions . They rather behave like nucleophilic reagents, so that their discussion is beyond the scope of this overview despite their utility in synthesis The same appiies to various derivatives of enamines, deprotonated in the vinyiic a-nitrogen position - . 

Similar results were obtained when the reaction of dimethyl ether with w-hexyllithium was studied by Ziegler and Gellert. Thus, the carbenoid 86 formed initially reacted with w-hexyllithium to give w-heptyllithium 87, which in turn reacted with 86 to give w-octyllithium 88 and so on (equation 50) . Although the chemistry of a-lithiated alkyl... 

Lithiated alkyl carbamates [e.g. 44 from 32a (Cb for Cby)] decompose above —40°C with migration of the carbamoyl group to produce a-hydroxy carboxamides 45 (equation 8) . ... 

Lithiation of aryltriazenes followed by treatment with an electrophile provides a new approach to benzylamines. The regioselectivity of the reaction can be controlled by means of the substituents on the aryl group. The reaction consists of an intramolecular carbon-carbon bond formation with the aryl ring of a lithiated alkyl group on a 3-nitrogen atom, a 1,2-proton shift, demonstrated by deuterium substitution, and the subsequent release of nitrogen gas.15... 

Note There are several ways to prepare Schollkopf s alkylated lactam ether substrates (for the preparation of a-amino acids) that do not imvolve the foregoing standard lithiation/alkylation procedures. Such variants are exemplified here. 

Diethoxypyrazine (87) gave the unisolated dihydro adduct (88), and thence racmic-2-butyl-3,6-diethoxy-2,5-dihydropyrazine (89) (BuLi, Et2NCH2CH2NEt2, THF, -70°C, 3 h then pH 7 buffer 75%) this underwent normal Schollkopf lithiation/alkylation at the 5-position but the product and derived amino acid were naturally both racemic.539... 

One of the main advantages of the anionic cyclizations is their regioespecificity and stereoselectivity when compared with radical or other types of reactions leading to cyclic systems. This is usually due to the formation of complexes involving the lithiated alkyl, vinyl or aryl substrate and an unsaturated, double or triple, C—C bond. In some cases, a heteroatom is involved in stabilizing the transition state for the reaction. In other cases, the stereoselectivity of the cyclization is determined by the presence of several functional groups in the substrate. 

Ethoxycarbonyl-l,3-dithiane (183), easily accessible from ethyl glyoxylate diethyl acetal, can be lithiated-alkylated to afford, after deprotection, a-ketoesters as exemplifies the product 184 (Scheme 53)237. This methodology has been used in the preparation of 3-deoxy-D-manno-2-octulosonic acid (KDO) derivatives238 and of the ABC ring system of manzamine A239. 

The cyclization in Step B is an improvement of Butler s procedure for the synthesis of which employs less convenient reagents, KNH and l-bromo-3-chloroacetone acetal. Beside the acetals derived from neopentyl glycol, those derived from ethanol, 1,3-propanediol and 2,4-pentanediol have been synthesized by the present method. The second part of Step B involves the formation and the electrophilic trapping of cyclopropenyl anion 2, which is the key element of the present preparations. Step B provides a simple route to substituted cyclopropenones, but the reaction is limited to alkylation with alkyl halides. The use of lithiated and zincated cyclopropenone acetal, on the other hand, is more general and permits the reaction with a variety of electrophiles alkyl, aryl and vinyl halides, Me3SiCl, Bu3SnCl, aldehydes, ketones, and epoxides. Repetition of the lithiation/alkylation sequence provides disubstituted cyclopropenone acetals. 

A sequential lithiation-alkylation based on the dianion chemistry was utilized in an efficient synthesis of (—)-mesembrine (Scheme 175 <1998TL8979>. 

Common synthetic pathways to obtain mono-, di-, tri- and tetraalkylsilanes are reactions of the respective halogenosilanes with lithiated alkyl compounds, with alkyl-magnesium halides (Grignard reactions) and with alkyl halides in a Wurtz-Fittig-type reaction, as well as the addition of silanes to alkenes, i.e. hydrosilylation. 

In this section we discuss the synthesis of tri- and tetraorganylsilanes. A routine method to obtain tetraorganylsilanes is the reaction of lithiated alkyl compounds with silicon halides which affords the desired organylsilanes (equation la) with yields of up to 97%—illustrated by the synthesis of tetrabutylsilane (3) (equation lb)21. Alternatively,... 

Steric effects (e.g. buikiness) are less important in reactions employing lithiated alkyl reagents compared to Grignard-type approaches. While it is feasible to obtain triisopro-pylsilane (9) by the reaction of isopropyllithium (8) and trichlorosilane (7) (equation 4)24, the corresponding Grignard reaction only yields diisopropylsilane. 

Hunig bases, polymeric = animated cbloro-methylated ethenylbenzene homopolymers deprotonation with of ketones, 11 or phosphonium salts, 32 removal of acids with, 32 Hybrid plasmids, 243-245 Hydration. See Alkenes or Alkynes Hydrazine hydrazinolysis with of esters, 239-240,331 of phthaloyl-protected amines, 162,163 reduction of ketones with, 97-98,109 Hydrazines, cyclic oxn., N3 extrusion, 35,331 Hydrazones WolfF-Kishner redn. of, 109 —, aryl- indole synth. with, 151-152, 296, 307 —, dialkyl-, lithiated alkylation, 12, 18, 25-26 enantioselective (SAMP-hydrozones), 25-26 ozonolysis of, 26... 

In a systematic study of lithiation of alkylarene ligands [96], steric inhibition by ortho substitution is clear. The unhindered positions tend to be comparably reactive. With mesitylene, only benzylic (a) lithiation/alkylation is observed. The cyclobutabenzene complex 14, on the other hand, is lithiated on the arene ring quenching with Me3SiCl results in primarily the ortho (15) product [97-99]. 

---