Lithiation heterocycles

Competitive metallation experiments with IV-methylpyrrole and thiophene and with IV-methylindole and benzo[6]thiophene indicate that the sulfur-containing heterocycles react more rapidly with H-butyllithium in ether. The comparative reactivity of thiophene and furan with butyllithium depends on the metallation conditions. In hexane, furan reacts more rapidly than thiophene but in ether, in the presence of tetramethylethylenediamine (TMEDA), the order of reactivity is reversed (77JCS(P1)887). Competitive metallation experiments have established that dibenzofuran is more easily lithiated than dibenzothiophene, which in turn is more easily lithiated than A-ethylcarbazole. These compounds lose the proton bound to carbon 4 in dibenzofuran and dibenzothiophene and the equivalent proton (bound to carbon 1) in the carbazole (64JOM(2)304). 

The relative stability of lithiated thiopyrans seems to depend upon the heterocyclic ring substitution. Thus, a-lithiated 2,6-diphenyl-2//-thiopyran 16 rearranges into the y-lithiated derivative 17 (Scheme 5) (82JOC680), while the reverse transformation occurs on lithiation of 2,6-diphenyl-4-diethylphosphonylthiopyran (80JOC2453). 

When lithiated, the ring strain of the three-membered heterocycle remains important, and this strain, combined with a weakening of the a-C-O bond, due to its greater polarization, make metalated epoxides highly electrophilic species [2], They react with strong nucleophiles (often the base that was used to perform the a-deprotonation) to give olefins following the elimination of M2O (Scheme 5.2, Path B), a process often referred to as reductive alkylation . 

In THF at -20°C the N-trimethylsilylated 2-pyrrolidinone 388 is converted by LDA into the a-anion which, on reaction with 1949 and subsequent acidification with AcOH, gives 43% 3-hydroxy-2-pyrrolidinone 1962 [150]. Lithium enolates of ketones such as camphor react with BTSP 1949 to give >95% of a mixture of exo-and mdo-2-hydroxycamphor [151]. Lithiated methyl heterocycles such as lithiated 2-methylpyridine 1963 are converted into mixtures of the 0-SiMe3 1964 and C-SiMe3 1965 compounds and C-methylated compounds such 1966 [152]. 2-Lithioto-luene 1967 is oxidized by 1949 into 1968 [140, 145] (Scheme 12.42). 

Narasimhan, N. S., Mali, R. S. Heteroatom Directed Aromatic Lithiation Reactions for the Synthesis of Condensed Heterocyclic Compounds, 138, 63-147 (1986). 

Interestingly, when the chloro analog was transmetallated and treated with 3-ethoxy cyclohexen-l-one, the expected enone (XI) was not observed, but an enone with a mass of 34 units greater than (XI) was noticed. It also indicated the enone carried the chloro analog. It was presumed that the hetero atoms in the heterocycle present in the starting material (VIII) had performed a directed metallated lithiation providing a different enone bearing the chloro moiety. 

A review covering homologation of heterocycles via lithiation-based reductive ring opening, electrophilic substitution, and cyclization includes applications to 2,7-dihydro benzothiepine derivatives <06AHC135>. 

Bailey described the first application of the Stille coupling to pyrroles, and one of the earliest examples of any such reaction involving heterocycles [66]. Lithiation of IV-methylpyrrole and quenching with trimethylstannyl chloride gives 2-(trimethylstannyl)pyrrole (76), and palladium-catalyzed coupling with iodobenzene affords l-methyl-2-phenylpyrrole (46) in good yield. 

Ogura and coworkers178,179 continued their study of the addition of lithiated heterocycles to 2,3 5,6-di-0-isopropylidene-L-gulono-l,4-lactone (50) and related compounds. In the case of the addition of lithiated 1,3-dithiane to 50, it was shown178 by X-ray crystal-structure analysis that l-(l,3-dithian-2-yl)-2,3 5,6-di-0-isopropylidene-/3-L-gulofuranose is R at the anomeric carbon atom. This demonstrates that the product of this reaction is, surprisingly, the more sterically hindered of the two products possible. This is the opposite of that predicted for addition of the lithiated dithiane from the less hindered side of 50 if no equilibration of the initial adduct is involved. 

Addition of lithiated heterocycles to aldonolactones yields carbon-linked nucleosides (56). Thus, the reaction of 2,3 5,6-di-O-isopropylidene-L-gu-lono-1,4-lactone (9b) or 2,3-O-isopropylidene-D-ribono-l,4-lactone (16a) with various lithiated heterocycles gave gulofuranosyl derivatives 53a-g or ribofuranosyl derivatives 54b,c. Gulonolactols 53a-g and ribonolactols 54b,c were acetylated with acetic anhydride in pyridine to yield their acetyl derivatives. The stereochemistry of compounds 53a-g and 54b,c was discussed in terms of the Cotton effect of circular-dichroism curves of the ring-opened alcohols formed upon reduction by sodium borohydride. The configuration at C-l of 53g was proved by means of X-ray analysis (57,58). 

Carbon-linked sugar-heterocycles were also obtained by reaction of the lithiated derivatives obtained from 2-bromopyridine, a-picoline, and ben-zothiazole with 4-0-benzyl-2,3 6,7-di-0-cydohexylidene-D-g(ycero-D-gulo-htplono-1,5-lactone (55). The corresponding o-glycero-D-gulo-hepto-pyranose-substituted compounds 56a-c were isolated in 35-43.5% yields. With other heterocycles (for example furan), 1-disubstituted guloheptitols were obtained (59). 

As mentioned above, the reactivity of alkoxyallenes is governed by the influence of the ether function, which leads to the expected attack of electrophiles at the central carbon C-2 of the cumulene. However, the alkoxy group also activates the terminal double bond by its hyperconjugative electron-withdrawing effect and makes C-3 accessible for reactions with nucleophiles (Scheme 8.3). This feature is of particular importance for cyclizations leading to a variety of heterocyclic products. The relatively high CH-acidity at C-l of alkoxyallenes allows smooth lithiation and subsequent reaction with a variety of electrophiles. In certain cases, deprotonation at C-3 can also be achieved. 

Each ion-radical reaction involves steps of electron transfer and further conversion of ion-radicals. Ion-radicals may either be consnmed within the solvent cage or pass into the solvent pool. If they pass into the solvent pool, the method of inhibitors will determine whether the ion-radicals are prodnced on the main pathway of the reaction, that is, whether these ion-radicals are necessary to obtain the hnal prodnct. Depending on its nature, the inhibitor may oxidize the anion-radical or reduce the cation-radical. Thns, quinones are such oxidizers whereas hydroquinones are reducers. Because both anion and cation-radicals are often formed at the first steps of many ion-radical reactions, qninohydrones— mixtures of quinones and hydroquinones—turn out to be very effective inhibitors. Linares and Nudehnan (2003) successfully used these inhibitors in studies on the mechanism of reactions between carbon monoxide and lithiated aromatic heterocycles. 

Amides of aminopyridines have also been widely used to direct lithiation, and are most effective when lithiated with BuLi in the absence of TMEDA (Scheme 38) . The lithiation of 80 can be used as a key step in the synthesis of naphthyridines and other condensed polycyclic heterocycles" . 

No heterocycle containing a C=N bond is as powerful a director as the oxazolines or tetrazoles described above, but their imidazoline analogues 132 direct well if deprotonated to the amidine equivalent 133 of a secondary amide anion (Scheme 61). Pyrazoles 134 also direct lithiation, but need protecting with a bulky Af-substituent to prevent nucleophilic attack by the base (Scheme 62). ... 

Successful lithiation of aryl halides—carbocyclic or heterocyclic—with alkyUithiums is, however, the exception rather than the rule. The instability of ortholithiated carbocyclic aryl halides towards benzyne formation is always a limiting feature of their use, and aryl bromides and iodides undergo halogen-metal exchange in preference to deprotonation. Lithium amide bases avoid the second of these problems, but work well only with aryl halides benefitting from some additional acidifying feature. Chlorobenzene and bromobenzene can be lithiated with moderate yield and selectivity by LDA or LiTMP at -75 or -100 °C . 

With even more electrophilic heterocycles, addition of the lithiated species to the starting material can become a problem—for example, LDA will lithiate pyrimidine 181 at — 10°C, but the product, after work up, is the biaryl 182 resulting from ortholithiation and readdition (Scheme 91). By lithiating in the presence of benzaldehyde, a moderate yield of the alcohol 183 is obtainable . Strategies for the lithiation of pyrimidines and other very electrophilic heterocycles are discussed below . 

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