Lithiated heterocycles

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). 

The ease with which brominated heterocycles may be prepared regioselectively makes the use of these compounds as starting materials for the synthesis of regioselectively lithiated heterocycles extremely attractive. Organolithium derivatives of all the simple heterocycles at all possible positions of substitution have been made by this method.80 The scheme below illustrates some classical methods for forming 2-lithio-,81 3-lithio-,81 and 4-lithiopyridines,82 along with 4-lithioquinoline.83 rc-BuLi works well in these reactions, and indeed may be better than r-BuLi in reactions with electron deficient heterocycles, with which it tends to undergo addition reactions. 

The transmetallation of lithiated heterocycles has been described as a method to provide NHC complexes, and other Fischer-type carbene complexes [161]. The method proceeds via the alkylation of an alkylimidazole with BuLi to generate the lithiated azole, which can transmetallate to the metal complex. Further reaction with an acid or an alkylating agent would provide the desired NHC - M complex (Scheme 47). 

In contrast to the 5-endo-trig anionic cyclization reactions, rarely observed, there are several examples in which 5-endo-dig processes are involved. Hence 2,3-disubstituted benzofurans, benzothiophenes and indoles 374 have been synthesized starting from triflu-oroethyl ethers, thioethers and anilines 373, respectively, and alkyllithium compounds. A 5-endo-dig carbolithiation reaction on 375, generated by two successive eliminations, one substitution and one ortho-lithiation reactions, is proposed to account for the formation of the corresponding 2-lithiated heterocycles. Further reaction of these intermediates with electrophiles affords compounds 374 (Scheme 98)159. In the case of thioether 373 (X = S) a bromine substituent must be present at the ortho position. 

F. Mixed Complexes between Chiral Lithium Amides containing Amines and Lithiated Heterocycles... 

Carbon dioxide protected pyrroles and indole (carbamates), generated by treatment of the iV-lithiated heterocycles with gaseous CO2, can be easily tracked by negative ion electrospray ionization mass spectrometry (ESI-MS) revealing invariable loss of CO2 from the anion <2002JMP541>. 

Benzo[fe]thiophenes, benzo[fc]furans and A -blocked indoles lithiate on the heterocyclic ring, a to the heteroatom. Lithiation at the other hetero-ring position can be achieved via halogen exchange, but low temperatures must be maintained to prevent equilibration to the more stable 2-lithiated heterocycle. 

Solutions of the lithiated heterocycles (0.20 mol) in THF (150 ml) and hexane (150 ml) are prepared as described in the Exps. 2, 3 and 5. The solutions are cooled to —105 °C, (occasional cooling in a bath with liquid nitrogen, avoiding formation of a solid crust on the bottom of the flask), after which 0.105 mol (10.8 g) of freshly distilled sulfur dichloride (Exp. 56) is added dropwise over 5 min with vigorous stirring. Occasional cooling is applied to keep the temperature between —90 and... 

The lithiation of hydrazones derived from (R)- or (S)-l-amino-2-methoxymethylpyrrolidine, followed by Michael addition, is the basis of a diastereoselective and enantioselective synthesis of 5-oxo-esters.4 Lithiated heterocyclic hydrazones can... 

Conformationally-locked C-nucleosides such as 147 have been reported from Imanishi s laboratory. These were prepared by formation of the C-T-O bond in Mitsunobu reactions, the necessary diols being formed by stereoselective addition of Grignard derivatives of the heterocycles to an aldehyde. Use of lithiated heterocycles gave substantially more of the other epimers of the diols, thus permitting access to the a-anomers after Mitsunobu reaction. The oxazole 147 and the compound without the phenyl group were incorporated into oUgonuc-leotides, and the triplex-forming ability of the these towards a purine sequence of duplex DNA was studied. ... 

In 1991, Sylvestre Julia reported a direct synthesis of olefins from carbonyl compounds and lithiated heterocyclic sulfones [132-134]. After the initial coupling... 

An improved route to 3-(p-D-ribofuranosyl)pyrazole has been described, starting from 2,3-O-isopropylidene-D-ribofuranose and involving acetylenic intermediates. A stereocontrolled route to 4(5)-(P-D-ribofuranosyl)imidazole (115) has also been developed the epimeric mixture 114 was obtained via addition of a lithiated imidazole to 2,3,5-tri-O-benzyl-D-ribofuranose, and cyclization of this under modified Mitsunobu conditions gave selectively the P-product. A mechanistic rationale was presented, and the 2 -deoxycompound was similarly made. Various other 2 -deoxy-C-nucleosides of type 116 have been prepared in a non-stereoselective way by reaction of lithiated heterocycles with 3,5-(9-Tips-2-deoxyribose, followed by acid-catalysed cyclization compoimds made included the 2-furyl, 2-indolyl, 2-pyridyl and benzothiophen-2-yl analogues. ... 

Scheme 1-212. Fragmentation of the lithiated heterocycles 265-267 producing lithium ynolates, ynethiolates, and yneamides.

Baudin JB, Hareau G, Julia SA, Lome R, Ruel O. Stereochemistry of direct olefin formation from carbonyl-compounds and lithiated heterocyclic sulfones. Bull. Soc. Chim. Fr. 1993 130(6) 856-878. 

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