Furan 3- lithio derivatives

The first proton to be removed from iV-methylpyrrole by w-butyllithium is from an a-position a second deprotonation occurs to give a mixture of 2,4- and 2,5-dilithiated derivatives. The formation of a 2,4-dilithio derivative is noteworthy since in the case of both furan and thiophene initial abstraction of a proton at C-2 is followed by proton abstraction from C-5 (77JCS(P1)887). iV-Methylindole, benzo[6]furan and benzo[6]thiophene are also deprotonated at C-2. Selenophene and benzo[6]selenophene and tellurophene and benzo[6]tellurophene similarly yield 2-lithio derivatives (77AHC(21)119). 

The synthesis of phosphonium iodide 24, the precursor of phos-Br phorus ylide 12, begins with the alkylation of 5-lithio-2-methyl- furan,10 derived from the action of n-butyllithium on 2-methylfuran 17 (16), with 1,4-dibromobutane (17) to give 15 in 75% yield (see... 

The lithio derivatives of dibenzofuran undergo the expected reactions. Carbonation yields carboxylic acids,reaction with sulfur dioxide yields sulfinic acids, and reaction with methyl sulfate yields methyl compounds. Alkylation can also be achieved by treatment of 4-lithio-dibenzofuran with alkyl halides. Silylation can be achieved with chlorotrimethyl- or chlorotriphenylsilane. " " Reaction of lithiodibenzo-furans with acetaldehyde and with benzonitrile take the expected course. 

Although a limited range of Grignard reagents is available, the most widely used group is undoubtedly the lithio group introduced by direct lithiation (see Section 3.3.1.6.2). The ready formation of the lithio derivatives of pyrroles, furans and thiophenes and their benzo-fused derivatives has had a most important impact on the chemistry of these heterocyclic systems. Reaction of the... 

The reactions of the lithio derivatives of benzo[ >]-fused systems indole, benzo[6]furan and benzo[h]thiophene are similarly diverse. Since indole and benzo[h]thiophene undergo electrophilic substitution mainly in the 3-position, the ready availability of 2-lithio derivatives by deprotonation with n-butyllithium is particularly significant and makes available a wide range of otherwise inaccessible compounds. The ready availability of 3-iodoselenophene and hence of 3-lithioselenophene (73CHE845) provides a convenient route to 3-substituted selenophenes. 2-Lithiotellurophenes are especially important precursors of tellurophene derivatives because of the restricted range of electrophilic substitution reactions which are possible on tellurophenes (77AHC(2l)ll9). 

The tendency for the 3-lithio derivatives of furans and thiophenes to undergo ring opening has been exploited for the synthesis of polyunsaturated acyclic compounds. A trimethylsilyl group in the... 

N-Substituted pyrroles, furans and thiophenes can be 2-lithiated, and these lithio derivatives are important synthetic intermediates (Section 3.3.3.8). 2-Mercuri and 2-palladio derivatives are also important (Sections 3.3.3.8.8 and 3.3.3.8.9). 

Furan is resinified by sulfuric acid but it can be sulfonated with the complex of sulfur trioxide with pyridine or dioxane. Depending on conditions the 2-sulfonic or the 2,5-disulfonic acid may be obtained. Furan-2-carboxylic acid can be sulfonated with oleum. Benzo[6]furan is polymerized by sulfuric acid. The 2-sulfonic acid has been obtained by oxidation of the sulfinic acid available in turn by treatment of the lithio derivative with sulfur dioxide. Benzo[6]furan with the sulfur trioxide-pyridine complex allegedly affords the 3-sulfonic acid. 

The halo-furans and -benzo[f>]furans are particularly important as precursors of the lithio derivatives (Section 3.11.3.9). Direct halogenation of furan (Section 3.11.2.2.5) is unsatisfactory, and halofurans are prepared by decarboxylation of halofurancarboxylic acids, from chloromercurio compounds, by decarboxylative halogenation of furancarboxylic acids or by partial dehalogenation of polyhalofurans. 

Butylpotassium and butylcesium deprotonate furan at the 2-position (75BSF1302), but butyllithium is the reagent of choice. When furan is treated with butyllithium the reactions in Scheme 114 occur (77JCS(P1)887>. The conditions, however, may be controlled to yield predominantly the mono- or the di-lithio derivative. By carbonation and esterification of the reaction mixture obtained by treatment of furan with butyllithium and TMEDA (1 1 1) in ether at 25 °C for 30 min, a 98% yield of methyl furan-2-carboxylate is obtained. Similarly, a butyllithium TMEDA furan ratio of 2.5 2.5 1 in boiling hexane for 30 min results in 91% of dimethyl furan-2,5-dicarboxylate and 9% of the monoester. Competition experiments indicate that furan reacts with butyllithium faster than thiophene under non-ionizing conditions but that the order is reversed in ether or in the presence of TMEDA. 

Tetraisopropylthiuram disulfide 447 is a reagent of choice for preparing thiols from the corresponding lithio derivatives (Scheme 142). 2,4-Disubstituted furans, difficult to prepare by classical methods, have been prepared from 2-phenylthio-5-alkylfurans as shown in Scheme 143. The starting material is obtained by treatment of 2-alkylfurans with -butyllithium followed by diphenyl disulfide. The practicality of this approach thus illustrates the potential of the phenylthio group as a protecting group. 

Synthetic procedures are available for the preparation of fluoro (e.g., 2-lithio-l-methyl-5-octylpyrrole with fV-fluoro-iV-(phenylsulfonyl)benzenesulfonamide <2003JFC(124)159>), chloro, bromo, and iodo compounds from the corresponding lithio derivatives, for example, 2-iodobenzo[A]furan via lithiation of the heterocycle then reaction with iodine <2002JOC7048>. Perchloryl fluoride (FCIO3), A-chlorosuccinimide, bromine, and iodine are examples of reagents which can be used to introduce fluorine, chlorine, bromine, and iodine, respectively. 

Alkyllithium reagents also yielded the corresponding alkylated sulfur-stabilized allenyl anions. Thus, treatment of 286 with -BuLi gave the lithio derivative 287 which was reacted with the aldehyde 288. Upon acidification with trifluoroacetic acid (TEA), the furan-containing diester 289 was obtained in 67% yield (Scheme 36) <2002CC2824>. 

Metalation of the heteroaromatic compounds furan and thiophene with alkyllithi-um reagents furnishes the corresponding 2-lithio derivatives. For example, sequential treatment of 2-methylfuran with ABuLi in THF, followed by alkylation of the organolithium intermediate and hydrolysis of the resultant bis-vinyl ether, produces an unsaturated 1,4-diketone. 

Thiophenes furans and pyridines are in general the most readily available of the various hetero-aromatic systems and therefore we have carried out a great deal of metallation and derivatization reactions with these compounds. Furan and thiophene are cheap starting compounds and the stability of their easily obtainable 2-lithio derivatives permits reactions with a variety of electrophilic reagents. Hetero-aromatics with two or more hetero atoms (e.g. thiazoles, pyrazoles, oxazoles) are less readily available, and some of their metal derivatives have a low thermostability (cyclofragmentations). For these reasons their metallation and functionalization reactions have been studied less extensively [1]. 

The reaction of 2-lithio derivative with trans-chlorovinyl iodoso-dichloride and sodium nitrite in dimethylformamide gives with furan, thiophene, and selenophene the corresponding 2-iodo and 2-nitro derivatives. The same reaction, when applied to tellurophene, gives 2-iodotellurophene (16) and the unforeseen compound di-2-tellurienyl telluride (17) the expected 2-nitrotellurophene was not obtained.25 Other attempts to prepare 2-nitrotellurophene were unsuccessful. 

Where a heterocyclic organometallic reagent is required, Grignard and zinc derivatives are often satisfactory complications sometimes attend the use of lithio derivatives. The use of boronic acids has become very popular on account of their clean reactions, general stability to air and water, and their compatibility with practically any functional group furan, thiophene, indole and pyridine boronic acids have all been used. " ... 

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