Furan deprotonation

Phthalides are versatile starting materials for a wide variety of benzo[c]furans. Deprotonation of the parent compound (91) with strong bases (e.g., Pr 2NLi) results in the generation of a deep red-... 

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 dianions derived from furan- and thiophene-carboxylic acids by deprotonation with LDA have been reacted with various electrophiles (Scheme 64). The oxygen dianions reacted efficiently with aldehydes and ketones but not so efficiently with alkyl halides or epoxides. The sulfur dianions reacted with allyl bromide, a reaction which failed in the case of the dianions derived from furancarboxylic acids, and are therefore judged to be the softer nucleophiles (81JCS(Pl)1125,80TL505l). 

The mechanism of the Feist-Benary reaction involves an aldol reaction followed by an intramolecular 0-alkylation and dehydration to yield the furan product. In the example below, ethyl acetoacetate (9) is deprotonated by the base (B) to yield anion 10 this carbanion reacts with chloroacetaldehyde (8) to furnish aldol adduct 11. Protonation of the alkoxide anion followed by deprotonation of the [i-dicarbonyl in 12 leads to... 

Dehydrobenzene or benzyne 158 can be trapped by all manner of species. 1,2-Dehydro-o-carborane 159 has been shown to undergo many of the same reactions as its two-dimensional relative, 1,2-dehydrobenzene. Although dehydroaromatic molecules can be formed in a variety of ways, synthetic pathways to 1,2-dehydro-o-carborane are quite limited. An effective procedure reported so far78 first forms the dianion by deprotonation of o-carborane with 2 equiv. of butyllithium. Precipitated dilithium carborane is then treated with 1 equiv. of bromine at 0°C to form the soluble bromo anion 160. Thermolysis of 160 with anthracene, furan, and thiophene as substrates leads to the adducts 161-164.79 80 1,2-Dehydro-o-carborane reacts with norbomadiene to give both homo 2+4 and 2+2 addition, leading to three products 165-167, in a 7 1 ratio79. An acyclic diene, 2,3-dimethyl-... 

We had two possible routes in which alcohol 72 could be used (Scheme 8.19). Route A would involve rearrangement of tertiary alcohol 72 to enone 76. Deprotonation at C5 and generation of the enolate followed by exposure to an oxaziridine or other oxygen electrophile equivalents might directly afford the hydrated furan C-ring of phomactin A (see 82) via hydroxy enone 81. We had also hoped to make use of a chromium-mediated oxidative rearrangement of tertiary allylic alcohols. Unfortunately, treatment of 72 to PCC produced only unidentified baseline materials, thereby quickly eliminating this route. 

The oxidation of 2,5-disubstuted furans by singlet oxygen was exploited for the synthesis of [5,5,5] and [6,5,6] bis-spiroketals <06OL1945>. An unusual regioselective photooxidation of 3-bromofuran to 2- and 3-bromo- hydroxybutenolides, as depicted below, was reported. The mechanism for the observed base-dependent regioselective deprotonation of the endoperoxide intermediate was not determined <06OL4831>. 

Benzo[c]furans (isobenzofurans) are reactive molecules usually employed as reactive dienes in the synthesis of more complex molecules. In the synthesis of spiro compounds related to fredericamycin A, Kumar generated the trimethylsiloxytrimethylsilylbenzo[c]furan 125 from phthalide via two consecutive deprotonations and silylations of the resulting anions. Diels-Alder reaction of the isobenzofuran as shown below with a spiroenedione leads to the formation of an endo-exo mixtures that can be smoothly converted to the dihydroxydione <00IJC(B)738>. 

Treating 2-furyltithium (derived from deprotonation of furan with n-BuLi) with ZnCh gave 2-furylzinc chloride, which then was coupled with 1,3-dibromobenzene to furnish bis-furylbenzene 12 [20, 21]. In addition, 2-furylzinc chloride was coupled with 4-iodobenzoic acid to give adduct 13. The Negishi reaction conditions were compatible with the carboxylic acid [22],... 

The [3 + 2] cycloaddition of furan proceeds in the reaction of 5M in protic solvent (HFIP), where deprotonation from the initially formed intermediate 28 does not take place and intramolecular cyclization predominates in the termi-... 

Scheme 6.39 Generation ofl62 by -elimination from 1 -bromo-1,4-cyclo-hexadiene (174), trapping of162 by furan and 2,5-dimethyl-furan and deprotonation of162 by KOtBu.

There are cases known in which the use of different precursors of 221 was not equally successful in the synthesis of a certain cydoadduct. Thus, when the bromo-fluorocyclopropane 239 and 1,3-cyclopentadiene were employed as source and trapping reagent for 221, respectively, the diene was deprotonated to a large extent [66, 139], whereas this process did not play a major part on utilization of the dibromocy-clopropane 254 (Scheme 6.55). Further, an experiment to prepare the furan adducts 231-233 (Scheme 6.53) from 239 failed [66], probably because of the metalation of furan by MeLi or the carbenoid resulting from 239. 

Electron-rich heterocycles, snch as pyrrole and furan, bear more resemblance to car-bocyclic rings their side chains are mnch less acidic, and undergo lateral lithiation mnch less readily. Without a second directing group, methyl groups only at the 2-position of fnran, pyrrole or thiophene may be deprotonated. 

Different heterocycles, such as furan, 2,3-dihydrofuran, iV-methylpyrrole, thiophene, iV-methylindol or 5-methyl-l,3-triazole, were deprotonated at the a-position with lithium and a catalytic amount of naphthalene or anthracene (1-7%) in THF at room temperature to give, after trapping with methyl iodide, the corresponding methylated products in 56-93%242. 

The mixed metal alkyl-amido base [BuNa(TMEDA)][TMP2Mg] (TMP = 2,2,6,6-tetramethylpiperidine) is capable of deprotonating furan selectively at its 2-position in THF as a solvent. The product obtained is a complex tris-furylmagnesiate, with the empirical formula [Na2(THF)3][2-furyl6Mg2(TMEDA)] (15) . An X-ray crystal-structure determination showed that in the solid state this compound exists as a coordination polymer of [Na2(THF)3][2-furyl6Mg2] units linked by bridging TMEDA molecules (Figure 16). 

Dehydrohalogenation of 2,3-dihalo-2,3-dihydrobenzofurans gives 3-halobenzo-furans [69]. Rate measurements have indicated higher difficulties in deprotonation... 

Nucleophilic attack on neutral pyrroles, furans and thiophenes without strongly electron-withdrawing substituents is restricted to deprotonation at N or C atoms. However, the cations formed by electrophilic attack on pyrrole, furan and thiophene rings react readily with weak nucleophiles, resulting in overall addition or ring-opening reactions. 

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). 

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