Butyllithium reaction with furan

Arynes with their reactive triple bond would be expected to participate readily in cycloaddition reactions. However, as demonstrated in the previous section, the addition of nucleophiles is extremely facile, and therefore reactions with non-nucleophilic reagents cannot usually be observed unless the aryne is generated in the absence of nucleophiles. In practice this usually means that routes involving the treatment of aryl halides with nucleophilic bases cannot be used. The first cycloaddition reaction of ortho-benzyne, the Diels-Alder reaction with furan was observed in 1955 by Wittig and used 2-fluorobromobenzene as the precursor. The cycloadduct was obtained in almost 90% yield, and the reaction has formed the basis for numerous synthetically useful Diels-Alder cycloadditions involving arynes. Tetrabromobenzene reacts with butyllithium to give the diaryne intermediate with furan to form a tetrahydroanthracene. The mixture of syn and anti conformers can be separated based on differences in methanol solubility (Scheme 7.26). 

Reaction of alkyl phenylmethanesulphinates 100 with n-butyllithium in tetrahydro-furan at — 80 °C afforded the corresponding benzyl n-butyl sulphoxide160 (equation 53). Preparation of optically active sulphoxides by this reaction will be discussed later in this chapter. 

A high endo selectivity is observed in the reaction of (phenylsulfonyl)allene (112) with furan (157) (equation 113)108. The endo adduct 158 can be readily transformed into highly substituted cyclohexenol 160 upon treatment with n-butyllithium after hydrogenation of the ring double bond (equation 114)108. 

Strong base treatment of the spiro salt 49 gives a benzyne (107) from which the isolated products were produced by further reaction. For example, with n-butyllithium and furan in tetrahydrofuran, 108 is produced after hydrogenation and acid treatment via 109. Reaction with phenyllithium gives 110 (R == Ph and Me) by subsequent addition of phenyl or methyl anion to the benzyne, respectively, and 110 (R = I) by subsequent reaction with iodine anion. Similarly the 9,9-diphenyl salt 111 gives 112 with phenyllithium. Pyrolysis of the spiro salt 49 gives 50. 

As shown in Equation (83), 2-iodobenzo[ ]furan was also prepared by reaction of benzo[, ]furan 82 with tert-butyllithium in ether at -78 °C, followed by reaction with iodine <2002JOC7048>. 

The procedure for 2-iodofuran is typical for the introduction of iodine via an organolithium intermediate. In contrast to bromine, iodine does not react with furan at temperatures up to at least 20 °C. This allows the use of an excess of furan to shorten the reaction time of the lithiation and to be sure that all butyllithium has reacted. This is absolutely necessary in connection with the fact that 2-iodofuran and butyl iodide can not be separated by distillation. 

Benzo[Z ]thiophene is somewhat less reactive in electrophilic substitutions than thiophene, and also less reactive than benzo[Z ]furan. Moreover, regioselectivity is poor, giving rise to mixtures. Frequently, the 3-position is attacked preferentially over the 2-position, e.g. in halogenation, nitration and acylation. Only the reaction with n-butyllithium is regioselective, giving 2-lithiated benzo[6]-thiophene. 

Trifluoromethyl)furan 147 was prepared in 67% yield by heating 4-methyl-oxazole 5 and 3,3,3-trifluoropropyne in toluene at 180°C for 13 h (Fig. 3.44). Metalation of 147 at the 2 position with n-butyllithium and subsequent reaction with aldehydes gave 3-(trifluoromethyl)-2-furyl carbinols 148. ... 

Interestingly, when the number of equivalents of t-butyllithium was reduced from 4.0 to 1.1, all three benzyne-furan cycloadducts (i.e., 97a, 102, and 103) resulting from the three possible dibromoindole starting materials (lOOa-c) were isolated in excellent yields (Scheme 28). It is noteworthy that while the ortho dichlOTO- and dibromo-substituted indoles (94, lOOa-c) resulted in clean formation of the aryne species, the ortho difluoro derivatives lOOd-f did not behave in the same way. The attempted Diels-Alder reactions with 4,5 and 6,7-difluoroindoles lOOe and lOOf resulted only in the recovery of starting material. However, in the case of 5,6-difluoroindole lOOd, the cycloaddition resulted in the formation of 103,... 

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-... 

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). 

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. 

A flexible means of access to functionalized supports for solid-phase synthesis is based on metallated, cross-linked polystyrene, which reacts smoothly with a wide range of electrophiles. Cross-linked polystyrene can be lithiated directly by treatment with n-butyllithium and TMEDA in cyclohexane at 60-70 °C [1-3] to yield a product containing mainly meta- and para-Iithiated phenyl groups [4], Metallation of noncross-linked polystyrene with potassium ferf-amylate/3-(lithiomethyl)heptane has also been reported [5], The latter type of base can, unlike butyllithium/TMEDA [6], also lead to benzylic metallation [7]. The C-Iithiation of more acidic arenes or heteroar-enes, such as imidazoles [8], thiophenes [9], and furans [9], has also been performed on insoluble supports (Figure 4.1). These reactions proceed, like those in solution, with high regioselectivity. 

An overcrowded PAH, 9,10,ll,20,21,22-hexaphenyltetrabenzo[a,c,I,n]pentacene (55), showed an interesting screw-type helicity (Fig. 15.21) [97]. An end-to-end twist of 144° was estimated from the X-ray structure of 55. Pentacene 55 was prepared by the reaction of l,3-diphenylphenanthro[9,10-c]furan 54 with the bisaryne equivalent generated from l,2,4,5-tetrabromo-3,6-diphenylbenzene in the presence of n-butyllithium, followed by deoxygenation of the double adduct with low-valent titanium. Pentacene 55 could be resolved by chromatography on a chiral support, but it racemized slowly at room temperature (t1/2 9 h at 25 °C). 

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