Lithiation of furan

Lithiation of furan and thiophene, followed by the reaction with 1,2-dichlorotetramethyldisilane, gave linear compounds 26 and 27 (Scheme 6). The second lithiation and reaction with 1,2-dichlorotetra-methyldisilane under the conditions of high dilution afforded the desired furanophane (28) and thiophenophane (29) (32). 

Furans and thiophenes normally undergo a-lithiation, but when substituted at the 2-position by an activating group, a competition arises between metalation at the 3-position (ortho lithiation) and the S-posi-tion (a-lithiation). 2-Oxazolinylthiophenes may be lithiated selectively at either the 3- or 5-position by adjusting the reaction conditions tertiary amides give little or no ortho selectivity, but secondary amides direct ortho lithiation reasonably well, as seen in Scheme 23. Both thiophenes and furans that are substituted with an oxazoline or tertiary amide at the 2-position may be dilithiated at the 3- and S-po-sitions. 76 Although secondary amides are less successful at directing ortho lithiation of furans than thiophenes, A, Af,M,lV -tetramethyldiamido phosphates work quite well. Subsequent hydrolysis affords access to butenolides. A typical example is shown in Scheme 24. 

An a-lithiation reaction is characterised by a lithiation occurring at an sp2 centre and a to a heteroatom28 152. Lithiation of furan with BuLi and reaction with benzaldehyde gives alcohol 154... 

Lithiation of furans with non-directing groups at C-2 provides a route to 2,5-disubstituted furans, but appropriate choice of Uthiating conditions can outweigh ortho-directing effects, as illustrated. ... 

Reactions of Furans. Furan is alkylated at position 2 on treatment with olefins in the presence of palladium(ii) acetate and copper(ii) acetate.2-Lithiofuran, formed by lithiation of furan, yields the ate complexes (30) on treatment with... 

Lithiation of furan and reaction with SiF, leads to tetrakis(furan-2-yl)silane (1) (Schemel). 

The successful us6 of the furan dianion (46) for the. synthesis of 2,5-disubstitutad furariB depends on the presence of TM.EDA during metallation. In the absen-ce of TMEDA, nucleophilic attack at the oxime may be observed., The course of the lithiation of furan-... 

The synthesis of non-peripherally substituted octa(alkoxymethyl)phthalocyanines is outlined in Seheme 57 [213, 214]. 2,5-fcij(Alkoxymethyl)furan can be prepared by lithiation of furan followed by quenching the anion with (bromomethyl)alkyl ether to give the mono-substituted furan, and repetition of the procedure to give the required product [213]. A more simple synthesis involves chlorination of 2,5-furan dimethanol with thionyl chloride, followed by nucleophilic displacement of chloride with sodium alkoxide [214]. The furan is equilibrated with fumaronitrile for about a week and the Diels-Alder adduct aromatized by treatment with lithium fcwftrimethylsilyl)-amide (a non-nucleophilic base), followed by an acidic work-up. The 3,6-/7i5(alkoxy-methyl)phthalonitrile is cyclized under standard conditions (lithium/pentanol). 

The ease with which furans may be formed from and hydrolyzed back to 1,4-dicarbonyl compounds, together with ready 5-lithiation of 2-substituted furans. 

In many ways, the electron-rich five-membered aromatic heterocycles behave very much like carbocyclic aromatic compounds when it comes to lithiation. Lithiation a to O or S of furan and thiophene is straightforward (Scheme 130) . The usual selection of orf/io-directing groups allows lithiation at other positions and some examples... 

Snieckus and co-workers reported the directed lithiation of 3-furanecarboxylic acid diethylamide (6.21.), which proceeded selectively in the 2-position, and the subsequent zinc-lithium exchange. The so formed fiiranylzinc reagent underwent Negishi-coupling with 2-bromotoluene in the presence of a palladium-triphenylphosphine catalyst to give 2-(o-tolyl)furane in good yield.26... 

The trialkylstannyl derivatives of furane are also frequently employed in Stille coupling. This reaction was utilised, for example, to introduce a chiral oxazoline moiety onto the furane core through the coupling of 2-trimethylstannylfurane and chiral 2-bromooxazoline derivatives (6.30.)40 The furylstannane can be conveniently prepared in a lithiation-stannylation sequence, which makes it an attractive reagent for the introduction of the 2-furyl moiety. 

Lithiation of thiazolo[5,4-b]pyridine-N-oxides (503) by n-butyllithium at -65°C is selectively directed by the pyridine N-oxide moiety, whereas lithiation of the parent heterocycle by LDA at -78°C exclusively occurs at the C-4 position (89TL183). Interestingly, no metalation of the furan ring occurred (Scheme 152). 

Disubstituted furans can be prepared by the 3-lithiation of 2-phenylthio-5-alkylfurans, followed by reaction with an electrophile and then desulfurization with Raney nickel (Section 3.3.3.8.4). 3-Furylmercuri acetate can be obtained from furan-2-carboxylic acid (CHEC 3.11.3.9) and transformed to other 3-substituted furans via the lithio compound. 

An unusual regioselectivity pattern for the ortho lithiation of 3-aryl-and 3-styryl-furans has been uncovered wherein lithiation occurs preferentially at the sterically... 

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

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