Furan. 2- - derivatives lithiation

In contrast to the rich chemistry of alkoxy- and aryloxyallenes, synthetic applications of nitrogen-substituted allenes are much less developed. Lithiation at the C-l position followed by addition of electrophiles can also be applied to nitrogen-containing allenes [10]. Some representative examples with dimethyl sulfide and carbonyl compounds are depicted in Scheme 8.73 [147, 157]. a-Hydroxy-substituted (benzotriazo-le) allenes 272 are accessible in a one-pot procedure described by Katritzky and Verin, who generated allenyl anion 271 and trapped it with carbonyl compounds to furnish products 272 [147]. The subsequent cyclization of 272 leading to dihydro-furan derivative 273 was achieved under similar conditions to those already mentioned for oxygen-substituted allenes. 

Formation of vinylic (trigonal C-Li), allylic or benzylic organolithiums a to O is more favourable. The useful acyl anion equivalent methoxyvinyllithium 11, for example, is formed on treatment of methyl vinyl ether with f-BuLi at -65 °C,13 and furan is lithiated by BuLi in Et20 at 0 °C to give 12.14 More complex carbohydrate-derived vinyl ethers such as 13 also lithiate readily.15... 

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. 

Another application of 2-lithiated benzo[ ]furan to generate a structurally interesting benzo[ ]furan derivative was realized by reaction of 2-lithiated benzo[ ]furan with 4,4-dimethoxy-4//-naphthalen-l-one, followed by hydrolysis, as shown in Equation (72) <2003JME532>. 

Symmetrical and unsymmetrical 2,5-fc/s-acetylenic furan derivatives were produced in high yield using Pd-catalyzed cross-coupling reaction of 2,5-/7M(butyltelluro)furan, which was prepared from furan through lithiation-transmetallation and alkylation <03TL1387>. 

Boron Derivatives. Lithiation and metal-metal exchange in thiophene or furan give... 

Magnesium Derivatives. Lithiation and metal-metal exchange with a magnesium halide in either A-methylpyrrole, furan, or thiophene give the organomagnesium substrates 24 and 25 for Pd-catalyzed cross-coupling (Scheme The method has been adapted for the preparation of the alternating thiophene-pyridine chain 26. ° ... 

Bis(trifluoromethyl)furan 87a did not react with bromine, however lithiation allowed one to insert Br-atom regioselectively at the C2 position [143], Many other electrophilic reagents can be involved into the reaction with lithiated furan derivatives, for example, carbon dioxide, aldehydes, silyl chlorides, various Michael acceptors, etc. [74, 84, 144], Treatment of vinylation products 226, 227 with alkyl-lithium afforded the corresponding alkynes 228, 229 [64, 143],... 

Directive effects on lithiation have also been studied. The regiospecific /3-metallation of A-methylpyrrole derivatives and 2-substituted furans has been effected by employing the directive effect of the oxazolino group (82JCs(Pl)1343). 2-Substituted furans and thiophenes are metallated in the 5-position. The formation of 2-lithio-3-bromofuran on treatment of... 

Carbon-linked sugar-heterocycles were also obtained by reaction of the lithiated derivatives obtained from 2-bromopyridine, a-picoline, and ben-zothiazole with 4-0-benzyl-2,3 6,7-di-0-cydohexylidene-D-g(ycero-D-gulo-htplono-1,5-lactone (55). The corresponding o-glycero-D-gulo-hepto-pyranose-substituted compounds 56a-c were isolated in 35-43.5% yields. With other heterocycles (for example furan), 1-disubstituted guloheptitols were obtained (59). 

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. 

Directive effects on lithiation have also been studied. The regiospecific (3-metallation of N-methylpyrrole derivatives and 2-substituted furans has been effected by employing the directive effect... 

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 ring-opening reactions of lithiated derivatives have been reviewed comprehensively. A well-known example of this latter possibility is the ring-opening of 3-lithiobenzo[ ]furan (401) to the lithium salt of 2-ethynylphenol (402) (78CHE353). 

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). 

Lithiation with the assistance of an ortho substituent is also valuable for example, the dianions derived from furan-and thiophenecarboxylic acids by deprotonation with LDA can be reacted with various electrophiles (Scheme 138). 

An efficient approach for asymmetric syntheses of benzo[ ]furan-l-alkylamines was developed by reaction of 2-lithiated benzoMfuran with aldehyde-SAMP-derived hydrazones (SAMP = (3 )-(—)-l-amino-2-methoxymethyl-pyrolidine Equation 84). In this way, an efficient synthesis of hydrazine 91 was achieved <2004TA747>. 

There has been almost no activity in connection with true furans of this class which are almost unknown. Recent attempts to prepare 2,4-dimethoxy-furan were fruitless.85 Lithiation of 4-methoxyfuran-2(5//)-one (60) produces the 5-anion normally, but this reacts only at carbon giving with iodomethane the homolog (61) and with aldehydes a variety of 5-ylidenefuranones (62). No enol ether is formed. Whereas this is not remarkable, the failure of acetylation and particularly silylation procedures to furnish enol derivatives is almost unprecedented.85 The situation is not yet understood. 

Older methods of preparing furanthiols and their derivatives have been overshadowed by lithiation techniques in which the metallated furan is treated with sulfur and alkylated to give the desired alkylthiofurans.198,199 Phosphoryl thioesters are obtained in the same way, as are their selenium equivalents.200 2-Furyllithium affords lithium furan-2-selenite when treated with selenium dioxide.201... 

Condensed furans hke coumarins belong to type 13 mentioned in page 8. As in the case of the synthesis of coumarins, the ortho disubstituted starting compounds are obtained by lithiation of phenol or its methyl or methoxymethyl derivatives (Type B synthesis). These are reacted with electrophilic reagents such as DMF, Br... 

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