Dihydrobenzofurans intramolecular carbolithiation

An effective and general method for the synthesis of 2,3-dihydrobenzofuran derivatives has been developed via an intramolecular carbolithiation reaction of o-lithioaryl ethers (Scheme 16).89 This process was the first example in which the carbolithiation reaction has been stopped at the 2,3-dihydrobenzofuran stage by appropriate selection of the ether moiety. 

Although the synthesis of dihydrobenzofuran derivatives seems to be not possible by this anionic cyclization methodology, there are some particular examples in which these heterocycles are prepared by an intramolecular carbolithiation reaction. In this respect Baldwin and coworkers described in 1980 the preparation of 350 by rearrangement of 349 when it was treated with BuLi in THF/TMEDA (Scheme 91)151. The most likely explanation starts with an orf/zo-lithiation giving a dilithium intermediate, which undergoes an intramolecular 5-exo carbolithiation reaction affording a 3-lithiomethyldihydrobenzofuran... 

An enantioselective method for the synthesis of 3-functionalized 2,3-dihydrobenzofuran derivatives via an intramolecular carbolithiation reaction of allyl 2-lithioaryl ethers uses (—)-sparteine as a chiral inductor. A variety of electrophiles can be reacted with the cyclized organolithium intermediate. With certain substrates, however, /3-elimination occurs instead (Equation 140) <2005CEJ5397>. 

Scheme 10.53 Synthesis of substituted dihydrobenzofuran by intramolecular carbolithiation of organolithium compounds 166 [45],...

Under the optimized conditions, allyl 2-bromophenyl ethers were treated with 2.0 equiv. of tert-butyllithium in diethyl ether at —78 °C to afford allyl 2-lithiophenyl ethers 166, which were stable at low temperature. Addition of TMEDA to the reaction mixture, followed by warming to 0°C, and subsequent treatment with various electrophiles led to the functionalized dihydrobenzofuran derivatives 165 in moderate to good yields (Scheme 10.53, path A). It is interesting to note that the 1,3-elimination pathway (Scheme 10.53, path B) could be avoided. Furthermore, this intramolecular carbolithiation reaction was completely diastereoselective, and only the trans diastereomers were obtained. This stereochemistry was explained considering the chairlike transition state 166 in which the a-substituent predominantly occupies a pseudoequatorial position resulting in high levels of... 

Scheme 10.54 Transfer of chirality in the intramolecular carbolithiation step in the preparation of trons-dihydrobenzofuran derivatives [46].

Scheme 10.56 Synthesis of enantiomerically enriched dihydrobenzofuran 172 by enantiose-lective intramolecular carbolithiation [46].

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