A new method for the preparation of 3,4-and 2,5-disubstituted furan rings is described. A variety of 2-silylated-3-(hydroxymethyl)furans and 2-silylated-3-furoic acids lithiate exclusively at C-4 when treated with 2.2 equivs of BuLi. The resulting dianions were quenched with a variety of electrophiles to provide 2-silylated-3-(hydroxymethyl)-4-substituted furans and 2-silylated-4-substituted 3-furoic acids in good to excellent yields. Removal of the silyl group (n-Bu 4 NF) provided a variety of 4-substituted-3-(hydroxymethyl)furans and methyl 4-substituted-3-furoates, respectively. The latter esters were prepared due to difficulties encountered in isolating 4-substituted-3-furoic acids. The site of lithiation was altered by protecting the 3-hydroxyl group with a triethylsilane. Lithiation of 2-silylated-3-(((triethylsilyl)oxy)methyl)furan with 1.2 equivs of BuLi followed by the addition of electrophiles provided 2-silylated-3-(((triethylsilyl)oxy)methyl)-5-substituted furan rings. Subsequent removal of both silyl groups provided 2,4-disubstituted furan rings in moderate to good yields. A rationale is provided to explain why protection of the hydroxyl group at C-3 leads to a change in lithiation from the C-4 to the C-5 position of the furan ring. In addition, an explanation for the observed effect of adding HMPA or LiCl to the solution during the lithiation of 2-(tertbutyldimethylsilyl)-3-(hydroxymethyl)furan is provided.In the preceding paper, 1 the difficulty in preparing 3,4and 2,4-disubstituted furan rings due to the preference for furan rings to lithiate 2 and add electrophiles 3 in the C-2 or C-5 positions was discussed. New synthetic routes toward the preparation of furan rings which contain groups in the 3 and/or 4 positions are useful, since many natural products incorporate furan rings with either a 3,4-or 2,4-disubstituted or 2,3,4-trisubstituted pattern. 4 This paper describes a full account of our work in this area.Some previous reports on the preparation of 3,4disubstituted furans have involved using Diels-Alder/ retro-Diels-Alder chemistry, 5 chemical modifications of 3,4-furandicarboxylic acid, 6 and the synthetic modification of acyclic precursors. 7 An alternative approach to the preparation of 3,4-disubstituted furans is the direct lithiation of substituted furan rings. The C-4 lithiation of a 3-substituted furan, however, has not been successful
To model the C-C β-scission reactions of backbone peptide alkoxy radicals, enthalpies and barriers for the fragmentation of four substituted alkoxy radicals have been calculated with a variety of ab initio molecular orbital theory and density functional theory procedures. The high-level methods examined include CBS-QB3, variants of the G3 family, and W1. Simpler methods include HF, MP2, QCISD, B3-LYP, BMK, and MPW1K with a range of basis sets. We find that good accuracy can be achieved with the G3(MP2)//B3-LYP and G3X(MP2)-RAD methods. Lower-cost methods producing reasonable results are single-point energy calculations with UB3-LYP/6-311+G(3df,2p), RB3-LYP/6-311+G(3df,2p), UBMK/6-311+G(3df,2p), and RBMK/6-311+G(3df,2p) on geometries optimized with UB3-LYP/6-31G(d) or UBMK/6-31G(d). Heats of formation at 0 K for the alkoxy radicals and their fragmentation products were also calculated. We predict ΔfH0 values for the alkoxy radicals of -71.4 ((•)OCH2CH [Formula: see text] O), -102.5 ((•)OCH(CH3)CH [Formula: see text] O), -176.6 ((•)OCH(CH3)C(NH2) [Formula: see text] O), and -264.6 ((•)OC(CH3)(NHCH [Formula: see text] O)CH [Formula: see text] O) kJ mol(-)(1). For the fragmentation products NH2C((•)) [Formula: see text] O and CH( [Formula: see text] O)NHC(CH3) [Formula: see text] O, we predict ΔfH0 values of -5.9 kJ mol(-)(1) and -352.8 kJ mol(-)(1).
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