Direct synthesis of unprotected phenols using palladium-catalysed cross coupling reactions of functionalised organozinc reagents

Abstract

Palladium-catalysed reaction of unprotected 2-, 3-, and 4-iodophenols with a range of amino acid derived organozinc reagents (not used in excess) gives the expected products in good to excellent yield, demonstrating that carbon-zinc bonds are not protonated by acidic phenols under the conditions of palladium-catalysed coupling reactions.

Synthesis of orthogonally protected biaryl amino acid derivatives

“…Previous studies established that 4-iodophenol, possessing an unprotected phenolic OH group, is compatible with the Negishi cross-coupling reaction of the organozinc iodide 4. 52 Attempted cross-coupling reaction of the unprotected biphenol derivative 3c, however, resulted in substantial amounts of alanine, presumably due to the increased acidity of the biphenolic derivative 3c arising from a co-operative effect of hydrogen-bonding interactions between the OH substituents (PhOH pK a = 10.0, 2,2 -biphenol pK a1 = 7.6 in water). [53][54][55] The dibenzyl (3b) and diacetyl (3d) protected biphenol derivatives reacted under palladium catalysis with the organozinc reagent 4 to afford the expected bis-coupled products 2a and 2b, respectively, together with varying amounts of the mono-coupled (6 and 7) and the homo-coupled (8) products (Scheme 4 and Table 1).…”

Gas-phase study of new organozinc reagents by IRMPD-spectroscopy, computational modelling and tandem-MS

“…While less reactive than Grignard reagents, 3 organozinc reagents are flexible sources of carbon nucleophiles. 4,5 The carbon-zinc bond has been shown to be largely compatible with acidic protons, 6 such as phenolic protons 7 and those of trifluoroacetamides, 8 providing experimental evidence for a significant lack of basicity. Functionalised alkylzinc iodides are frequently used in dipolar aprotic media such as N,N-dimethylformamide (DMF), which has proven to be the solvent of choice in regard to reactivity, ease of preparation and solution stability.…”

Ionisation of the ZincIodine Bond of Alkylzinc Iodides in Dimethylformamide from Theory and Experiment

“…[1,2] Functionalised alkylzinc iodides are compatible with acidic protons, [3] including phenolic protons [4] and trifluoroacetamides, [5] attesting to the lack of basicity of these reagents. The reasons for this behaviour, which is somewhat counterintuitive, are not at present well understood.…”

“…[18] It is known that loss of a halide ligand is a reasonably general mechanism for the ionisation of neutral coordination and organometallic complexes under positive ion ESI-MS conditions, [19] but the technique does not appear to have been used to characterise alkylzinc halides. ESI-MS has been used in negative ion mode to identify the zincate [tBu 4 ZnLi 2 ]…”