Acetylenes from Aldehydes. Preparation of Ethynylphenols and Phenylacetylenes by Flash Vacuum Pyrolysis of Isoxazolones

Abstract

The flash vacuum pyrolysis method of synthesis of acetylenes from aldehydes via isoxazolones is a convenient method for the preparation of a variety of derivatives, including kinetically unstable, sensitive compounds such as the ethynylphenols. As acetylenes have numerous important uses in organic synthesis and materials science, efficient syntheses of acetylenes are highly desirable. [1][2][3] Particularly noteworthy is the advent of 'click chemistry', which has made terminal acetylenes the molecules of choice for linking large molecular moieties. [3d-g] We have previously reported the synthesis of a variety of alkynes 3 in high yields using flash vacuum pyrolysis (FVP) of 4-methylideneisoxazol-5(4H)-ones 1, which themselves are readily synthesized from aldehydes and 3-methylisoxazol-5(4H)-ones. This permitted the preparation of kinetically unstable but thermodynamically stable compounds such as ethynylpyrroles, -thiophens, -furans, and -indoles 3a-f (Scheme 1). [1,4,5] Computational studies have confirmed that these isoxazolone decompositions take place via transient vinylidenes 2. [6] A 1,2-H shift affords the alkynes 3. [6] Although a 1,2-R shift is also possible, this has a higher activation barrier. [2,7] 3-Alkylidene-1-azirines may also be involved as transient intermediates. [6] In addition, ethynylamines RR 0 N-C C-H and RNH-C C-H and ketenimines R-N¼C¼CH 2 have also been generated by FVP of 4-aminomethyleneisoxazolones. [8] However, isoxazolones with large substituents can become too involatile for conventional FVP. For this reason, we developed falling solid flash vacuum pyrolysis (FS-FVP), [1,9] which allows the efficient, rapid, automated, and usually high-yielding pyrolysis of solids in high vacuum. We have recently applied this method to the synthesis of a variety of arylacetylenes, including compounds 4-8 (Scheme 2). [1] Ethynylphenols are known, but they have not been widely used in synthesis, and only very few methods of preparation have been reported. [10][11][12] We were interested in easy access to ethynylphenols and have therefore investigated the synthesis of the title compounds by FVP. The isoxazolones 10 (Scheme 3) were synthesized from 3-methylisoxazolone 9 and the appropriate substituted benzaldehyde using the previously reported procedure. [1,4] Compounds 10 were subjected to FVP at 8008C and ,10 À3 hPa. The acetylene products 11 were isolated in liquid-nitrogen cold traps, purified by distillation and/or sublimation, and characterized spectroscopically and by comparison with literature data. The ethynylphenols 11a,b were obtained in good yields (67-87 %) but should be stored in the cold and dark under exclusion of air to prevent polymerization. While the ethynylphenols 11a,b have been prepared previously by wet methods, [10][11][12] the FVP yields are superior for these compounds, and the advantage of this method is that the products Preparative yields of products on a 1-2 g scale given in percent. [4]

RACI Research Awards 2014

“…[7] This author, winner of the Arthur Birch Medal, reports on an efficient synthesis of acetylenes, including ethynylphenols, from aldehydes via flash vacuum pyrolysis of isoxazolone derivatives. [8]…”