Convenient One-Pot Synthesis of 2-Oxazolines from Carboxylic Acids

Kazuhito Hioki, Yumiko Takechi, Noriyo Kimura, Hiroyuki Tanaka, Munetaka Kunishima
2008 Chemical and pharmaceutical bulletin  
Notes Preparation of 2-oxazoline, a versatile intermediate in synthetic chemistry, from carboxylic acids is a classical and useful method. [1] [2] [3] [4] [5] Since 2-oxazolines can be readily re-converted into carboxylic acids, they can be used as a protecting group for carboxylic acids. 3,6) Among various methods employed to convert derivatives of carboxylic acids to the oxazolines, intramolecular dehydrohalogenation of N-(bhaloethyl)amides to give 2-oxazolines is well established. 1, 4, 5,
more » ... Although the reaction readily takes place by treatment with either base or silver ion, such reactions have not adapted well to the preparation of 2-oxazolines, presumably because of the cumbersome method used to prepare N-(b-haloethyl)amides. For example, they have been prepared by Ritter reaction of nitriles with halohydrins or haloalkenes, 8) chlorination of N-(b-hydroxyethyl)amides with thionyl chloride, 9) and coupling of 2-haloethylammonium salts with acid chlorides 10,11) or acid anhydrides. 12) We report here a simple and general one-pot method to prepare 2-oxazolines from carboxylic acids; the reaction involves dehydrocondensation of carboxylic acids and 2haloethylammonium salts leading to the formation of N-(bhaloethyl)amides, which then can be readily converted into 2-oxazolines by base treatment. Results and Discussion Because dehydrocondensation between carboxylic acids and amines using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4methylmorpholinium chloride (DMT-MM) can proceed efficiently in water or alcohols, 13,14) polar 2-haloethylammonium salts, which are insoluble in common less polar organic solvents, are directly available by using methanol as a solvent. First, we attempted a reaction using 3-phenylpropionic acid 1a and 2-chloroethylammonium chloride 2 (XϭCl) as model compounds (Table 1) . A methanol solution of 1a (1.0 eq), 2 (XϭCl) (1.2 eq), and N-methylmorpholine (NMM: 1.2 eq) was treated with DMT-MM (1.2 eq) at room temperature for 1 h followed by addition of KOH (4.2 eq) dissolved in methanol. The resulting mixture was refluxed for 1.5 h to give 2-(2-phenethyl)-2-oxazoline 3a in 74% yield. 2-Bromoethylammonium bromide 2 (XϭBr) is also available for the reaction and gives a similar result (run 2). Reaction with Et 3 N, a weaker base than KOH, resulted in decreasing the yield of 3a despite prolongation of refluxing time to 4 h. Since N-(b-chloroethyl)amide 4a (XϭCl) was isolated in 91% yield after finishing the first step using DMT-MM, the reaction proceeds by the mechanism shown in Chart 1. Employing solvents in which the ammonium salt 2 is soluble is essential. Thus, the oxazoline was obtained in a good yield in polar solvents, DMF as well as methanol, whereas the yield was very low in a less polar THF, in which 2 is insoluble. As shown in Table 2 , preparation of 2-oxazolines 3b-g from various carboxylic acids was conducted using methanol, which has advantages over DMF in terms of cost and boiling point; methanol can be readily removed by a rotary evaporator. Benzoic acid 1b, a,b-unsaturated carboxylic acid 1e, and secondary carboxylic acids 1c or 1f could be converted into the corresponding oxazolines in fair to good yields. In contrast to the ring-closing reaction of b-hydroxyamide, which
doi:10.1248/cpb.56.1735 pmid:19043250 fatcat:rvrwgu3duzgvzokbc4llkblvby