Thermal Cyclisation of β-Hydroxyamides to Oxazolines

Abstract

A common approach to the synthesis of oxazolines is ring closure of hydroxyamides using a dehydrating agent such as SOCl 2 , P 2 O 5 , EtO 2 CN=NCO 2 Et/PPh 3 and, more recently, Burgess reagent. [1][2][3][4][5] The mechanism for this ring closure is believed to involve an internal S N 2 displacement of an alcohol derived leaving group, for example, a phosphate group, with accompanying inversion at the carbon carrying the hydroxyl group. 3 An alternative mechanistic pathway for oxazoline synthesis would be an initial hydroxyl group attack on the amide carbonyl followed by elimination of water leading to the oxazoline, but this has never been established. Such a process would involve retention of configuration at the carbon carrying the hydroxyl group, opposite to what is observed when a chemical dehydrating agent is used. Such a mechanism might take place under thermal conditions, in the absence of a dehydrating agent, to give other stereospecific oxazolines. To establish this mechanism we selected norephedrine (erythro) and norpseudoephedrine (threo) as our precursors to the β-hydroxyamides (1,2). In our work, reaction of the β-hydroxyamide (1) derived from norephedrine (erythro) with P 2 O 5 in refluxing toluene gave only the trans-oxazoline (3) with inversion at C-1, while the norpseudoephedrine (threo) derived hydroxyamide (2) gave the cis-oxazoline (4) as the major product; trans-oxazoline (3) was always less than 15%.However, thermal cyclization (heating to 290°C, 2 min) of threo-(2) gave only trans-oxazoline (3), i.e., retention of configuration at C-1; similar treatment of erythro-(1) gave cisoxazoline (4) as the major product, again retention of configuration at C-1, along with trans-(3) (33-40%). The trans and cis-oxazolines were clearly distinguished from each other by proton-NMR (trans-(3a), 5.08 ppm, J 4,5 =8.3 Hz; cis-(4a), 5.78 ppm, J 4,5 =10 Hz). 6 That the same β-hydroxyamide gives two different oxazolines with opposite configurations, depending on the conditions used (chemical or thermal), clearly supports our assumption that, under thermal conditions, the hydroxyl group initially attacks the carbonyl carbon, followed by elimination of water to give the oxazoline. The formation of mixtures of oxazolines (cis and trans) in the reaction threo (2) with P 2 O 5 and erythro (1) under thermal conditions may arise from a dual mechanistic pathway (S N 2 and S N 1). This aspect is under study.Thermal conversion is described of amides derived from erythro and threo ephedrines yields stereospecific oxazolines.

Нові Оксазоліни З Сульфолановим Фрагментом

“…Известно, что замыкание оксазолинового цикла в амидах может происходить по двум механизмам: внутримолекуляному S N 2-подобному механизму, в роли уходящей выступает гидроксильная группа, имеет место обращение конфигурации атома углерода при гидрокси-группе; активированная гидрокси-группа атакует карбонильный атом углерода амидной группы, что приводит к отщеплению воды и замыканию оксазолинового цикла с сохранением конфигурации атома углерода при гидрокси-группе [29]. Для выяснения механизма образования оксазолинов с сульфолановым фрагментом, нами был проведен встречный синтез оксазолинов (11, 13) из цис-N-ацильных производных (17, 18), полученных из цис-аминоспирта (16).…”

“…Амиды (6-8, 17, 18) получены по общей методике [29]. К раствору 3 ммоль соответствующего 3-гидрокси-4-аминосульфолана (1, 16) в 10 мл воды по каплям добавляли эквимольное количество хлорангидрида (2-4), растворенного в бензоле.…”