Enantioseparation and racemization of α-aryl-α-fluoroacetonitriles.
Enantioseparation and racemization of α-aryl-α-fluoroacetonitriles.
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作者：
Steber SE;Pham ANDL;Nelson E;Wolf C
2-芳基-2-氟乙腈作为不对称合成中的多功能结构单元受到越来越多的关注。然而，这些有机氟的构型稳定性知之甚少，可用于区分其对映体的分析方法仍然不发达。本研究通过对常用手性固定相的筛选，实现了10种2-芳基-2-氟乙腈对映体的基线HPLC拆分。虽然Chiralcel OD、Chiralpak AD和Chiralpak AS被证明是最广泛使用的，但2-（2-萘基）-2-氟乙腈的对映体的制备分离在Chiralcel OJ上是可能的。这使得在各种温度下和在有机碱存在下的外消旋研究成为可能，这表明该化合物在中性条件下加热至130 ℃ 6小时后构型稳定，但在室温下在化学计量量的胍碱存在下在10小时内发生完全外消旋。外消旋化可能通过形成非手性酮亚胺中间体进行，并遵循可逆的一级反应动力学，在23.2 oC下在乙醇己烷中的半衰期为87.7分钟。当胍被较弱的脒碱取代时，外消旋反应明显较慢，在22.4 °C下发生，半衰期为23.1小时。
2-Aryl-2-fluoroacetonitriles have garnered increasing interest as versatile building blocks in asymmetric synthesis. However, the configurational stability of these organofluorines is poorly understood and analytical methods that can be used to differentiate between their enantiomers remain underdeveloped. In this study, baseline HPLC enantioseparation of ten 2-aryl-2-fluoroacetonitriles was achieved by screening frequently used chiral stationary phases. While Chiralcel OD, Chiralpak AD and Chiralpak AS proved to be most broadly useful, preparative separation of the enantiomers of 2-(2-naphthyl)-2-fluoroacetonitrile was possible on Chiralcel OJ. This enabled racemization studies at various temperatures and in the presence of organic bases which showed that this compound is configurationally stable under neutral conditions upon heating to 130 oC for 6 hours but undergoes complete racemization within 10 hours in the presence of stoichiometric amounts of a guanidine base at room temperature. The racemization is likely to proceed via formation of an achiral keteniminate intermediate and obeys reversible first order reaction kinetics with a half-life time of 87.7 minutes in ethanolic hexanes at 23.2 oC. Racemization is significantly slower and occurs with a half-life time of 23.1 hours at 22.4 °C when the guanidine is replaced with a weaker amidine base.
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