Carter Nicholas, Li Xiabing, Reavey Lewis, Meijer Anthony J H M, Coldham Iain
Department of Chemistry , University of Sheffield , Brook Hill , Sheffield , S3 7HF , UK . Email:
Chem Sci. 2017 Dec 14;9(5):1352-1357. doi: 10.1039/c7sc04435f. eCollection 2018 Feb 7.
Treatment of -Boc-2-aryl-1,2,3,4-tetrahydroquinolines with -butyllithium in THF at -78 °C resulted in efficient lithiation at the 2-position and the organolithiums were trapped with a variety of electrophiles to give substituted products. Variable temperature NMR spectroscopy gave kinetic data that showed that the rate of -butoxycarbonyl (Boc) rotation was fast (Δ ≈ 45 kJ mol at -78 °C) and ReactIR spectroscopy showed fast lithiation at -78 °C. By carrying out the lithiation in the presence of the chiral ligand sparteine, kinetic resolutions with very high levels of enantioselectivity were achieved. The resulting enantioenriched -Boc-2-aryltetrahydroquinolines were converted to 2,2-disubstituted products without significant loss in enantiopurity. Most electrophiles add at the 2-position and the chemistry provides a way to access tetrahydroquinolines that are fully substituted alpha to the nitrogen atom. Notably, either enantiomer of the 2,2-disubstituted tetrahydroquinolines can be obtained with high selectivity from the same enantiomer of the chiral ligand. Unusually, when methyl cyanoformate was used as the electrophile, substitution occurred in the ortho position of the aryl ring attached at C-2. This change in regioselectivity on changing the electrophile was probed by deuterium isotope studies and by DFT calculations which suggested that the binding of the cyanoformate altered the structure of the intermediate organolithium. Secondary amine products can be prepared by removing the Boc group with acid or by inducing the Boc group to rearrange to the 2-position in the presence of triethylborane and this carbonyl N-to-C rearrangement occurs with retention of configuration from the intermediate enantiomerically enriched organolithium species.
在-78°C下，于四氢呋喃（THF）中用丁基锂处理-Boc-2-芳基-1,2,3,4-四氢喹啉，可在2-位实现高效锂化，所得有机锂化合物能与多种亲电试剂反应，生成取代产物。变温核磁共振光谱给出的动力学数据表明，-丁氧基羰基（Boc）的旋转速率很快（在-78°C时，Δ≈45 kJ/mol），反应红外光谱显示在-78°C时锂化迅速。通过在手性配体鹰爪豆碱存在下进行锂化反应，可实现具有极高对映选择性的动力学拆分。所得对映体富集的-Boc-2-芳基四氢喹啉可转化为2,2-二取代产物，且对映体纯度无显著损失。大多数亲电试剂在2-位加成，该化学方法为获取氮原子α位完全取代的四氢喹啉提供了一条途径。值得注意的是，从手性配体的同一对映体出发，可高选择性地获得2,2-二取代四氢喹啉的任意一种对映体。异常的是，当使用氰基甲酸甲酯作为亲电试剂时，取代反应发生在连接于C-2的芳环的邻位。通过氘同位素研究和密度泛函理论计算探究了改变亲电试剂时区域选择性的这种变化，结果表明氰基甲酸酯的结合改变了中间有机锂化合物的结构。二级胺产物可通过用酸除去Boc基团或在三乙基硼存在下诱导Boc基团重排至2-位来制备，这种羰基从氮到碳的重排发生时，中间体对映体富集的有机锂物种的构型得以保留。
