Benzylic Functionalisation of Phenyl all-cis-2,3,5,6-Tetrafluorocyclohexane Provides Access to New Organofluorine Building Blocks
Benzylic Functionalisation of Phenyl all-cis-2,3,5,6-Tetrafluorocyclohexane Provides Access to New Organofluorine Building Blocks
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DOI：
10.1002/chem.201802166
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发表时间：
2018-09-06
影响因子：
4.3
通讯作者：
O'Hagan, David
中科院分区：
文献类型：
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作者：
Bykova, Tetiana;Al-Maharik, Nawaf;O'Hagan, David
选择性氟化烃在农用化学品和药物发现方案中继续引起人们对调整药代动力学特性的关注。本研究确定了苯基全顺式-2，3，5，6-四氟环己烷2的苄基溴化是获得含有全顺式-2，3，5，6-四氟环己烷环系统的结构单元的关键反应。这些环己烷是令人感兴趣的，因为氟仅在环己烷的一面上，这赋予了不寻常的极性方面，与其他疏水性环己烷非常不同。苄基溴4与DMF和乙腈的Ritter型反应分别生成相应的苄醇6和苄基乙酰胺7。将苄基乙酰胺7水解成苄基胺8和顺式氨基醇9，并分别将苯环氧化裂解以提供羧酸乙酰胺10，其在水解后得到四氟环己基氨基酸11。苄基溴4与AgF 2的转卤化得到苄基氟13。然后氧化裂解芳环得到五氟环己基羧酸14。该羧酸容易地转化为酰胺23-26，并且通过DFT、X射线结构和H-1-（FHOESY）-F-19 NMR分析探索了这些α-氟代酰胺的优选构象。
Selectively fluorinated hydrocarbons continue to attract attention for tuning pharmacokinetic properties in agrochemical and pharmaceutical discovery programmes. This study identifies benzylic bromination of phenyl all-cis-2,3,5,6-tetrafluorocyclohexane 2 as a key reaction for accessing building blocks containing the all-cis-2,3,5,6-tetrafluorocyclohexane ring system. These cyclohexanes are of interest as the fluorines are only on one face of the cyclohexane, and this imparts an unusual polar aspect, very different to an otherwise hydrophobic cyclohexane. Ritter type reactions of benzyl bromide 4 with DMF and acetonitrile generated the corresponding benzyl alcohol 6 and benzylacetamide 7 respectively. Benzylacetamide 7 was hydrolysed to benzyl amine 8 and syn-amino-alcohol 9, and separately the phenyl ring was oxidatively cleaved to furnish carboxylic acid acetamide 10, which after hydrolysis gave the tetrafluorocyclohexyl amino acid 11. A trans-halogenation of benzylbromide 4 with AgF2 gave benzyl fluoride 13. Oxidative cleavage of the aryl ring then gave pentafluorocyclohexyl carboxylic acid 14. This carboxylic acid was readily converted to amides 23-26 and the preferred conformations of these alpha-fluoroamides were explored by DFT, X-ray structure and H-1-(FHOESY)-F-19 NMR analysis.