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Abstract
Introduction
Protocol
Results
Discussion
Disclosures
Acknowledgements
Materials
References
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Chemistry

协议的合成<em>邻</em> -trifluoromethoxylated苯胺类化合物

Published: January 19, 2016
doi:
10.3791/53789
,
1Department of Chemistry,State University of New York at Stony Brook, 2Institute of Chemical Biology and Drug Discovery,State University of New York at Stony Brook

Summary

An operationally simple procedure for the synthesis of ortho-trifluoromethoxylated aniline derivatives via a two-step sequence of O-trifluoromethylation of N-aryl-N-hydroxyacetamide followed by thermally induced intramolecular OCF3-migration is reported.

Abstract

分子轴承三氟甲氧基（OCF 3）基团常表现所需的药理学和生物学性质。然而，trifluoromethoxylated芳香族化合物的简便合成保持在有机合成中一个巨大的挑战。传统的方法往往来自贫困基底范围受到影响，或要求使用高毒，难以处理，和/或热不稳定的试剂。此，我们报告为甲基-4-乙酰氨基-3-（三氟甲氧基）苯甲酸甲酯的使用合成一个用户友好的协议-1-三氟甲基-1,2-苯碘酰-3-（1H） -酮（TOGNI试剂Ⅱ）。在碳酸铯的催化量存在下处理甲基4-（N- -hydroxyacetamido）苯甲酸甲酯（1a）与 TOGNI试剂II（铯2 CO 3）的氯仿在室温，得到4-（N – （三氟甲氧基）乙酰氨基）苯甲酸甲酯（2a）中 。然后将该中间体转化为最终产物甲基-4-乙酰氨基-3-（trifluoromethoxy）苯甲酸甲酯（3a）的硝基甲烷中，在120℃。此过程是一般性的，可以应用到邻 -trifluoromethoxylated苯胺衍生物的广谱性，这可以作为有用的合成构建模块的新药物，农用化学品和功能材料的发现和开发的合成。

Introduction

该三氟甲氧基（OCF 3）集团已在1935年2，因为三氟甲基醚的首次合成生命和材料科学的研究产生深远的影响。由于其独特的电负性高的组合（χ= 3.7）3和优良的亲脂性（ΠX = 1.04），4三氟甲氧基发现在医药，农业和材料行业有着广泛的应用。5-10但是，轻便引入OCF 3组分成有机分子，尤其是芳香族化合物，保留在合成化学的一个重大挑战。

在过去的几十年中，努力解决这一挑战导致少数变换为trifluoromethoxylated芳烃的合成的发展5-7,9-11这些包括：（i）氯/氟对三氯化前体交换; 1,12- -17（ⅱ）deoxyfluorination fluoroformates的; 18 </SUP>（ⅲ）氧化fluorodesulfurization; 19-21（ⅳ）醇的亲电三氟甲基化; 22-25（v）的亲核trifluoromethoxylation; 26-30，（ⅵ）过渡金属-介导的芳基硼酸盐和锡烷的trifluoromethoxylation; 31及（vii ）基团trifluoromethoxylation。32,33然而，许多这些方法要么患有差基板范围，或需要使用高毒性和/或热不稳定的试剂。因此，由于缺乏合成OCF 3含化合物的一般的和用户友好的方法，该OCF 3组的潜力还没有得到充分利用在化学。

作为我们在trifluoromethoxylation反应利益的一部分，34我们描述本文的两步协议 （即， 自由基 O2 -trifluoromethylation和热诱导OCF 3 -migration）为甲基-4-乙酰氨基-3-（三氟甲氧基的合成）苯甲酸甲酯（3a）的选自甲基4-（N- -hydroxyacetamido）苯甲酸甲酯（1a）中 。该策略是易于操作，适用于大范围的邻 -trifluoromethoxylated苯胺衍生物的合成。

Protocol

1.前体的制备：4-（N -hydroxyacetamido）苯甲酸（1a）的合成 还原甲基-4-硝基苯甲酸甲酯。 加甲基5.00克4-硝基苯甲酸酯（27.6毫摩尔，1.00当量），5％铑炭（铑/℃，0.300摩尔％的Rh）159毫克，和磁力搅拌棒的烘箱干燥的250个ml的双颈圆底烧瓶中（在150℃下干燥18小时）。 注：试剂可以在环境气氛下进行称重。然而，反应需要在氮气氛下，以进行。 烧瓶中的一?…

Representative Results

甲基-4-（N- -hydroxyacetamido）苯甲酸甲酯（1a）的合成在92％分离产率，通过一个两步骤的过程（即，减少甲基-4-硝基苯甲酸甲酯用肼用5％的Rh / C作为催化剂，以形成4-（ Ñ-hydroxyamino）苯甲酸甲酯，然后将所得羟胺乙酰保护）1a中与TOGNI试剂II在的碳酸铯的催化量存在的O-三氟甲基化（铯2 CO 3）的氯仿?…

Discussion

由于缺乏一个全面和人性化的程序trifluoromethoxylated芳烃的合成，许多OCF 3含芳香族化合物是非常昂贵的。34我们的策略取代了广阔的官能团耐受性，并提供了一个易于访问各种trifluoromethoxylated芳烃。这些化合物可以作为用于新药物，农用化学品，和材料的发现和开发作为有价值积木。

肼用作氢的来源为铑催化的还原硝基芳烃的。其质量是在获得还原产物中高产…

Disclosures

The authors have nothing to disclose.

Acknowledgements

我们感谢来自纽约州立大学石溪分校大手笔启动资金，支持这项工作。我们也感谢TOSOH F-科技有限公司为我们提供TMSCF 3试剂TOGNI试剂II的合成。

Materials

5% Rhodium on carbon Aspira Scientific 300835 5% wt% dry loading
hydrazine monohydrate Sigma-Alderich 13696HMV Reagent grade, 98%
Acetyl chloride Alfa Aesar 10176887 98%
Sodium bicarbonate Fisher Scientific 134826 Chemical pure
Cesium carbonate Alfa Aesar 12887 99.9%, metals basis
Togni Reagent II Prepared according to the literature procedure (ref 37). Caution: Pure Togni reagent II is impact and friction sensitive, treat it with great care (see ref. 36).
Tetrahydrofuran BDH BDH1149-4LG Distilled from deep purple sodium benzophenone ketyl.
Diethyl Ether Fisher Scientific 148221 Distilled from deep purple sodium benzophenone ketyl.
Chloroform Fisher Scientific 141739 Dried over CaH2 and distilled
nitro methane Alfa Aesar J03z053 Dried over CaSO4 and distilled
Silica gel SILICYCLE 60514 40-63 µm (230-400 mesh)
Cilite EMD 2012040674 Not acid washed
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Tags

Ortho-trifluoromethoxylated AnilineAniline DerivativesReductionHydrogenationAcetyl ProtectionRhodium CatalystCelite FiltrationTLC MonitoringAnhydrous SolventsNitrogen Atmosphere
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Feng, P., Ngai, M. Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives. J. Vis. Exp. (107), e53789, doi:10.3791/53789 (2016).
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