Transition Metal Catalyzed Direct C-H Functionalization of Formamides and Ethers for the Synthesis of Carbamates and Acetals from 2-Carbonyl Substituted Phenols

• Main Authors: Balaji D. Barve, 巴拉吉
• Other Authors: Jeh-Jeng Wang
• Format: Others
• Language: en_US
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/8p2w29

博士 === 高雄醫學大學 === 醫藥暨應用化學研究所 === 102 === The thesis entitled “Transition Metal Catalyzed Direct C-H Bond Functionalization Reactions of Formamides and Ethers for the Synthesis of Carbamates and Acetals from 2-Carbonyl-Substituted Phenols” is divided into four chapters. Chapter 1: Copper-Catalyzed Synthesis of Carbamates from β-Ketoesters and 2-Carbonyl Substituted Phenol by Direct C-H Bond Functionalization of Formamides In this chapter a brief summary was introduced on the recent advances in the synthesis of organic carbamates, transition metal catalyzed C–H bond functionalization/activation reactions and N,N-dimethylformamide as the reaction precursor. Our approach for the synthesis of carbamates was accomplished through the reaction of β-ketoesters or 2-carbonyl substituted phenols with formamides using 1 mol% of copper chloride and 6.0 equiv. of oxidant (Scheme 1)1. Sixteen aliphatic as well as 14 aromatic carbamates were prepared in good to excellent yields. Halogen-substituted 2-carbonyl-phenols reacted smoothly without any dehalogenation, providing novel halogenated carbamates. Notably, all reactions were performed in open air and were not sensitive to moisture. The developed methodology was also applied to the single step synthesis of carbaryl insecticides derivative. Scheme 1. Synthesis of carbamates from β-ketoesters or 2-carbonyl substituted phenols Chapter 2: Copper-Catalyzed Direct C-H Bond Functionalization and Oxidative Coupling of Formamides with Salicylaldehydes: Synthesis of Carbamates in the Presence of a Sensitive Aldehyde Group This chapter describes an overview on the preparation of ortho aldehyde containing carbamates. It also discusses the aldehyde reactivity under different catalytic, oxidant systems. In our protocol, diverse library of novel carbamates was synthesized utilizing copper-catalyzed oxidative C-O coupling of formamides and salicylaldehydes. The reaction proceeded through the direct C-H bond functionalization of formamides (Scheme 2).2 In chapter 1, the starting materials were 2-keto phenols which are comparatively more stable under oxidative conditions, where in this chapter 2-keto group of phenols was replaced by 2-formyl group (2-formyl phenols). Transition metal and oxidant sensitive formyl group was preserved in this protocol providing selectively the corresponding carbamates. Salicylaldehydes bearing electron donating, electron withdrawing, and halogen groups as well as 1-hydroxy-2-naphthaldehydes provided the desired carbamates in good to excellent yields. We have also investigated the ortho effect on the substrate reactivity by replacing the o-formyl group with different substituents. The practicality of the method has been demonstrated by performing the reaction on a multigram scale. Scheme2. Preparation of carbamates from formamides and salicylaldehydes Chapter 3: Iron-Catalyzed Oxidative Direct α-C_H Bond Functionalization of Cyclic Ethers: Selective C_O Bond Formation in the Presence of a Labile Aldehyde Group This chapter discusses the utilization of cyclic ethers as building blocks for important natural products and pharmaceutical drugs. It also reviews recent advances in the metal catalyzed coupling reactions for the formation of C-C and C-O bonds utilizing α-C-H functionalization of ethers. Our study involves iron catalyzed oxidative coupling of salicylaldehydes with cyclic ethers, preceded through the direct α-C-H functionalization of ethers, forming the corresponding acetals in moderate to excellent yields. This is the first report on iron catalyzed selective C-O bond formation in the presence of a labile aldehyde moiety (Scheme 3).3 The application of this protocol was demonstrated by single step synthesis of an important starting material in the preparation of immunomodulatory drug, tucaresol and related analogues. Scheme 3. Iron catalyzed oxidative coupling of salicylaldehydes with cyclic ethers Chapter 4: Copper-Catalyzed Selective C_O Bond Formation by Oxidative C(sp3)_H/O_H Coupling between Ethers and Salicylaldehydes This chapter continuing to the chapter three in which thirty-nine acetal derivatives were synthesized by applying the copper catalyzed α-C_H bond functionalization reaction of ethers with salicylaldehydes, napththaldehydes and heterocyclic aldehyde. The protocol provides the corresponding acetals with moderate to excellent yields in presence of copper chloride as a catalyst and TBHP as oxidant (Scheme 4).4 Although, we reported the iron catalyzed synthesis of acetals utilizing the salicylaldehyes and cyclic ethers in previous chapter. The protocol associated with certain drawbacks and applied only for the cyclic ethers as coupling partners. This method was successfully applied for the first time synthesis of acetals from salicylaldehydes with electron withdrawing group (-NO2), aliphatic ethers and heterocyclic aldehydes. Scheme 4. Selective C_O bond formation by oxidative coupling between ethers and salicylaldehydes