Ruthenium(II)-and Cobalt(III)-Catalyzed Cyclization and Alkenylation of Substituted Aromatics with π-Components

Abstract

The thesis entitled “Ruthenium(II) and Cobalt(III) Catalyzed Cyclization and Alkenylation of Substituted Aromatics with π-Components” comprises of four chapters. The transition metal catalyzed chelation-assisted C–H functionalization of substituted aromatics with electrophiles or nucleophiles is an efficient method to construct chemical bonds in highly atom and step economical manner. Various transition metal complexes of palladium, rhodium, ruthenium and iridium are widely employed as catalysts for this type of transformations. Among them, due to the unique reactivity and selectivity, a less expensive ruthenium arene complex has gained much attention for this type of reactions. In addition, the reactions catalyzed by ruthenium arene complexes can be performed under air atmosphere and water can be employed as solvent. Meanwhile, the development of new C–H bond transformation reactions by using more abundant, biologically tolerated and sustainable first row transition metal catalysts is also highly important. Recently, the air stable and inexpensive cobalt complexes are recognized as one of the efficient catalysts for the C–H functionalization reaction. In this thesis, we aim to develop methods for synthesizing heterocylic moieties using Ru(II) and Co(III) catalysts with a combination of suitable directing groups and C–C π-components. Chapter 1 of this thesis discusses the history and classification of C–H activation reactions. A brief introduction of chelation-assisted C–H bond activation via oxidative addition pathway as well as deprotonation pathway was also discussed with appropriate examples. In particular this part discusses about the types and the reaction mechanisms of ruthenium and cobalt catalyzed C–H bond activation reactions. Chapter 2 of this thesis describes an efficient method for the Ru-catalyzed oxidative cyclization reaction to synthesize structurally diverse isoindolines and pyrroloquinolinones. It contains two sub-divisions as follows: Section 2A: Synthesis of Isoindolinones: Isoindolinone is a core structure unit present in various natural products and biologically active molecules. Particularly, 3-substituted isoindolinone skeleton is found in various biologically active molecules. It has also been serving as a key synthetic intermediate for synthesizing various highly useful organic molecules and natural products. Herein, we describe a ruthenium catalyzed cyclization of N-substituted benzamides with allylic alcohols to give 3-substituted isoindolinone derivatives in good yields (Scheme 1). A possible reaction mechanism involving a five-membered ruthena cycle intermediate was proposed and strongly supported by experimental evidences. Interestingly, the reaction pathway such as enoloization vs β-hydride elimination can be tuned, by changing the reaction conditions.

Scheme 1: Ruthenium Catalyzed Cyclization of N-substituted Benzamides with Allylic Alcohols Section 2B: Synthesis of Pyrroloquinolinones: The pyrroloquinoline unit is present in various agrochemicals, drug molecules, natural products and materials. Pyrroloquinoline derivatives show potent biological activities towards asthma, obesity, anti-acetylcholinesterase and epilepsy. In addition, pyrroloquinoline derivative can also be used as a key intermediate for synthesizing various biologically active molecules and natural products. Herein, we describe a convenient route to synthesize pyrroloquinolinone derivatives via a ruthenium catalyzed oxidative cyclization of N-carbamoyl indolines with alkynes (Scheme 2). Generally, a metal acetate base is used to activate the C–H bond of organic moieties. In the reaction, a catalytic amount of organic acid, 1-adamantanecarboxylic acid (1-Adm-COOH), was used. The role of 1-Adm-COOH is unique in the reaction, as it plays a role of proton source as well as base for activating the C7 H bond of indoline moieties.

Scheme 2: Ruthenium Catalyzed Synthesis of Pyrroloquinolinones The cyclization reaction was compatible with various functional group substituted indolines, symmetrical and unsymmetrical alkynes including substituted propiolates. The cyclization reaction is highly regioselective particularly with unsymmetrical alkynes and the coordinating group such as aryl or ester substituent on the alkyne moiety prefers to stay adjacent to the carbonyl group of quinolinone derivative. Later, pyrroloquinolinone derivatives were converted into pyrroloindolones in the presence of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). Chapter 3 describes a cobalt catalyzed regioselective allyllation and alkenylation of quinoline benzamides with unactivated alkenes and allyl acetates. The transition metal catalyzed chelation-assisted selective olefination at the inactive C–H bond of substituted aromatics with alkenes is an efficient method for synthesizing arylated alkenes in a highly atom- and step-economical manner from easily available starting materials. However, in this type of alkenylation reactions, only conjugated alkenes such as acrylates, vinyl sulfones, acrylonitriles, acrylamides and styrenes were extensively used. The selective C–H olefination with unactivated alkenes are rare and very challenging to succeed due to the less reactivity of alkenes and formation of mixtures of linear as well as branched isomers. In a metal catalyzed C–H bond functionalization reaction, allyl acetates or alcohols always serve as an allylating agent, providing allylated product with a removal of OAc or OH. Meanwhile, most of this C–H bond transformation relies on second and third row noble metals such as palladium, rhodium, ruthenium and iridium. However, these noble metals are less abundant in nature and very expensive. Thus, the development of new C–H bond transformation reaction by using more abundant, biologically tolerated and sustainable first row transition metal catalysts is highly important.

Scheme 3: Cobalt Catalyzed C–H Allylation and alkenylation Herein, we describe an unprecedented cobalt catalyzed C–H olefination of aromatic and heteroaromatic amides with unactivated alkenes, allyl acetates and allyl alcohols. This method offers an efficient route for the synthesis of vinyl and allyl benzamides in a highly stereoselective manner. In the transition metal catalyzed C–H bond functionalization reaction via chelation-assisted metalation pathway, allyl acetates or alcohols mostly serve as an allylating agent, providing allylated product with a removal of OAc or OH group. This report describes a typical Heck-type vinylation reaction without cleavage of OAc and OH. Meanwhile, in the other reported alkenylation with unactivated alkenes, a mixture of linear as well as branched vinyl alkenes was observed. In the present method, exclusively a linear allyl aromatics was observed in a highly stereoselective manner. Chapter 4 describes chelation-assisted cobalt-catalyzed oxidative cyclization of arylamides with maleimides and alkynes to synthesize structurally diverse spirosuccinimides and isoquinolinoes respectively. It contains two sub-divisions as follows: Section 4A: Synthesis of Isoindolone Spirosuccinimides: Isoindolone derivatives are synthesized in a highly atom-economical and environmentally friendly manner by oxidative cyclization of aromatic amides with alkenes by using transition metal catalysts. In this type of cyclization reaction, only terminal alkenes are efficiently involved and internal alkenes including cyclic alkenes are less explored. Recently, maleimides are efficiently used as an alkene source in the C–H alkenylation reaction. Mostly, substituted aromatics undergoes 1,4-addition with maleimides providing ortho alkylated aromatics. For this type of alkylation reaction, ruthenium, rhodium, cobalt and manganese complexes are widely used. Herein, we describe a cobalt-catalyzed 8-aminoquinoline directed oxidative cyclization of benzamides with maleimides. The oxidative cyclization reaction provides isoindolone spirosuccinimides in good to excellent yields. The reaction was compatible with various functional group substituted benzamides as well as N-substituted maleimides (Scheme 4). A possible reaction mechanism involving the C–H bond activation as a key step was proposed. The competition experiment and deuterium labelling studies were performed to investigate the mechanism of the present cyclization reaction. The competition experiment and deuterium labelling studies clearly reveals that the irreversible C−H bond cleavage might not be the rate-limiting step of the reaction.

Scheme 4: Synthesis of Isoindolone Spirosuccinimides Section 4B: Synthesis of Isoquinolone: Isoquinolone is an important heterocyclic structural unit which presents in various natural products, biologically active molecules and conjugated materials. In addition, isoquinolone derivatives are widely used as a key intermediate in various organic transformations. Herein, we have described the synthesize of isoquinolone derivatives from benzamides with alkynes assisted by 8-aminoquinoline ligand in the presence of Co(OAc)2.4H2O and pivalic acid under air. In the reaction, the active Co(III) species is regenerated by the reaction of Co(I) species with pivalic acid under air with hydrogen evolution. The proposed mechanism was supported by competition experiments, deuterium labelling studies, radical scavenger experiment and kinetic studies.

Scheme 6: Synthesis of Isoquinolones