Introduction

1.1 The Importance of Heterocycles

In Asia, the life expectancy of a human was 40 years in 1960, which increased to 68 years in 2013 and will increase to 78 years in 2050. In all the possible positive effects to increase lifetime, the development of pharmaceuticals plays a crucial role. Importantly, most of the best selling drugs contain a heterocyclic moiety as their core structure. Additionally, more than 90% of naturally occurring compounds have a heterocyclic structure. Based on this importance of heterocycles, their preparation has become one of the main branches in modern organic synthesis. Although the current trend in methodology development is C–H activation, the requirements of reaction efficiency and functional group tolerance mean that the pharmaceutical industry still have to look at double-functionalized aromatic compounds.

In this book, we are going to discuss the application of transition metal catalysts in the synthesis of heterocycles by using double-functionalized arenes as substrates. The chapters are organized by the size of the rings formed and sub-divided by the substrates applied. In order to make this book more applicable and readable, the preparation of the double-functionalized arenes applied will be mentioned first.

1.2 The Preparation of Double-functionalized Arenes

For the double-functionalized arenes applied, in general, they can be divided into three main analogues (Table 1.1). One is 1,2-dihaloarenes, also called 1,2-di-electrophilic arenes (DEA); the next is ortho-halogen activated arenes, also called 1,2-electrophilic-nulceophilic coexisted arenes (ENA); the third is called 1,2-di-nulceophilic arenes (DNA).

1.2.1 1,2-Dihaloarenes

1,2-Dihalogenized arenes are an important class of compounds that have been reported with broad applications in coupling reactions. As the halogen mentioned here normally refers to fluoride, chloride, bromide and iodide, the combination of these elements offers several possibilities for the 1,2-dihaloarenes formed. The symmetrical 1,2-dihaloarenes (such as 1,2- diiodobenzene, 1,2-dibromobenzene, 1,2-dichlorobenzene and 1,2-difluoro- benzene) can be easily prepared by the reaction of the corresponding arenes with a halogen atom (I2, Br2, Cl2, F2) in acidic media. Regarding the non-symmetrical arenes, they can be synthesized by the halogenation of the pre-monohalogenated arenes.

1.2.2 2-Halophenol Derivatives

2-Halophenols have broad applications in the synthesis of oxygen-containing heterocycles. Typically, 2-halophenol can be prepared by the halogenation of phenols. Then, 2-halophenol can be used for the preparation of the other derivatives. Notably, 2-halophenol also acts as the precursor for arynes by activation of the C–O bond.

1.2.3 2-Haloaniline Derivatives

2-Haloaniline derivatives are widely available from chemical suppliers and have been applied extensively in nitrogen-containing heterocycle synthesis. Additionally, 2-haloanilines can act as 1,2-dihaloarene precursors as well in the Sandmeyer reaction. As bulky chemicals, anilines are usually applied as substrates for the synthesis of 2-haloanilines after halogenation.

1.2.4 1-Carbon-2-haloarenes

For 1-carbon-2-haloarenes, such as 2-bromoacetophenone, 2-bromotoluene, 2-bromobenzyl amine, 2-bromobenzaldehyde and so on, in general, they can all be prepared by the halogenation of their parent molecules.

Here, we can conclude that halogenation can effectively activate the parent molecules of double-functionalized arenes.

Five-membered Heterocycle Synthesis

In this chapter, the applications of double-functionalized arenes in the synthesis of five-membered heterocycles will be discussed. The contents are divided according to the different types of substrates applied. The sub-chapters are organized based on the types of nucleophiles ortho-substituted to aryl halides. For the heterocycle synthesis based on C–X bond activation, in general, transition metal catalyst promoted activation of the C–X bond initiated the reaction sequence and was followed by intramolecular or intermolecular cyclization.

2.1 1,2-Dihaloarenes

The application of 1,2-dihaloarenes in organic synthesis has experienced long-term development. The most common application is the in situ generation of benzyne derivatives. However, using transition metal catalysts with 1,2-dihaloarenes as substrates offers more diversity for the outcome.

In 1991, Perry and Turner reported the preparation of N-substituted phthalimides by palladium-catalyzed carbonylation of 1,2-dihaloarenes with primary amines. Various desired products were produced in moderate to good yields under CO pressure (7 bar) in the presence of a palladium catalyst (Scheme 2.1a). In this procedure, both aromatic and aliphatic primary amines were successfully applied. In the case of 1,2-diiodobenzenes, the nitro group cannot be tolerated and no desired product could be detected. 1,2-Dibromocyclopentene was tested as a substrate as well; 20% of the desired imide was formed and several by-products were formed. This transformation was studied further by Alper's group, Kollár's group and our group. In the report from Alper and co-worker, they found PSIL 102 (trihexyl(tetradecyl)phosphonium bromide) is a particularly effective general reaction media for the palladium-catalyzed double carbonylation reactions of dihaloarenes and amines. The desired products were afforded in excellent yields. Remarkably, the catalyst system can be reused. After the reaction, the ionic liquid was partitioned with hexane, and the substituted phthalimide product was extracted into hexane. The IL phase containing active palladium catalyst was dried under vacuum and recharged with starting material and base. After 24 h, the target products were isolated in 65 and 73% yield. The nature of the base played an important role in the reaction. DBU was found to be the best base, while NEt3 gave no desired product. In our report, we studied the use of 2-aminopyridines as coupling partners with...