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 1,2-dibromo-benzenes. Some very sterically hindered amines were checked as well, such as 2, 6-diisopropylaniline and 1-adamantylamine; in addition to the corresponding phthalimides, some isomers were isolated too (Scheme 2.1b).

In 2011, Bhanage and co-workers reported a carbon monoxide-free one-step synthesis of phthalimides by using formamides as an amine and CO source. With POCl3 as the activator, various phthalimides were produced in moderate to excellent yields (Scheme 2.2). In addition to 1,2-dihalobenzenes, 2-iodobenzoic acid and methyl 2-iodobenzoate can be applied as substrates for phthalimide preparation with formamides as an amine and CO source as well. This methodology was extended and applied in the synthesis of isobenzofuran-1(3H)-one (70% yield) by using o-iodobenzyl alcohol as the substrate.

Meanwhile the same group found palladium on carbon can be used as an efficient and reusable heterogeneous catalyst for the carbonylative synthesis of N-substituted phthalimides. 1,2-Diiodoarenes were dicarbonylated with amines and provided the corresponding N-substituted phthalimides in excellent yields. o-Halobenzoates and o-halobenzoic acid can be applied as substrates as well. During their optimization process, they observed that the nature of the solvent affected the yield of the reaction. Solvents such as DMF, DMSO and THF provided lower yields of the expected product whereas acetonitrile did not furnish the desired product. The best result was observed in toluene. Remarkably, no phosphine ligands were needed here and the catalyst can be reused for up to eight consecutive cycles with maintenance of high activity and selectivity (Scheme 2.3). The authors performed ICP-AES (inductively coupled plasma atomic emission spectroscopy) analysis of the 1st and 8th recycle runs, where below 0.01 ppm of palladium in solution was estimated thus indicating no significant leaching of the palladium catalyst. In 2014, they immobilized a palladium catalyst on an ionic liquid and applied it in the double carbonylation of 1,2-diiodobenzene as well. Good yields of the desired products can be isolated and the catalyst can be reused.

At the end of 2013, our group described a palladium-catalyzed carbonylative synthesis of phthalimides from 1,2-dibromoarenes. Molybdenum hexacarbonyl was applied as a CO source here. In this easy and convenient way, various N-substituted phthalimides were produced in a one-pot manner. A wide range of different primary amines as well as a variety of miscellaneous 1,2-dibromobenzenes can be applied as substrates, and the corresponding phthalimides were obtained in moderate to excellent yields (Scheme 2.4).

Miura and co-workers reported a palladium-catalyzed cross-coupling of benzyl ketones and 1,2-dibromobenzenes to benzofurans. By using already available substrates and with the assistance of a palladium catalyst, various desired benzofurans were produced in moderate to good yields (Scheme 2.5). Regarding the reaction mechanism, the initial step was proposed to be the C–C coupling of the C–Br bond with the benzylic position of benzyl ketones followed by intramolecular cyclization to give the desired product. Interestingly, 1-naphthol and 2-tert-butylphenol can be applied as coupling partners with 1,2-dibromobenzene as well. The corresponding oxygen-containing heterocycles were isolated in moderate yields under identical conditions. Later on, Domínguez and co-workers studied this transformation further and polymer-anchored palladium (FibreCat™) was applied in the benzofuran synthesis in addition to a homogeneous catalyst.

A palladium-catalyzed intramolecular cyclization of enolate O-arylation and thio-enolate S-arylation was reported by Willis and co-workers in 2006. A catalyst generated from Pd2 (dba)3 and the ligand DPEphos effects the key bond formation to deliver a variety of substituted products from both cyclic and acyclic precursors. The analogous thio-ketones undergo C–S bond formation using identical reaction conditions and were converted to benzothiophene products. A cascade sequence that produces the required α-aryl ketones in situ has also been developed (Scheme 2.6).

In addition to palladium catalysts, copper as a cheaper transitional metal catalyst was explored in the synthesis of benzofurans as well. In 2007, a CuI-catalyzed coupling of 1-bromo-2-iodobenzenes with β-keto esters in THF at 100 °C leading to 2,3-disubstituted benzofurans was developed by Ma and co-workers. This domino transformation involves an intermolecular C–C bond formation and a subsequent intramolecular C–O bond formation process. Benzofurans with different substituents at the 5- and 6-position were accessible in good yields by employing the corresponding 1-bromo-2-iodobenzenes as substrates (Scheme 2.7a). This transformation was further studied by Beifuss and co-workers in 2012. They found the reaction conditions from Ma's group failed in the case of 1,3-diketones. In their reported procedure, the reaction of 1-bromo-2-iodobenzenes and other 1,2-dihalo- benzenes with 1,3-cyclohexanediones proceeded selectively in DMF at 130 °C using Cs2CO3 as a base and pivalic acid as an additive. The corresponding 3,4-dihydrodibenzo[b, d]furan-1(2H)-ones were isolated with yields ranging from 47 to 83% (Scheme 2.7b). The highly regioselective domino process is based on an intermolecular Ullmann-type C-arylation followed by an intra- molecular Ullmann-type O-arylation. Substituted products are accessible by employing substituted 1-bromo-2-iodobenzenes and substituted 1,3-cyclo-hexanediones as substrates. Reaction with an acyclic 1,3-diketone leads to the corresponding benzo[b]furan.

Benzoxazoles are an important class of compounds containing one oxygen atom and one nitrogen atom, and have been reported with many applications in various areas. Traditionally, they can be prepared by a reaction between 2-aminophenols and aldehydes or carboxylic acids under relatively harsh conditions. In 2004, Glorius's group reported a copper-catalyzed C–N and C–O coupling procedure for the synthesis of benzoxazoles. Readily available 1,2-dihaloarenes and primary amides were applied as substrates, the desired products were isolated in good yields in a single step (Scheme 2.8). This procedure was later applied by our group in the successive synthesis of benzoxazoles from aryl bromides and 1,2-dibromo-benzenes. By the combination of palladium-catalyzed aminocarbonylation and copper-catalyzed coupling reactions, a variety of substituted benzoxazoles were produced in moderate to good yields.

In 2013, Xiang, Wang and co-workers developed a copper-catalysed annulation reaction of 1,2-dihaloarenes with nitriles. In this procedure, the nitriles were hydrated by a base into the corresponding primary amides in situ and then coupled with 1,2-dihaloarenes. In this system, combined bases (Cs2CO3 and KOH) and a relative high temperature were needed. Later on, they found that the reaction conditions can be much milder by adding acetaldoxime as an additive. In this new procedure, the role of acetaldoxime is to hydrolyse nitriles to the corresponding amides. The desired products were formed in moderate to good yields (Scheme 2.9).

Nitrogen-containing heterocycles are important heterocyclic compounds with broad applications in various areas. Among the known compounds, carbazoles are a representative example. In 2007, a procedure based on palladium-catalyzed N–H/C–H activation was developed by Ackermann and co-workers. By using 1,2-dichloroarenes and anilines as substrates and palladium as the catalyst, the desired products were isolated in moderate to good yields (Scheme 2.10). Additionally, naturally occurring murrayafoline A was synthesized in a good yield by this protocol as well. In their further study, they found that IPr · HCl and PPh3 can be effective ligands as well if 1,2-dibromobenzene is applied. The reaction temperature can be decreased to 105 ºC by using NaOtBu as a base.

Another procedure was developed by Kan and co-workers in 2008 by applying Suzuki-Miyaura and amination reactions as the two key elemental steps. 2-Aminophenylboronic acid and 1,2-diiodobenzene were applied as the starting materials; the corresponding carbazole was formed in a one-pot two-step manner in good yield (Scheme 2.11). In their optimizations, they found that the choice of suitable palladium precursor and solvent had a very important effect; Pd2(dba)3 or toluene resulted in much lower yields.

The reaction between vinylogous amides and aryl halides was studied by Edmondson and co-workers in 2000. In this report, the first tandem Hartwig-Buchwald-Heck cyclization was described as well and applied to the synthesis of 2,3-disubstituted indole derivatives. The reaction between enaminone and 2-bromobenzaldehyde could lead to a quinoline derivative under their reaction conditions (Scheme 2.12).

Due to the importance of indoles, Joergensen and co-worker reported a palladium-catalyzed amination, followed by a Heck reaction of 1,2-dihaloarenes in 2008. Various 3-substituted indoles were isolated in moderate to good yields by using allylamine as a coupling partner (Scheme 2.13). In their study, they showed that the first step for this transformation was C–N coupling and the intermediate was isolated as well.

Kurth and co-worker developed a versatile one-pot three component assembly route to highly substituted indoles in 2012. Their procedure was based on palladium-catalyzed coupling reactions and 1,2-dihaloarenes, primary amines and ketones or aldehydes were applied as the substrates. Indole formation can be accomplished using suitable reaction conditions that favour in situ generation of an aniline, condensation to an arylenamine, and a subsequent arene-alkene coupling reaction to close the ring. A single palladium catalyst/ligand system mediated both coupling reactions. A detailed mechanistic study and DFT calculation for the palladium-catalyzed ring closing step was presented as well. Moderate to good yields of the desired indoles were produced (Scheme 2.14).