Heterocycles constitute the largest and the most diverse family of organic compounds Among them, aromatic heterocycles represent structural motifs found in a great number of biologically active natural and synthetic compounds, drugs, and agrochemicals Moreover, aromatic heterocycles are widely used for synthesis of dyes and polymeric materials of high value 1 There are numerous reports on employment of aromatic heterocycles as intermediates in organic synthesis 2

Although, a variety of highly efficient methodologies for synthesis of aromatic heterocycles and their derivatives have been reported in the past, the development of novel methodologies is in cuntinious demand Particlularly, development of new synthetic approaches toward heterocycles, aiming at achieving greater levels of molecular complexity and better functional group compatibilities in a convergent and atom economical fashions from readily accessible starting materials and under mild reaction conditions, is one of a major research endeavor in modern synthetic organic chemistry Transition metal-catalyzed transformations, which often help to meet the above criteria, are among the most attractive synthetic tools

Several excellent reviews dealing with transition metal-catalyzed synthesis of heterocyclic compounds have been published in literature during recent years Many of them highlighted the use of a particular transition metal, such as gold,3 silver,4 palladium,5 copper,6 cobalt,7 ruthenium,8 iron,9 mercury,10 rare-earth metals,11 and others Another array of reviews described the use of a specific kind of transformation, for instance, intramolecular nucleophilic attack of heteroatom at multiple C–C bonds,12 Sonogashira reaction,13 cycloaddition reactions,14 cycloisomerization reactions,15 C–H bond activation processes,16 metathesis reactions,17 etc Reviews devoted to an application of a particular type of starting materials have also been published Thus, for example, applications of isocyanides,18 diazocompounds,19 or azides20 have been discussed In addition, a significant attention was given to transition metal-catalyzed multicomponent syntheses of heterocycles21 Finally, syntheses of heterocycles featuring formation of intermediates, such as nitrenes,22 vinylidenes,23 carbenes, and carbenoids24 have also been reviewed

The main focus of the present review is a transition metal-catalyzed synthesis of aromatic monocyclic heterocycles The organization of the review is rather classical and is based on a heterocycle, categorized in the following order: (a) ring size of heterocycle, (b) number of heteroatoms, (c) type of heterocycle, and (d) a class of transformation involved A brief mechanistic discussion is given to provide information about a possible reaction pathway when necessary The review mostly discusses recent literature, starting from 200425 until the end of 2011, however, some earlier parent transformations are discussed when needed

Transition Metal-Mediated Synthesis of Monocyclic Aromatic Heterocycles

Metal-catalyzed cross-coupling reactions belong to the most important transformations in organic synthesis Copper catalysis has received great attention owing to the low toxicity and low cost of copper However, traditional Ullmann-type couplings suffer from limited substrate scopes and harsh reaction conditions The introduction of several bidentate ligands, such as amino acids, diamines, 1,3-diketones, and oxalic diamides, over the past two decades has totally changed this situation as these ligands enable the copper-catalyzed coupling of aryl halides and nucleophiles at both low reaction temperatures and catalyst loadings The reaction scope has also been greatly expanded, rendering this copper-based cross-coupling attractive for both academia and industry In this Review, we have summarized the latest progress in the development of useful reaction conditions for the coupling of (hetero)aryl halides with different nucleophiles Additionally, recent advances in copper-catalyzed coupling reactions with aryl boronates and the copper-based trifluoromethylation of aromatic electrophiles will be discussed

Selected Copper-Based Reactions for C-N, C-O, C-S and C-C Bond Formation

Recent advances in transition metal-catalyzed C–H bond functionalization have profoundly impacted synthetic strategy Since organic substrates typically contain several chemically distinct C–H bonds, controlling the regioselectivity of C–H bond functionalization is imperative to harness its full potential Moreover, the ability to alter reaction pathways to selectively functionalize different C–H bonds in a substrate represents a greater opportunity and challenge The choice of catalysts, ligands, solvents, and even more subtle variations of the reaction conditions have been shown to allow the formation of regioisomeric C–H functionalization products starting from the same precursors This review describes recent advances in transition metal-catalyzed divergent C–H bond functionalization that highlight its potential in organic synthesis

Transition metal-catalyzed site- and regio-divergent C–H bond functionalization

The indole scaffold will continue to play a vital part in the future of drug discovery and agrochemical development. Because of this, the necessity for elegant techniques to enable selective C–H functionalization is vast. Early developments have led to primarily C2 and C3 functionalization because of the inherent reactivity of the pyrrole ring. Despite this, elegant methods have been developed to enable selective C–H functionalization on the benzenoid moiety at C4, C5, C6, and C7. This review focuses on the contributions made in benzenoid C–H functionalization of indoles and other related heteroaromatics such as carbazoles.

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Beyond C2 and C3: Transition-Metal-Catalyzed C–H Functionalization of Indole

In recent years, transition-metal-catalyzed C-H activation has become a key strategy in the field of organic synthesis. Rhodium complexes are widely used as catalysts in a variety of C-H functionalization reactions because of their high reactivity and selectivity. The availability of a number of rhodium complexes in various oxidation states enables diverse reaction patterns to be obtained. Regioselectivity, an important issue in C-H activation chemistry, can be accomplished by using a directing group to assist the reaction. However, to obtain the target functionalized compounds, it is also necessary to use a directing group that can be easily removed. A wide range of directed C-H functionalization reactions catalyzed by rhodium complexes have been reported to date. In this Review, we discuss Rh-catalyzed C-H functionalization reactions that are aided by the use of a removable directing group such as phenol, amine, aldehyde, ketones, ester, acid, sulfonic acid, and N-heteroaromatic derivatives.

Rhodium-Catalyzed C(sp 2 )- or C(sp 3 )-H Bond Functionalization Assisted by Removable Directing Groups

Synthesis of 3-substituted and 2,3-disubstituted quinazolinones via Cu-catalyzed aryl amidation.

An efficient rhodium-catalyzed method for direct C-H functionalization at the C7 position of a wide range of indoles has been developed. Good to excellent yields of alkenylation products were observed with acrylates, styrenes, and vinyl phenyl sulfones, whereas the saturated alkylation products were obtained in good yield with α,β-unsaturated ketones. Both the N-pivaloyl directing group and the rhodium catalyst proved to be crucial for high regioselectivity and conversion.

Rhodium‐Catalyzed Regioselective C7‐Functionalization of N‐Pivaloylindoles

https://pubs.acs.org/doi/pdf/10.1021/ol500545s

The N-Aryl Aminocarbonyl ortho-Substituent Effect in Cu-Catalyzed Aryl Amination and Its Application in the Synthesis of 5-Substituted 11-Oxo-dibenzodiazepines

The synthesis of substituted furans is an old but still active research area in organic chemistry. The continuing interest in this topic stems from the fact that these heterocycles play an important role in many aspects. For example, furan is the key structural subunit in an enormous number of bioactive natural products and pharmaceutically important substances, and forms the skeleton of many flavor and fragrance compounds. Additionally, substituted furans are useful and versatile intermediates in synthetic organic chemistry. Among the existing methods for synthesizing substituted furans, cycloisomerization of (Z)-2-en-4-yn-1-ols is one of the most attractive approaches because of the potential to form polysubstituted furans with great diversity. For this transformation, the often-used promoters or catalysts are strong bases (such as KOtBu) or transition-metal (like ruthenium, palladium, e] and gold ) complexes. In 1990, V gh and co-workers disclosed that copper(II) could catalyze the conversion of (Z)-3-methyl-2-penten-4yn-1-ol into 3,3-dimethylfuran. Although only this one example has been examined, the potential of copper salts as the catalysts for the cycloisomerization of (Z)-2-en-4-yn-1ols prompted us to develop a cascade process to synthesize substituted furans from substituted 3-iodoprop-2-en-1-ols 2 and 1-alkynes 1. As outlined in Scheme 1, we envisaged that after CuI/amino acid catalyzed cross-coupling of 1 and 2 to afford substituted (Z)-2-en-4-yn-1-ols 3, the free hydroxyl group would attack the C C triple bond under the assistance of the copper salt (complex 4) to give cyclization products 5. From the intermediates 5, substituted furans 7 could be formed through two possible pathways. One is protonation of 5 and subsequent isomerization of the heterocycles 6. The other possible pathway involves isomerization of 5, followed by protonation of the resultant intermediates 8. With this idea in mind, we conducted a CuI/amino acid catalyzed reaction of 1-ethynylbenzene 1 a with (Z)-3-iodo2-phenylbut-2-en-1-ol 2 a. It was found that under our previous reaction conditions for cross-coupling of vinyl iodides and terminal alkynes (N,N-dimethylglycine as the ligand, Cs2CO3 as the base, dioxane as the solvent, 80 8C) [6a] the desired furan 7 a was isolated in 70 % yield (Table 1, entry 1). Encouraged by this result, we attempted to improve the yield by changing the reaction conditions. It was found that a better yield could be obtained by using l-proline as a ligand (Table 1, entry 2), which is consistent with results observed in our indole formation. Switching the base to K2CO3 and K3PO4 failed to give better results (Table 1, en[a] Y. Wang, L. Xu Department of Chemistry Fudan University Shanghai 200433 (China) [b] Prof. Dr. D. Ma State Key Laboratory of Bioorganic & Natural Products Chemistry Shanghai Institute of Organic Chemistry Chinese Academy of Sciences 354 Fenglin Lu, Shanghai 200032 (China) Fax: (+86) 21-64166128 E-mail : madw@mail.sioc.ac.cn Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.200900523. Scheme 1. Coupling/cycloisomerization cascade process to polysubstituted furans from substituted 3-iodoprop-2-en-1-ols and 1-alkynes.

CuI/L‐Proline‐Catalyzed Coupling of Substituted 3‐Iodoprop‐2‐en‐1‐ols with 1‐Alkynes and Subsequent Cyclization: A Convenient Approach for Synthesizing Polysubstituted Furans

CuBr-catalyzed coupling reaction of 2-halobenzonitriles with hydrazine carboxylic esters and CuBr/4-hydroxy-l-proline-catalyzed coupling reaction of 2-bromobenzonitriles with N′-arylbenzohydrazides proceed smoothly at 60–90 °C to provide substituted 3-aminoindazoles through a cascade coupling/condensation (or coupling/deacylation/condensation) process. A wide range of 3-aminoindazoles with substituents at both the 1-position and the phenyl ring part can be prepared from the corresponding coupling partners.

Lanting Xu

Papers

Synthesis of 3-substituted and 2,3-disubstituted quinazolinones via Cu-catalyzed aryl amidation.

Rhodium‐Catalyzed Regioselective C7‐Functionalization of N‐Pivaloylindoles

The N-Aryl Aminocarbonyl ortho-Substituent Effect in Cu-Catalyzed Aryl Amination and Its Application in the Synthesis of 5-Substituted 11-Oxo-dibenzodiazepines

CuI/L‐Proline‐Catalyzed Coupling of Substituted 3‐Iodoprop‐2‐en‐1‐ols with 1‐Alkynes and Subsequent Cyclization: A Convenient Approach for Synthesizing Polysubstituted Furans

Assembly of Substituted 3-Aminoindazoles from 2-Bromobenzonitrile via a CuBr-Catalyzed Coupling/Condensation Cascade Process