Vaibhav P. Mehta

Microwave-assisted C–C bond forming cross-coupling reactions: an overview

Among the fundamental transformations in the field of synthetic organic chemistry, transition-metal-catalyzed reactions provide some of the most attractive methodologies for the formation of C-C and C-heteroatom bonds. As a result, the application of these reactions has increased tremendously during the past decades and cross-coupling reactions became a standard tool for synthetic organic chemists. Furthermore, a tremendous upsurge in the development of new catalysts and ligands, as well as an increased understanding of the mechanisms, has contributed substantially to recent advances in the field. Traditionally, organic reactions are carried out by conductive heating with an external heat source (for example, an oil bath). However, the application of microwave irradiation is a steadily gaining field as an alternative heating mode since its dawn at the end of the last century. This tutorial review focuses on some of the recent developments in the field of cross-coupling reactions assisted by microwave irradiation.

Recent advances in transition-metal-free direct C–C and C–heteroatom bond forming reactions

The efficient generation of biaryl compounds and heterocycles via the advent of the transition-metal-free coupling reaction constitutes an important development in the last few years. Although early methods for the construction of such molecules involved transition metals, recent advances in the field have witnessed a myriad of elegant reports without the use of metal sources. The serendipitous discovery and observation of synthetic chemists have realized that there lies a great potential in exploiting the inherent reactivity of molecules in absence of transition metal. The key to the success of such coupling reactions is the use of a strong base, oxidant and a catalytic amount of N-donor ligands which contribute significantly. This review aims to highlight the recent progress in the field of transition-metal-free direct C–C and C–heteroatom bond forming reactions via the use of a strong base and (or) an oxidant.

Ruthenium-catalyzed cascade C-H functionalization of phenylacetophenones

Three orthogonal cascade C—H functionalization processes are described, based on ruthenium-catalyzed C—H alkenylation. 1-Indanones, indeno indenes, and indeno furanones were accessed through cascade pathways by using arylacetophenones as substrates under conditions of catalytic [{Ru(p-cymene)Cl2}2] and stoichiometric Cu(OAc)2. Each transformation uses C—H functionalization methods to form C—C bonds sequentially, with the indeno furanone synthesis featuring a C—O bond formation as the terminating step. This work demonstrates the power of ruthenium-catalyzed alkenylation as a platform reaction to develop more complex transformations, with multiple C—H functionalization steps taking place in a single operation to access novel carbocyclic structures.

S-, N-, and Se-Difluoromethylation Using Sodium Chlorodifluoroacetate

A simple protocol for the difluoromethylation of thiols is reported using chlorodifluoroacetate as the difluoromethylating agent. This cheap reagent undergoes smooth decarboxylation at 95 °C to afford difluorocarbene, which can be trapped with a variety of aromatic and heteroaromatic thiols. The reaction is also effective for the difluoromethylation of heterocyclic nitrogen compounds and phenylselenol.

A Microwave-Assisted Diastereoselective Multicomponent Reaction To Access Dibenzo[c,e]azepinones: Synthesis and Biological Evaluation

An unprecedented microwave-assisted multicomponent strategy has been elaborated for the fast, efficient, and diastereoselective generation of the dibenzo[c,e]azepinone scaffold. The generated compounds were evaluated for their bioactivity.

The First Palladium-Catalyzed Desulfitative Sonogashira-Type Cross-Coupling of (Hetero)aryl Thioethers with Terminal Alkynes

An unprecedented desulfitative Sonogashira-type cross-coupling protocol is exemplified by the synthesis of substituted 5-chloro-3-alkynylpyrazinones from the corresponding 5-chloro-3-(phenylsulfanyl) pyrazin-2(1H)-ones. The applicability of the method is extended to solid-phase linked pyrazin-2(1H)-ones as well as to some oxazinones, pyrazines, and phenyl thioesters.

Palladium‐Catalyzed Mono‐α‐Arylation of Acetone with Aryl Imidazolylsulfonates

Palladium-catalyzed arylations of a-C H acidic compounds have emerged as reliable tools for the formation of C ACHTUNGTRENNUNG(sp3) C ACHTUNGTRENNUNG(sp2) bonds. In particular, pioneering studies by the groups of Miura, Buchwald, and Hartwig have set the stage for broadly applicable a-arylations of various carbonyl compounds. Despite this remarkable progress, generally applicable mono-a-arylations of the simplest ketone, acetone, have until very recently proven elusive. This is largely because the monoarylated acetone derivatives are inherently more reactive than acetone itself, which can lead to mixtures of oligoand polyarylated products that are difficult to separate. Stradiotto and co-workers’ elegantly designed DalPhos P,N ligands were very recently found to be the key to controlling the chemoselectivity and reactivity of challenging mono-a-arylations of acetone. In recent years, the focus on transition-metal-catalyzed arylations has shifted to the use of phenol-derived, fluorine-free electrophiles as arylating reagents because these electrophiles are readily accessible and can be easily utilized as directing groups in versatile arene functionalization strategies. In this context, airand moisture-stable aryl imidazolylsulfonates 1 are particularly attractive because of the self-destructive, and thus nongenotoxic properties, of the byproduct imidazolylsulfonic acid. Within our research program on the use of phenolbased electrophiles for metal-catalyzed C H bond arylations, we became interested in employing user-friendly imidazolylsulfonates for a-arylations of ketones, with a particular focus on the use of acetone (2), which we wish to report herein. Our optimization studies were initiated by probing a set of ligands for the difficult mono-a-arylation of acetone (2) with aryl imidazolylsulfonate 1 a in 1,4-dioxane as the solvent (Table 1 and Table S1 in the Supporting Information). Interestingly, although monodentate phosphine ligands only provided unsatisfactory results, chemoselective and efficient catalysis was accomplished with bisphosphines 1,1’-bis(diphenylphosphino)ferrocene (dppf) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos) (Table 1, entries 1–3). Among a variety of bases, Cs2CO3 proved to be optimal, whereas NaOtBu led to an undesired decomposition of the organic electrophile 1 a (Table 1, entry 6). Reactions proceeded most satisfactorily in 1,4-dioxane as the solvent, with transformations performed in THF, toluene, or MeCN being less successful. Different palladium(II) compounds served as viable precatalysts; the most efficient catalysis was achieved by employing inexpensive Pd ACHTUNGTRENNUNG(OAc)2 which ensured high catalytic efficacy even at a significantly lower reaction temperature (Table 1, entries 7–17). It is worth noting that in a previous study the inexpensive precursor Pd ACHTUNGTRENNUNG(OAc)2 led to a low conversion of acetone (2) (< 5 %). [a] Prof. Dr. L. Ackermann, Dr. V. P. Mehta Institut f r Organische und Biomolekulare Chemie Georg-August-Universit t, Tammannstrasse 2 37077 Gçttingen (Germany) Fax: (+49)551-39-6777 E-mail : Lutz.Ackermann@chemie.uni-goettingen.de Homepage: http://www.org.chemie.uniso-goettingen.de/ackermann/ Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201201394. Table 1. Optimization studies on the mono-a-arylation of acetone (2) with aryl imidazolylsulfonate 1 a.

Diversity-Oriented Synthesis of Dibenzoazocines and Dibenzoazepines via a Microwave-Assisted Intramolecular A3-Coupling Reaction

An unprecedented, diversity-oriented strategy for the generation of 6,7-dihydro-5H-dibenzo[c,e]azepines and 5,6,7,8-tetrahydrodibenzo[c,e]azocines by a microwave-assisted copper-catalyzed intramolecular A(3)-coupling reaction is presented.

An expeditious route toward pyrazine-containing nucleoside analogues.

An improved and convenient methodology for the synthesis of asymmetrically substituted pyrazines starting from 3,5-dichloropyrazin-2(1H)-ones has been elaborated. Several nucleoside analogues have been synthesized containing the pyrazine core as the organic base coupled with the sugar via a triazole linkage. The beneficial effect of microwave irradiation throughout the sequence has been demonstrated.

Microwave-assisted palladium-catalyzed phosphonium coupling of 2(1H)-pyrazinones.

An expedient route for the synthesis of differently substituted 2(1H)-pyrazinones applying a microwave-assisted palladium-catalyzed phosphonium coupling procedure is reported. The method has also been successfully extended to some other tautomerizable heterocycles for efficient C-C cross-coupling.