Regioselective (site-selective) functionalization of unsaturated halogenated nitrogen, oxygen and sulfur heterocycles by Pd-catalysed cross-couplings and direct arylation processes

This tutorial review focuses on several practical synthetic transformations utilising palladium catalysis that facilitate the synthesis of functionalized unsaturated heterocycles in a regioselective (site-selective) manner. Cross-couplings of electron-deficient, electron-neutral and electron-rich unsaturated halogenated heterocycles with various organometallic reagents, and other types of nucleophiles, are detailed. Direct arylation of electron-rich unsaturated heterocyclic compounds by C-H functionalization is also presented.     

Cyclizations via Palladium-Catalyzed Allylic Alkylations [New Synthetic Methods (79)]

The history of ring systems in organic chemistry parallels their synthetic accessibility. Transition-metal-catalyzed cyclizations offer a new opportunity to create carbo- and heterocyclic compounds with great facility. Among these methods, allylic alkylations catalyzed by palladium have proven unusually productive because of the extraordinary chemo-, regio-, and diastereoselectivity and the continuing possibility for the development of enantioselectivity. The rules for ring closure differ from those for non-transition-metal-catalyzed reactions. A major benefit is the ability to generate medium (eight-, nine-, ten-, and eleven-membered) and large rings in preference to normal (five-, six- and seven-membered) rings. With the appropriate substrate, efficient macrocyclizations are possible under conditions of normal concentrations. A second major benefit derives from the complementary stereochemistry of the metalcatalyzed substitution (net retention of configuration) compared to non-metal-catalyzed reactions (inversion of configuration). Further, the requirement for the substrate to conform to the transition-metal template may impose a stereochemical preference in the intermediate that ultimately translates into the thermodynamically less stable organic product regardless of the stereochemistry of the starting material. While more work has focused on carbocyclic synthesis, the possibilities for heterocyclic synthesis are just beginning to be tapped. In addition to forming heterocycles by C? C bond formation, use of a heteroatom as a nucleophile has already proven effective for oxygen and nitrogen, with other nucleophiles awaiting investigation. New dimensions for cyclization via allylic alkylation arise by generating the requisite π-allylpalladium intermediates by methods other than palladium(0)-initiated allylic ionizations. In addition, metals other than palladium will clearly expand the possibilities, but as yet remain untapped.     

N‐Heterocyclic Carbenes: A New Concept in Organometallic Catalysis

N‐Heterocyclic carbenes have become universal ligands in organometallic and inorganic coordination chemistry. They not only bind to any transition metal, be it in low or high oxidation states, but also to main group elements such as beryllium, sulfur, and iodine. Because of their specific coordination chemistry, N‐heterocyclic carbenes both stabilize and activate metal centers in quite different key catalytic steps of organic syntheses, for example, C−H activation, C−C, C−H, C−O, and C−N bond formation. There is now ample evidence that in the new generation of organometallic catalysts the established ligand class of organophosphanes will be supplemented and, in part, replaced by N‐heterocyclic carbenes. Over the past few years, this chemistry has been the field of vivid scientific competition, and yielded previously unexpected successes in key areas of homogeneous catalysis. From the work in numerous academic laboratories and in industry, a revolutionary turning point in oraganometallic catalysis is emerging.     

One-pot access to a privileged library of six membered nitrogenous heterocycles through multi-component cascade approach

The presence of heterocycles and heteroaromatics as ubiquitous components in a diverse variety of synthetic drugs, biologically active molecules, and natural products has inspired the researchers to develop new strategies and technologies for their easy accessibility. Among them, six membered nitrogenous heterocycles gained immense interest, and significant efforts have been made to the development of synthetic strategies which could lead to the discovery of architecturally complex and diverse molecules with high efficiency, low cost, less organic waste and shorter reaction time. Access to such systems by one-pot multi-component approach with inherent advantages of step-economy, operational simplicity, synthetic efficiency, and environmental compatibility is particularly attractive. The current review article highlights the recent developments in the synthesis of six membered nitrogen-containing heterocyclic scaffolds through one-pot multi-component assembly approach.     

金属有机化合物催化的环化反应新进展

综述了近年来金属有机化合物催化的环化反应在合成碳20环及杂环化合物中的应用。     

Transition-metal-catalyzed denitrogenative transannulation: converting triazoles into other heterocyclic systems

Transition metal catalyzed denitrogenative transannulation of a triazole ring has recently received considerable attention as a new concept for the construction of diverse nitrogen-containing heterocyclic cores. This method allows a single-step synthesis of complex nitrogen heterocycles from easily available and cheap triazole precursors. In this Minireview, recent progress of the transition metal catalyzed denitrogenative transannulation of a triazole ring, which was discovered in 2007, is discussed.     

Total Synthesis of Dimethyl Sulfomycinamate

Dimethyl sulfomycinamate (1), a methanolysis product from the natural antibiotic sulfomycin I, is synthesized in 11 steps (Scheme 19). The chemistry of various pyridine, thiazole, and oxazole heterocycles and their coupling reactions under palladium catalysis are examined. The key transformations in the synthesis are the selective palladium-catalyzed coupling reactions on doubly activated pyridine 62 and the condensation reaction between bromo ketone 69 and amide 28 to form the oxazole moiety 76. The first preparation of oxazole triflates is described, as are some of their chemical properties.     

Development of environmentally benign organometallic catalysis for drug discovery and its application

We have developed a novel organometallic catalysis and applied it to drug discovery. Two new catalysts were found, ruthenium hydride with a nitrogen-containing heterocyclic carbene (A) and an organopalladium catalyst supported on a sulfur-terminated semiconductor, gallium arsenide (001) (B). Both catalysts are environmentally benign, because A can yield indole derivatives with good atom economy, and B can catalyze the Mizoroki-Heck reaction more than 10 times with only trace amounts of leached palladium (ppb level). We also describe our synthetic study of nitrogen-containing heterocycles using ring-closing metathesis (RCM), such as chiral bicyclic lactams, azacycloundecenes, axially chiral macrolactams, 1,2-dihydroquinolines and indoles, including the development of silyl-enol ether ene metathesis, selective isomerization of terminal olefin, enamide metathesis and cycloisomerization and its application to the syntheis of 4 natural products, (-)-coniceine, (S)-pyrrolam A, angustureine, and fistulosin.     

A Continuum of Progress: Applications of N‐Hetereocyclic Carbene Catalysis in Total Synthesis

N‐Heterocyclic carbene (NHC) catalyzed transformations have emerged as powerful tactics for the construction of complex molecules. Since Stetter’s report in 1975 of the total synthesis of cis‐jasmon and dihydrojasmon by using carbene catalysis, the use of NHCs in total synthesis has grown rapidly, particularly over the last decade. This renaissance is undoubtedly due to the recent developments in NHC‐catalyzed reactions, including new benzoin, Stetter, homoenolate, and aroylation processes. These transformations employ typical as well as Umpolung types of bond disconnections and have served as the key step in several new total syntheses. This Minireview highlights these reports and captures the excitement and emerging synthetic utility of carbene catalysis in total synthesis.     

Stirring the porphyrin alphabet soup--functionalization reactions for porphyrins

Advances in the synthesis of unsymmetrically meso substituted porphyrins are based on the development of new total syntheses and porphyrin functionalization methods. These methods have replaced earlier mixed condensation reactions and give synthetic access to almost any desired meso-substituted porphyrin. They include the complete series of porphyrin homologues and regioisomers of the A(x)-series with either alkyl or aryl residues, and numerous examples of ABCD-type chromophores. The syntheses are based on a combination of classic functionalization reactions, the use of organolithium reagents in S(N)Ar reactions, and organometallic reactions with Pd, Ni, Cr, Ru, B, and Sn catalysis. This feature article gives an account of our work in the past decade to develop synthetic methods for the A(x)- and ABCD-type porphyrins and their use as optical materials and photosensitizers.     

Synergistic N‐Heterocyclic Carbene/Palladium‐Catalyzed Umpolung 1,4‐Addition of Aryl Iodides to Enals

An umpolung 1,4‐addition of aryl iodides to enals promoted by cooperative (terpy)Pd/NHC catalysis was developed that generates various bioactive β,β‐diaryl propanoate derivatives. This system is not only the first reported palladium‐catalyzed arylation of NHC‐bound homoenolates but also expands the scope of NHC‐induced umpolung transformations. A diverse array of functional groups such as esters, nitriles, alcohols, and heterocycles are tolerated under the mild conditions. This method also circumvents the use of moisture‐sensitive organometallic reagents.     

Palladium‐Titanium Relay Catalysis Enables Switch from Alkoxide‐π‐Allyl to Dienolate Reactivity for Spiro‐Heterocycle Synthesis

Reported herein is the divergent syntheses of [5,5] and [6,5] spiro‐heterocycles under Lewis‐acid‐assisted palladium catalysis. In particular, an unprecedented switch from alkoxide‐π‐allyl to dienolate reactivity was achieved by the use of palladium‐titanium relay catalysis, and represents umpolung reactivity of vinylethylene carbonates. This method uses a simple procedure and commercially available catalysts, and delivers both classes of spiro‐heterocycles, bearing three contiguous stereocenters, in high yield and uniformly excellent diastereoselectivity.     

Total Syntheses of (+)‐Grandilodine C and (+)‐Lapidilectine B and Determination of their Absolute Stereochemistry

Enantioselective total syntheses of the Kopsia alkaloids (+)‐grandilodine C and (+)‐lapidilectine B were accomplished. A key intermediate, spirodiketone, was synthesized in 3 steps and converted into the chiral enone by enantioselective deprotonation followed by oxidation with up to 76 % ee. Lactone formation was achieved through stereoselective vinylation followed by allylation and ozonolysis. The total synthesis of (+)‐grandilodine C was achieved by palladium‐catalyzed intramolecular allylic amination and ring‐closing metathesis to give 8‐ and 5‐membered heterocycles, respectively. Selective reduction of a lactam carbonyl gave (+)‐lapidilectine B. The absolute stereochemistry of both natural products was thereby confirmed. These syntheses enable the scalable preparation of the above alkaloids for biological studies.     

Recent trends in synthetic strategies using magnetic nanostructures as green catalysts in synthesis of pyran analogues

In recent years, magnetic nanoparticles and nanocomposites play an important role as a nanocatalyst in the creation of a wide range of bioactive heterocycles with extraordinarily high activity and selectivity, low energy consumption, and extended life. Among all heterocycles, many natural products, pharmaceuticals, and bioactive compounds contain pyran scaffolds which have a wide range of uses in biomedical research, industry, and medicine. Additionally, these are also widely used in the synthesis of novel heterocyclic systems as precursors. This study focused on recent advances in the last 5 years in using various magnetic recoverable and recycled nanoparticles and nanocomposites to synthesize pyran derivatives and their pharmacological activity. This article has been classified into three subsections: (i) MNPs-metal nanocomposite catalyzed reactions, (ii) MNPs-organic based nanocomposite catalyzed reactions, and (iii) MNPs-ionic liquid nanocomposite catalyzed reactions and (iv) MNPs-acid based nanocomposite to describe catalytic efficiency of magnetic nanocomposites for the synthesis of pyran derivatives. A comparative study of nanocomposites and different approaches for green synthesis of pyrans by highlighting the advantages and disadvantages along with catalyst recovery and recyclability has been mentioned, which will help scientists to probe and stimulate the study of these scaffolds.     

Synthesis and Reactions of Ketenimines

Ketenimines R¹R²C?C?N? R³ were first reported in 1919, but the development of the chemistry of these compounds is of relatively recent origin. These heterocumulenes are becoming of increasing interest as a dehydrating agent for peptide syntheses, as a coreagent in dimethyl sulfoxide oxidations, and as a substrate in the synthesis of heterocycles by condensation with polar multiple bonds and dipolar systems. The cycloadditions are of special interest from the viewpoint of orbital symmetry considerations. Some unusual organometallic complexes of ketenimines have also been synthesized. Recently some triaryl ketenimines have been found to have insecticidal and miticidal activity. Polymeric ketenimines have been implicated as molecular precursors of life.     

Enantioselective Synthesis of Spiro Heterocyclic Compounds Using a Combination of Organocatalysis and Transition-Metal Catalysis

Over the last ten years, the combination of organocatalysis with transition metal (TM) catalysis has become one of the most important toolboxes used for synthesizing optically pure compounds containing chiral quaternary centers, including spiro heterocyclic molecules. The dominant method in the enantioselective synthesis of spiro heterocyclic compounds based on synergistic catalysis includes chiral aminocatalysis and NHC catalysis, as already established covalent organocatalytic strategies. Another area of organocatalysis widely combined with TM catalysis producing enantiomerically enriched spiro heterocyclic compounds is non-covalent catalysis, dominated by chiral phosphoric acids, thiourea, and squaramide derivatives. This review article aims to summarize enantioselective methods used for constructing spirocyclic heterocycles based on a combination of organocatalysis and transition metal catalysis.     

N‐Heterocyclic Carbene Catalysis via Azolium Dienolates: An Efficient Strategy for Remote Enantioselective Functionalizations

N‐heterocyclic carbene (NHC) catalysis has emerged as a powerful strategy in organic synthesis. In recent years a number of reviews have been published on NHC‐catalyzed transformations involving Breslow intermediates, acyl azoliums, α,β‐unsaturated acyl azoliums, homoenolate equivalents, and azolium enolates. However, the azolium dienolate intermediates generated by NHCs have been employed in asymmetric synthesis only very recently, especially in cycloadditions dealing with remote functionalization. This Minireview highlights all the developments and the new advances in NHC‐catalyzed asymmetric cycloaddition reactions involving azolium dienolate intermediates.     

Regioselective Synthesis of Quinazolinone‐/Phenanthridine‐Fused Heteropolycycles by Pd‐Catalyzed Direct Intramolecular Aerobic Oxidative C−H Amination from Aromatic Strained Amides

A new route for the expedient synthesis of specific regioisomer of quinazolinone‐ and phenanthridine‐fused heterocycles through a palladium‐catalyzed regioselective intramolecular oxidative C?H amination from cyclic strained amides of aromatic amido–amidine systems (quinazolinones) has been developed. The amine functionalization of an aromatic C?H bond from a strained amide nitrogen involved in aromaticity has been a challenging work so far. The fusion of two heterocyclic cores, quinazolinone and phenanthridine, can occur in two different ways (linear and angular), but under the conditions reported here, only linear type isomer is exclusively produced. This approach provides a variety of substituted quinazolinone‐ and phenanthridine‐fused derivatives in moderate to excellent yields. Moreover, such fused molecules show excellent fluorescent properties and have great potential to be a new type of fluorophores for the use in medicinal and material science.     

金属促进的1H-磷杂环戊二烯的合成方法学研究

1H-磷杂环戊二烯的合成、反应和性质的研究已成为有机合成化学和金属有机化学的主要研究热点之一并得到了迅猛的发展,它们在光电材料、配位化学和选择性催化等方面有重要的应用价值.从金属有机化学的角度,系统地总结了近十年来1H-磷杂环戊二烯的合成化学新反应、新方法及应用.     

Recent advances in iron(III) chloride catalyzed synthesis of heterocycles

Heterocyclic compounds particularly five, six and seven membered ring containing heterocycles are the most abundant which constitute a staggeringly diverse and important class of molecules that occur ubiquitously in a variety of synthetic drugs, bioactive natural products, pharmaceuticals and agrochemicals. Owing to the glorious past and impressive present of the biologically active heterocyclic scaffolds, these skeletons have long been a subject of immense interest. Hence, substantial efforts have been made to the development of new and innovative synthetic strategies for the synthesis of these heterocycles involving use of different metal catalysts, organic and inorganic reagents etc. Among the different types of metal catalysts used, iron catalysts are one of the cheap and easily available. In recent time, several new and innovative iron(III) chloride catalyzed synthesis of heterocycles with structural diversity are coming in the forefront of the literature by the scientific community. This review highlights the advancements made so far by iron(III) chloride for the synthesis of different assemblies of small heterocycles covering the year 2014–2018.