A concept for intramolecular denitrogenative C(sp3)–H amination of 1,2,3,4-tetrazoles bearing unactivated primary, secondary, and tertiary C–H bonds is discovered. This catalytic amination follows ...an unprecedented metalloradical activation mechanism. The utility of the method is showcased with the short synthesis of a bioactive molecule. Moreover, an initial effort has been embarked on for the enantioselective C(sp3)–H amination through the catalyst design. Collectively, this study underlines the development of C(sp3)–H bond functionalization chemistry that should find wide application in the context of drug discovery and natural product synthesis.
An efficient strategy for the intramolecular denitrogenative transannulation/C(sp2)–H amination of 1,2,3,4-tetrazoles bearing C8-substituted arenes, heteroarenes, and alkenes is described. The ...process involves the generation of the metal–nitrene intermediate from tetrazole by the combination of Cp*IrCl22 and AgSbF6. It has been shown that the reaction proceeds via an unprecedented electrocyclization process. The method has been successfully applied for the synthesis of a diverse array of α-carbolines and 7-azaindoles.
A unique concept for the intermolecular denitrogenative annulation of 1,2,3,4‐tetrazoles and alkynes was discovered by using a catalytic amount of Fe(TPP)Cl and Zn dust. The reaction precludes the ...traditional, more favored click reaction between an organic azide and alkynes, and instead proceeds by an unprecedented metalloradical activation. The method is anticipated to advance access to the construction of important basic nitrogen heterocycles, which will in turn enable discoveries of new drug candidates.
1,2,3,4: A unique intermolecular denitrogenative annulation of 1,2,3,4‐tetrazoles and alkynes was discovered by employing a catalytic amount of Fe(TPP)Cl and Zn dust. This reaction precludes the traditional click reaction between organic azides and alkynes.
A general catalytic method using a Mn‐porphyrin‐based catalytic system is reported that enables two different reactions (click reaction and denitrogenative annulation) and affords two different ...classes of nitrogen heterocycles, 1,5‐disubstituted 1,2,3‐triazoles (with a pyridyl motif) and 1,2,4‐triazolo‐pyridines. Mechanistic investigations suggest that although the click reaction likely proceeds through an ionic mechanism, which is different from the traditional click reaction, the denitrogenative annulation reaction likely proceeds via an electrophilic metallonitrene intermediate rather than a metalloradical intermediate. Collectively, this method is highly efficient and offers several advantages over other methods. For example, this method excludes a multi‐step synthesis of the N‐heterocyclic molecules described and produces only environmentally benign N2 gas a by‐product.
A Mn‐porphyrin‐based catalytic method that enables access to two different classes of nitrogen heterocycles is reported. Mechanistic investigations found that a 1,3‐cycloaddition click reaction occurs directly via the Mn‐bound complex, whereas denitrogenative annulation proceeds through an Mn‐N complex. The reported method is compatible with a wide range of substrates for both reactions.
A catalytic system for intermolecular benzylic C(sp3)–H amination is developed utilizing 1,2,3,4-tetrazole as a nitrene precursor via iron catalysis. This method enables direct installation of ...2-aminopyridine into the benzylic and heterobenzylic position. The method selectively aminates 2° benzylic C(sp3)–H bond over the 3° and 1° benzylic C(sp3)–H bonds. Experimental studies reveal that the C(sp3)–H amination undergoes via the formation of a benzylic radical intermediate. This study reports the discovery of new method for 2-pyridine substituted benzylamine synthesis using inexpensive, biocompatible base metal catalysis that should have wide application in the context of medicinal chemistry and drug discovery.
Conspectus The pursuit for the discovery of new and powerful synthetic methods to access high-value N-heterocycles has been at the forefront of organic chemistry research for more than a century. ...Considering the importance of N-scaffolds in modern science, over the past few decades, great research efforts have been made to develop efficient synthetic methods for the construction of nitrogen-rich molecules. Among many efforts, transition metal catalyzed denitrogenative annulation reaction has emerged as a cornerstone due to its innate versatility and wider scope of application. The denitrogenative annulation approach offers clear advantages over many existing methods, as it enables effective, single-step interconversion of easily available feedstocks into a variety of other important N-containing heterocyclic frameworks. Recently, transition metal catalyzed denitrogenative annulation reaction of the 1,2,3-triazole via a metal carbene intermediate sparked significant interest in the application of various important heterocycle syntheses. Denitrogenative annulation reaction of 1,2,3-triazoles proceeds via an ionic mechanism. Recently, we demonstrated a new concept for the denitrogenative reaction of triazoles with alkenes and alkynes via in situ generated 2-(diazomethyl)pyridines. The method takes advantage of the inherent properties of a Co(III)–carbene radical intermediate and is the first report of the denitrogenative annulation/cyclopropanation by a radical-activation mechanism. On the other hand, in contrast to the denitrogenative annulation of 1,2,3-triazole, annulation reaction of 1,2,3,4-tetrazole (a surrogate of azide having an important pyridyl unit) via metal nitrene remains a big challenge. Previously, flash vacuum pyrolysis studies had been used for nitrene–nitrene rearrangement of 1,2,3,4-tetrazole at high temperature. This Account summarizes our recent efforts in developing transition metal catalyzed denitrogenative annulation of 1,2,3-triazoles via a radical mechanism and 1,2,3,4-tetrazoles via metal nitrene to access important nitrogen-rich molecules. We demonstrated that the 1,2,3,4-tetrazole under Ir-catalyzed reaction conditions can produce a productive Ir–nitrene intermediate that can successfully be employed for the construction of a wide number of α-carbolines and 7-azaindoles. Moreover, we developed an iron-based unique strategy for the intermolecular denitrogenative annulation reaction between tetrazoles and alkynes. The reaction overcomes the traditional click reaction and proceeds via an unprecedented metalloradical activation mechanism. Furthermore, we used our understanding of tetrazole reactivity to design an iron-catalyzed intramolecular denitrogenative C(sp3)-H amination reaction of primary, secondary, and tertiary centers by using a metalloradical activation concept. At the same time, we also developed a general catalytic method to enable two distinct reactions (1,3-cycloaddition and denitrogenative annulation) using Mn(TPP)Cl that afforded two different classes of nitrogen heterocycles. Mechanistic studies showed that although the click reaction likely proceeds through an ionic mechanism and the denitrogenative annulation reaction likely proceeds via an electrophilic metallonitrene intermediate rather than a metallonitrene radical intermediate. Finally, we report an iron-catalyzed rearrangement reaction (ring expansion/migration) that proceeded with an unprecedented level of selectivity, reactivity, and functional group tolerance offering rapid access to numerous complex N-heterocycles. We believe that our continuous efforts in this field would be beneficial for pharmaceutical industries, drug discovery, and other fields of medicinal chemistry.
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•Iron catalysis for CN bond formation.•Iron-porphyrin catalysis.•Iron catalysis for C(sp2)–H & C(sp3)–H activation & CN bond formation.•Iron catalysis for high-valued ...N-heterocycles/molecules.•Metalloradical catalysis by iron-porphyrin catalysis.•Denitrogenative transformation of tetrazoles by iron catalysis.
Direct CN bond forming reaction by utilizing the non-precious transition metals is an attractive field of research in organic synthesis. Unlike the conventional use of precious metals like rhodium, palladium, ruthenium, and iridium that are commonly used in these reactions, the use of non-precious metals, particularly those are non-toxic and high abundant, holds distinct attention owing to the increasing demand of sustainable chemical processes. Among them, iron catalysis offers notable advantages for sustainable chemical synthesis. Iron-catalysed nitrene transfer reactions have emerged as robust and eco-friendly methods for constructing various valuable CN bonds. In this review, we provide a comprehensive overview of the advancements in iron catalysis for the nitrene transfer reactions aimed at synthesizing diverse CN bonds.
An iron‐catalyzed denitrogenative rearrangement of 1,2,3,4‐tetrazole is developed over the competitive C(sp3)–H amination. This catalytic rearrangement reaction follows an unprecedented ...metalloradical activation mechanism. Employing the developed method, a wide number of complex‐N‐heterocyclic product classes have been accessed. The synthetic utility of this radical activation method is showcased with the short synthesis of a bioactive molecule. Collectively, this discovery underlines the progress of radical activation strategy that should find wide application in the perspective of medicinal chemistry, drug discovery and natural product synthesis research.
An iron‐catalyzed rearrangement of 1,2,3,4‐tetrazole is developed over the competitive C(sp3)–H amination. This catalytic rearrangement follows an unprecedented metalloradical activation mechanism. Employing the developed method, a wide number of complex‐N‐heterocyclic product classes have been accessed.
Keywords: homogeneous catalysis; denitrogenative annulation; Fe-nitrene; metalloradicals; nitrogen heterocycles An iron-catalyzed denitrogenative rearrangement of 1,2,3,4-tetrazole is developed over ...the competitive C(sp.sup.3)-H amination. This catalytic rearrangement reaction follows an unprecedented metalloradical activation mechanism. Employing the developed method, a wide number of complex-N-heterocyclic product classes have been accessed. The synthetic utility of this radical activation method is showcased with the short synthesis of a bioactive molecule. Collectively, this discovery underlines the progress of radical activation strategy that should find wide application in the perspective of medicinal chemistry, drug discovery and natural product synthesis research. Article Note: These authors contributed equally to this work. Supporting information: Additional Supporting Information may be found in the online version of this article As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. CAPTION(S): Supplementary Byline: ,, Hillol Khatua, Subrata Das, Krishna Nand Singh, Buddhadeb Chattopadhyay
