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Substrate scope. For the scXRD structures, the ellipsoids are shown at 50% probability and hydrogen atoms are omitted for clarity.a 1H-NMR yield of 0.05-mmol scale crude reaction mixture using 1,1,2,2-tetrachloroethane as the internal standard.b Isolated yield of a 1.00-mmol scale reaction, conditions: indene (1.0 mmol), PIDA (2.5 mmol), ammonium carbamate (4.0 mmol), methanol (0.07 M), 0 °C for 20 min, then rt for 10 min
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We report a convenient protocol for a nitrogen atom insertion into indenes to afford isoquinolines. The reaction uses a combination of commercially available phenyliodine(iii) diacetate (PIDA) and ammonium carbamate as the nitrogen source to furnish a wide range of isoquinolines. Various substitution patterns and commonly used functional groups are...
Citations
... To be sure, the incorporation of 15 N labels can aid in food safety analysis and nutrient metabolism research 41 , the study of organic and organometallic mechanisms 42 , structural biology 43 , biogeochemistry 44 and chemical biology pursuits 45 . There is a documented need for new approaches to molecules incorporating 15 N without the need for expensive reagents or a complete redesign of synthetic pathways for their preparation [46][47][48] . Given the ease with which nitroamide 16 can be prepared, the corresponding 15 N-labelled reagent was prepared from inexpensive NH 4 15 NO 3 (ca. ...
Tertiary nitroalkanes, as well as their reduced products, α-tertiary amines, play an essential role in drug discovery as either key synthetic precursors or final motifs in targeted molecules. Existing methods to prepare tertiary nitro compounds generally rely on polar-bond disconnections, in which strong bases or highly active electrophiles are needed. Here we report the development of an anomeric nitroamide-based reagent that enables selective metal-hydride hydrogen atom transfer-based Co-catalysed alkene hydronitration for the preparation of valuable tertiary nitro compounds. This mild, scalable reaction shows broad functional group tolerance. Its synthetic application is demonstrated via late-stage nitration of complex alkenes derived from drugs and natural products, and simplifying the synthesis of a rare naturally occurring nitro sugar. Simple access to isotopically labelled ¹⁵N-containing nitro compounds is also disclosed. The anomeric nitroamide reagent was deemed safe by energetic measurements and its reactivity rationalized based on X-ray crystallographic analysis.
... The Morandi group advanced this area by applying their iodonitrene 67-based approach for nitrogen insertion in indenes 69, leading to isoquinolines 70 synthesis via an aziridination-fragmentation-aromatization pathway (Scheme 9B). 113 However, their protocol required strong oxidizing agents (hypervalent iodine), further constraining its substrate scope. 113 In 2024, Alcarazo and colleagues introduced a novel electrophilic nitrogen source, N-(sulfonio)sulfilimine 71 acting as sulfonitrene 72 precursors under rhodium catalysis. ...
... 113 However, their protocol required strong oxidizing agents (hypervalent iodine), further constraining its substrate scope. 113 In 2024, Alcarazo and colleagues introduced a novel electrophilic nitrogen source, N-(sulfonio)sulfilimine 71 acting as sulfonitrene 72 precursors under rhodium catalysis. These reactive species 72 enabled the same reactivity for indenes 69 without the need for oxidizing agents, via aziridination followed by ring expansion (Scheme 9C). ...
Skeletal editing is an emerging approach in synthetic chemistry that enables precise atom-level modifications within molecular cores, facilitating complex transformations and minimizing resource-intensive synthesis. This review provides a comprehensive overview...
... [11][12][13][14] An analogous N-atom transfer was demonstrated by Morandi, with nitrogen insertion promoted through in situ reaction between ammonia and iodine(III) oxidants. [15,16] Though powerful, the lack of a well-defined single-component reagent in this latter case introduces mechanistic ambiguity and limits the potential applications of this reagent system due to competing oxidations. [17,18] Though a range of other reagents have advanced the opportunities for nitrogen atom transfer, including anomeric amides, [19][20][21] sulphenyl nitrene precursors, [22][23][24] N-(sulfonio)sulfilimines, [25] oxadiazoles, [26] diazirines, [27] and osmium nitrides, [28] many desirable classes of nitrogen atom insertions remain elusive. ...
Controllable installation of a single nitrogen atom is central to many major goals in skeletal editing, with progress often gated by the availability of an appropriate N‐atom source. Here we introduce a novel reagent, termed DNIBX, based on dibenzoazabicycloheptadiene (dbabh), which allows the electrophilic installation of dbabh to organic substrates. When indanone β‐ketoesters are aminated by DNIBX, the resulting products undergo divergent ring expansions depending on the mode of activation, producing heterocycles in differing oxidation states under thermal and photochemical conditions. The mechanism of each transformation is discussed, and the different reactivity modes of the indanone‐dbabh adducts are compared to other nitrogenous precursors.
... [18] Recently, Morandi and coworkers reported operationally simple direct Natom insertion into a broad range of indenes and cyclopentadienes with commercially available (diacetoxyiodo)benzene (PIDA) as the oxidant and ammonium carbamate as the nitrogen source to access the library of isoquinolines (Scheme 1). [19] Morandi and coworkers have also summarized the isoelectronic approach of indenes to indoles to access quinazolines (Scheme 1). [20] In 2020, Yu and coworkers used a catalytic system of FeCl 2 / NHC SIPr.HCl for 9-azidofluorene to phenanthridine synthesis (Scheme 2). ...
Phenanthridines are prevalent core in several natural products and staining agents that could be assembled in various manners. However, to our knowledge, the skeletal editing of azides via solid‐state melt rearrangement (SSMR) without catalysts, bases, and additives to access phenanthridines is not reported in the literature. Herein, we report solvent‐free and catalyst‐free thermolytic SSMR of azidofluorenes to phenanthridine derivatives. This protocol successfully demonstrates 21 examples of phenanthridines by SSMR of symmetrical and unsymmetrical azidofluorenes in good to excellent yields. The green metrics of the developed protocol are in good accordance with ideal green chemistry metrics.
... [56][57][58] Numerous advancements have been achieved and thoroughly documented, illustrating the versatile behavior of nitrene intermediates in facilitating the straightforward and efficient incorporation of nitrogen atoms into hydrocarbon systems to produce N-heterocycles. [59][60][61] Notably, several comprehensive reviews focusing on single nitrene insertion reactions catalyzed transition metals [36] using suitable nitrene precursors, [62] CÀ N bond formation, [63][64][65][66] selective CÀ H functionalization, [67,68] applications of hypervalent iodine reagents in N-heterocycles synthesis are available, [69][70][71] but none specifically highlight the literature reports on hypervalent iodine mediated single-nitrogen insertion techniques for skeletal editing using nitrenes as N 1 synthons. Therefore, the aim of this review is to provide a comprehensive overview on the recent trends of transition-metal and photo-catalyzed singlenitrogen skeletal editing techniques specifically occurring with the backing of hypervalent iodine reagents. ...
... In 2023, Morandi and co-workers, developed a straightforward approach for the conversion of indenes (27) to isoquinolines (28) through single-nitrogen insertion using a hypervalent iodine reagent and ammonium carbamate as the nitrogen source (Scheme 14A). [59] Indenes can be converted into seminal isoquilone derivatives through various processes, such as transition metal catalysts, [76,87] electrochemical ammonium insertion, [88] and a multi-step ozonolysis [89] protocol (Scheme 14B). In contrast, hypervalent iodine-mediated isoquinolines are generally considered less hazardous and utilize nontoxic reagents. ...
Hypervalent iodine reagents are versatile and readily accessible reagents that have been extensively applied in contemporary synthesis in modern organic chemistry. Among them, iodonitrene (ArI=NR), is a powerful reactive species, widely used for a single‐nitrogen‐atom insertion reaction, and skeletal editing to construct N‐heterocycles. Skeletal editing with reactive iodonitrene components has recently emerged as an exciting approach in modern chemical transformation. These reagents have been extensively used to produce biologically relevant heterocycles and functionalized molecular architectures. Recently, the insertion of a nitrogen‐atom into hydrocarbons to generate N‐heterocyclic compounds using hypervalent iodine reagents has been a significant focus in the field of molecular editing reactions. In this review, we discuss the rapidly emerging field of nitrene insertion, including skeletal editing and nitrogen insertion, using hypervalent iodine reagents to access nitrogen‐containing heterocycles, and the current mechanistic understanding of these processes.
... Cyclopentenones, which are abundant and versatile building blocks in synthetic organic chemistry, [14] could be ideal precursors for the synthesis of a wide range of pyridones through oxidatively introducing a nitrogen atom in the carbon skeleton. [15][16][17][18][19][20][21][22][23][24][25][26][27] An analogous process is the Beckmann rearrangement, which has found broad applications in the synthesis of saturated lactams from cyclic ketones through oxime intermediates under acid catalysis, as illustrated by the industrial synthesis of Nylon (Scheme 1B). [28][29][30][31][32][33][34] Inspired by the Beckmann rearrangement and the experience of our group in electrophilic amination, [35][36][37][38] we hypothesised that instead of NÀ O reagents, the highly electrophilic species formed upon mixing an iodine(III) reagent and a nitrogen source could serve as an efficient reactant in achieving a direct cyclopentenone to pyridone conversion. ...
... [28][29][30][31][32][33][34] Inspired by the Beckmann rearrangement and the experience of our group in electrophilic amination, [35][36][37][38] we hypothesised that instead of NÀ O reagents, the highly electrophilic species formed upon mixing an iodine(III) reagent and a nitrogen source could serve as an efficient reactant in achieving a direct cyclopentenone to pyridone conversion. [23][24][25][39][40][41][42][43][44] Such bis-electrophilic species would not only serve as a nitrogen source, but also provide a synthon in which the nitrogen atom has the correct oxidation state to directly enable the desired oxidative process. We further reasoned that forming silyl enol ethers [45] from the cyclo-pentenones in situ would be highly beneficial, firstly for leveraging their high nucleophilicity, and secondly for enabling full control over the regioselectivity of the subsequent nitrogen atom insertion step (Scheme 1C). ...
Herein we report the development of an oxidative amination process for the streamlined synthesis of pyridones from cyclopentenones. Cyclopentenone building blocks can undergo in situ silyl enol ether formation, followed by the introduction of a nitrogen atom into the carbon skeleton with successive aromatisation to yield pyridones. The reaction sequence is operationally simple, rapid, and carried out in one pot. The reaction proceeds under mild conditions, exhibits broad functional group tolerance, complete regioselectivity, and is well scalable. The developed method provides facile access to the synthesis of ¹⁵N‐labelled targets, industrially relevant pyridone products and their derivatives in a fast and efficient way.
... [15] In addition, after the carbonyl group was reduced to a hydroxyl group, an N atom was successfully inserted into the indene to form an isoquinoline core (Scheme 6c). [16] In summary, we have discovered and developed a radical-induced furan ring-opening reaction enabled by excited-palladium catalysis. The homolytic cleavage of the CÀ O bond in the furan ring is achieved initially through the designed substrate and radical relay process. ...
A photoinduced palladium‐catalyzed ring‐opening hydroarylation of furans to form functionalized indenes was achieved via an intramolecular reductive coupling of aryl bromide with furan using silane as the reductant. Deuterium tracking and DFT analysis revealed a reasonable reaction pathway involving: 1) the homolytic cleavage of the furan C−O bond induced by the α‐allyl radical; 2) a 1,6‐H atom transfer from carbon to oxygen.
... Single-atom skeletal editing has become an extremely powerful tool for straightforwardly modifying the core skeleton of organic molecules. Recently, a limited number of single-atom insertion or deletion reactions have been developed to reshape the underlying molecular skeletons [8][9][10][11][12][13][14][15][16][17][18][19][20][21] . However, the direct modification of valuable core structures by replacing one atom in a ring system without changing the ring size and aromaticity remains elusive [22][23][24][25][26][27][28][29][30][31] , although it has been recognized as a highly desirable transformation. ...
... Considering the optimal reaction conditions, the substrate scope was determined (Fig. 2). Various arenols, including phenanthrol (1-10), naphthol (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), anthranol (33) benzo(a)anthranol (34), and benzo[c] phenanthrol (35), can effectively undergo the desired carbon-nitrogen transmutation. Both electron-rich and electrondeficient aromatic substrates were suitable for the process. ...
Developing skeletal editing tools is not a trivial task, and realizing the corresponding single-atom transmutation in a ring system without altering the ring size is even more challenging. Here, we introduce a skeletal editing strategy that enables polycyclic arenols, a highly prevalent motif in bioactive molecules, to be readily converted into N-heteroarenes through carbon–nitrogen transmutation. The reaction features selective nitrogen insertion into the C–C bond of the arenol frameworks by azidative dearomatization and aryl migration, followed by ring-opening, and ring-closing (ANRORC) to achieve carbon-to-nitrogen transmutation in the aromatic framework of the arenol. Using widely available arenols as N-heteroarene precursors, this alternative approach allows the streamlined assembly of complex polycyclic heteroaromatics with broad functional group tolerance. Finally, pertinent transformations of the products, including synthesis complex biheteroarene skeletons, were conducted and exhibited significant potential in materials chemistry.
... [1][2][3] Among them, the single-atom insertion skeletal editing is one of the most atomeconomical strategies, which enables people to effectively obtain diverse heterocyclic compounds. It can modularize the construction of valuable heterocyclic scaffolds in the fields of pharmaceutical chemistry, pesticides, and materials by inserting nitrogen atoms into carbon-cyclic ring [4][5][6][7][8][9] or by inserting a carbon atom into heterocyclic ring. [10][11][12][13][14][15] Given the prevalence of hydroquinazoline scaffolds in a variety of active pharmaceutical ingredients and biologically active compounds ( Figure 1A), [16][17][18] there is a growing interest in how to access such core skeletons in a straightforward and atom-economic manner. ...
Given the prevalence of heterocyclic scaffolds in drug‐related molecules, converting these highly modular heterocyclic scaffolds into structural diversified and dearomatized analogs is an ideal strategy for improving their physicochemical and pharmacokinetic properties. Here, we described an efficient method for silver carbene‐mediated dearomative N−N bond cleavage leading to skeletal hopping between indazole and 1,2‐dihydroquinazoline via a highly selective single‐carbon insertion procedure. Using this methodology, a series of dihydroquinazoline analogues with diarylmethylene‐substituted quaternary carbon centers were constructed with excellent yields and good functional group compatibility, which was further illustrated by the late‐stage diversification of important pharmaceutically active ingredients. DFT calculations indicated that the silver catalyst not only induces the formation of the silver carbene, but also activates the diazahexatriene intermediate, which plays a crucial role in the formation of the C−N bond.
... Of particular interest are those transformations in which ring expansion is achieved through the insertion of a carbon atom. Compared with other single-atom insertion reactions [9][10][11][12][13][14] , the advantage of the carbon atom is that it contains four covalent bonds, allowing the introduction of a functional group and providing more strategies for molecular diversification. The utilization of single-atom insertion reactions into aromatic ring systems is a formidable challenge given the high energy barriers associated with de-aromatization and cleavage of carbon-carbon bonds 15,16 . ...
Skeletal editing has received unprecedented attention as an emerging technology for the late-stage manipulation of molecular scaffolds. The direct achievement of functionalized carbon-atom insertion in aromatic rings is challenging. Despite ring-expanding carbon-atom insertion reactions, such as the Ciamician–Dennstedt re-arrangement, being performed for more than 140 years, only a few relevant examples of such transformations have been reported, with these limited to the installation of halogen, ester and phenyl groups. Here we describe a photoredox-enabled functionalized carbon-atom insertion reaction into indene. We disclose the utilization of a radical carbyne precursor that facilitates the insertion of carbon atoms bearing a variety of functional groups, including trifluoromethyl, ester, phosphate ester, sulfonate ester, sulfone, nitrile, amide, aryl ketone and aliphatic ketone fragments to access a library of 2-substituted naphthalenes. The application of this methodology to the skeletal editing of molecules of pharmaceutical relevance highlights its utility.
