A Direct Synthesis of Highly Substituted π‐Rich Aromatic Heterocycles from Oxetanes

The ubiquitous use of π‐rich five‐membered heterocycles has driven the development of new methods for their synthesis for more than a century. Here, we disclose a general and reliable reaction manifold for the construction of highly substituted heterocycles through a facile Lewis‐acid‐catalyzed oxetane rearrangement. Notably, this methodology employs a keto‐oxetane motif as a 1,4‐dicarbonyl surrogate, which can be synthesized using robust alkylation or alkenylation reactions, and thus obviates the need to access 1,4‐dicarbonyl compounds via umpoled starting materials. We harnessed this reactivity to generate a broad range of substituted furans and pyrroles, and extended this methodology to produce benzo‐fused versions thereof.     

“ESHC (sopron) plenary lecture” exciting fields in P‐heterocyclic chemistry

In our laboratory, we have been dealing with the synthesis and utilization of P‐heterocycles for almost two decades. In this paper, our recent results are summarised. In the first part, the synthesis and properties of phospholes with sterically demanding substituent on the phosphorus atom and the fragmentation‐related properties of phosphole oxide‐related 7‐phosphanorbornenes are discussed. Then, new families of 6‐membered P‐heterocycles are introduced available by a ring enlargement method and subsequent modifications. In the next part, I show how bridged P‐heterocycles were prepared and how they were utilised in fragmentation‐related phosphorylations. Finally a novel reaction providing heterocyclic phosphoranes/ylides is discussed.     

Synthesis of Anionic Phosphorus‐Containing Heterocycles by Intramolecular Cyclizations Involving N‐Functionalized Phosphinecarboxamides

We report that the 2‐phosphaethynolate anion (PCO^?) reacts with propargylamines in the presence of a proton source to afford novel N‐derivatized phosphinecarboxamides bearing alkyne functionalities. Deprotonation of these species gives rise to novel five‐ and six‐membered anionic heterocycles resulting from intramolecular nucleophilic attack of the resulting phosphide at the alkyne functionality (via 5‐exo‐dig or 6‐endo‐dig cyclizations, respectively). The nature of the substituents on the phosphinecarboxamide can be used to influence the outcome of these reactions. This strategy represents a unique approach to phosphorus‐containing heterocylic systems that are closely related to known organic molecules with interesting bio‐active properties.     

Pd‐Catalyzed Enantioselective [6+4] Cycloaddition of Vinyl Oxetanes with Azadienes to Access Ten‐Membered Heterocycles

We report herein the first enantioselective cycloaddition of vinyl oxetanes, the reaction of which with azadienes provided unprecedented access to ten‐membered heterocycles through a [6+4] cycloaddition. By using a commercially available chiral Pd‐SIPHOX catalyst, a wide range of benzofuran‐ as well as indole‐fused heterocycles could be accessed in excellent yield and enantioselectivity. A unique Lewis acid induced fragmentation of these ten‐membered heterocycles was also discovered.     

Construction of Nine‐Membered Heterocycles through Palladium‐Catalyzed Formal [5+4] Cycloaddition

The first catalytic formal [5+4] cycloaddition to prepare nine‐membered heterocycles is presented. Under palladium catalysis, the reaction of N‐tosyl azadienes and substituted vinylethylene carbonates (VECs) proceeds smoothly to produce benzofuran‐fused heterocycles in uniformly high efficiency. Highly diastereoselective functionalization of the nine‐membered heterocycles through peripheral attack is also demonstrated.     

The Selective Cross‐Coupling of Secondary Alkyl Zinc Reagents to Five‐Membered‐Ring Heterocycles Using Pd‐PEPPSI‐IHeptCl

The ability to cross‐couple secondary alkyl centers is fraught with a number of problems, including difficult reductive elimination, which often leads to β‐hydride elimination. Whereas catalysts have been reported that provide decent selectivity for the expected (non‐rearranged) cross‐coupled product with aryl or heteroaryl oxidative‐addition partners, none have shown reliable selectivity with five‐membered‐ring heterocycles. In this report, a new, rationally designed catalyst, Pd‐PEPPSI‐IHept^Cl, is demonstrated to be effective in selective cross‐coupling reactions with secondary alkyl reagents across an impressive variety of furans, thiophenes, and benzo‐fused derivatives (e.g., indoles, benzofurans), in most instances producing clean products with minimal, if any, migratory insertion for the first time.     

Postfunctionalization of BN‐Embedded Polycyclic Aromatic Compounds for Fine‐Tuning of Their Molecular Properties

New BN‐embedded, thiophene‐fused, polycyclic aromatic compounds with planar geometry were designed and synthesized. The molecules showed excellent stability and chemical robustness. Postfunctionalization on this skeleton was demonstrated with a series of electrophilic bromination, palladium‐catalyzed cross‐coupling, and Knoevenagel condensation reactions. The π skeleton remained intact during these late‐stage transformations. The optical and electronic properties have been well tuned through incorporation of electron‐rich and ‐deficient groups on the backbone. This work shows the great advantage of the postfunctionalization strategy on BN‐containing polycyclic aromatic compounds for fast diversification and materials screening.     

Phosphorus heterocycles from 2‐(2‐hydroxyphenyl)‐1H‐benzimidazole

Sixteen different P(III) and P(V) heterocycles derived from 2‐(2‐hydroxyphenyl)‐1H‐benzimidazole ( 1 ) are reported. In these heterocycles the phosphorus atom is part of a six‐membered unsaturated ring. They were mainly studied by multinuclear NMR. The X‐ray diffraction of 3,4‐ benzimidazole‐5,6‐benzo‐2‐dimethylamino‐2‐seleno‐ 1,3,2‐oxazaphosphorinane is reported. Phosphoranes derived from 1 and 3,5‐di‐tert‐butylcatechol, and bearing Cl, NMe₂, or phenyl as substituent at phosphorus are presented. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:307–320, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20021     

Synthesis of Highly Substituted Cyclobutane Fused‐Ring Systems from N‐Vinyl β‐Lactams through a One‐Pot Domino Process

In this contribution, aminocyclobutanes, as well as eight‐membered enamide rings, have been made from N‐vinyl β‐lactams. The eight‐membered products have been formed by a [3,3]‐sigmatropic rearrangement, whereas the aminocyclobutanes have been derived from a domino [3,3]‐rearrangement/6π‐electrocyclisation process. The aminocyclobutanes have been obtained in a highly diastereoselective fashion. The cyclobutane ring system tolerates fusion even if adjacent quaternary centres are present. Systems containing up to four fused rings are readily accessible. The reaction profile has been investigated by using Gaussian 03. This study suggests that two reaction pathways for aminocyclobutane formation are possible. In one pathway the [3,3]‐sigmatropic rearrangement is the rate‐limiting step and in the second pathway the electrocyclisation is rate limiting. Taken together, these reactions should facilitate the construction of fused heterocycles.     

Base‐Selective Five‐ versus Six‐Membered Ring Annulation in Palladium‐Catalyzed C–C Coupling Cascade Reactions: New Access to Electron‐Poor Polycyclic Aromatic Dicarboximides

Palladium‐catalyzed base‐selective annulation of dibromonaphthalimide to different aryl boronate esters by combined Suzuki–Miyaura cross‐coupling and direct C−H arylation afforded a series of new five‐ and six‐membered ring annulated electron‐poor polycyclic aromatic hydrocarbons. Cesium carbonate (Cs₂CO₃) as auxiliary base in these C−C coupling cascade reactions led exclusively to six‐membered ring annulation, while the use of organic base diazabicycloundecene (DBU) afforded the corresponding five‐membered ring annulated products. This base‐dependent selective mode of annulation is attributed to different mechanistic pathways directed by the applied base. The selective annulation was revealed by single crystal X‐ray analysis of the respective five‐ and six‐membered ring annulated products. The optical and redox properties of the new polycyclic aromatic dicarboximides were characterized by UV/Vis absorption and fluorescence spectroscopy and cyclic voltammetry.     

Carbaborane‐Substituted 1,2,3‐Triphospholanes and 1‐Aza‐2,5‐diphospholane: New Synthetic Approaches

New phosphorus‐containing, five‐membered P,P,P and P,N,P heterocycles were synthesized and fully characterized. The P,P,P heterocycles, 1,2,3‐triphospholanes, can be synthesized by two different facile pathways, whereas the P,N,P compound, a 1‐aza‐2,5‐diphospholane, can only be obtained with silylamine.     

Synthesis of Organofluoro Compounds Using Methyl Perfluoroalk‐2‐ynoates as Building Blocks

This review provides an overview of several synthetic applications of methyl perfluoroalk‐2‐ynoates, leading to convenient preparation of many perfluoroalkylated compounds. The use of these important substrates in the synthesis of various five‐, six‐, and seven‐membered heterocycles, cyclopentadienes, and biphenyls is described, alongside a discussion of the mechanistic aspects of these reactions.     

Synthesis of biologically active phosphorus heterocycles via cyclization reactions of Lawesson's reagent

2,4‐Bis(4‐methoxyphenyl)‐1,3,2,4‐dithiaphosphetane‐2,4‐disulfide (Lawesson's reagent, LR) reacted with certain bifunctional compounds, such as glycinamides 1, 1‐glyceryl monoesters 4, and 3‐mercapto‐4‐amino‐5‐substituted‐1,2,4‐triazoles 6, to yield five‐membered phosphorus heterocycles 3,5, and 7, respectively. The cycloaddition reaction of LR with 1,3‐butadiene 8 was investigated to form the six‐membered heterocycle 9. The results of preliminary bioassays showed that these heterocycles obtained via cyclization reactions of LR possess significant selective herbicidal activity. The QSAR of 3 was also made. In conclusion, the cyclization reactions of LR with bifunctional substrates and 1,3‐dienes afford novel routes to the syntheses of biologically active phosphorus heterocycles. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 105–111, 1999     

Controlled Heterocyclization/Cross‐Coupling Domino Reaction of β,γ‐Allendiols and α‐Allenic Esters: Method and Mechanistic Insight for the Preparation of Functionalized Buta‐1,3‐dienyl Dihydropyrans

Starting from β,γ‐allendiols and α‐allenic acetates, a chemo‐ and regiocontrolled palladium‐catalyzed methodology has provided access to enantiopure 3,6‐dihydropyrans that bear a buta‐1,3‐dienyl moiety. Thus, it has been demonstrated for the first time that the preparation of six‐membered heterocycles through cross‐coupling reactions of two different allenes can be accomplished. These heterocyclization/cross‐coupling reactions have been developed experimentally and their mechanisms have additionally been investigated by a computational study.     

Ruthenium‐Catalyzed C−C Bond Cleavage of 2H‐Azirines: A Formal [3+2+2] Cycloaddition to Fused Azepine Skeletons

2H‐azirines can serve as three‐atom synthons by C?C bond cleavage, however, it involves a high energy barrier under thermal conditions (>50.0 kcal mol^?1). Reported is a ruthenium‐catalyzed [3+2+2] cycloaddition reaction of 2H‐azirines with diynes, thus leading to the formation of fused azepine skeletons. This approach features an unprecedented metal‐catalyzed C?C bond cleavage of 2H‐azirines at room temperature, and the challenging construction of aza‐seven‐membered rings from diynes. The results of this study provide a new reaction pattern for constructing nitrogen‐containing seven‐membered rings and may find applications in the synthesis of other complex heterocycles.     

Benign Approaches for the Microwave‐assisted Synthesis of Five‐membered 1,2‐N,N‐heterocycles

The development of new strategies for the synthesis of small‐sized heterocycles has remained a highly attractive but challenging proposition. An overview of the application of microwave irradiation in the synthesis of two nitrogen atoms containing five‐membered heterocyclic compounds is presented, focusing on the developments in the last 5–10 years. This contribution covers the literature concerning the total synthesis of five‐membered 1,2‐N,N‐heterocycles.     

Ladder‐Type π‐Conjugated 4‐Hetero‐1,4‐dihydrophosphinines: A Structure–Property Study

π‐Conjugated six‐membered 1,4‐dihydrophosphinines containing a heteroatom (Si, P, S) at the 4 position were synthesized and systematically studied. X‐ray crystallographic analyses showed that the central six‐membered heterocyclic rings are almost planar. The sum of the angles around the phosphorus atom increases by 23° from the trivalent phosphorus to the phosphonium atom in the thiaphosphinine system, which is consistent with the NMR spectroscopic studies. UV/Vis spectroscopy and theoretical calculations revealed that the communication between the phosphorus center and the benzothiophene moiety is enhanced by the incorporation of a sulfur atom into the molecular scaffold. The increased conjugation endows the thiaphosphinines with interesting emission properties. Theoretical calculations supported the postulation that the orbital coupling between the π system and a σ* orbital could be enhanced in the thiaphosphinine system, especially through a phosphonium center. Cyclic voltammetry studies revealed that the thiaphosphinine oxide, thiaphosphonium, and cis‐diphosphinine oxide exhibit quasi‐reversible reduction processes, which demonstrate that simple changes in the bridge heteroatoms help to efficiently tune the redox properties of the ladder‐type 4‐hetero‐1,4‐dihydrophosphinines.     

Synthesis of Three‐Membered and Four‐Membered Heterocycles with the Assistance of Photochemical Reactions

Some transformations are not possible with ground‐state reactions even in the presence of a catalyst; hence, they are performed under photochemical conditions. Electron transfer occurred even with the photochemical excitement of one molecule where redox reaction is not possible at the ground state. The side products were obtained from ground‐state reactions. For C─C bond formation during photochemical reactions, there was no requirement of any chemical activation of the substrates. Therefore, these reactions are presented here for the synthesis of three‐membered and four‐membered heterocycles in the context of sustainable processes.     

Design of Trifluoroalkenyl Iodonium Salts for a Hypervalency‐Aided Alkenylation–Cyclization Strategy: Metal‐Free Construction of Aziridine Rings

The synthesis of fluorinated compounds and their use as pharmaceutical ingredients or synthetic building blocks have been in the focus of chemical and medicinal research. However, the efficient synthesis of trifluoromethylated nitrogen heterocycles is sometimes challenging. Herein, we disclose a simple aziridination process that relies on the use of amines and novel alkenyl iodonium reagents for the synthesis of strained, trifluoromethylated heterocycles. With the utilization of a newly designed and bench‐stable but highly reactive hypervalent alkenyl iodonium species, these three‐membered‐ring heterocyclic compounds can be efficiently constructed from simple amines under mild conditions in the absence of transition‐metal catalysts. The special reactivity of the new trifluoropropenyl synthon towards nucleophilic centers could be exploited in more general cyclization and alkenylation reactions in the future.     

Reagent‐Based DOS: Developing a Diastereoselective Methodology to Access Spirocyclic‐ and Fused Heterocyclic Ring Systems

Herein, we report a diversity‐oriented‐synthesis (DOS) approach for the synthesis of biologically relevant molecular scaffolds. Our methodology enables the facile synthesis of fused N‐heterocycles, spirooxoindolones, tetrahydroquinolines, and fused N‐heterocycles. The two‐step sequence starts with a chiral‐bicyclic‐lactam‐directed enolate‐addition/substitution step. This step is followed by a ring‐closure onto the built‐in scaffold electrophile, thereby leading to stereoselective carbocycle‐ and spirocycle‐formation. We used in silico tools to calibrate our compounds with respect to chemical diversity and selected drug‐like properties. We evaluated the biological significance of our scaffolds by screening them in two cancer cell‐lines. In summary, our DOS methodology affords new, diverse scaffolds, thereby resulting in compounds that may have significance in medicinal chemistry.