Radical Cyclization/ipso‐1,4‐Aryl Migration Cascade: Asymmetric Synthesis of 3,3‐Difluoro‐2‐propanoylbicyclo[3.3.0]octanes

A novel method for the asymmetric synthesis of 3,3‐difluoro‐2‐propanoylbicyclo‐[3.3.0]octanes involves an unprecedented intramolecular radical cyclization/ipso‐1,4‐aryl migration cascade.     

Synthesis of C2 Substituted Benzothiophenes via an Interrupted Pummerer/[3,3]‐Sigmatropic/1,2‐Migration Cascade of Benzothiophene S‐Oxides

Functionalized benzothiophenes are important scaffolds found in molecules with wide ranging biological activity and in organic materials. We describe an efficient, metal‐free synthesis of C2 arylated, allylated, and propargylated benzothiophenes. The reaction utilizes synthetically unexplored yet readily accessible benzothiophene S‐oxides and phenols, allyl‐, or propargyl silanes in a unique cascade sequence. An interrupted Pummerer reaction between benzothiophene S‐oxides and the coupling partners yields sulfonium salts that lack aromaticity and therefore allow facile [3,3]‐sigmatropic rearrangement. The subsequently generated benzothiophenium salts undergo a previously unexplored 1,2‐migration to access C2 functionalized benzothiophenes.     

One‐Pot Synthesis of Pyrazoles through a Four‐Step Cascade Sequence

A one‐pot synthesis of 3,4,5‐ and 1,3,5‐pyrazoles from tertiary propargylic alcohols and para‐tolylsulfonohydrazide has been accomplished. The pyrazoles are formed through a four‐step cascade sequence, including FeCl₃‐catalyzed propargylic substitution, aza‐Meyer–Schuster rearrangement, base‐mediated 6π electrocyclization, and thermal [1,5] sigmatropic shift. In this reaction, the 3,4,5‐ and 1,3,5‐pyrazoles are produced selectively according to different substituents in the starting alcohols.     

Highly Enantioselective Construction of Strained Spiro[2,3]hexanes through a Michael Addition/Ring Expansion/Cyclization Cascade

We herein report a general organocatalytic enantioselective strategy for the construction of highly strained spiro[2,3]hexane skeletons from methylenecyclopropanes and a broad selection of α,β‐unsaturated aldehydes. The reaction proceeds through a Michael addition followed by ring expansion of methylenecyclopropanes and nucleophilic attack of an enamine to realize the construction of spiro[2,3]hexanes. Key to the success of this approach are the utilization of an electron‐deficient difluoro‐substituted secondary amine catalyst and the intrinsic reactivity of methylenecyclopropanes.     

Single‐Electron/Pericyclic Cascade for the Synthesis of Dienes

The highly efficient and diastereoselective synthesis of E dienes has been accomplished through radical cyclization of bromoallyl hydrazones. This methodology has been further extended to generate these products through a one‐pot condensation/radical cyclization/cycloreversion cascade from simple aldehyde starting materials in high yields (>75 %) and high diastereoselectivities (>95:5). Mechanistic investigations suggest that the cascade reaction proceeds through a cyclic diazene intermediate prior to the cycloreversion.     

Programming Organic Molecules: Design and Management of Organic Syntheses through Free‐Radical Cascade Processes

Cascade, domino, or tandem processes, that link together two or more transformations in one pot, are increasing in popularity because they lead to improvements in synthetic efficiency and decreases in environmental impact. Not only do these cascades contain choice mechanistic gems but they also deliver compact and elegant syntheses of complex natural products. Longer cascades require more functional groups precisely configured within carefully designed initial molecular architectures. Such “purposeful” molecules can be thought of as chemical algorithms.This article surveys the phenomenal range of unimolecular free‐radical cascades. A convenient system for classifying free‐radical cascades is described that is useful for evaluating and comparing cascades and aids the design of synthetic routes to polycyclic structures.Double cyclization cascades lead to cyclopentylcyclopentane or bicyclo[3.3.0]octane derivatives. Precursors that contain a ring as a template have been used to control stereochemistry in syntheses of triquinanes and many related compounds. Of the cascades containing ring‐cleavage steps, the most useful are the ring expansions which have opened up new synthetic routes to medium ring polycycles.The key design features of three‐stage unimolecular free‐radical cascades that yielded steroid structures, are linear arrays of radical acceptor units associated with methyl groups distributed every fifth C‐atom in the precursor polyenes. Ring cleavage is the reverse of cyclization. In special, symmetrical structures, therefore, this led to sequences that were reversible, thus launching endlessly repeating cascades supported by delightfully fluxional structures. The science of “programming” organic molecules to achieve particular target structures is maturing rapidly. Coordination and classification of the welter of information in this area is intended to facilitate design and hence to extend the range and complexity of attainable structures.     

[3,3]‐Sigmatropic Rearrangement/Allylboration/Cyclization Sequence: Enantioenriched Seven‐Membered‐Ring Carbamates and Ring Contraction to Pyrrolidines

The combination of in situ generated α‐isocyanato allylboronic esters and aldehydes afforded seven‐membered‐ring enecarbamates with high levels of diastereo‐ and enantiocontrol. They were easily converted into diversely substituted 1,3‐oxazepan‐2‐ones. An unprecedented rearrangement of 5‐acetoxy‐7‐aryl or styryl derivatives led to tetrasubstituted pyrrolidines. A computational study provides evidence on the feasibility of the proposed mechanism of this unusual ring contraction.     

Tandem Double‐Michael‐Addition/Cyclization/Acyl Migration of 1,4‐Dien‐3‐ones and Ethyl Isocyanoacetate: Stereoselective Synthesis of Pyrrolizidines

Up to four adjacent stereocenters can be formed stereoselectively in the construction of a pyrrolizidine unit through a novel organocatalytic reaction that involves treatment of various dienones with ethyl isocyanoacetate (see scheme; DBU=1,8‐diazabicyclo[5.4.0]undec‐7‐ene). Mechanisms for this atom‐economic, one‐pot synthesis have been proposed.

     

Domino Radical Addition/Oxidation Sequence with Photocatalysis: One‐Pot Synthesis of Polysubstituted Furans from α‐Chloro‐Alkyl Ketones and Styrenes

A new domino reaction has been developed that allows the combination of styrenes and α‐alkyl ketone radicals to afford a wide array of polysubstituted furans in good to excellent yields under mild and simple reaction conditions. The key to success of this novel protocol is the use of photocatalyst fac‐Ir(ppy)₃ and oxidant K₂S₂O₈. Mechanistic studies by a radical scavenger and photoluminescence quenching suggest that a radical addition/oxidation pathway is operable.     

A Visible‐Light‐Mediated Radical Smiles Rearrangement and its Application to the Synthesis of a Difluoro‐Substituted Spirocyclic ORL‐1 Antagonist

A visible‐light‐mediated radical Smiles rearrangement has been developed to address the challenging synthesis of the gem‐difluoro group present in an opioid receptor‐like 1 (ORL‐1) antagonist that is currently in development for the treatment of depression and/or obesity. This method enables the direct and efficient introduction of the difluoroethanol motif into a range of aryl and heteroaryl systems, representing a new disconnection for the synthesis of this versatile moiety. When applied to the target compound, the photochemical step could be conducted on 15 g scale using industrially relevant [Ru(bpy)₃Cl₂] catalyst loadings of 0.01 mol %. This transformation is part of an overall five‐step route to the antagonist that compares favorably to the current synthetic sequence and demonstrates, in this specific case, a clear strategic benefit of photocatalysis.     

Facile Assembly of Benzo[b]naphtho[2,3‐d]azocin‐6(5 H)‐ones by a Palladium‐Catalyzed Double Carbometalation

The palladium‐catalyzed reaction of 2‐alkynylanilines with 2‐(2‐bromobenzylidene)cyclobutanone as an efficient route to 7,8‐dihydrobenzo[b]naphtho[2,3‐d]azocin‐6(5 H)‐ones was developed. The fused eight‐membered ring was constructed conveniently. During the reaction process, double carbometalation was involved, which resulted in excellent selectivity with the formation of three new bonds. This transformation is highly efficient and leads to fused polycycles in good to excellent yields with good functional group tolerance.     

Visible‐Light Photoredox Catalysis: Direct Synthesis of Sulfonated Oxindoles from N‐Arylacrylamides and Arylsulfinic Acids by Means of a Cascade C−S/C−C Formation Process

A novel photocatalytic synthesis of sulfonated oxindoles from N‐arylacrylamides and arylsulfinic acids was developed by means of a cascade C?S/C?C bond‐formation process. This method provides mild, efficient, and atom‐economical access to various sulfonated oxindoles in water.     

Conjugated Dienyne‐Imides as Robust Precursors of 1‐Azatrienes for 6π Electrocyclizations to Furo[2,3‐b]dihydropyridine Cores

A novel strategy to generate functionalized 1‐azatriene intermediates for 6π electrocyclizations was developed by using readily accessible dienyne‐imides and various terminal olefins under Pd^II catalysis. Taking advantage of the sequential cooperation between preloaded and incorporated functional handles at 1,3‐dien‐5‐yne skeletons, this method not only enables the selective generation of putative 1‐azatrienes but significantly accelerates their thermal 6π‐electrocyclic ring‐closure processes to a series of highly substituted furo[2,3‐b]dihydropyridine derivatives in good yields.     

Recent Advances in the Synthesis of Indole and Quinoline Derivatives through Cascade Reactions

One right after the other : Cascade reactions represent an efficient method for accessing highly functionalized final products from simple starting materials in a single synthetic operation. This Focus Review surveys the most representative and interesting recent reports on the synthesis of indoles and quinolines through cascade reactions.