The design and implementation of cascade reactions is a challenging facet of organic chemistry, yet one that can impart striking novelty, elegance, and efficiency to synthetic strategies. The application of cascade reactions to natural products synthesis represents a particularly demanding task, but the results can be both stunning and instructive. This Review highlights selected examples of cascade reactions in total synthesis, with particular emphasis on recent applications therein. The examples discussed herein illustrate the power of these processes in the construction of complex molecules and underscore their future potential in chemical synthesis.

Cascade reactions in total synthesis.

Palladium-catalyzed amination reactions of aryl halides have undergone rapid development in the last 12 years, largely driven by the implementation of new classes of ligands. Biaryl phosphanes have proven to provide especially active catalysts in this context. This Review discusses the application of these catalysts in C-N cross-coupling reactions in the synthesis of heterocycles and pharmaceuticals, in materials science, and in natural product synthesis.

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Biaryl Phosphane Ligands in Palladium‐Catalyzed Amination

C–H activation has surfaced as an increasingly powerful tool for molecular sciences, with notable applications to material sciences, crop protection, drug discovery, and pharmaceutical industries, among others. Despite major advances, the vast majority of these C–H functionalizations required precious 4d or 5d transition metal catalysts. Given the cost-effective and sustainable nature of earth-abundant first row transition metals, the development of less toxic, inexpensive 3d metal catalysts for C–H activation has gained considerable recent momentum as a significantly more environmentally-benign and economically-attractive alternative. Herein, we provide a comprehensive overview on first row transition metal catalysts for C–H activation until summer 2018.

3d Transition Metals for C-H Activation.

Fraser F. Fleming,* Lihua Yao, P. C. Ravikumar, Lee Funk, and Brian C. Shook Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, Pennsylvania 15282-1530, Mylan Pharmaceuticals Inc., 781 Chestnut Ridge Road, Morgantown, West Virginia 26505, and Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Welsh and McKean Roads, P.O. Box 776, Spring House, Pennsylvania 19477

Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore

A simple and mild strategy for the direct trifluoromethylation of unactivated arenes and heteroarenes that acts via a radical-mediated mechanism and uses commercial photocatalysts. Premature metabolic decomposition can stop potentially promising drugs from reaching their intended targets. One way of blocking this metabolism involves the addition of a trifluoromethyl (CF3) group to aromatic or heteroaromatic moieties in a candidate drug molecule. David Nagib and David MacMillan report a new method for this synthesis that is more economical than current methods in terms of both raw materials and energy input. They use an energy-saving compact fluorescent light bulb to excite a variety of commercially available photocatalysts, which promote the addition of CF3 to unactivated arenes and heteroarenes through a radical-mediated mechanism. The potential of the method is demonstrated by the trifluoromethylation of three molecules: a uracil analogue, a precursor of the acetylcholinesterase inhibitor donepezil and a vitamin (flavone). Modern drug discovery relies on the continual development of synthetic methodology to address the many challenges associated with the design of new pharmaceutical agents1. One such challenge arises from the enzymatic metabolism of drugs in vivo by cytochrome P450 oxidases, which use single-electron oxidative mechanisms to rapidly modify small molecules to facilitate their excretion2. A commonly used synthetic strategy to protect against in vivo metabolism involves the incorporation of electron-withdrawing functionality, such as the trifluoromethyl (CF3) group, into drug candidates3. The CF3 group enjoys a privileged role in the realm of medicinal chemistry because its incorporation into small molecules often enhances efficacy by promoting electrostatic interactions with targets, improving cellular membrane permeability, and increasing robustness towards oxidative metabolism of the drug4,5,6. Although common pharmacophores often bear CF3 motifs in an aromatic system, access to such analogues typically requires the incorporation of the CF3 group, or a surrogate moiety, at the start of a multi-step synthetic sequence. Here we report a mild, operationally simple strategy for the direct trifluoromethylation of unactivated arenes and heteroarenes through a radical-mediated mechanism using commercial photocatalysts and a household light bulb. We demonstrate the broad utility of this transformation through addition of CF3 to a number of heteroaromatic and aromatic systems. The benefit to medicinal chemistry and applicability to late-stage drug development is also shown through examples of the direct trifluoromethylation of widely prescribed pharmaceutical agents.

/pdf/trifluoromethylation-of-arenes-and-heteroarenes-by-means-of-3c3fkdyt4x.pdf

Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis

The demonstration of protein sequence and functional homology of the Caenorhabditis elegans programmed cell death gene product, CED-3, with human caspase-1 in 1993 triggered an explosion of research activities toward the understanding of molecular mechanisms of apoptosis. During the past 15 years, a plethora of knowledge has been obtained on the mammalian caspases, the homologs of CED-3, with regard to their distinct physiological functions, their substrates, different activation mechanisms, the signal transduction pathways that lead to their activation as well as their involvement in the pathogenesis of diseases. Such knowledge is beginning to be translated into new therapies for the treatment of human diseases.

Caspases in apoptosis and beyond.

Foreword Preface Contributing Authors PART 1 THREE- AND FOUR-MEMBERED HETEROCYCLES Chapter 1 Aziridines and Epoxides 11 Blum Aziridine Synthesis 12 Gabriel Heine Aziridine Isomerization 13 Shi Epoxidation PART 2 FIVE-MEMBERED HETEROCYCLES Chapter 2 Pyrroles and Pyrrolidines 21 Clauson Kass Pyrrole Synthesis 22 Houben Hoech Acylation of Pyrroles 23 Overman Pyrrolidine Synthesis 24 Trofimov Synthesis of Pyrroles Chapter 3 Indoles 31 Bischler Mohlau Indole Synthesis 32 Borsche Drechsel Cyclization 33 Buchwald Hartwig Indole Synthesis 34 Cadogan Sundberg Indole Synthesis 35 Fukuyama Indole Synthesis 36 Gassman Oxindole Synthesis 37 Larock Indole Synthesis 38 Matinet Dioxindole Synthesis 39 Mori Ban Indole Synthesis 310 Sandmeyer Isatin Synthesis 311 Sommelet Hauser Rearrangement 312 Stolle Oxindole Synthesis Chapter 4 Furans and Oxazoles 41 Nierenstein Reaction 42 Davidson Oxazole Synthesis 43 Fischer Oxazole Synthesis 44 Japp Oxazole Synthesis 45 Schollkopf Oxazole Synthesis Chapter 5 Other Five-Membered Heterocycles 51 Bamberger Imidazole Cleavage 52 Dimroth Triazole Synthesis 53 Finnegan Tetrazole Synthesis 54 Hantsch Thiazole Synthesis 55 Huisgen Tetrazole Rearrangement 56 Knorr Pyrazole Synthesis 57 Pechmann Pyrazole Synthesis PART 3 SIX-MEMBERED HETEROCYCLES Chapter 6 Pyridines 61 Baeyer Pyridine Synthesis 62 Katrizky Reaction Chapter 7 Quinolines and Isoquinolines 71 Betti reaction 72 Bernthsen Acridine Synthesis 73 Lehmstedt Tanasescu Reaction 74 Niementowski Quinoline Synthesis 75 Povarov Reaction Chapter 8 Six-Membered Heterocycles 81 Balaban Nenitzescu Praill Reaction 82 Borsche Cinnoline Synthesis 83 Gutknecht Pyrazine Synthesis 84 Niementowski Quinazoline Synthesis 85 Pechmann Coumarin Synthesis 86 Robinson Schopf Condensation 87 Simonis Chromone Cyclization 88 Wesseley Moser Rearrangement 89 Widman Stoermer Cinnoline Synthesis 810 Wichterle Reaction Chapter 9 Miscellaneous Name Reactions 91 ANRORC Mechanism 92 Boulton Katritzky Rearrangement 93 Chichibabin Amination Reaction 94 Dimroth Rearrangement 95 Hantzsch Synthesis 96 Ortoleva King Reaction Appendices Appendix 1, Table of Contents for Volume 1: Name Reactions in Heterocyclic Chemistry Appendix 2, Table of Contents for Volume 2: Name Reactions for Functional Group Transformations Appendix 3, Table of Contents for Volume 3: Name Reactions for Homologations-I Appendix 4, Table of Contents for Volume 4: Name Reactions for Homologations-II Appendix 5, Table of Contents for Volume 5: Name Reactions for Ring Formations

Name reactions in heterocyclic chemistry

Alder ene reaction -- Aldol condensation -- Algar-Flynn-Oyamada Reaction -- Allan-Robinson reaction -- Appel reaction -- Arndt-Eistert homologation -- Baeyer-Villiger oxidation -- Baker-Venkataraman rearrangement -- Bamberger rearrangement -- Bamford-Stevens reaction -- Barbier coupling reaction -- Bargellini reaction -- Bartoli indole synthesis -- Barton radical decarboxylation -- Barton-McCombie deoxygenation -- Barton nitrite photolysis -- Barton-Zard reaction -- Batcho-Leimgruber indole synthesis -- Baylis-Hillman reaction -- Beckmann rearrangement -- Beirut reaction -- Benzilic acid rearrangement -- Benzoin condensation -- Bergman cyclization -- Biginelli pyrimidone synthesis -- Birch reduction -- Bischler-Mohlau indole synthesis -- Bischler-Napieralski reaction -- Blaise reaction -- Blanc chloromethylation -- Blum aziridine synthesis -- Boekelheide reaction -- Boger pyridine synthesis -- Borch reductive amination -- Borsche-Drechsel cyclization -- Boulton-Katritzky rearrangement -- Bouveault aldehyde synthesis -- Bouveault-Blanc reduction -- Boyland-Sims oxidation -- Bradsher reaction -- Brook rearrangement -- Brown hydroboration -- Bucherer carbazole synthesis -- Bucherer reaction -- Bucherer-Bergs reaction -- Buchner-Curtius-Schlotterbeck reaction -- Buchner method of ring expansion -- Buchwald-Hartwig C-N and C-O bond formation reactions -- Burgess dehydrating reagent -- Cadiot-Chodkiewicz coupling -- Camps quinolinol synthesis -- Cannizzaro disproportionation -- Carroll rearrangement -- Castro-Stephens coupling -- Chan alkyne reduction -- Chan-Lam coupling reaction -- Chapman rearrangement -- Chichibabin pyridine synthesis -- Chugaev elimination -- Ciamician-Dennsted rearrangement -- Claisen condensation -- Claisen isoxazole synthesis -- Claisen rearrangements -- Clemmensen reduction -- Combes quinoline synthesis -- Conrad-Limpach reaction -- Cope elimination reaction -- Cope rearrangement -- Corey-Bakshi-Shibata (CBS) reduction -- Corey-Chaykovsky reaction -- Corey-Fuchs reaction -- Corey-Kim oxidation -- Corey-Nicolaou macrolactonization -- Corey-Seebach reaction -- Corey-Winter olefin synthesis -- Criegee glycol cleavage -- Criegee mechanism of ozonolysis -- Curtius rearrangement -- Dakin oxidation -- Dakin-West reaction -- Danheiser annulation -- Darzens glycidic ester condensation -- Davis chiral oxaziridine reagents -- Delepine amine synthesis -- de Mayo reaction -- Demjanov rearrangement -- Dess-Martin periodinane oxidation -- Dieckmann condensation -- Diels-Alder reaction -- Dienone-phenol rearrangement -- Di-?-methane rearrangement -- Doebner quinoline synthesis -- Dotz reaction -- Dowd-Beckwith ring expansion -- Erlenmeyer-Plochl azlactone synthesis -- Eschenmoser-Tanabe fragmentation -- Eschweiler-Clarke reductive alkylation of amines -- Evans aldol reaction -- Favorskii rearrangement and quasi-Favorskii rearrangement -- Feist-Benary furan synthesis -- Ferrier carbocyclization -- Ferrier glycal allylic rearrangement -- Fiesselmann thiophene synthesis -- Fischer indole synthesis -- Fischer oxazole synthesis -- Fleming-Kumada oxidation -- Friedel-Crafts reaction -- Friedlander quinoline synthesis -- Fries rearrangement -- Fukuyama amine synthesis -- Fukuyama reduction -- Gabriel synthesis -- Gabriel-Colman rearrangement -- Gassman indole synthesis -- Gattermann-Koch reaction -- Gewald aminothiophene synthesis -- Glaser coupling -- Gomberg-Bachmann reaction -- Gould-Jacobs reaction -- Grignard reaction -- Grob fragmentation -- Guareschi-Thorpe condensation -- Hajos-Wiechert reaction -- Haller-Bauer reaction -- Hantzsch dihydropyridine synthesis -- Hantzsch pyrrole synthesis -- Heck reaction -- Hegedus indole synthesis -- Hell-Volhard-Zelinsky reaction -- Henry nitroaldol reaction -- Hinsberg synthesis of thiophene derivatives -- Hiyama cross-coupling reaction -- Hofmann rearrangement -- Hofmann-Loffler-Freytag reaction -- Horner-Wadsworth-Emmons reaction -- Houben-Hoesch reaction -- Hunsdiecker-Borodin reaction -- Hurd-Mori 1,2,3-thiadiazole synthesis -- Jacobsen-Katsuki epoxidation -- Japp-Klingemann hydrazone synthesis -- Jones oxidation -- Julia-Kocienski olefination -- Julia-Lythgoe olefination -- Kahne-Crich glycosidation -- Keck macrolactonization -- Knoevenagel condensation -- Knorr pyrazole synthesis -- Koch-Haaf carbonylation -- Koenig-Knorr glycosidation -- Kolbe-Schmitt reaction -- Kostanecki reaction -- Krohnke pyridine synthesis -- Kumada cross-coupling reaction -- Lawesson’s reagent -- Leuckart-Wallach reaction -- Lossen rearrangement -- McFadyen-Stevens reduction -- McMurry coupling -- MacMillan catalyst -- Mannich reaction -- Marshall boronate fragmentation -- Martin’s sulfurane dehydrating reagent -- Masamune-Roush conditions -- Meerwein-Ponndorf-Verley reduction -- Meisenheimer complex -- [1,2]-Meisenheimer rearrangement -- [2,3]-Meisenheimer rearrangement -- Meth-Cohn quinoline synthesis -- Meyers oxazoline method -- Meyer-Schuster rearrangement -- Michael addition -- Michaelis-Arbuzov phosphonate synthesis -- Midland reduction -- Mislow-Evans rearrangement -- Mitsunobu reaction -- Miyaura borylation -- Moffatt oxidation -- Montgomery coupling -- Morgan-Walls reaction -- Mori-Ban indole synthesis -- Mukaiyama aldol reaction -- Mukaiyama Michael addition -- Mukaiyama reagent -- Myers-Saito cyclization -- Nazarov cyclization -- Neber rearrangement -- Nef reaction -- Negishi cross-coupling reaction -- Nenitzescu indole synthesis -- Nicholas reaction -- Nicolaou dehydrogenation -- Nicolaou hydroxy-dithioketal cyclization -- Nicolaou hydroxy-ketone reductive cyclic ether formation -- Nicolaou oxyselenation -- Noyori asymmetric hydrogenation -- Nozaki-Hiyama-Kishi reaction -- Oppenauer oxidation -- Overman rearrangement -- Paal thiophene synthesis -- Paal-Knorr furan synthesis -- Parham cyclization -- Passerini reaction -- Paterno-Buchi reaction -- Pauson-Khand cyclopentenone synthesis -- Payne rearrangement -- Pechmann coumarin synthesis -- Perkin reaction -- Petasis reaction -- Peterson olefination -- Pictet-Gams isoquinoline synthesis -- Pictet-Spengler tetrahydroisoquinoline synthesis -- Pinacol rearrangement -- Pinner reaction -- Polonovski reaction -- Polonovski-Potier reaction -- Pomeranz-Fritsch reaction -- Prevost trans-dihydroxylation -- Prins reaction -- Pschorr cyclization -- Pummerer rearrangement -- Ramberg-Backlund reaction -- Reformatsky reaction -- Regitz diazo synthesis -- Reimer-Tiemann reaction -- Reissert aldehyde synthesis -- Reissert indole synthesis -- Ring-closing metathesis (RCM) -- Ritter reaction -- Robinson annulation -- Robinson-Gabriel synthesis -- Robinson-Schopf reaction -- Rosenmund reduction -- Rubottom oxidation -- Rupe rearrangement -- Saegusa oxidation -- Sakurai allylation reaction -- Sandmeyer reaction -- Schiemann reaction -- Schmidt reaction -- Schmidt’s trichloroacetimidate glycosidation reaction -- Shapiro reaction -- Sharpless asymmetric amino hydroxylation -- Sharpless asymmetric epoxidation -- Sharpless asymmetric dihydroxylation -- Sharpless olefin synthesis -- Simmons-Smith reaction -- Skraup quinoline synthesis -- Smiles rearrangement -- Sommelet reaction -- Sommelet-Hauser rearrangement -- Sonogashira reaction -- Staudinger ketene cycloaddition -- Staudinger reduction -- Sternbach benzodiazepine synthesis -- Stetter reaction -- Still-Gennari phosphonate reaction -- Stille coupling -- Stille-Kelly reaction -- Stobbe condensation -- Stork enamine reaction -- Strecker amino acid synthesis -- Suzuki coupling -- Swern oxidation -- Takai iodoalkene synthesis -- Tebbe olefination -- TEMPO-mediated oxidation -- Thorpe-Ziegler reaction -- Tsuji-Trost reaction -- Ugi reaction -- Ullmann reaction -- van Leusen oxazole synthesis -- Vilsmeier-Haack reaction -- Vilsmeier mechanism for acid chloride formation -- Vinylcyclopropane-cyclopentene rearrangement -- von Braun reaction -- Wacker oxidation -- Wagner-Meerwein rearrangement -- Weiss-Cook reaction -- Wharton oxygen transposition reaction -- Willgerodt-Kindler reaction -- Wittig reaction -- [1,2]-Wittig rearrangement -- [2,3]-Wittig rearrangement -- Wohl-Ziegler reaction -- Wolff rearrangement -- Wolff-Kishner reduction -- Yamaguchi esterification -- Zincke reaction.

Name Reactions: A Collection of Detailed Reaction Mechanisms

After an inordinately long induction period, organopalladium chemistry has finally been embraced by synthetic organic chemists Currently, it is being utilized across the spectrum of organic synthesis, from applications to complex natural product syntheses to the synthesis of polymers A substantial portion of organopalladium methodology has been developed in the context of heterocyclic chemistry and applications to heterocyclic syntheses abound In this new book, Jack Li and Gordon Gribble have compiled an array of referenced examples of the use of palladium in heterocyclic chemistry The book is organized by class of heterocycle (pyrroles, indoles, pyridines, etc) and each chapter contains the syntheses of heterocyclic precursors, as well as details of uses of palladium to both synthesize and functionalize these heterocyclic systems

http://www.dlfiles24.com/pdf92/158307369-palladium_in_heterocyclic_chemistry_a_guide_for_the_synthetic_chemist.pdf

Palladium in Heterocyclic Chemistry: A Guide for the Synthetic Chemist

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Jie Jack Li

Papers

Caspases in apoptosis and beyond.

Name reactions in heterocyclic chemistry

Name Reactions: A Collection of Detailed Reaction Mechanisms

Palladium in Heterocyclic Chemistry: A Guide for the Synthetic Chemist

Heterocyclic Chemistry in Drug Discovery