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2016

Continuous flow synthesis of heterocyclic scaffolds. Design principles of multistep systems – A review, Klára Lövei, Péter Bana, Róbert Örkényi, György I. Túrós, János Éles, Zoltán Novák, Ferenc Faigl, Chim. Oggi Chem. Today, 2016, 34, 18-21. Link

KEYWORDS: Continuous flow synthesis, condensed heterocycles, scaffold, multistep flow synthesis, telescoping.

ABSTRACT: The synthesis of novel heterocycles is an essential task in small-molecule drug discovery. Continuous flow processing opens the way for a new paradigm in laboratory-scale synthesis as well as pharmaceutical manufacturing. Based on our experiences with the multistep synthesis of condensed benzothiazoles, we gathered some of the key design features in light of literature examples.

Recent advances in dual transition metal–visible light photoredox catalysisBalázs L. Tóth, Orsolya Tischler,  Zoltán Novák, Tetrahedron Lett. 2016, 57, 4505–4513. DOI: 10.1016/j.tetlet.2016.08.081 |

In this Digest Letter, we collected and shortly summarized the recently developed dual transition metal–visible light photoredox catalytic processes including arylation, alkynylation, alkenylation, allylation, alkylation, fluoroalkylation, benzylation, acylation, and cyclization reactions. The utilization of multimetallic catalytic systems provides new synthetic strategies for the synthesis and functionalization of versatile and novel organic compounds.

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Understanding and Exploitation of Neighboring Heteroatom Effect for the Mild N‑Arylation of Heterocycles with Diaryliodonium Salts under Aqueous Conditions: A Theoretical and Experimental Mechanistic Study, Tamás Bihari, Bence Babinszki, Zsombor Gonda, Szabolcs Kovács, Zoltán Novák, András Stirling, J. Org. Chem. 2016, 81, 5417-5422. DOI: 10.1021/acs.joc.6b00779 | [Full Text Link] [Supp. Info. Link]

The mechanism of arylation of N-heterocycles with unsymmetric diaryliodonium salts is elucidated. The fast and efficient N-arylation reaction is interpreted in terms of the bifunctionality of the substrate: The consecutive actions of properly oriented Lewis base and Brønsted acid centers in sufficient proximity result in the fast and efficient N-arylation. The mechanistic picture points to a promising synthetic strategy where suitably positioned nucleophilic and acidic centers enable functionalization, and it is tested experimentally.

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Diaryliodonium Salts in Organic Syntheses: A Useful Compound Class for Novel Arylation Strategies, Klára Aradi, Balázs L. Tóth, Gergely L. Tolnai, Zoltán Novák, Synlett 2016, 27, 1456-1485. DOI: 10.1055/s-0035-1561369 | [Full Text Link]

Keywords: arylation - diaryliodonium salts - hypervalent iodine reagents - metal-free - copper-catalyzed - palladium-catalyzed - C–H activation - direct functionalization

This account aims to give a description of the usefulness of diaryliodonium salts in organic chemistry, including their synthesis and applications in the presence and absence of transition-metal catalysts. Herein, we briefly summarize the structural properties and reactivity of diaryliodonium salts. We describe several applications of these hypervalent reagents including metal-free arylations of C-, O-, N- and S-nu­cleophiles. The synthesis and functionalization of aromatic and heteroaromatic systems via copper- and palladium-catalyzed transformations are also discussed in this account.

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Content:

1 Introduction
2 Structural Properties and Reactivity
3 Applications of Diaryliodonium Salts in Organic Syntheses
3.1 Transition-Metal-Free Arylations of Heteroatom and Carbon Nucleophiles
3.1.1 Arylation of Oxygen Nucleophiles
3.1.1.1 Arylation of (Hetero)aromatic Alcohols
3.1.1.2 Arylation of Aliphatic Alcohols
3.1.1.3 Arylation of Acids
3.1.2 Arylation of Nitrogen Nucleophiles
3.1.2.1 N-Arylation of Amines and Amides
3.1.2.2 N-Arylation of Heterocycles
3.1.3 Arylation of Sulfur Nucleophiles
3.1.4 Arylation of Inorganic Anions
3.1.5 Arylation of Carbon Nucleophiles
3.1.5.1 Electron-Rich Heterocycles
3.1.5.2 Arylation of Carbonyl and Nitro Compounds
3.2 Synthesis and Functionalization of Aromatic and Heteroaromatic Molecules with Diaryliodonium Salts in the Presence of Copper and Palladium Catalysts
3.2.1 C–H Functionalizations by Copper-Catalyzed C–H Arylations
3.2.2 Copper-Catalyzed Cyclization of Unsaturated Compounds with Diaryliodonium Salts
3.2.3 Palladium-Catalyzed Arylations
3.2.3.1 Electrophilic Palladation and Arylation
3.2.3.2 Directing-Group-Assisted C–H Bond Activation and Arylation
4 Conclusion

Activation of C–H Activation: The Beneficial Effect of Catalytic Amount of Triaryl Boranes on Palladium-Catalyzed C–H Activation, Orsolya Tischler, Zsófia Bokányi, Zoltán Novák, Organometallics 2016, 35, 741-746. DOI: 10.1021/acs.organomet.5b01017 | [Full Text Link] [Supp. Info. Link]

Herein we report a novel approach to the acceleration of palladium-catalyzed C–H activation reactions. We demonstrated that the utilization of electron-deficient triaryl boranes as Lewis acidic cocatalysts of palladium enables the directed cross dehydrogenative coupling of aldehydes and anilides under mild reaction conditions. Study of the kinetic profile of the transformation reveals a unique, unexpectedly long induction period of the transformation.

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Mild and Efficient Palladium-Catalyzed Direct Trifluoroethylation of Aromatic Systems by C-H Activation, Balázs L. Tóth, Szabolcs Kovács, Gergő Sályi, Zoltán Novák, Angew. Chem. Int. Ed. 2016, 55, 1988-1992. DOI: 10.1002/anie.201510555 | [Full Text Link] [Supp. Info. Link]

The introduction of trifluoroalkyl groups into aromatic molecules is an important transformation in the field of organic and medicinal chemistry. However, the direct installation of fluoroalkyl groups onto aromatic molecules still represents a challenging and highly demanding synthetic task. Herein, a simple trifluoroethylation process that relies on the palladium-catalyzed C-H activation of aromatic compounds is described. With the utilization of a highly active trifluoroethyl(mesityl)iodonium salt, the developed catalytic method enables the first highly efficient and selective trifluoroethylation of aromatic compounds. The robust catalytic procedure provides the desired products in up to 95 % yield at 25 °C in 1.5 to 3 hours and tolerates a broad range of functional groups. The utilization of hypervalent reagents opens new synthetic possibilities for direct alkylations and fluoroalkylations in the field of transition-metal-catalyzed C-H activation.

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Simple: Anilides can be trifluoroethylated with a 2,2,2-trifluoroethyl-substituted iodonium salt in the presence of a palladium catalyst under mild conditions (see scheme). The reaction proceeds by CH activation at the ortho position and features a broad substrate scope.

Frontispiece: Mild and Efficient Palladium-Catalyzed Direct Trifluoroethylation of Aromatic Systems by C−H Activation, DOI: 10.1002/anie.201680661

Trifluoroethylation In their Communication on page 1988 ff., Z. Novák and co-workers describe the use of a trifluoroethyl(mesityl)iodonium salt for the simple and efficient palladium-catalyzed trifluoroethylation of aromatic compounds by C−H activation.

Modular Copper-Catalyzed Synthesis of Chromeno[4,3-b]quinolines with the Utilization of Diaryliodonium Salts, Klára Aradi, Petra Bombicz, Zoltán Novák, J. Org. Chem. 2016, 81, 920-931. DOI: 10.1021/acs.joc.5b02490 | [Full Text Link] [Supp. Info. Link, CIF]

A novel, highly modular synthetic method with high functional group tolerance was developed for the construction of chromenoquinoline derivatives from arylpropynyloxy-benzonitriles and diaryliodonium triflates via an oxidative arylation–cyclization path. The copper(I) chloride catalyzed reaction is presumed to involve the formation of highly active arylcopper(III) species.

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