Compounds Currently in Phase II−III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas Yu Zhou,† Jiang Wang,† Zhanni Gu,† Shuni Wang,† Wei Zhu,† Jose ́ Luis Aceña,*,‡,§ Vadim A. Soloshonok,*,‡,∥ Kunisuke Izawa,* and Hong Liu*,† †Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ‡Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizab́al 3, 20018 San Sebastiań, Spain Department of Organic Chemistry, Autońoma University of Madrid, Cantoblanco, 28049 Madrid, Spain IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, 48013 Bilbao, Spain Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka, Japan 533-0024

Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II–III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas

This Minireview highlights recent developments in radical trifluoromethylation reactions. The trifluoromethyl group belongs to the privileged moieties in medicinal chemistry. Many drugs and drug candidates contain a trifluoromethyl substituent. Also in agrochemicals, the CF3 moiety often appears. The present article addresses the radical trifluoromethylation of alkenes and arenes mainly focussing on recent achievements. However, important earlier work in this field is also covered.

A "Renaissance" in radical trifluoromethylation

Carbon trifluoromethylation reactions of hydrocarbon derivatives and heteroarenes.

Trifluoromethylations and related reactions in organic chemistry

Transition metal-catalyzed C–H bond functionalizations have been the focus of intensive research over the last decades for the formation of C–C bonds from unfunctionalized arenes, heteroarenes, alkenes These direct transformations provide new approaches in synthesis with high atom- and step-economy compared to the traditional catalytic cross-coupling reactions However, such methods still suffer from several limitations including functional group tolerance and the lack of regioselectivity In addition, they often require harsh reaction conditions and some of them need the use of strong oxidant, in a stoichiometric amount, avoiding these processes to be truly eco-friendly The use of photoredox catalysis has contributed to a significant expansion of the scope of C(sp2)–H bond functionalizations which include the direct arylations, (perfluoro)alkylations, acylations, and even cyanations Most of these transformations involve the photochemical induced generation of a radical followed by its regioselective a

Photoredox Catalysis for Building C-C Bonds from C(sp2)-H Bonds.

Vergleich der trifluormethylierungseigenschaften von(CF3)Hg, CF3I und (CF3)2te am beispiel der reaktionen mit cyclohexen, benzol und pyridin

Trifluoromethylierungsreaktionen von CF3I, Te(CF3)2, Sb(CF3)3, Hg(CF3)2, und Cd(CF3)2·D mit furan, Thiophen, Pyrrol und p-Benzochinon [1]

Trifluormethylierungsreaktionen von Te(CF3)2 mit halogenbenzolen und methylbenzolen [1]

(CF3)2Te2 entsteht als Hauptprodukt bei der photochemischen Reaktion von (CF3)2Te mit z. B. Furan und kann in mehr als 40% Ausbeute isoliert werden. (CF3)2Te2 reagiert quantitativ mit Hg und Cd zu den neuen Verbindungen (CF3Te)2Hg bzw. (CF3Te)2Cd. Mit Cu werden nicht isolierbare CF3Cu-Verbindungen gebildet, wahrend mit Ag keine Reaktion stattfindet.



The Preparation of CF3TeTeCF3 and Reactions with the Elements Hg, Cd, Cu, and Ag



(CF3)2Te2 is a main product of the photochemical reaction of (CF3)2Te with e.g. furan and can be separated in more than 40% yield. It quantitatively reacts with mercury and cadmium to give the new compounds (CF3Te)2Hg and (CF3Te)2Cd, respectively. With copper some CF3Cu compounds are formed, whereas with silver no reaction takes place.

Die Synthese von CF3TeTeCF3 und Reaktionen mit den Elementen Hg, Cd, Cu und Ag

CF3I, Te(CF3)2 und Sb(CF3)3 addieren in guten bis sehr guten Ausbeuten an Cyclohexen unter Bildung von CF3C6H10I, CF3C6H10TeCF3 bzw. CF3C6H10Sb(CF3)2, die zu den entsprechenden Organo-iod-, -tellur- bzw. -antimondihalogeniden oxidiert werden konnen. Die Darstellungen, Eigenschaften und 19F-NMR-Spektren der neuen Verbindungen werden beschrieben.



Oxidation Reactions of the Addition Products of CF3I, Te(CF3)2, and Sb(CF3)3 to Cyclohexene



CF3I, Te(CF3)2, and Sb(CF3)3 add to cyclohexen in good to very good yields to form CF3C6H10I, CF3C6H10TeCF3, and CF3C6H10Sb(CF3)2, respectively, which can be oxidized to the corresponding organo iodine, tellurium, and antimony dihalides. The preparations, properties, and 19F NMR spectra of the new compounds are described.

Jürgen Kischkewitz

Papers

Vergleich der trifluormethylierungseigenschaften von(CF3)Hg, CF3I und (CF3)2te am beispiel der reaktionen mit cyclohexen, benzol und pyridin

Trifluoromethylierungsreaktionen von CF3I, Te(CF3)2, Sb(CF3)3, Hg(CF3)2, und Cd(CF3)2·D mit furan, Thiophen, Pyrrol und p-Benzochinon [1]

Trifluormethylierungsreaktionen von Te(CF3)2 mit halogenbenzolen und methylbenzolen [1]

Die Synthese von CF3TeTeCF3 und Reaktionen mit den Elementen Hg, Cd, Cu und Ag

Oxidationsreaktionen der Additionsprodukte von CF3l, Te(CF3)2 und Sb(CF3)3 an Cyclohexen