Copper-Catalyzed Trifluoromethylation Research Articles

Copper-Catalyzed Trifluoromethylation of (Hetero)aryl Boronic Acid Pinacol Esters with YlideFluor.

A copper-catalyzed trifluoromethylation of (hetero)arylboronic acid pinacol esters with YlideFluor for the preparation of trifluoromethylated (hetero)arenes was described. The reaction conditions are mild and compatible with a broad range of functional groups. Heteroaryl boronic acid pinacol esters could also be trifluoromethylated in high yields. Application of this protocol for trifluoromethylation of drug and OLED molecules was demonstrated.

Copper-Catalyzed Trifluoromethylation of Alkoxypyridine Derivatives.

The trifluoromethylation of aromatic and heteroaromatic cores has attracted considerable interest in recent years due to its pharmacological relevance. We studied the extension of a simple copper-catalyzed trifluoromethylation protocol to alkoxy-substituted iodopyridines and their benzologs. The trifluoromethylation proceeded smoothly in all cases, and the desired compounds were isolated and characterized. In the trifluoromethylation of 3-iodo-4-methoxyquinoline, we observed a concomitant O-N methyl migration, resulting in the trifluoromethylated quinolone as a product. Overall, the described procedure should facilitate the broader use of copper-catalyzed trifluoromethylation in medicinal chemistry.

Enantioselective Copper-Catalyzed Trifluoromethylation of Benzylic Radicals via Ring Opening of Cyclopropanols

Summary The asymmetric trifluoromethylation of aryl-substituted cyclopropanols via a radical ring-opening pathway is reported herein, which provides an easy and straightforward access to structurally diverse β-CF3 ketones in good yields and excellent enantioselectivities under very mild conditions. Critical to the success of the copper-catalyzed radical relay is that a benzylic radical intermediate can be enantioselectively trapped by reactive (L∗)CuIICF3. In addition, a novel quinolinyl-containing bisoxazoline ligand plays a significant role in the asymmetric trifluoromethylation.

Copper-Catalyzed Trifluoromethylation of Ynones Coupled with Dearomatizing Spirocyclization of Indoles: Access to CF3-Containing Spiro[cyclopentane-1,3'-indole

A one-pot protocol for the Cu(I)-catalyzed difunctionalization of indolyl ynones has been achieved via trifluoromethylation of alkyne followed by dearomatizing spirocyclization of indoles. This cascade process enables constructing diverse CF3-containing spiro[cyclopentane-1,3'-indole] scaffolds in moderate to excellent yields which have challenging quaternary spirocyclic carbon and tetrasubstituted alkenes.

Ligand- and Additive-Free 2-Position-Selective Trifluoromethylation of Heteroarenes Under Ambient Conditions.

A highly selective copper-catalyzed trifluoromethylation of indoles is reported with the assistance of a removable directing group. This protocol provides an easy and rapid method to various 2-position-selective trifluoromethylated heteroarenes including indoles, pyrroles, benzofuran, and acetanilide. What is more, the reaction takes place at ambient conditions without any external ligand or additive.

Copper-Catalyzed Trifluoromethylation of Alkyl Bromides

Copper oxidative addition into organohalides is a challenging two-electron process. In contrast, formal oxidative addition of copper to Csp2 carbon-bromine bonds can be accomplished by employing latent silyl radicals under photoredox conditions. This novel paradigm for copper oxidative addition has now been applied to a Cu-catalyzed cross-coupling of Csp3-bromides. Specifically, a copper/photoredox dual catalytic system for the coupling of alkyl bromides with trifluoromethyl groups is presented. This operationally simple and robust protocol successfully converts a variety of alkyl, allyl, benzyl, and heterobenzyl bromides into the corresponding alkyl trifluoromethanes.

Copper-Catalyzed Remote Trifluoromethylation

Copper-Catalyzed Remote Trifluoromethylation

Qilong Shen

Angewandte Chemie International EditionVolume 58, Issue 23 p. 7524-7524 Author ProfileFree Access Qilong Shen First published: 25 October 2018 https://doi.org/10.1002/anie.201811328AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract “My favorite food is steamed whole fish. If I were not a scientist, I would be a writer …” Find out more about Qilong Shen in his Author Profile. Qilong Shen The author presented on this page has published more than 10 articles in Angewandte Chemie in the last 10 years, most recently: “Enantioselective Construction of Trifluoromethoxylated Stereogenic Centers by a Nickel-Catalyzed Asymmetric Suzuki–Miyaura Coupling of Secondary Benzyl Bromides”: W. Huang, X. Wan, Q. Shen, Angew. Chem. Int. Ed. 2017, 56, 11986; Angew. Chem. 2017, 129, 12148. The work of Q. Shen has been featured on the back cover of Angewandte Chemie: “An Electrophilic Hypervalent Iodine Reagent for Trifluoromethylthiolation”: X. Shao, X. Wang, T. Yang, L. Lu, Q. Shen, Angew. Chem. Int. Ed. 2013, 52, 3457; Angew. Chem. 2013, 125, 3541. Date of birth: October 4, 1974 Position: Professor, Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Sciences (CAS) E-mail: shenql@mail.sioc.ac.cn Homepage: http://shenqilong.sioc.ac.cn ORCID: 0000-0001-5622-153X Education: 1996 BS, Nanjing University 1999 MSc, SIOC, CAS 2002 MSc, University of Massachusetts, Dartmouth 2007 PhD with Prof. John F. Hartwig, Yale University 2007–2010 Postdoc with Prof. Jeffrey S. Moore, University of Illinois at Urbana-Champaign Awards: 2016 National Natural Science Fund for Distinguished Young Scholars, NSFC; 2018 Roche Chinese Young Investigator Award Current research interests: Organofluorine chemistry; electrophilic fluoroalkylating reagents; organometallic fluorine chemistry Hobbies: Hiking, reading My favorite food is steamed whole fish. If I were not a scientist, I would be a writer. If I won the lottery, I would set up my own research institute. The most important thing I learned from my parents is to stand up straight and do your best. I chose chemistry as a career because I was chosen as a member of my high-school chemistry olympiad team and I fell love with the subject. My greatest achievement has been the development of a family of electrophilic fluoroalkylating reagents. My favorite author (fiction) is Romain Rolland (who wrote the novel Jean Christophe). My favorite piece of music is Beethoven's “Moonlight” Sonata. My favorite quote is “If winter comes, can spring be far behind?” (Percy Bysshe Shelley). The most significant scientific advance of the last 100 years has been the discovery of the DNA structure. My 5 top papers: 1“Copper-Catalyzed Trifluoromethylation of Aryl and Vinyl Boronic Acids with An Electrophilic Trifluoromethylating Reagent”: T. Liu, Q. Shen, Org. Lett. 2011, 13, 2342. (Site-specific trifluoromethylation made easy.) 2“N-Trifluoromethylthiosaccharin: An Easily Accessible, Shelf-Stable, Broadly Applicable Trifluoromethylthiolating Reagent”: C.-F. Xu, B.-Q. Ma, Q. Shen, Angew. Chem. Int. Ed. 2014, 53, 9316; Angew. Chem. 2014, 126, 9470. (With a sweet component, this reagent makes trifluoromethylthiolated compounds readily accessible.) 3“Cooperative dual palladium/silver catalyst for direct difluoromethylation of aryl bromides and iodides”: Y. Gu, X. Leng, Q. Shen, Nat. Commun. 2014, 5, 5405. (A two-catalyst relay led to the first reported transition-metal-catalyzed difluoromethylation reaction.) 4“N-Difluoromethylthiophthalimide: A Shelf-Stable Electrophilic Regent for Difluoromethylthiolation”: D. Zhu, Y. Gu, L. Lu, Q. Shen, J. Am. Chem. Soc. 2015, 137, 10547. (A stable yet reactive “one-stop-shop” reagent for difluoromethylthiolation.) 5“Direct of Difluoromethylation of Alcohols with an Electrophilic Difluoromethylated Sulfonium Ylide”: J. Zhu, Y. Liu, Q. Shen, Angew. Chem. Int. Ed. 2016, 55, 9050; Angew. Chem. 2016, 128, 9196. (Umpolung reactivity in a sulfonium ylide—now it is electrophilic.) Volume58, Issue23June 3, 2019Pages 7524-7524 ReferencesRelatedInformation

Copper-Catalyzed Trifluoromethylation via Aryl Radicals

Copper-Catalyzed Trifluoromethylation via Aryl Radicals

Copper-Catalyzed Trifluoromethylation of Alkyl Iodides

Copper-Catalyzed Trifluoromethylation of Alkyl Iodides

Progress in copper-catalyzed trifluoromethylation.

The introduction of trifluoromethyl groups into organic molecules has attracted great attention in the past five years. In this review, we describe the recent efforts in the development of trifluoromethylation via copper catalysis using nucleophilic, electrophilic or radical trifluoromethylation reagents.

Mechanistic insights into copper-catalyzed trifluoromethylation of aryl boronic acids: a theoretical study

Density functional theory (DFT) calculations were employed to study the mechanism for copper-catalyzed trifluoromethylation of aryl boronic acids by Togni’s reagent. Computational results suggest that the catalytic cycle proceeds with the transmetallation between phenylboronic acid and copper(I) species, which generates a phenylcopper(I) intermediate. Subsequent coordination of Togni’s reagent and the electrophilic substitution of CF3 group to phenyl group finally afford the trifluoromethylation product through a concerted five-membered ring transition state. The transmetallation process with an activation free energy of 21.7 kcal/mol is determined to be the rate-determining step of this reaction. Moreover, the reactivity of alkylboronic acid was also calculated and proven to be unfavorable due to the higher activation free energy of transmetallation process.

A redox-economical synthesis of trifluoromethylated enamides with the Langlois reagent

A redox-economical strategy for the synthesis of trifluoromethylated enamides using copper catalysis is reported. The reaction employs the inexpensive Langlois reagent (CF3SO2Na) and takes place without the need of an external oxidant. The trifluoromethylated enamide products can easily be converted into the corresponding ketone, saturated amide or oxazole.

Copper-catalyzed trifluoromethylation of styrene derivatives with CF3SO2Na

A radical-type copper(i)-catalyzed direct trifluoromethylation of styrene derivatives using CF3SO2Na as a trifluoromethylating source for accessing trifluoromethylated alkenes has been developed.

ChemInform Abstract: Copper‐Catalyzed Tandem Trifluoromethylation—Cyclization of Olefinic Carbonyls: Synthesis of Trifluoromethylated 2,3‐Dihydrofurans and 3,4‐Dihydropyrans.

A copper-catalyzed trifluoromethylation–cyclization of olefinic carbonyls was developed. With this method, a variety of 2,3-dihydrofuran and 3,4-dihydropyran derivatives containing a CF3 group were selectively obtained in moderate to good yields. This chemistry represents a rare example of direct construction of trifluoromethylated oxygen-containing heterocycles via the combination of radical trifluoromethylation with endo-type radical addition to carbonyls.

Copper-Catalyzed Trifluoromethylation of Alkenes with Redox-Neutral Remote Amidation of Aldehydes.

A room-temperature and one-pot synthesis of ε-CF3-substituted amides via the copper-catalyzed trifluoromethylation of alkenes with redox-neutral remote amidation of aldehydes is described. This reaction is featured by an unprecedented 1,5-H atom abstraction from aldehydic C-H bonds by α-CF3-alkyl radicals resulting from the radical trifluoromethylation of alkenes, thus enabling a new possibility of the trifluoromethylation-initiated remote sp(2) C-H functionalization.

Copper-catalyzed tandem trifluoromethylation–cyclization of olefinic carbonyls: synthesis of trifluoromethylated 2,3-dihydrofurans and 3,4-dihydropyrans

A copper-catalyzed trifluoromethylation–cyclization of olefinic carbonyls was developed. With this method, a variety of 2,3-dihydrofuran and 3,4-dihydropyran derivatives containing a CF3 group were selectively obtained in moderate to good yields.

Copper-catalysed synthesis of trifluoromethyl(hetero)arenes from di(hetero)aryl-λ3-iodanes

Efficient regioselective copper-catalyzed trifluoromethylation of symmetrical and unsymmetrical diaryl-λ3-iodanes have been achieved for the synthesis of trifluoromethyl(hetero)arenes in good yield.

Iron- or Copper-Catalyzed Trifluoromethylation of Acrylamide-Tethered Alkylidenecyclopropanes: Facile Synthesis of CF3-Containing Polycyclic Benzazepine Derivatives

A novel iron- or copper-catalyzed trifluoromethylation of acrylamide-tethered alkylidenecyclopropanes with Togni reagent II to construct CF3-containing tetracyclic benzazepine derivatives under mild and convenient conditions has been disclosed. The chemoselective addition of in situ generated trifluoromethyl radical onto the activated alkenes triggers the reaction followed by a ring-opening process of alkylidenecyclopropanes, leading to the formation of two types of CF3-containing tetracyclic benzazepine derivatives in moderate to good yields, respectively, with excellent functional group tolerance.

Copper-Catalyzed Trifluoromethylation of Polysubstituted Alkenes Assisted by Decarboxylation.

An efficient copper-catalyzed trifluoromethylation of polysubstituted alkenes assisted by decarboxylation of β,γ-unsaturated carboxylic acids has been achieved. The reaction provides a general method to construct allylic and vinylic CF3-substituted compounds under mild conditions.