Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

• Shahboz Yakubov and
• Joshua P. Barham

Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

• reactions. Keywords: C–H activation; energy transfer; fluorination; photocatalysis; photosensitization; visible light; Review 1 Introduction 1.1 Importance of direct C–H fluorination/trifluoromethylation and photosensitization in organic synthesis 1.1.1 Importance of fluorine atoms in organic molecules

• advantages of photosensitization, it is clear that this field has attracted less attention than PRC methods. Moreover, PS TTET is a powerful method for the fluorination and trifluoromethylation of C–H bonds. We believe this may stem from the lack of dedicated reviews grouping together the theory [103][104

• trifluoromethylation. Section 2 equips readers with the basic theory of PS TTET and provides detailed property information tables on commonly utilized PSCats in organic synthesis and especially in C–H fluorinations, grouped by their properties relevant to PS TTET. Due to the importance of moving away from transition

Reactions of 3-aryl-1-(trifluoromethyl)prop-2-yn-1-iminium salts with 1,3-dienes and styrenes

• Thomas Schneider,
• Michael Keim,
• Bianca Seitz and
• Gerhard Maas

Beilstein J. Org. Chem. 2020, 16, 2064–2072, doi:10.3762/bjoc.16.173

• ], trifluoroacetaldehyde hemiaminals [16][17][18], N,O-acetals [19] and N,N-acetals [20], 2-(trifluoromethyl)-1,3-oxazolidines [21], and N-(tert-butylsulfinyl)trifluoroacetaldimine [11][22]. Other synthetic approaches to α-CF3-substituted amines include nucleophilic trifluoromethylation strategies [17], such as the

When metal-catalyzed C–H functionalization meets visible-light photocatalysis

• Lucas Guillemard and
• Joanna Wencel-Delord

Beilstein J. Org. Chem. 2020, 16, 1754–1804, doi:10.3762/bjoc.16.147

Pauson–Khand reaction of fluorinated compounds

• Jorge Escorihuela,
• Daniel M. Sedgwick,
• Alberto Llobat,
• Mercedes Medio-Simón,
• Pablo Barrio and
• Santos Fustero

Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138

• obtained using the less reactive triphenylphosphine dicobaltpentacarbonyl complex 63 as the catalyst (Scheme 35). In a later study [72], Riera and Fustero generalized the use of trifluoromethylalkynes as substrates for the PKR. The copper-catalyzed trifluoromethylation of terminal alkynes described by Qing

Heterogeneous photocatalysis in flow chemical reactors

• Christopher G. Thomson,
• Ai-Lan Lee and
• Filipe Vilela

Beilstein J. Org. Chem. 2020, 16, 1495–1549, doi:10.3762/bjoc.16.125

• demonstrated the safe use of gaseous CF3I as a reagent for the continuous flow PRC trifluoromethylation of 5-membered heterocycles, such as N-methylpyrrole (1, Scheme 1), with a high conversion and selectivity for the monofunctionalised product 2 [62]. The system achieved full conversion for a variety of

Photocatalyzed syntheses of phenanthrenes and their aza-analogues. A review

• Alessandra Del Tito,
• Havall Othman Abdulla,
• Davide Ravelli,
• Stefano Protti and
• Maurizio Fagnoni

Beilstein J. Org. Chem. 2020, 16, 1476–1488, doi:10.3762/bjoc.16.123

• ]phenanthridine 8.6 by the trifluoromethylation of methylenecyclopropane 8.2. The reaction started with the generation of the trifluoromethyl radical via the IrIII photocatalyzed reduction of Togni’s reagent 8.1. The fluorinated radical added onto the isonitrile group present in 8.2 to give radical 8.3·, which in

Photocatalytic trifluoromethoxylation of arenes and heteroarenes in continuous-flow

• Alexander V. Nyuchev,
• Ting Wan,
• Borja Cendón,
• Carlo Sambiagio,
• Job J. C. Struijs,
• Michelle Ho,
• Moisés Gulías,
• Ying Wang and
• Timothy Noël

Beilstein J. Org. Chem. 2020, 16, 1305–1312, doi:10.3762/bjoc.16.111

• recently reported [8][9][11], for example the trifluoromethylation of hydroxyaryls [12][13][14], and the direct introduction of the -OCF3 moiety into an organometallic species [15], a diazo compound [16][17], or an unfunctionalized C–H bond (Scheme 1B). The latter method is particularly interesting

Copper-based fluorinated reagents for the synthesis of CF₂R-containing molecules (R ≠ F)

• Louise Ruyet and
• Tatiana Besset

Beilstein J. Org. Chem. 2020, 16, 1051–1065, doi:10.3762/bjoc.16.92

• -based fluorinated reagents appeared over the years as a powerful tool in various transformations for the introduction of fluorinated moieties. Such strategy has already demonstrated a significant synthetic value for the trifluoromethylation of various compounds [16][17][18][19][20][21][22][23][24][25

• the functionalization of different classes of compounds (benzyl and vinyl bromides, 4-biphenylboronic acid, phenylacetylene for instance). From these pioneering reports of perfluoroalkylation (trifluoromethylation, pentafluoroethylation and heptafluoropropylation), several groups studied the synthesis

• dealt with the copper-mediated perfluororalkyaltion of (hetero)aryl bromides using the previously developed PhenCuRF [69]. Although the trifluoromethylation reaction was mainly studied, the methodology was efficiently extended to the pentafluoroethylation of various heteroarenes such as pyridine

Copper catalysis with redox-active ligands

• Agnideep Das,
• Yufeng Ren,
• Cheriehan Hessin and
• Marine Desage-El Murr

Beilstein J. Org. Chem. 2020, 16, 858–870, doi:10.3762/bjoc.16.77

• Chaudhuri [11][12][13] using well-defined copper complex 7, originally reported as a GAO mimic [20][21][22], we showed that this ability could be extended to the catalytic generation of trifluoromethyl radicals (Scheme 7) [29]. The synthetic efficiency of complex 7 in trifluoromethylation was reported on a

• trifluoromethylation of heteroaromatics with redox-active iminosemiquinone ligands. Reversal of helical chirality upon redox stimuli and enantioselective Michael addition with a redox-reconfigurable copper catalyst. Interaction of guanidine-copper catalyst with oxygen and representative coupling products. a4 mol

Cascade trifluoromethylthiolation and cyclization of N-[(3-aryl)propioloyl]indoles

• Ming-Xi Bi,
• Shuai Liu,
• Yangen Huang,
• Xiu-Hua Xu and
• Feng-Ling Qing

Beilstein J. Org. Chem. 2020, 16, 657–662, doi:10.3762/bjoc.16.62

• and agrochemical industries [3][4][5]. Traditional methods to access these compounds mainly include halogen–fluorine exchange of halomethyl sulfides and trifluoromethylation of sulfur-containing compounds [6][7][8]. Over the last decade, tremendous efforts have been triggered to develop methods for

Recent advances in photocatalyzed reactions using well-defined copper(I) complexes

• Mingbing Zhong,
• Xavier Pannecoucke,
• Philippe Jubault and
• Thomas Poisson

Beilstein J. Org. Chem. 2020, 16, 451–481, doi:10.3762/bjoc.16.42

• )(dap)2]Cl. Trifluoromethyl methoxylation of styryl derivatives using [Cu(I)(dap)2]PF6. All redox potentials are reported vs SCE. Trifluoromethylation of silyl enol ethers. Synthesis of annulated heterocycles upon oxidation with the Sauvage catalyst. Oxoazidation of styrene derivatives using [Cu(dap)2

Copper-promoted/copper-catalyzed trifluoromethylselenolation reactions

• Clément Ghiazza and
• Anis Tlili

Beilstein J. Org. Chem. 2020, 16, 305–316, doi:10.3762/bjoc.16.30

• trifluoromethylation in a one-pot procedure with the Ruppert–Prakash reagent (Scheme 15, conditions III) [41]. The corresponding trifluoromethylselenylated (hetero)aryl products were obtained in moderate to good yields using both electron-deficient and -rich starting materials, respectively. Interestingly, the authors

Recent developments in photoredox-catalyzed remote ortho and para C–H bond functionalizations

• Rafia Siddiqui and
• Rashid Ali

Beilstein J. Org. Chem. 2020, 16, 248–280, doi:10.3762/bjoc.16.26

• products was assembled with moderate to high yields using this powerful synthetic strategy, and the scope of the reaction can be seen in Scheme 12. C–H trifluoromethylation The introduction of a CF3 group into pharmaceutical agents can enhance their performance in medicinal chemistry [129][130][131]. In

• catalyst. Proposed mechanism for the trifluoromethylation of 88. Plausible mechanism for the synthesis of substituted coumarins. Mechanism proposed for the phosphonylation reaction of 100. Plausible mechanism for the nitration of aniline derivatives via photoredox catalysis. Proposed mechanism for the

• purines via dual photoredox catalysis. Arylation of substituted arenes with an organic photoredox catalyst. C–H trifluoromethylation. Synthesis of benzo-3,4-coumarin derivatives. Oxidant-free oxidative phosphonylation. Nitration of anilines. Synthesis of carbazoles via intramolecular amination. Synthesis

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups

• Xiaowei Li,
• Xiaolin Shi,
• Xiangqian Li and
• Dayong Shi

Beilstein J. Org. Chem. 2019, 15, 2213–2270, doi:10.3762/bjoc.15.218

• trifluoromethylation before 2011, and Besset [21] focused on the direct introduction of fluorinated groups into alkenes and alkynes. Then, Toste [1] covered advances in catalytic enantioselective fluorination, mono‑, di‑, and trifluoromethylation, and trifluoromethylthiolation reactions. Recently, Zhang [14] offered a

• trifluoromethylation reported between 2011 and 2019. Meanwhile, we also present the incorporation of difluoromethyl, trifluoromethylthiol and trifluoromethoxy groups. Some sections of this review are structured around the synthesis of alkyl-, aryl- and vinyl- as well as alkynyl organofluorides. Notably, the current

• . Trifluoromethylation Transition-metal-catalyzed trifluoromethylation reactions have made great progress in the joint efforts of organic fluorination scientists and metalorganic chemists over the past decade. Introducing trifluoromethyl groups into organic molecules can significantly alter their properties, such as

Diaminoterephthalate–α-lipoic acid conjugates with fluorinated residues

• Leon Buschbeck,
• Aleksandra Markovic,
• Gunther Wittstock and
• Jens Christoffers

Beilstein J. Org. Chem. 2019, 15, 981–991, doi:10.3762/bjoc.15.96

• indicated that trifluoromethylation is an excellent tool for the detection of surface-bound materials by XPS. Keywords: chromophore; diaminoterephthalate; fluorine surface marker; fluorescence dye; lipoic acid; self-assembled monolayers; Introduction Diaminoterephthalates (DATs) are powerful fluorescence

• . The elemental compositions of these two SAMs were characterized by high-resolution XPS of the C 1s, O 1s, S 2p, N 1s and F 1s emissions. As is indicated by the high signal-to-noise ratio of the F 1s peaks, the trifluoromethylation is an excellent tool for the detection of surface-bound materials by

Catalytic asymmetric oxo-Diels–Alder reactions with chiral atropisomeric biphenyl diols

• Chi-Tung Yeung,
• Wesley Ting Kwok Chan,
• Wai-Sum Lo,
• Ga-Lai Law and
• Wing-Tak Wong

Beilstein J. Org. Chem. 2019, 15, 955–962, doi:10.3762/bjoc.15.92

• low yield of catalyst 4 may be due to steric bulkiness of the mesityl group that hampers close approach of d during coupling. For the synthesis of catalyst 6, the CF3 substituent was introduced to f by trifluoromethylation (Scheme 4). A racemic mixture of g was obtained after the TMS group was removed

Oxidative radical ring-opening/cyclization of cyclopropane derivatives

• Yu Liu,
• Qiao-Lin Wang,
• Zan Chen,
• Cong-Shan Zhou,
• Bi-Quan Xiong,
• Pan-Liang Zhang,
• Chang-An Yang and
• Quan Zhou

Beilstein J. Org. Chem. 2019, 15, 256–278, doi:10.3762/bjoc.15.23

• -arylselanylnaphthaldehyde 25. In 2015, Shi and co-workers reported a novel and efficient method to construct CF3-substituted dihydronaphthalene derivatives 31 in moderate to excellent yields under mild conditions through the Cu(I)-catalyzed trifluoromethylation/ring-opening/cyclization of MCPs 1 with Togni reagent II (30

• oxidation and dehydrogenation gives the target product 49. A new and first achievement for the synthesis of CF3-contained seven-membered ring compounds 55 and 56 through trifluoromethylation of acrylamide-tethered alkylidenecyclopropanes 54 was presented by Shi and co-workers (Scheme 13) [78]. The possible

• trifluoromethylation of cyclopropanols 91 to construct β-trifluoromethyl-substituted ketones 106 (Scheme 23) [101]. Additionally, a series of cyclopropanols with different functional R groups were successfully scaled up to 1 mmol. In this transformation, there exist two possible pathways to produce the target product

Learning from B₁₂ enzymes: biomimetic and bioinspired catalysts for eco-friendly organic synthesis

• Keishiro Tahara,
• Ling Pan,
• Toshikazu Ono and
• Yoshio Hisaeda

Beilstein J. Org. Chem. 2018, 14, 2553–2567, doi:10.3762/bjoc.14.232

• obtained through isomerization with 1,2-migration of the ester groups. The B12-TiO2 hybrid catalyst can be regarded as a good alternative for conventional radical-involved organic syntheses using tin compounds. Recently, we discovered that the B12 derivative 1 can mediate trifluoromethylation and

• the presence of photosensitizers. 1,2-Migration of a phenyl group mediated by the visible-light-driven catalytic system composed of 1 and Irdfppy. Ring-expansion reactions mediated by the B12-TiO2 hybrid catalyst with UV-light irradiation. Trifluoromethylation and perfluoroalkylation of aromatic

Determining the predominant tautomeric structure of iodine-based group-transfer reagents by ¹⁷O NMR spectroscopy

• Nico Santschi,
• Cody Ross Pitts,
• Benson J. Jelier and
• René Verel

Beilstein J. Org. Chem. 2018, 14, 2289–2294, doi:10.3762/bjoc.14.203

• structural elucidation technique to predict the constitution of an electrophilic iodine-based cyano-transfer reagent as an NC–I–O motif and study the acid-mediated activation of Togni's trifluoromethylation reagent. Keywords: electrophilic; hypervalent iodine; 17O NMR spectroscopy; trifluoromethylation

• ; trifluoromethylthiolation; Introduction The remarkable stability and reactivity of Togni's hypervalent iodine-based trifluoromethylation reagents (e.g., 4a) [1] have inspired the development of analogous compounds, including a well-known SCF3-transfer reagent 5 in 2013 by Shen and co-workers [2][3]. In the presence of

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• it a uniquely suited method for LSF. For example, Scaiano et al. have demonstrated the direct C–H trifluoromethylation of heterocycles using TMEDA, visible light from white LEDs, Methylene Blue as the photocatalyst and Togni’s reagent as the trifluoromethyl source (Scheme 26) [71]. The reaction is

• caffeine. The yields are good (44–92%), with regioselectivity being observed in a few cases. As with the trifluoromethylation by Pitre et al., this procedure does fit all the criteria for LSF, as it is very mild and simple, even though no complex structures are exemplified. Although it does not fit the

Hypervalent organoiodine compounds: from reagents to valuable building blocks in synthesis

• Gwendal Grelier,
• Benjamin Darses and
• Philippe Dauban

Beilstein J. Org. Chem. 2018, 14, 1508–1528, doi:10.3762/bjoc.14.128

• reagents: CF3-benziodoxolone (Togni’s reagent) The ability to introduce the 2-iodobenzoic acid motif released from benziodoxolones has first been noticed by Ochiai in an isolated example of radical benzoyloxylation of THF [32], and by Gouverneur in the study of trifluoromethylation of allylsilanes [33

• ]. The use of this acid as an oxygen nucleophile, then, has been more fully investigated by the groups of Szabó and Sodeoka who have simultaneously described the copper-catalyzed benzoyloxy-trifluoromethylation of alkenes and alkynes using Togni’s reagent 5. The group of Szabó has first reported the use

• cyanotrifluoromethylation reaction. The mechanistic study of the oxy-trifluoromethylation of phenylacetylene has then led to demonstrate that the reaction is accelerated in the presence of additives such as B2pin2 [35]. A mechanism involving an initial step of transmetallation of B2pin2 with the Cu(I) catalyst was proposed

Synthesis of trifluoromethylated 2H-azirines through Togni reagent-mediated trifluoromethylation followed by PhIO-mediated azirination

• Jiyun Sun,
• Xiaohua Zhen,
• Huaibin Ge,
• Guangtao Zhang,
• Xuechan An and
• Yunfei Du

Beilstein J. Org. Chem. 2018, 14, 1452–1458, doi:10.3762/bjoc.14.123

• (PhIO)-mediated intramolecular azirination in a one-pot process. Keywords: azirination; 2H-azirine; iodosobenzene; Togni reagent; β-trifluoromethylation; Introduction The trifluoromethyl group is a striking structural motif, which can be widely found in the fields of pharmaceutical and agrochemical

• CF3 group into various organic molecules, the further development of novel routes for the selective trifluoromethylation is of continuing interest for synthetic and medicinal chemists. Togni reagents, including 1-(trifluoromethyl)-1,2-benziodoxol-3(1H)-one (1) and trifluoromethyl-1,3-dihydro-3,3

• -dimethyl-1,2-benziodoxole (1’, Figure 2), are effective and efficient hypervalent iodine reagents for trifluoromethylation reactions of a variety of substrates [22][23]. These reagents have found wide applications in the area of organofluorine chemistry, synthetic method development as well as medicinal

Synthesis of fluoro-functionalized diaryl-λ³-iodonium salts and their cytotoxicity against human lymphoma U937 cells

• Prajwalita Das,
• Etsuko Tokunaga,
• Hidehiko Akiyama,
• Hiroki Doi,
• Norimichi Saito and
• Norio Shibata

Beilstein J. Org. Chem. 2018, 14, 364–372, doi:10.3762/bjoc.14.24

• actively working in this direction for decades [12][13][16][17][18][19][20][21][22][23]. Our primary goal has been to develop fluorinating and fluoro-functionalized reagents for fluorination [18][19], trifluoromethylation [13][18][19], trifluoromethylthiolation [12][21] and pentafluoroarylation [22][23

• developed, including Shibata reagents I [20] and II [21] (trifluoromethylation reagent 1 and trifluoromethylthiolation reagent 2a, respectively), pentafluorophenylating reagent 2b and several hypervalent iodine reagents, i.e., diaryliodonium salts with a mesitylene ligand (3a–o) and a triisopropylphenyl

One-pot sequential synthesis of tetrasubstituted thiophenes via sulfur ylide-like intermediates

• Jun Ki Kim,
• Hwan Jung Lim,
• Kyung Chae Jeong and
• Seong Jun Park

Beilstein J. Org. Chem. 2018, 14, 243–252, doi:10.3762/bjoc.14.16

• reactions involving sulfonium and sulfoxonium ylides have been reported recently [26][27][28][29][30][31][32]. For example, Shen and co-workers reported the use of trifluoromethyl-substituted sulfonium ylide 5 in electrophilic trifluoromethylation reactions [33][34]. Moreover, Maulide and co-workers

Nucleophilic fluoroalkylation/cyclization route to fluorinated phthalides

• Masanori Inaba,
• Tatsuya Sakai,
• Shun Shinada,
• Tsuyuka Sugiishi,
• Yuta Nishina,
• Norio Shibata and
• Hideki Amii

Beilstein J. Org. Chem. 2018, 14, 182–186, doi:10.3762/bjoc.14.12

• good yields. Keywords: cyclization; fluorine; lactone; phthalide; trifluoromethylation; Introduction Phthalides (1(3H)-isobenzofuranones) are frequently found in natural products and exhibit a range of bioactivity (Scheme 1) [1][2]. Substituted phthalides have been used as building blocks for the

• and hexafluoroacetone to give 3-(trifluoromethyl)phthalide derivatives [11]. In 2006, Pedrosa et al. reported the nucleophilic trifluoromethylation of protected ortho-phthalaldehyde, followed by deprotection and oxidation to afford 3-(trifluoromethyl)phthalide [12]. Pohmakotr et al. demonstrated the

• nucleophilic trifluoromethylation of acid anhydrides to produce γ-hydroxy-γ-trifluoromethyl-γ-butyrolactones, which acted as good precursors in the synthesis of γ-trifluoromethyl-γ-butyrolactones with organometallic reagents [16]. All these protocols involve multiple steps to obtain trifluoromethylphthalides