Synthesis of trifluoromethyl ketones by nucleophilic trifluoromethylation of esters under a fluoroform/KHMDS/triglyme system

• Yamato Fujihira,
• Yumeng Liang,
• Makoto Ono,
• Kazuki Hirano,
• Takumi Kagawa and
• Norio Shibata

Beilstein J. Org. Chem. 2021, 17, 431–438, doi:10.3762/bjoc.17.39

• biologically attractive trifluoromethyl ketones from readily available methyl esters using the potent greenhouse gas fluoroform (HCF3, HFC-23) was developed. The combination of fluoroform and KHMDS in triglyme at −40 °C was effective for this transformation, with good yields as high as 92%. Substrate scope of

• the trifluoromethylation procedure was explored for aromatic, aliphatic, and conjugated methyl esters. This study presents a straightforward trifluoromethylation process of various methyl esters that convert well to the corresponding trifluoromethyl ketones. The tolerance of various pharmacophores

• under the reaction conditions was also explored. Keywords: fluoroform; greenhouse gas; HFC-23; trifluoromethyl ketones; trifluoromethylation; Introduction In recent decades, organofluorine molecules have received widespread attention in the field of medicinal chemistry [1][2][3][4]. The introduction

Unexpected rearrangements and a novel synthesis of 1,1-dichloro-1-alkenones from 1,1,1-trifluoroalkanones with aluminium trichloride

• Beatrice Lansbergen,
• Catherine S. Meister and
• Michael C. McLeod

Beilstein J. Org. Chem. 2021, 17, 404–409, doi:10.3762/bjoc.17.36

• -dichloro-1-alkenone 6a in 23% yield, without cleavage of the methyl ether [26] (Scheme 1). A similar AlCl3-promoted conversion of vinylic trifluoromethyl groups to 1,1-dichloroalkenes has previously been reported [27][28]. Additionally, 1,1-dichloroalkenes have also been prepared by the elimination of HCl

• trifluoromethyl to a trichloromethyl group with AlCl3 has been previously reported [30][31][32], investigations into the analogous transformation of aliphatic CF3 groups has been limited to adamantly-trifluoromethyl moieties [33][34]. An NMR analysis of the crude product mixture obtained using our original

CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

• long been investigated. This review highlights recent and past reports focusing on their study and potential in modern synthetic transformations. Keywords: carbocation; organic synthesis; superelectrophile; trifluoromethyl; Introduction Carbocations are pivotal intermediates in organic chemistry, and

• cations is probably the α-(trifluoromethyl) carbocation. Many efforts are currently devoted to develop methods allowing the efficient insertion of fluorine atoms or fluorinated groups into organic molecules [7][8][9][10][11][12]. The increasing demand for fluorinated scaffolds, due to the striking

• material sciences [14][15][16][17]. In this context, deciphering the impact that can be exerted by the trifluoromethyl group on a cation and the associated consequences when facing the challenge of developing innovative synthetic methods are the subjects of this review. Review Quantitative parameters

¹⁹F NMR as a tool in chemical biology

• Diana Gimenez,
• Aoife Phelan,
• Cormac D. Murphy and
• Steven L. Cobb

Beilstein J. Org. Chem. 2021, 17, 293–318, doi:10.3762/bjoc.17.28

• general, of reactive trifluoromethyl derivatives such as 2,2,2-trifluoroethanethiol (TFET, 17) [23], 3-bromo-1,1,1-trifluoroacetone (BTFA, 18) [24] and fluorinated haloacetamides [25] that can react with nucleophilic side chains on the protein of interest. This approach has been extensively applied to

• study both soluble proteins [26] and membrane proteins [27]. Fluorine tags such at TFET (17) or BFTA (18) offer a good degree of sensitive and narrow 19F NMR line widths due to rapid rotation about the trifluoromethyl symmetry axis. Thus, they are very effective tools when studying small conformational

• include the tags based on fluorinated phenylacetamides, such as the 2-bromo-N-(4-(trifluoromethyl)phenyl)acetamide (BTFMA, 19) and N-(4-bromo-3-(trifluoromethyl)phenyl)acetamide (3-BTFMA, 20) developed by Manglik et al. to study the structural dynamics of the cytoplasmic domain of the β2-adrenergic

The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

• , preparation, and ease of storage. The generation of difluorocarbene from trimethyl(trifluoromethyl)silane: One more modified method, which also increases the rate of the reaction, is the generation of difluorocarbene from TMSCF3 (31), which is also known as the Ruppert–Prakash reagent [39]. The advantages of

• the avoidance of gaseous byproducts [49]. Other mild sources of difluorocarbene include trifluoro(trifluoromethyl)silane (CF3SiF3 [50]) and difluorotris(trifluoromethyl)phosphorane ((CF3)3PF2 [51]). Difluorocarbene generation through the decomposition of hexafluoropropylene oxide upon heating

• Difluorocarbene methods with organometallic sources Decomposition of phenyl(trifluoromethyl)mercury in the presence of sodium iodide: The preparation of difluorocyclopropanes using phenyl(trifluoromethyl)mercury (PhHgCF3, 45, Seyferth's reagent) as a source of difluorocarbene, results in good yields of the

Decarboxylative trifluoromethylthiolation of pyridylacetates

• Ryouta Kawanishi,
• Kosuke Nakada and
• Kazutaka Shibatomi

Beilstein J. Org. Chem. 2021, 17, 229–233, doi:10.3762/bjoc.17.23

• achieved using N-(trifluoromethylthio)benzenesulfonimide as the electrophilic trifluoromethylthiolation reagent. The reaction afforded the corresponding trifluoromethyl thioethers in good yield. Furthermore, the preparation of lithium pyridylacetates by saponification of the corresponding methyl esters and

• ]. Introducing a trifluoromethylthio group (CF3S–), which has high lipophilicity and strong electron-withdrawing properties, into medicinal compounds can improve their pharmacokinetic properties [7][8][9][10][11]. Hence, the development of a synthetic method for the preparation of trifluoromethyl thioethers has

• trifluoromethyl thioethers would be useful for the preparation of various medicinally relevant compounds. Electrophilic decarboxylative functionalization of 2-pyridylacetates. One-pot procedure for the synthesis of 2a. Substrate scope. aSaponification was carried out with 2.5 equiv of LiOH, and 2.5 equiv of 6 was

Exploring the possibility of using fluorine-involved non-conjugated electron-withdrawing groups for thermally activated delayed fluorescence emitters by TD-DFT calculation

• Dongyang Chen and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2021, 17, 210–223, doi:10.3762/bjoc.17.21

• Dongyang Chen Eli Zysman-Colman Organic Semiconductor Centre, EaStCHEM School of Chemistry, University of St Andrews, St Andrews, Fife, KY16 9ST, UK 10.3762/bjoc.17.21 Abstract The trifluoromethyl group has been previously explored as a non-conjugated electron-withdrawing group in donor–acceptor

• ]. Huang et al. also adopted a multiple donor strategy in concert with the weak trifluoromethyl (CF3) acceptor group in their TADF emitter design. The blue-emitting TADF emitter 5CzCF3 possessed a miniscule measured ΔEST of 0.02 eV and ΦPL of 43% in oxygen-free toluene [25]. The solution-processed device

• within TADF emitter design (Figure 1) [25][26][27]. In the present study, we report on the impact of incorporating other fluorine-containing electron-withdrawing groups beyond trifluoromethyl (CF3), including trifluoromethoxy (OCF3), trifluoromethylthio (SCF3), and pentafluorosulfanyl (SF5) groups, and

Facile preparation and conversion of 4,4,4-trifluorobut-2-yn-1-ones to aromatic and heteroaromatic compounds

• Takashi Yamazaki,
• Yoh Nakajima,
• Minato Iida and
• Tomoko Kawasaki-Takasuka

Beilstein J. Org. Chem. 2021, 17, 132–138, doi:10.3762/bjoc.17.14

• Sandford group clarified the high potency of these compounds for the conjugate addition of N- as well as O-nucleophiles [21]. On the basis of such an idea, we tried two routes to gain access to 1) 4-substituted 6-(trifluoromethyl)salicylate derivatives (C-nucleophiles) and 2) 6-substituted 4

• -(trifluoromethyl)pyrimidines (N-nucleophiles), both in a concise fashion, with the full details, including the preparation of 2, being reported herein. Results and Discussion Investigations on the reaction conditions were carried out for the oxidation of propargylic alcohols 1, which were readily accessible by our

• obtained in good to excellent yield without contamination by the deacetylated products 5. With the success of the regiospecific formation of 4-substituted 6-(trifluoromethyl)salicylate derivatives 4, as shown in Table 4, the application of ynones 2 was demonstrated at the next stage for the construction of

Synthesis of aryl 2-bromo-2-chloro-1,1-difluoroethyl ethers through the base-mediated reaction between phenols and halothane

• Yukiko Karuo,
• Ayaka Kametani,
• Atsushi Tarui,
• Kazuyuki Sato,
• Kentaro Kawai and
• Masaaki Omote

Beilstein J. Org. Chem. 2021, 17, 89–96, doi:10.3762/bjoc.17.9

• . Particularly, the latter approach is useful for obtaining liquid crystal materials [35][36][37][38]. In the case of using 2-chloro-3,3,3-trifluoroprop-1-ene (route (c), Scheme 1), the aryl enol ether with a trifluoromethyl group was obtained [39][40]. A further example for the formation of an aryl fluoroalkyl

Benzothiazolium salts as reagents for the deoxygenative perfluoroalkylthiolation of alcohols

• Armin Ariamajd,
• Nils J. Gerwien,
• Benjamin Schwabe,
• Stefan Dix and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2021, 17, 83–88, doi:10.3762/bjoc.17.8

• species with 19F and 1H spectra consistent with the trifluoromethyl thionoester 4a (7% NMR yield, Table 1, entry 1). The formation of both species can be explained by the mechanism shown in Scheme 3 [36]. Nucleophilic attack of the alcohol in the presence of NEt(iPr)2 at the C2-position of the BT reagent

An atom-economical addition of methyl azaarenes with aromatic aldehydes via benzylic C(sp³)–H bond functionalization under solvent- and catalyst-free conditions

• Divya Rohini Yennamaneni,
• Vasu Amrutham,
• Krishna Sai Gajula,
• Rammurthy Banothu,
• Murali Boosa and
• Narender Nama

Beilstein J. Org. Chem. 2020, 16, 3093–3103, doi:10.3762/bjoc.16.259

• ) also reacted well and provided the alcohol 3e in 55% yield along with the alkene product 4e in 19% yield (Table 2, entry 5). Exceptionally, substrates with groups such as cyano, trifluoromethyl, and formyl were reacted and provided the respective dehydrated alkenylpyridine compounds 4i–k in 77%, 71

Silver-catalyzed synthesis of β-fluorovinylphosphonates by phosphonofluorination of aromatic alkynes

• Yajing Zhang,
• Qingshan Tian,
• Guozhu Zhang and
• Dayong Zhang

Beilstein J. Org. Chem. 2020, 16, 3086–3092, doi:10.3762/bjoc.16.258

• . Among the strategies for constructing diverse alkenes containing two-heteroatom bonds, such as disulfonylation [14][15][16], heterohalogenation [17][18][19][20], bis(trifluoromethyl)thiolation [21], and phosphorylation [22], the direct heterodifunctionalization of alkynes using three-component reactions

Deoxyfluorination of acyl fluorides to trifluoromethyl compounds by FLUOLEAD^®/Olah’s reagent under solvent-free conditions

• Yumeng Liang,
• Akihito Taya,
• Zhengyu Zhao,
• Norimichi Saito and
• Norio Shibata

Beilstein J. Org. Chem. 2020, 16, 3052–3058, doi:10.3762/bjoc.16.254

• the formation of trifluoromethyl compounds from acyl fluorides has been developed. The combination of FLUOLEAD® and Olah’s reagent in solvent-free conditions at 70 °C initiated the significant deoxyfluorination of the acyl fluorides and resulted in the corresponding trifluoromethyl products with high

• yields (up to 99%). This strategy showed a great tolerance for various acyl fluorides containing aryloyl, (heteroaryl)oyl, or aliphatic acyl moieties, providing good to excellent yields of the trifluoromethyl products. Synthetic drug-like molecules were also transformed into the corresponding

• trifluoromethyl compounds under the same reaction conditions. A reaction mechanism is proposed. Keywords: acyl fluorides; deoxyfluorination; fluorine; solvent-free; trifluoromethyl group; Introduction Due to an impressively wide effect of fluorine on the biological activity, the insertion of fluorine atoms or

Synthesis of purines and adenines containing the hexafluoroisopropyl group

• Viacheslav Petrov,
• Rebecca J. Dooley,
• Alexander A. Marchione,
• Elizabeth L. Diaz,
• Brittany S. Clem and
• William Marshall

Beilstein J. Org. Chem. 2020, 16, 2739–2748, doi:10.3762/bjoc.16.224

• were prepared by the reaction of 2,2,4,4-tetrakis(trifluoromethyl)-1,3-dithietane (1) with the corresponding substrates, resulting in the selective alkylation of one of the nitrogen atoms of the imidazole ring. The reaction proceeds under mild conditions in a polar solvent, giving the alkylated

• formation of a new derivative of caffeine. Keywords: adenine; caffeine; cyclic dimer of hexafluorothioacetone; hexafluoroisopropyl group; purine; 2,2,4,4-tetrakis(trifluoromethyl)-1,3-dithietane; theophylline; Introduction Despite significant progress in the last 20–30 years, the selective introduction of

• , and the conversion of the ketoester into an amino acid [2]; and the reaction of aldehydes with either Ph3P/(CF3)2CCl2 [3] or 2,2,4,4-tetrakis(trifluoromethyl)-1,3-dithietane [4][5]. The last method was employed in the synthesis of 16,16,16,17,17,17-hexafluororetinal, as reported by the Haas group [5

Activation of pentafluoropropane isomers at a nanoscopic aluminum chlorofluoride: hydrodefluorination versus dehydrofluorination

• Maëva-Charlotte Kervarec,
• Thomas Braun,
• Mike Ahrens and
• Erhard Kemnitz

Beilstein J. Org. Chem. 2020, 16, 2623–2635, doi:10.3762/bjoc.16.213

• need the presence of a hydrogen source in order to promote the activation of at least one C–F bond by the formation of the thermodynamically stable Si–F bond. This observation is consistent with a decrease of the bond dissociation energies of C–F bonds from trifluoromethyl via difluoromethyl to

Thermodynamic and electrochemical study of tailor-made crown ethers for redox-switchable (pseudo)rotaxanes

• Henrik Hupatz,
• Marius Gaedke,
• Hendrik V. Schröder,
• Julia Beerhues,
• Arto Valkonen,
• Fabian Klautzsch,
• Sebastian Müller,
• Felix Witte,
• Kari Rissanen,
• Biprajit Sarkar and
• Christoph A. Schalley

Beilstein J. Org. Chem. 2020, 16, 2576–2588, doi:10.3762/bjoc.16.209

• ion, which resulted in binding constants in the optimal range for ITC titrations [52][53]. The even more weakly coordinating tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (BArF24−) anion exemplarily served for comparison to study the influence of the anion on the binding constant. Two different

• construction of new architectures with emergent properties. Structures of the compounds used in this study: a) crown-8 analogs; b) crown-7 analogs; c) secondary ammonium axles. BArF24− represents tetrakis(3,5-bis(trifluoromethyl)phenyl)borate. Solid-state structures of a) exTTFC7 (CH3CN molecule omitted for

Catalytic trifluoromethylation of iodoarenes by use of 2-trifluoromethylated benzimidazoline as trifluoromethylating reagent

• Tatsuhiro Uchikura,
• Nanami Kamiyama,
• Taisuke Ishikawa and
• Takahiko Akiyama

Beilstein J. Org. Chem. 2020, 16, 2442–2447, doi:10.3762/bjoc.16.198

• ; catalysis; copper; fluorine chemistry; trifluoromethylation; Introduction The introduction of a trifluoromethyl group is one of the most attractive reactions in drug discovery [1][2]. In the past decade, trifluoromethylation reactions of aryl halides in the presence of transition-metal complexes were

• conditions by use of p-iodonitrobenzene (1a) and 2-phenyl-2-trifluoromethyl-1-methylbenzimidazoline (2) (Table 1). Using 3 equiv of CuI gave 4-trifluoromethyl-1-nitrobenzene (3a) quantitatively, as we had reported previously (Table 1, entry 1) [22]. Decreasing the CuI catalyst loading to 20 mol % lowered the

• , entries 9 and 10). However, we selected the most stable and readily available CuI as the catalyst for further investigations. Thus, the trifluoromethylation of p-iodonitrobenzene proceeded by use of 2-phenyl-2-trifluoromethyl-1-methylbenzimidazoline in the presence of catalytic amounts of CuI and 2,2

Chan–Evans–Lam N1-(het)arylation and N1-alkеnylation of 4-fluoroalkylpyrimidin-2(1H)-ones

• Viktor M. Tkachuk,
• Oleh O. Lukianov,
• Mykhailo V. Vovk,
• Isabelle Gillaizeau and
• Volodymyr A. Sukach

Beilstein J. Org. Chem. 2020, 16, 2304–2313, doi:10.3762/bjoc.16.191

• , heterocyclic analogues of activated ketimines (Figure 1), thus offering potential applications in the design of new heterocyclic chemotypes [21][22][23][24][25]. Compounds I are precursors of trifluoromethyl-substituted dihydropyrimidine derivatives which appear as original and potent scaffolds in medicinal

• -deficient pyrimidyl instead of the pyridyl residue was completely unreactive to N1-hetarylation of substrate 1a under the conditions used. Contrary to this case, the method developed allowed electron-rich heterocyclic nuclei including the 3-thienyl (but not isomeric 2-thienyl), 5-trifluoromethyl-3-thienyl

• -arylation process. As evidenced by LCMS analysis, the reaction with 6-methyl-4-(trifluoromethyl)pyrimidin-2(1H)-one provided a mixture of three cross-coupling products (not separated), with a total yield of no more than 18%, which suggests a poor regioselectivity. Conclusion We have optimized the reaction

Regioselective cobalt(II)-catalyzed [2 + 3] cycloaddition reaction of fluoroalkylated alkynes with 2-formylphenylboronic acids: easy access to 2-fluoroalkylated indenols

• Tatsuya Kumon,
• Miroku Shimada,
• Jianyan Wu,
• Shigeyuki Yamada and
• Tsutomu Konno

Beilstein J. Org. Chem. 2020, 16, 2193–2200, doi:10.3762/bjoc.16.184

• C. Then, dehydration of C using p-TsOH⋅H2O, followed by a 1,2-reduction led to 3-fluoroalkylated indenol D. All of these reactions produced the desired products in good yield, however, this protocol is limited to the introduction of a trifluoromethyl group at the 3-position of the indenol. To the

• 2-fluoroalkylated indanone 7, also possess a trifluoromethyl group at the 2-position. Each Ha–Hb coupling of 5aA and each Hc–Hd coupling of 7 appeared as a doublet, with J = 4.0 Hz and 4.6 Hz, respectively. These NMR results suggested that the fluoroalkylated indanones 5aA and 7 were trans-isomers

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

• atoms, including drugs used to treat cancer, HIV, smallpox and malarial infections (Figure 1) [5][6]. Moreover, fluorine atoms and trifluoromethyl groups have dramatic effects on the biological activity of agrochemicals, such as herbicides, insecticides and fungicides, as reflected by a plethora of

• = 1.20 Å) [9][14], the fluorine atom is often used as a bioisostere for the hydrogen atom. Furthermore, the trifluoromethyl group was recently identified as a bioisostere for the nitro (NO2) group, which is important due to the strong binding ability of the nitro group and the high reactivity, which is

• and co-workers first synthesized the NFPYs [186]. Further synthesis of similar compounds resulted in the synthesis of N-fluorobis(phenyl)sulfonimide (NFSI) [187], N-fluorobis[(trifluoromethyl)sulfonyl]imide [188][189], N-fluoropyridinium salts [186], N-fluorosaccharinsultam and 4-nitro-substituted N

Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups

• Benjamin Jeffries,
• Zhong Wang,
• Robert I. Troup,
• Anaïs Goupille,
• Jean-Yves Le Questel,
• Charlene Fallan,
• James S. Scott,
• Elisabetta Chiarparin,
• Jérôme Graton and
• Bruno Linclau

Beilstein J. Org. Chem. 2020, 16, 2141–2150, doi:10.3762/bjoc.16.182

• existing appendages is also commonly employed. For example, an isopropyl and a trifluoromethyl group have very similar volumes, but a very different shape [6]. However, even the introduction of relatively small methyl groups can impart profound consequences (“the magic methyl effect”) [7][8][9] on the

• ). With one (A4) and two (A5) trifluoromethyl groups, large increases in lipophilicity are observed. An interesting series (B) of phenylcyclopropanes was reported by O’Hagan [25][26]. All-cis vicinal trifluorination as in B2 led to a significant reduction in lipophilicity compared to the nonfluorinated B1

• when the “cyclisation” operation is achieved from geminal motifs (Figure 7B). Significant logP reductions are observed, especially from the internal geminal fluorination motif as in G9 to E2 (0.72 logP units). Starting from a trifluoromethyl group (Figure 7C), similar logP reductions are achieved (e.g

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

• Thomas Schneider Michael Keim Bianca Seitz Gerhard Maas Institute of Organic Chemistry I, Ulm University, Albert-Einstein-Allee 11, D-89081 Ulm, Germany 10.3762/bjoc.16.173 Abstract 3-Aryl-1-(trifluoromethyl)prop-2-yn-1-iminium triflate salts represent a novel, highly reactive class of acetylenic

• even anthracene. At higher temperature, the cycloadducts undergo an intramolecular SE(Ar) reaction leading to condensed carbocycles incorporating a 1-(trifluoromethyl)-1-(dimethylamine)indene ring system. With styrenes and some substituted styrenes, cascade reactions take place, which likely include

• years, a trifluoromethyl substituent has been included quite often in the design of compounds which were developed for applications in various fields, such as biological and medicinal chemistry, agrochemicals, transition metal ligands, and materials science [1][2][3][4][5]. The particular

Synthesis of 3(2)-phosphonylated thiazolo[3,2-a]oxopyrimidines

• Ksenia I. Kaskevich,
• Anastasia A. Babushkina,
• Vladislav V. Gurzhiy,
• Dmitrij M. Egorov,
• Nataly I. Svintsitskaya and
• Albina V. Dogadina

Beilstein J. Org. Chem. 2020, 16, 1947–1954, doi:10.3762/bjoc.16.161

• observed in the case of 6-trifluoromethyl-2-thiouracil that afforded 2- and 3-phosphonylated 5-oxothiazolopyrimidines in a 1:1 ratio. Keywords: chloroethynylphosphonate; heterocyclization; phosphonylated thiazolopyrimidines; phosphonylation; thiazolopyrimidine; 2-thiouracil; Introduction

• in the 31P NMR spectrum upon standing at room temperature for 24 hours. The analysis of the formed precipitate identified product 6aa, representing the monodealkylation product of the dimethylphosphonate group. A similar phenomenon has been reported earlier [41]. In the case of 6-trifluoromethyl-2

• presence of a trifluoromethyl group in position 6 favored an attack by the N3-nitrogen atom, resulting in the formation of the 5-oxo isomer. The formation of the 2-phosphonylated thiazolopyrimidine-5-one could be explained by a primary attack of the electrophilic carbon atom bonded to the chlorine atom by

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

• Vladimir Kubyshkin

Beilstein J. Org. Chem. 2020, 16, 1837–1852, doi:10.3762/bjoc.16.151

• isomerism were examined for diastereomeric 4-fluoroprolines, 4-(trifluoromethyl)prolines, and 1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylates. The preferred conformation on the proline ring originated from a preferential axial positioning for a single fluorine atom, and an equatorial positioning for a

• trifluoromethyl- or a difluoromethylene group. This orientation of the substituents explains the observed trends in the pKa values, lipophilicity, and the kinetics of the amide bond rotation. The study also provides a set of evidences that the transition state of the amide-bond rotation in peptidyl-prolyl favors

• phenomena in two typical examples: 4-fluoroprolines and 4-(trifluoromethyl)prolines (Figure 2). The study aims to provide experimental characterization of these amino acids in the context of simple molecular models. Thereby, it may help to build predictions for the amino acid use in the context of more

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

• performed under air at high temperatures. The coupling exhibited a broad substrate scope and the procedure tolerated a variety of even sensitive functional groups, including trifluoromethyl, ketone, or ester motifs. Unsymmetrical alkynes were also compatible, although the cyclization provided the desired

• , ethoxy, trifluoromethyl, nitro, and ester underwent efficiently the desired perfluoroalkylation. This coupling was sensitive to steric hindrance as ortho-substituted substrates were less efficiently converted into the desired products. Furthermore, various perfluoroalkyl iodides with different chain

• lengths were potent substrates, affording the corresponding perfluoralkylated products in moderate to good yields, except for trifluoromethyl iodide, presumably due to the low boiling point of CF3I. Finally, the removal of the DG allowed the post-modification of the products into the corresponding