Fluorine-containing substituents: metabolism of the α,α-difluoroethyl thioether motif

• Andrea Rodil,
• Alexandra M. Z. Slawin,
• Nawaf Al-Maharik,
• Ren Tomita and
• David O’Hagan

Beilstein J. Org. Chem. 2019, 15, 1441–1447, doi:10.3762/bjoc.15.144

• trifluoromethyl sulfonyl ether bioactives. Comparison of log P values of comparative aryl thioether motifs [18]. α,α-Difluoroethyl thioether substrates for metabolism studies. Fluorometabolites 6–8 isolated after incubation of 4 with C. elegans. Ratios are the average of three incubations. The structure of 7 was

Synthesis of aryl cyclopropyl sulfides through copper-promoted S-cyclopropylation of thiophenols using cyclopropylboronic acid

• Emeline Benoit,
• Ahmed Fnaiche and
• Alexandre Gagnon

Beilstein J. Org. Chem. 2019, 15, 1162–1171, doi:10.3762/bjoc.15.113

• was produced in a low 31% yield. Electron-withdrawing groups such as a fluorine, bromine, chlorine, trifluoromethyl and a nitro group as well as electron-donating groups such as a methoxy group at the para-position were found to be well tolerated, as indicated by aryl cyclopropyl sulfides 1h–m which

• ) δ 7.39 (d, J = 8.4 Hz, 4H), 7.27 (d, J = 8.7, 4H). Cyclopropyl(4-(trifluoromethyl)phenyl)sulfane (1k). The general procedure was followed on 0.400 mmol scale starting from 4-(trifluoromethyl)benzenethiol (14k). The residue was purified on silica gel (100% Hex) to afford 1k (63.2 mg, 72%) as a light

Stereo- and regioselective hydroboration of 1-exo-methylene pyranoses: discovery of aryltriazolylmethyl C-galactopyranosides as selective galectin-1 inhibitors

• Alexander Dahlqvist,
• Axel Furevi,
• Niklas Warlin,
• Hakon Leffler and
• Ulf J. Nilsson

Beilstein J. Org. Chem. 2019, 15, 1046–1060, doi:10.3762/bjoc.15.102

• -fluorophenyltriazolyl)methyl galactopyranoside 1b having an affinity of 170 ± 2 µM and fourfold better than for galectin-3 (Table 1). The (4-(trifluoromethyl)phenyltriazolyl)methyl galactopyranoside 1k displayed a comparable affinity of 240 ± 61 µM, but slightly lower selectivity over galectin-3. (1-Naphthyltriazolyl

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

• sequence including one deprotection reaction. One functional unit is α-lipoic acid (ALA) for binding the dye to gold surfaces. It was introduced to the DAT scaffold by an amidation reaction. The other functional unit is a para-(trifluoromethyl)benzyl group for facile detection of the surface-bound material

• suitability for molecular surface labeling. Conclusion Two bifunctional diaminoterephthalate (DAT) fluorescence dyes have been prepared. One functional unit is α-lipoic acid (ALA) for binding the dye to gold surfaces. The other carries a trifluoromethyl group for facile detection of the surface-bound material

• by X-ray photoelectron spectroscopy (XPS). In the first of two target structures, compound 3, the fluorinated residue was introduced by reductive amination of mono-N-Boc-protected diethyl DAT 1 with para-(trifluoromethyl)-substituted benzaldehyde. After N-deprotection, the ALA unit was introduced by

An efficient and concise access to 2-amino-4H-benzothiopyran-4-one derivatives

• Peng Li,
• Yongqi Wu,
• Tingting Zhang,
• Chen Ma,
• Ziyun Lin,
• Gang Li and
• Haihong Huang

Beilstein J. Org. Chem. 2019, 15, 703–709, doi:10.3762/bjoc.15.65

• -aminobenzothiopyranones containing 8-nitro and 6-trifluoromethyl substituents in low to moderate yields through the transformation of a 2-methylthio substituent under harsh conditions (method F, Scheme 1) [5]. In addition, the nucleophile imidazole could also react with 3-bromobenzothiopyranones to afford 2

• , the 2-position of the benzopyranone scaffold is easier to be attacked by nucleophiles than that the corresponding benzothiopyranone. We anticipate that the electron-withdrawing effect of a cyano, carbonyl, nitro or trifluoromethyl group, especially at the 3-position could render the sulfide, sulfinyl

• such as trifluoromethyl gave the desired products, e.g., 4m,n in high yields. Substrates bearing electron-donating groups also reacted with aliphatic amines giving products 4o–q in good yields. It was noted that the treatment of substrate 2 containing a chloro substituent with weaker nucleophilic

The LANCA three-component reaction to highly substituted β-ketoenamides – versatile intermediates for the synthesis of functionalized pyridine, pyrimidine, oxazole and quinoxaline derivatives

• Tilman Lechel,
• Roopender Kumar,
• Mrinal K. Bera,
• Reinhold Zimmer and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2019, 15, 655–678, doi:10.3762/bjoc.15.61

• detected in the crude product. The reactions of β-ketoenamides KE60, KE61 and KE68 (R2 = tert-butyl or adamantanyl, R3 = methyl, trifluoromethyl or cyclopropyl) provided mixtures of oxazoles OX7, OX8 and OX10, respectively, and of 1,2-diketones DK4, DK5 and DK11 (Table 6, entries 9, 10, and 16). For

Dirhodium(II)-catalyzed [3 + 2] cycloaddition of N-arylaminocyclopropane with alkyne derivatives

• Wentong Liu,
• Yi Kuang,
• Zhifan Wang,
• Jin Zhu and
• Yuanhua Wang

Beilstein J. Org. Chem. 2019, 15, 542–550, doi:10.3762/bjoc.15.48

• -withdrawing groups at the aromatic substuituent proceeded slowly, producing considerably lower yields of the corresponding products. For instance, multiple-substituted compound 1 (with a 3,5-disubstitued trifluoromethyl 1f) generated product 3f with a yield of 36% (88% brsm) after 24 h (Table 2, entry 5), but

Sigmatropic rearrangements of cyclopropenylcarbinol derivatives. Access to diversely substituted alkylidenecyclopropanes

• Guillaume Ernouf,
• Jean-Louis Brayer,
• Christophe Meyer and
• Janine Cossy

Beilstein J. Org. Chem. 2019, 15, 333–350, doi:10.3762/bjoc.15.29

• )(aminocyclopropanes) 42 and 43, substituted by a p-fluorophenyl and a p-(trifluoromethyl)phenyl group, respectively, were isolated in moderate yield (53%). Moreover, (p-nitrophenylmethylene)cyclopropane 44 could not be obtained under these conditions [53]. These results indicate that the [3,3]-sigmatropic

• substituents at C2 were viable substrates. The sequence allowed access to benzylidenecyclopropane 58d (93%) and to (arylmethylene)cyclopropane 58e in excellent yield (90%), despite the presence of the electron-withdrawing trifluoromethyl substituent at the para-position of the aromatic ring. Some

Application of olefin metathesis in the synthesis of functionalized polyhedral oligomeric silsesquioxanes (POSS) and POSS-containing polymeric materials

• Patrycja Żak and
• Cezary Pietraszuk

Beilstein J. Org. Chem. 2019, 15, 310–332, doi:10.3762/bjoc.15.28

• dispersed over all loadings. No improvements in thermal properties were observed in the copolymers obtained. Another POSS-containing monomer – N-(propyl-POSS)-7-oxanorbornene-5,6-dicarboximide was tested in ring-opening metathesis copolymerization with 3-(trifluoromethyl)phenyl-7-oxanorbornene-5,6

• of polymers and copolymers with 3-(trifluoromethyl)phenyl-7-oxanorbornene-5,6-dicarboximide (Scheme 25) [48]. It was found that the increase in the content of POSS units in the copolymer results in a decrease in thermal stability and Tg values. TEM and AFM microimages show spherical POSS aggregates

• subsequent hydrogenation. ROMP of norbornenylethyl-POSS with 1,5-cyclooctadiene. Copolymerization of POSS-functionalized norbornene with DCPD. Copolymerization of tris(norbornenylethyl)-POSS with DCPD. Copolymerization of N-(propyl-POSS)-7-oxanorbornene-5,6-dicarboximide with 3-(trifluoromethyl)phenyl-7

A novel and efficient synthesis of phenanthrene derivatives via palladium/norbornadiene-catalyzed domino one-pot reaction

• Yue Zhong,
• Wen-Yu Wu,
• Shao-Peng Yu,
• Tian-Yuan Fan,
• Hai-Tao Yu,
• Nian-Guang Li,
• Zhi-Hao Shi,
• Yu-Ping Tang and
• Jin-Ao Duan

Beilstein J. Org. Chem. 2019, 15, 291–298, doi:10.3762/bjoc.15.26

• , trifluoromethyl and ester, gave 75–95% yields of the corresponding products y-9–y-13, which were precursors for further transition metal-catalyzed cross-coupling reactions. To further explore the generality of this reaction, different substituted ortho-bromobenzoyl chlorides were then tested (Scheme 3). The ortho

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

• 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

• clinical trials for type 2 diabetes mellitus. Xu et al. also presented the similar ring-opening/trifluoromethylation of cyclopropanols for the synthesis of various β-trifluoromethyl ketones [103]. In this year, Loh et al. [104] and Zhu et al. [105] proposed a oxidative ring-opening and fluorination of

• -trifluoromethyl ketones 128 at room temperature and in an open flask (Scheme 33) [113]. The presented results provided an efficient and convenient method for the synthesis of diverse fulorinated ketones from cyclopropanols. In the same year, this group developed a similar copper-catalyzed ring-opening and

Gold-catalyzed ethylene cyclopropanation

• Silvia G. Rull,
• Andrea Olmos and
• Pedro J. Pérez

Beilstein J. Org. Chem. 2019, 15, 67–71, doi:10.3762/bjoc.15.7

• directly converted into ethyl 1-cyclopropylcarboxylate upon reaction with ethyl diazoacetate (N2CHCO2Et, EDA) in the presence of catalytic amounts of IPrAuCl/NaBArF4 (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene; BArF4 = tetrakis(3,5-bis(trifluoromethyl)phenyl)borate). Keywords: carbene

• = tetrakis(3,5-bis(trifluoromethyl)phenyl)borate) catalyzes the ethylene cyclopropanation with ethyl diazoacetate as the carbene precursor, under mild conditions, with moderate yields (ca. 70%, EDA-based). Results and Discussion Diazo compounds N2=CRR’ usually react with metal complexes of groups 8–11 with

Ruthenium-based olefin metathesis catalysts with monodentate unsymmetrical NHC ligands

• Veronica Paradiso,
• Chiara Costabile and
• Fabia Grisi

Beilstein J. Org. Chem. 2018, 14, 3122–3149, doi:10.3762/bjoc.14.292

• -trifluoromethyl benzimidazolidene NHCs With the goal to develop chemoselective catalysts, ruthenium complexes containing unsymmetrical N-trifluoromethyl NHCs were introduced by Togni et al. (150–152, Figure 29) [49]. The presence of one N-trifluoromethyl substituent was supposed to impart positive effects on the

• . Catalyst 154 containing an N-isopropyl group (Figure 29), which is considered to be sterically equivalent to the N-trifluoromethyl group, disclosed a substantially lower selectivity in both alternating copolymerization and ethenolysis reaction, underlining that the electronic effect determined by the

Synthesis of unnatural α-amino esters using ethyl nitroacetate and condensation or cycloaddition reactions

• Glwadys Gagnot,
• Vincent Hervin,
• Eloi P. Coutant,
• Sarah Desmons,
• Racha Baatallah,
• Victor Monnot and
• Yves L. Janin

Beilstein J. Org. Chem. 2018, 14, 2846–2852, doi:10.3762/bjoc.14.263

• focused on the model preparation of the trifluoromethyl-bearing α-nitro ester 6j from acylals 7 depicted in Scheme 2. As well reviewed [14], acylals can be prepared from aldehydes and anhydrides using a variety of acids as catalysts. In our case, 1H NMR monitoring of the reaction between 2

• -(trifluoromethyl)benzaldehyde (3j) and acetic anhydride using indium(III) chloride [15] as a Lewis acid catalyst [16] without any solvent at room temperature pointed out a complete conversion into acylal 7 overnight. A similar reaction using pivaloyl anhydride and either indium(III) chloride or tetrafluoroboric

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

• perfluoroalkylation of aromatic and heteoaromatic compounds by means of electrolysis [119][120]. Introducing trifluoromethyl and perfluoroalkyl groups (RF) into organic compounds is an important target in organic synthesis because the corresponding fluoroalkylated molecules have received significant interest because

Cobalt- and rhodium-catalyzed carboxylation using carbon dioxide as the C1 source

• Tetsuaki Fujihara and
• Yasushi Tsuji

Beilstein J. Org. Chem. 2018, 14, 2435–2460, doi:10.3762/bjoc.14.221

• α,β-unsaturated carboxamides 9 (Scheme 9). By using 10 mol % of Co(acac)2 and 4 equiv of Et2Zn, N-methylanilide derivatives 9a–f were smoothly converted into the corresponding products 10a–f in high yields. Trifluoromethyl and chloro substituents were tolerated in these reactions, judging by the

• Zn was performed. After treatment with H2O and allyl bromide, the corresponding products 19a-H and 19a-Allyl were obtained in high yields. Chloro and trifluoromethyl functionalities were well tolerated under the reaction conditions, and 19b-Me and 19c-Me were obtained in 55% and 57% yields

• trifluoromethylbenzene (32d) afforded the corresponding carboxylic acids 33b, 33c, and 33d in good TON. o-Xylene yielded its corresponding mixture of carboxylic acids 33e. When 1,3-bis(trifluoromethyl)benzene (32f) was used as the substrate at 145 °C, the corresponding carboxylic acid 33f was site-selectively obtained

Synthesis of indolo[1,2-c]quinazolines from 2-alkynylaniline derivatives through Pd-catalyzed indole formation/cyclization with N,N-dimethylformamide dimethyl acetal

• Antonio Arcadi,
• Sandro Cacchi,
• Giancarlo Fabrizi,
• Francesca Ghirga,
• Antonella Goggiamani,
• Antonia Iazzetti and
• Fabio Marinelli

Beilstein J. Org. Chem. 2018, 14, 2411–2417, doi:10.3762/bjoc.14.218

• -(o-aminophenyl)indole derivatives followed by further cyclization [19][20][21][22]. Our interest in this field led to the development of an original approach to 6-trifluoromethyl-12-aryl(vinyl)indolo[1,2-c]quinazolines 4 through sequential Pd-catalyzed reactions of bis(o-trifluoroacetamidophenyl

• accomplished, without competitive formation of products derived from C-3 functionalization at the indole moiety. Synthesis of 6-trifluoromethyl-12-aryl(vinyl)indolo[1,2-c]quinazolines 4. Present and previously reported reactions starting from 5. DMFDMA: dimethylformamide dimethyl acetal. Two-step synthesis of

Some mechanistic aspects regarding the Suzuki–Miyaura reaction between selected ortho-substituted phenylboronic acids and 3,4,5-tribromo-2,6-dimethylpyridine

• Piotr Pomarański,
• Piotr Roszkowski,
• Jan K. Maurin,
• Armand Budzianowski and
• Zbigniew Czarnocki

Beilstein J. Org. Chem. 2018, 14, 2384–2393, doi:10.3762/bjoc.14.214

• -substituted boronic acids to obtain the desired coupling products with good selectivity and yield [15]. Recently, the synthesis of some differently para- and meta-substituted derivatives of 2,6-diaryl-3-(trifluoromethyl)pyridine by regioselective Suzuki–Miyaura reactions was also described [16]. In this case

Practical tetrafluoroethylene fragment installation through a coupling reaction of (1,1,2,2-tetrafluorobut-3-en-1-yl)zinc bromide with various electrophiles

• Ken Tamamoto,
• Shigeyuki Yamada and
• Tsutomu Konno

Beilstein J. Org. Chem. 2018, 14, 2375–2383, doi:10.3762/bjoc.14.213

• - (3d) or p-trifluoromethyl-substituted iodobenzene (3e) could also participate in the coupling reaction, leading to the corresponding products 4d and 4e in 53% and 75% NMR (49% and 13% isolated) yields, respectively. Notably, iodoarenes with an ethoxycarbonyl (3f) or a nitro group (3g) at the para

Tetrathiafulvalene – a redox-switchable building block to control motion in mechanically interlocked molecules

• Hendrik V. Schröder and
• Christoph A. Schalley

Beilstein J. Org. Chem. 2018, 14, 2163–2185, doi:10.3762/bjoc.14.190

• station by hydrogen bonds as shown by the high association constant of a structurally similar pseudorotaxane precursor (Ka = 590,000 M−1). The high association constant is a result of the weakly coordinating anion (WCA) used, i.e., tetrakis(3,5-bis(trifluoromethyl)phenyl)borate. Comparison to a

Calix[6]arene-based atropoisomeric pseudo[2]rotaxanes

• Carmine Gaeta,
• Carmen Talotta and
• Placido Neri

Beilstein J. Org. Chem. 2018, 14, 2112–2124, doi:10.3762/bjoc.14.186

• formation of a white precipitate. The solid was collected by filtration, washed with MeOH (10 mL) and CH3CN (10 mL) and dried under vacuum to give the ammonium chloride derivative. The chloride salt (0.68 mmol) and sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (0.60 g, 0.68 mmol) were dissolved in

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

• the modified substituted imidazo[1,2-a]pyridines contains scaffolds commonly found in pharmaceuticals, such as sulfones 9a and trifluoromethyl groups 9b. Hence, this publication provides an easy route to access scaffolds with diverse aromatic systems, allowing for the construction of interesting

• trifluoromethyl are not tolerated. No functional group tolerance towards other carbonyls such as esters or aldehydes is demonstrated. The use of terminal or trisubstituted alkenes is limited and the reaction times are long. However, the authors do report that the reaction is somewhat diastereoselective, favouring

• groups, e.g., methyl, fluoro, chloro, trifluoromethyl etc., or can be aimed at installing larger functional groups, e.g., heterocycles, amides or long alkyl chains. The previous two sections outlined how mild the reaction conditions employed in visible light organophotoredox catalysis usually are, making

Asymmetric Michael addition reactions catalyzed by calix[4]thiourea cyclohexanediamine derivatives

• Zheng-Yi Li,
• Hong-Xiao Tong,
• Yuan Chen,
• Hong-Kui Su,
• Tangxin Xiao,
• Xiao-Qiang Sun and
• Leyong Wang

Beilstein J. Org. Chem. 2018, 14, 1901–1907, doi:10.3762/bjoc.14.164

• ]. In 2016, Hernández-Rodríguez and co-workers reported the preparation of bifunctional thioureas that contained either a methyl or trifluoromethyl group [14]. They discovered that the employment of chiral moieties with an α-trifluoromethyl group in thioureas show a positive effect on the selectivity

• the reaction. The presence of a strong electron-withdrawing trifluoromethyl group afforded the product 9e (76% ee) with higher enantioselectivity than a strong-electron donating methoxy group (9c, 46% ee), while products with methyl and halogen groups showed moderate enantioselectivities (59–72% ee

Diazirine-functionalized mannosides for photoaffinity labeling: trouble with FimH

• Femke Beiroth,
• Tomas Koudelka,
• Thorsten Overath,
• Stefan D. Knight,
• Andreas Tholey and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1890–1900, doi:10.3762/bjoc.14.163

• olefin formation through abstraction of α-H atoms. Therefore, aryl(trifluoromethyl)diazirines were introduced, which lack hydrogen atoms in α-position of the diazirine function and consequently do not form olefins. Thus, aryl(trifluoromethyl)diazirines have become reagents of first choice for

• steps of diazirine compounds were performed in the dark. N-{2-Oxo-2-[(4-(α-D-mannopyranosyloxy)phenyl)amino]ethyl}-4-(3-trifluoromethyl-3H-diazirin-3-yl)benzamide (3). The glycoamino acid 7 (52.8 mg, 160 µmol) was dissolved in distilled water which contained 50% TFA (5 mL). The solution was then stirred

• MHz, MeOH-d4) δ −66.87 (s) ppm; ESIMS m/z: 579.12 [M + K]+, 563.14 [M + Na]+, 535.13 [(M + Na) − N2]+; HRESIMS m/z: [M + H]+ calcd. for C23H23F3N4O8, 541.15408; found, 541.15424. {N-[4-(α-D-Mannopyranosyloxy)phenyl]-N’-[2’-(4’’-(3-trifluoromethyl-3H-diazirin-3-yl)phenylamido)ethyl]}squaric acid

β-Hydroxy sulfides and their syntheses

• Mokgethwa B. Marakalala,
• Edwin M. Mmutlane and
• Henok H. Kinfe

Beilstein J. Org. Chem. 2018, 14, 1668–1692, doi:10.3762/bjoc.14.143

• synthesis of β-hydroxy sulfides, with a catalytic amount of tert-butyl hydroperoxide (TBHP) as an initiator (Scheme 28) [66]. Even styrenes bearing powerful electron withdrawing groups such as nitriles (CN), trifluoromethyl (CF3) and ester groups (COOCH3) gave the corresponding β-hydroxy sulfides, albeit in