Electrophilic trifluoromethylselenolation of terminal alkynes with Se-(trifluoromethyl) 4-methylbenzenesulfonoselenoate

• Clément Ghiazza,
• Anis Tlili and
• Thierry Billard

Beilstein J. Org. Chem. 2017, 13, 2626–2630, doi:10.3762/bjoc.13.260

• the nucleophilic addition of Se-(trifluoromethyl) 4-methylbenzenesulfonoselenoate, a stable and easy-to-handle reagent, to alkynes is described. This reaction provides trifluoromethylselenylated vinyl sulfones with good results and the method was extended also to higher fluorinated homologs. The

• obtained compounds are valuable building blocks for further syntheses of fluoroalkylselenolated molecules. Keywords: alkynes; nucleophilic addition; perfluoroalkylselenolation; Se-(trifluoromethyl) 4-methylbenzenesulfonoselenoate; trifluoromethylselenolation; Introduction Over the last decades

• developed another easier-to-use reagent with a more controlled reactivity to perform electrophilic trifluoromethylselenolations, namely Se-(trifluoromethyl) 4-methylbenzenesulfonoselenoate (1a). This reagent is easily obtained by reacting sodium toluenesulfinate with in situ formed CF3SeCl [68]. With this

Regioselective decarboxylative addition of malonic acid and its mono(thio)esters to 4-trifluoromethylpyrimidin-2(1H)-ones

• Sergii V. Melnykov,
• Andrii S. Pataman,
• Yurii V. Dmytriv,
• Svitlana V. Shishkina,
• Mykhailo V. Vovk and
• Volodymyr A. Sukach

Beilstein J. Org. Chem. 2017, 13, 2617–2625, doi:10.3762/bjoc.13.259

• malonic acid and its mono(thio)esters have been poorly investigated so far despite the potential to become a convenient route to β-trifluoromethyl-β-amino acid derivatives and to their partially saturated heterocyclic analogues. Results: In this paper we show that 4-trifluoromethylpyrimidin-2(1H)-ones

• synthesis of novel isomeric 4(6)-trifluoromethylated 1,2,3,4-tetrahydro- and perhydro-(2-oxopyrimidin-4-yl)acetic acid derivatives. Keywords: ketimines; malonic acid; Michael- and Mannich-type decarboxylative addition; pyrimidin-2(1H)-ones; regioselectivity; trifluoromethyl group; Introduction

• conventional functionalization or (hetero)cyclization [15][16][17]. Among these reagents, trifluoromethylketimines have drawn much research interest in recent years as key starting materials for the synthesis of trifluoromethyl-substituted amines [18][19], α-amino acids [20][21][22][23] as well as nitrogen

Palladium-catalyzed Heck-type reaction of secondary trifluoromethylated alkyl bromides

• Tao Fan,
• Wei-Dong Meng and
• Xingang Zhang

Beilstein J. Org. Chem. 2017, 13, 2610–2616, doi:10.3762/bjoc.13.258

• delivers trifluoromethylated allylic products 3 and 4. Conclusion In conclusion, we have developed an efficient method for preparation of aliphatic alkenes branched with a trifluoromethyl group by palladium catalyzed Heck-type reaction of secondary trifluoromethylated alkyl bromides. The reaction proceeds

A concise flow synthesis of indole-3-carboxylic ester and its derivatisation to an auxin mimic

• Marcus Baumann,
• Ian R. Baxendale and
• Fabien Deplante

Beilstein J. Org. Chem. 2017, 13, 2549–2560, doi:10.3762/bjoc.13.251

• [42]. Heating for the 52 mL flow coils was provided using a Polar Bear Plus unit [43]. Ethyl 2-cyano-2-(2-nitro-4-(trifluoromethyl)phenyl)acetate (11) [44]: Process 1 (DCM): Two stock solutions in DCM were prepared. Solution A: TMG (1.25 M, 2.5 equiv) and solution B: a mixture of 4-chloro-3

• ), 1324 (s), 1257 (s), 1182 (s), 1138 (s), 1090 (s), 1012 (m), 866 (m), 825 (m), 698 (m); LC–MS (TOF+) 302.1 (M + H); HRMS (ESI) m/z: calcd for C12H8N2O4F3, 301.0436; found, 301.0452 (Δ = 5.3 ppm); melting range: 60.5–61.6 °C; X-ray crystal data: CCDC 1572810. Ethyl 6-(trifluoromethyl)-1H-indole-3

• -(trifluoromethyl)-1H-indole-3-carboxylate (14) [45]: 1H NMR (400 MHz, DMSO-d6) δ 10.90 (br s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.00 (s, 2H), 4.26 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 165.9 (C), 155.3 (C), 132.5 (C), 130.5 (C), 126.0 (CF3

One-pot three-component route for the synthesis of S-trifluoromethyl dithiocarbamates using Togni’s reagent

• Azim Ziyaei Halimehjani,
• Martin Dračínský and
• Petr Beier

Beilstein J. Org. Chem. 2017, 13, 2502–2508, doi:10.3762/bjoc.13.247

• /bjoc.13.247 Abstract A one-pot three-component route for the synthesis of S-trifluoromethyl dithiocarbamates by the reaction of secondary amines, carbon disulfide and Togni’s reagent is described. The reactions proceed in moderate to good yields. A similar reaction using a primary aliphatic amine

• novel dithiocarbamates. Nevertheless, new synthetic methods towards dithiocarbamates are sought after and research in this area is still intense. The introduction of a trifluoromethyl group into organic compounds is a very productive strategy of modification of molecules for various applications in the

• been reported to introduce the trifluoromethyl group in organic structures including nucleophilic, electrophilic, radical and transition metal-mediated trifluoromethylations. Among the electrophilic trifluoromethylation methods, reagents based on hypervalent iodine (Togni's reagents I and II, Scheme 1b

Syntheses, structures, and stabilities of aliphatic and aromatic fluorous iodine(I) and iodine(III) compounds: the role of iodine Lewis basicity

• Tathagata Mukherjee,
• Soumik Biswas,
• Andreas Ehnbom,
• Subrata K. Ghosh,
• Ibrahim El-Zoghbi,
• Nattamai Bhuvanesh,
• Hassan S. Bazzi and
• John A. Gladysz

Beilstein J. Org. Chem. 2017, 13, 2486–2501, doi:10.3762/bjoc.13.246

• to the triflates RfnCH2OTf using pyridine and triflic anhydride (Tf2O) in (trifluoromethyl)benzene (CF3C6H5), an amphoteric solvent that is usually able to dissolve appreciable quantities of both fluorous and non-fluorous solutes [33]. The reactions with n = 11 and 13 were conducted at 0 °C, and work

Diastereoselective Mannich reactions of pseudo-C₂-symmetric glutarimide with activated imines

• Tatsuya Ishikawa,
• Tomoko Kawasaki-Takasuka,
• Toshio Kubota and
• Takashi Yamazaki

Beilstein J. Org. Chem. 2017, 13, 2473–2477, doi:10.3762/bjoc.13.244

• , Nakanarusawa 4-12-1, Hitachi 316-8511, Japan 10.3762/bjoc.13.244 Abstract As an extension of the boron enolate-based aldol reactions, the oxazolidinone-installed bisimide 1a from 3-(trifluoromethyl)glutaric acid was employed for Mannich reactions with tosylated imines 2 as electrophiles to successfully obtain

• the corresponding adducts in a stereoselective manner. Keywords: chiral oxazolidinones; diastereoselectivity; Mannich reactions; pseudo-C2 symmetry; trifluoromethyl; Introduction During these decades, we have been keenly interested in the 3-(trifluoromethyl)glutaric acid derivatives and developed a

• imines seemed to match favorably with a construction of the least sterically demanding conformation, leading to formation of the obtained diastereoisomer 3a. Conclusion As shown above, the oxazolidinone-installed imide from 3-(trifluoromethyl)glutaric acid 1a was found to afford the corresponding adducts

Hydrolysis, polarity, and conformational impact of C-terminal partially fluorinated ethyl esters in peptide models

• Vladimir Kubyshkin and
• Nediljko Budisa

Beilstein J. Org. Chem. 2017, 13, 2442–2457, doi:10.3762/bjoc.13.241

•  1). The observed checkmark shape differs from that previously reported for an isolated partially fluorinated methyl group at the end of a saturated aliphatic chain. In the latter case, the methyl group is the most lipophilic, more than a trifluoromethyl group; and the same has been reported for the

Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics

• Matthias Wünsch,
• David Schröder,
• Tanja Fröhr,
• Lisa Teichmann,
• Sebastian Hedwig,
• Nils Janson,
• Clara Belu,
• Jasmin Simon,
• Shari Heidemeyer,
• Philipp Holtkamp,
• Jens Rudlof,
• Lennard Klemme,
• Alessa Hinzmann,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2017, 13, 2428–2441, doi:10.3762/bjoc.13.240

• of larger peptides. The trifluoromethyl moiety has been reported to enhance the activity, stability and selectivity of various pharmacologically active compounds [65][66], e.g., trifluridine [67][68][69][70], efavirenz [71][72][73], fluoxetine [74][75][76] and fluozolate [77]. As the general

• trifluoromethyl nucleophiles, such as TMS–CF3 [84][85] has been described to be inefficient. Still, the asymmetric synthesis of CF3-substituted propargylamines has been described, using (R)-2-methoxy-1-phenylethan-1-amine as chiral auxiliary [86][87][88]. However, cleavage of the protective group requires

• reductive conditions, which also affects the CF3 group and the alkyne [86][87][88]. Various trifluoromethyl-substituted ketones have been converted into N-sulfinylimines, which were subsequently transformed into sulfinamides attached to a tertiary C-atom by addition of nucleophiles [89][90][91][92]. N

Synthesis, effect of substituents on the regiochemistry and equilibrium studies of tetrazolo[1,5-a]pyrimidine/2-azidopyrimidines

• Elisandra Scapin,
• Paulo R. S. Salbego,
• Caroline R. Bender,
• Alexandre R. Meyer,
• Anderson B. Pagliari,
• Tainára Orlando,
• Geórgia C. Zimmer,
• Clarissa P. Frizzo,
• Helio G. Bonacorso,
• Nilo Zanatta and
• Marcos A. P. Martins

Beilstein J. Org. Chem. 2017, 13, 2396–2407, doi:10.3762/bjoc.13.237

• , leading to the formation of the 5-aryl-substituted compound 3a. On the other hand, when R = CF3, the highest LUMO coefficient (0.262) is located at the C3 carbon of the β-enaminone (Figure 2b). Therefore, the initial nucleophilic attack leads to the formation of the 7-trifluoromethyl-substituted compound

• , our research group demonstrated a highly regioselective synthesis of a series of trifluoromethylated tetrazolo[1,5-a]pyrimidines with potent antimicrobial activity [37]. The reaction between several β-alkoxyvinyl trifluoromethyl ketones [CF3C(O)CH=C(R)OCH3] (in which R = Ph, 4-F–C6H4, 4-Cl–C6H4, 4-Br

• –C6H4, 4-I–C6H4, 4-CH3–C6H4, 4-OCH3–C6H4, thien-2-yl, 4-Ph–C6H4, CH3) and 5-aminotetrazole, by using conventional heating in an oil bath or microwave irradiation, was performed in IL. Here, only the 5-trifluoromethyl-substituted tetrazolo[1,5-a]pyrimidines 6a–g were obtained in all cases. Some important

Solvent-free copper-catalyzed click chemistry for the synthesis of N-heterocyclic hybrids based on quinoline and 1,2,3-triazole

• Martina Tireli,
• Silvija Maračić,
• Stipe Lukin,
• Marina Juribašić Kulcsár,
• Dijana Žilić,
• Mario Cetina,
• Ivan Halasz,
• Silvana Raić-Malić and
• Krunoslav Užarević

Beilstein J. Org. Chem. 2017, 13, 2352–2363, doi:10.3762/bjoc.13.232

• reactions using Cu(II), Cu(I) and Cu(0) catalysts have been successfully implemented to provide novel 6-phenyl-2-(trifluoromethyl)quinolines with a phenyl-1,2,3-triazole moiety at O-4 of the quinoline core. Milling procedures proved to be significantly more efficient than the corresponding solution

• containing a trifluoromethyl group at C-2 and a p-halogen-substituted and non-substituted phenyl-1,2,3-triazole moieties. The synthesis of 2-(trifluoromethyl)-6-phenylquinolone was achieved by Conrad–Limpach reaction of a primary aromatic amine with a β-ketoester [37][38]. Namely, thermal condensation of 4

• -aminobiphenyl (1) with ethyl 4,4,4-trifluoro-3-oxobutanoate in polyphosphoric acid (PPA) followed by the cyclization of the Schiff base intermediate afforded the 2-(trifluoromethyl)-6-phenylquinolone 3 (Scheme 1). O-Alkynylquinoline derivative 4 required for the click synthesis of target triazoles was obtained

Comparative profiling of well-defined copper reagents and precursors for the trifluoromethylation of aryl iodides

• Peter T. Kaplan,
• Jessica A. Lloyd,
• Mason T. Chin and
• David A. Vicic

Beilstein J. Org. Chem. 2017, 13, 2297–2303, doi:10.3762/bjoc.13.225

• bear the trifluoromethyl group have great importance in the life sciences and materials fields as well as discovery chemistry in general [1][2][3]. Consequently, transition-metal-catalyzed methods for preparing aromatic trifluoromethyl compounds from readily available aryl halides are an area that has

• seen rapid growth in the past ten years. Copper is one of the most successfully used metals for mediating the trifluoromethylation of aryl halides, and the active form of the reagents is typically a copper(I) complex bearing a trifluoromethyl ligand, i.e., [LnCu–CF3]. Sporadic examples of

• published procedure were used to ensure homogeneity for all the different complexes described in Scheme 1. Conversions to 4-(trifluoromethyl)-1,1’-biphenyl were then monitored by gas chromatography relative to a calibrated internal standard. Experiments were performed in triplicate, and the average yields

Preparation of imidazo[1,2-a]-N-heterocyclic derivatives with gem-difluorinated side chains

• Layal Hariss,
• Kamal Bou Hadir,
• Mirvat El-Masri,
• Thierry Roisnel,
• René Grée and
• Ali Hachem

Beilstein J. Org. Chem. 2017, 13, 2115–2121, doi:10.3762/bjoc.13.208

• could be of interest for bioorganic and medicinal chemistry studies. Several synthetic approaches for imidazopyridines are available, but only a few examples have been reported to date for the construction of this scaffold with introduction of fluorine [22], trifluoromethyl [23] or trifluoroethyl groups

One-pot multistep mechanochemical synthesis of fluorinated pyrazolones

• Joseph L. Howard,
• William Nicholson,
• Yerbol Sagatov and
• Duncan L. Browne

Beilstein J. Org. Chem. 2017, 13, 1950–1956, doi:10.3762/bjoc.13.189

• compatible with both the electron-withdrawing and electron-donating groups. However, a poorer yield was obtained for the electron-withdrawing trifluoromethyl substituent (5). The scope of phenylhydrazines was also briefly investigated, with several examples demonstrating good isolated yields, again an

• electron-withdrawing trifluoromethyl substituent was an exception to this (7) [31]. For this case, crude 19F NMR after the first step shows a 41% conversion, suggesting that the pyrazolone formation is the limiting factor in this example. An alkyl β-ketoester (ethyl acetoacetate) was also used, affording

Synthesis of benzannelated sultams by intramolecular Pd-catalyzed arylation of tertiary sulfonamides

• Valentin A. Rassadin,
• Mirko Scholz,
• Anastasiia A. Klochkova,
• Armin de Meijere and
• Victor V. Sokolov

Beilstein J. Org. Chem. 2017, 13, 1932–1939, doi:10.3762/bjoc.13.187

• -withdrawing groups (EWG), e.g., alkoxycarbonyl, aryl, cyano, or trifluoromethyl, we have chosen methoxycarbonyl (CO2Me) and aryl (Ar), since the corresponding starting sulfonyl chlorides are the most easily accessible ones. Results and Discussion To begin with, methyl 2-[N-(2-iodophenyl)sulfamoyl]acetate (3a

Mechanochemical synthesis of thioureas, ureas and guanidines

• Vjekoslav Štrukil

Beilstein J. Org. Chem. 2017, 13, 1828–1849, doi:10.3762/bjoc.13.178

• enantiomerically-pure chiral reagents, availability of which in a laboratory is dictated by their high costs. For that reason, we looked into the possibility to convert these reagents into functional chiral molecules with the highest synthetic efficiency. The privileged 3,5-di(trifluoromethyl)phenyl motif in

• organocatalyst design was first introduced by reacting 3,5-di(trifluoromethyl)phenyl isothiocyanate with 3,5-di(trifluoromethyl)aniline and 4-chloroaniline in a 1:1 ratio under LAG conditions using methanol as the grinding liquid. This led to quantitative formation of the Schreiner's catalyst 5 and thiourea 17

Base-promoted isomerization of CF₃-containing allylic alcohols to the corresponding saturated ketones under metal-free conditions

• Yoko Hamada,
• Tomoko Kawasaki-Takasuka and
• Takashi Yamazaki

Beilstein J. Org. Chem. 2017, 13, 1507–1512, doi:10.3762/bjoc.13.149

• the toluene refluxing temperature, and utilization of the corresponding optically active substrates unambiguously demonstrated that this transformation proceeded in a highly stereoselective fashion. Keywords: allylic alcohols; chirality; computation; 1,3-proton shift; trifluoromethyl; Introduction

• work is considered to draw a clear line with these instances because of the apparently convenient metal-free process. Moreover, the same type of proton shift has also reported by two groups. For example, during the reaction of (E)-2-(trifluoromethyl)vinylsilane and benzaldehyde in the presence of an

1-Imidoalkylphosphonium salts with modulated C_α–P⁺ bond strength: synthesis and application as new active α-imidoalkylating agents

• Jakub Adamek,
• Roman Mazurkiewicz,
• Anna Węgrzyk and
• Karol Erfurt

Beilstein J. Org. Chem. 2017, 13, 1446–1455, doi:10.3762/bjoc.13.142

• arenes can be markedly facilitated using 1-imidoalkylphosphonium salts derived from triarylphosphines with electron-withdrawing substituents such as tris(m-chorophenyl)phosphine, tris(p-chlorophenyl)phosphine and tris[p-(trifluoromethyl)phenyl]phosphine. Microwave irradiation also considerably

• salts derived from triarylphosphines with electron-withdrawing substituents such as tris(m-chorophenyl)phosphine, tris(p-chlorophenyl)phosphine and tris[p-(trifluoromethyl)phenyl]phosphine were synthesized and tested in the reaction. As expected, the phosphonium salts with a reduced Cα–P+ bond strength

• reacted with anisole and 1,3-dimethoxybenzene at much lower temperatures (Table 3, entries 3–7, 10, 11, 13, 17–19, 22 and 23). The most clear-cut results were obtained for tris[p-(trifluoromethyl)phenyl]phosphine derivatives. 1-Phthalimidoethyltris[p-(trifluoromethyl)phenyl]phosphonium tetrafluoroborate

Transition-metal-catalyzed synthesis of phenols and aryl thiols

• Yajun Liu,
• Shasha Liu and
• Yan Xiao

Beilstein J. Org. Chem. 2017, 13, 589–611, doi:10.3762/bjoc.13.58

• scope of functional groups including ether, halo, hydroxy, carboxylic acid and trifluoromethyl groups were well tolerated in their protocol. Even hindered substrates such as 2,6-diisopropyl iodobenzene also afforded the corresponding phenol in satisfying yield. The developed protocol was further applied

• , amide, bromo and trifluoromethyl were tolerated in this process. They also showed the application of the developed protocol in the synthesis of aryl alkyl sulfides via a “one-pot reaction”. In 2011, the Xu and Feng group applied CuI-nanoparticles to synthesize aryl thiols through a coupling reaction of

• converted in situ to aryl thiols through C–S bond cleavage by an intramolecular nucleophilic substitution. The protocol tolerated a broad range of functional groups such as amino, hydroxy, trifluoromethyl, ester, carboxy and formyl groups. As described above, although it seems more difficult to develop an

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

• Flavio Fanelli,
• Giovanna Parisi,
• Leonardo Degennaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2017, 13, 520–542, doi:10.3762/bjoc.13.51

• . The optimized conditions were suitable for the functionalization of 2-fluoropyridine, 2,6- difluoropyridine and 4-(trifluoromethyl)pyridine leading to products 7a–g reported in Scheme 10. Another promising field is the sustainable flow organocatalysis, and recently Pericàs reported an interesting

Synthesis of 1-indanones with a broad range of biological activity

• Marika Turek,
• Dorota Szczęsna,
• Marek Koprowski and
• Piotr Bałczewski

Beilstein J. Org. Chem. 2017, 13, 451–494, doi:10.3762/bjoc.13.48

• . Fluoroorganic compounds play a significant role as very effective therapeutics, and for this reason, Prakash, Olah et al. synthesized in 2010 trifluoromethyl-substituted arylpropanoic acids 12, 1-indanones 13 and dihydrocoumarins 14 (Scheme 5) [17]. These products have been obtained by utilizing arenes/phenols

• 11 (X = H/OH) and 2-(trifluoromethyl)acrylic acid (10) as a result of a Friedel–Crafts alkylation. An efficient and scalable one-pot process for the preparation of 1-indanones from benzoic acids has been described by Huang et al. [18]. In this synthesis, acyl chlorides formed in the reaction of

The reductive decyanation reaction: an overview and recent developments

• Jean-Marc R. Mattalia

Beilstein J. Org. Chem. 2017, 13, 267–284, doi:10.3762/bjoc.13.30

• other functional groups (Scheme 19). The ether bonds (33b, 49), ester (45), hydroxy (39c) and keto groups (46) are tolerated. With method B, aryl cyanides with amide (54), trifluoromethyl (55) and fluoro groups (47c) are reduced in attractive yields. For substrates bearing dicyano groups

• the position of the methyl substituent from the para to the ortho or meta positions decreases the yield in toluene. Dimethylamino and thioether groups display a lower yield with method B (34b,g) contrary to the trifluoromethyl group (34i). With p-fluorobenzonitrile the decyanation is observed with

New approaches to organocatalysis based on C–H and C–X bonding for electrophilic substrate activation

• Pavel Nagorny and
• Zhankui Sun

Beilstein J. Org. Chem. 2016, 12, 2834–2848, doi:10.3762/bjoc.12.283

• demonstrated by Schreiner in a detailed study of hydrogen-bonding thiourea organocatalysts containing a 3,5-bis(trifluoromethyl)phenyl group as the privileged motif [56][57][58]. A recent example of utilizing such interactions in catalysis was demonstrated by Bibal and co-workers [58]. In this study, Bibal and

Enzymatic synthesis and phosphorolysis of 4(2)-thioxo- and 6(5)-azapyrimidine nucleosides by E. coli nucleoside phosphorylases

• Vladimir A. Stepchenko,
• Anatoly I. Miroshnikov,
• Frank Seela and
• Igor A. Mikhailopulo

Beilstein J. Org. Chem. 2016, 12, 2588–2601, doi:10.3762/bjoc.12.254

• pioneering works of Friedkin and co-workers (testing of 5-amino- and halogeno derivatives of uracil for TP from horse liver) and Heidelberger and co-workers (practical synthesis of 5-fluoro- and 5-trifluoromethyl-2'-deoxyurines) substrate properties of 5-substituted uracil derivatives were studied in a

Facile synthesis of indolo[3,2-a]carbazoles via Pd-catalyzed twofold oxidative cyclization

• Chao Yang,
• Kai Lin,
• Lan Huang,
• Wei-dong Pan and
• Sheng Liu

Beilstein J. Org. Chem. 2016, 12, 2490–2494, doi:10.3762/bjoc.12.243

• , thus the complete cyclization needed longer time and the yield was relatively lower. Moreover, a chlorine atom at the aromatic ring was tolerated under these conditions. The meta-substituted starting materials 2i and 2j gave good regioselectivity. When a trifluoromethyl group was located at the meta