Direct synthesis of acyl fluorides from carboxylic acids using benzothiazolium reagents

• Lilian M. Maas,
• Alex Haswell,
• Rory Hughes and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2024, 20, 921–930, doi:10.3762/bjoc.20.82

• afford (trifluoromethyl)thioethers, while subsequent work focused on the direct deoxygenative synthesis of fluorinated thioesters from carboxylic acids [29][30][31]. In each case, the reactions proceeded smoothly under operationally simple conditions while BT-SCF3 and related BT-SRF reagents are easy-to

• -handle solids that can be readily produced on a multigram scale from relatively inexpensive starting materials. During the optimisation studies for the latter process with carboxylic acid substrates, in addition to the desired (trifluoromethyl)thioester products, small amounts of the corresponding acyl

• , reacting BT-SCF3 with carboxylic acids 1 under similar conditions provides (trifluoromethyl)thioesters 3 via a concerted deoxytrifluoromethylthiolation process from tetrahedral intermediate A affording thiocarbamate by-product B [31]. To test whether thioester species could act as intermediates in the

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

Ortho-ester-substituted diaryliodonium salts enabled regioselective arylocyclization of naphthols toward 3,4-benzocoumarins

• Ke Jiang,
• Cheng Pan,
• Limin Wang,
• Hao-Yang Wang and
• Jianwei Han

Beilstein J. Org. Chem. 2024, 20, 841–851, doi:10.3762/bjoc.20.76

• this reaction, regardless of the electronic nature and position of the substituents. The desired 3,4-benzocoumarin products 3ba–ma were obtained in yields of 21–59%. Notably, substituents such as halogens (F, Cl, and Br), methyl, methoxy, and trifluoromethyl groups at the ortho-, meta-, or para

Ligand effects, solvent cooperation, and large kinetic solvent deuterium isotope effects in gold(I)-catalyzed intramolecular alkene hydroamination

• Ruichen Lan,
• Brock Yager,
• Yoonsun Jee,
• Cynthia S. Day and
• Amanda C. Jones

Beilstein J. Org. Chem. 2024, 20, 479–496, doi:10.3762/bjoc.20.43

• than those in CD2Cl2). However, this did not hold true uniformly. When a commercially available electron-acceptor ligand known as “Jackiephos” (bis(3,5-bis(trifluoromethyl)phenyl)(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine was used as the AuNTf2 salt (6a), in CD2Cl2, the reaction rate

• further (see Supporting Information File 1, Figure S19). This comparison reveals that the Jackiephos supported gold accelerates the reaction more than (PhO)P(o-biphenyl)2 does, although this may be in part an anion effect [7]. The bis(trifluoromethyl)aryl substituent is expected to be more electron

(E,Z)-1,1,1,4,4,4-Hexafluorobut-2-enes: hydrofluoroolefins halogenation/dehydrohalogenation cascade to reach new fluorinated allene

• Nataliia V. Kirij,
• Andrey A. Filatov,
• Yurii L. Yagupolskii,
• Sheng Peng and
• Lee Sprague

Beilstein J. Org. Chem. 2024, 20, 452–459, doi:10.3762/bjoc.20.40

• the formation of the corresponding olefin [12]. Another area of application of olefins 1a,b is based on C=C double bond addition reactions. As early as 1968, Atherton and Fields showed that (Z)- and (E)-butenes 1a,b reacted with diazotrifluoroethane to give 3,4,5-tris(trifluoromethyl)pyrazoline [13

• demonstrated that 1,1,1,4,4,4-hexafluorobut-2-ene reacts with dithietane, sulfur and KF with the formation of the corresponding 1,3-dithiole [16]. Also, a recent patent presents a method for the preparation of 5,6-bis(trifluoromethyl)-1,2,4-triazine-3-carboxylic acid ethyl ester starting from 1,1,1,4,4,4

• completion of the reaction and subsequent treatment of the reaction mixture with 2 N hydrochloric acid, 2,3-bis(trifluoromethyl)-1-(4-fluorophenyl)prop-2-ene-1-ol (10) was detected in the 19F NMR spectrum. It should be noted that, in addition to the unreacted starting aldehyde 9, the formation of olefin 1b

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• with aryl thiols [70]. Further studies showed that 4-(trifluoromethyl)thiophenol (97) could act as a catalytic reductant in the aminodecarboxylation reaction of NHPI esters derived from α-amino acids [71] (Scheme 19). Accordingly, visible light irradiation of a mixture consisting of N-Boc-alanine NHPI

Copper-catalyzed multicomponent reaction of β-trifluoromethyl β-diazo esters enabling the synthesis of β-trifluoromethyl N,N-diacyl-β-amino esters

• Youlong Du,
• Haibo Mei,
• Ata Makarem,
• Ramin Javahershenas,
• Vadim A. Soloshonok and
• Jianlin Han

Beilstein J. Org. Chem. 2024, 20, 212–219, doi:10.3762/bjoc.20.21

• IKERBASQUE, Basque Foundation for Science, Alameda Urquijo 36-5, Plaza Bizkaia, 48011 Bilbao, Spain 10.3762/bjoc.20.21 Abstract An efficient multicomponent reaction of newly designed β-trifluoromethyl β-diazo esters, acetonitrile, and carboxylic acids via an interrupted esterification process under copper

• -catalyzed conditions has been developed, which affords various unsymmetrical β-trifluoromethyl N,N-diacyl-β-amino esters in good to excellent yields. The reaction features mild conditions, a wide scope of β-amino esters and carboxylic acids, and also applicability to large-scale synthesis, thus providing an

• efficient way for the synthesis of β-trifluoromethyl β-diacylamino esters. Furthermore, this reaction represents the first example of a Mumm rearrangement of β-trifluoromethyl β-diazo esters. Keywords: β-carbonyl diazo; copper catalyst; fluoroalkyl diazo; Mumm rearrangement; unsymmetrical β-diacylamino

Visible-light-induced radical cascade cyclization: a catalyst-free synthetic approach to trifluoromethylated heterocycles

• Chuan Yang,
• Wei Shi,
• Jian Tian,
• Lin Guo,
• Yating Zhao and
• Wujiong Xia

Beilstein J. Org. Chem. 2024, 20, 118–124, doi:10.3762/bjoc.20.12

• Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China 10.3762/bjoc.20.12 Abstract A visible-light-promoted research protocol for constructing dihydropyrido[1,2-a]indolone skeletons is herein described proceeding through a cascade cyclization mediated by trifluoromethyl

• enables a rapid access to heterocycles containing a trifluoromethyl group. Keywords: cascade reaction; indole derivatives; photocatalysis; radical chain process; trifluoromethylation; Introduction Dihydropyrido[1,2-a]indolone (DHPI) skeletons are commonly found in natural products and pharmaceutical

• an electron-withdrawing functional moiety into drug molecules would increase their metabolic stability [20], by avoiding, e.g., fast oxidation by cytochrome P450 oxidases [21]. In particular, the introduction of a trifluoromethyl group (–CF3) was shown to increase the metabolic stability of molecules

Using the phospha-Michael reaction for making phosphonium phenolate zwitterions

• Matthias R. Steiner,
• Max Schmallegger,
• Larissa Donner,
• Johann A. Hlina,
• Christoph Marschner,
• Judith Baumgartner and
• Christian Slugovc

Beilstein J. Org. Chem. 2024, 20, 41–51, doi:10.3762/bjoc.20.6

• trifluoromethyl groups [20] and the cross-coupling of aryl halides [21]. Like phosphonium salts in general are used as catalysts [22][23], phosphonium salts based on ortho-hydroxy-substituted phosphines received particular attention because of their zwitterionic nature and have been used as catalysts in the

Synthesis of N-acyl carbazoles, phenoxazines and acridines from cyclic diaryliodonium salts

• Nils Clamor,
• Mattis Damrath,
• Thomas J. Kuczmera,
• Daniel Duvinage and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2024, 20, 12–16, doi:10.3762/bjoc.20.2

• the robustness of this method. Substrates with multiple electron-withdrawing substituents such as trifluoromethyl and bromide gave good yields. The ethyl carbamate 2q proved to be a valid substrate for the reaction with a 74% yield. Phenylacetamide as the substrate resulted in the formation of 2r in

Substituent-controlled construction of A₄B₂-hexaphyrins and A₃B-porphyrins: a mechanistic evaluation

• Seda Cinar,
• Dilek Isik Tasgin and
• Canan Unaleroglu

Beilstein J. Org. Chem. 2023, 19, 1832–1840, doi:10.3762/bjoc.19.135

• were between 7–18%. Synthesis of tripyrrane 5 5,10-Bis(4-trifluoromethylphenyl)tripyrromethane (5) was obtained as side product of dipyrromethane synthesis by the condensation of pyrrole and 4-(trifluoromethyl)benzaldehyde. A typical procedure involves 4-(trifluoromethyl)benzaldehyde (28.7 mmol) and

Trifluoromethylated hydrazones and acylhydrazones as potent nitrogen-containing fluorinated building blocks

• Zhang Dongxu

Beilstein J. Org. Chem. 2023, 19, 1741–1754, doi:10.3762/bjoc.19.127

• organofluorine compounds has become a major research focus. The use of difluoromethylating and trifluoromethylating reagents is a popular approach applied to prepare di/trifluoromethyl-containing molecules [8][9][10][11][12][13][14][15][16][17][18]. Also the reaction of diverse di/trifluoromethyl-containing

• building blocks offers another mainstream approach to introducing fluorine. Among these, di/trifluorodiazoethane [19][20][21][22], trifluoromethyl aldimines [23][24][25], trifluoroacetimidoyl halides [26], and fluoroalkyl N-sulfonyl hydrazones [27] have emerged as powerful nitrogen-containing fluorinated

• the synthesis of diverse di/trifluoromethyl-containing molecules by using di/trifluoromethylated hydrazones, acylhydrazones, and their related compounds. Review Trifluoroacetaldehyde hydrazones Hydrazones possess diverse biological and pharmacological properties and have been employed in the treatment

Quinoxaline derivatives as attractive electron-transporting materials

• Zeeshan Abid,
• Liaqat Ali,
• Sughra Gulzar,
• Faiza Wahad,
• Raja Shahid Ashraf and
• Christian B. Nielsen

Beilstein J. Org. Chem. 2023, 19, 1694–1712, doi:10.3762/bjoc.19.124

• copolymer, benzodithiophene-thiadiazolo-quinoxaline (Qx54), by introducing trifluoromethyl groups to the Qx moiety (Qx55). This strategic modification changed the HOMO and LUMO levels, resulting in a conversion from ambipolar charge transport to n-type charge transport. The polymeric thin-film transistors

• , based on 6-(trifluoromethyl)quinoxaline or 6-cyanoquinoxaline acceptors, respectively. The small energy splitting values (0.03–0.04 eV) and long fluorescence lifetimes (5.0 μs) indicated efficient TADF processes. The utilization of these emitters in full-TADF white OLEDs, along with a sky-blue emitter

Decarboxylative 1,3-dipolar cycloaddition of amino acids for the synthesis of heterocyclic compounds

• Xiaofeng Zhang,
• Xiaoming Ma and
• Wei Zhang

Beilstein J. Org. Chem. 2023, 19, 1677–1693, doi:10.3762/bjoc.19.123

• ketones can result in a different kind of AMYs to address the issue. The reaction of trifluoromethyl ketones with glycine or α-substituted amino acids generated stabilized AMY 8 which underwent cycloaddition with maleimides to give 2-CF3-substituted pyrrolidines 9 in 50–76% yield (Scheme 5) [65]. Both the

Morpholine-mediated defluorinative cycloaddition of gem-difluoroalkenes and organic azides

• Tzu-Yu Huang,
• Mario Djugovski,
• Sweta Adhikari,
• Destinee L. Manning and
• Sudeshna Roy

Beilstein J. Org. Chem. 2023, 19, 1545–1554, doi:10.3762/bjoc.19.111

• generated via an azide–alkyne cycloaddition or a multicomponent reaction between carbonyls and azides [17]. α-Trifluoromethyl (α-CF3) carbonyls were recently utilized to generate NH-1,2,3-triazoles and fully substituted 1,2,3-triazoles [28][29]. However, there are no reports of a formal [3 + 2

• -withdrawing group, such as trifluoromethyl (4h), was obtained in 44% yield. When morpholine was replaced with piperidine (5a) or seven-membered azepane (5b) as a solvent, a decreased yield was observed (30–42%). The addition of piperidine offers an advantage in expanding the substrate scope to medicinal

Visible-light-induced nickel-catalyzed α-hydroxytrifluoroethylation of alkyl carboxylic acids: Access to trifluoromethyl alkyl acyloins

• Feng Chen,
• Xiu-Hua Xu,
• Zeng-Hao Chen,
• Yue Chen and
• Feng-Ling Qing

Beilstein J. Org. Chem. 2023, 19, 1372–1378, doi:10.3762/bjoc.19.98

• trifluoromethyl alkyl acyloins in good yields with broad substrate compatibility. The complex bioactive molecules were also compatible with this catalytic system to afford the corresponding products. Keywords: alkyl carboxylic acids; cross coupling; EDA complex; nickel catalysis; trifluoromethyl acyloins

• important functional groups such as dicarbonyls [15], diols [16], amino ketones [17] and so on. Recently, the introduction of a trifluoromethyl group into organic molecules has received great attention due to their wide applicability in medicinal [18][19] and materials [20][21] chemistry. The toxicological

• experiments showed that trifluoromethyl acyloins can selectively induce apoptosis in human oral cancer cells [22][23] and have therefore attracted much more attention. However, trifluoromethyl acyloins were not widely used due to the challenge associated with their synthesis. Certain progress has been made in

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

Aromatic C–H bond functionalization through organocatalyzed asymmetric intermolecular aza-Friedel–Crafts reaction: a recent update

• Anup Biswas

Beilstein J. Org. Chem. 2023, 19, 956–981, doi:10.3762/bjoc.19.72

• process was achieved through the C3–H functionalization of indole derivatives 4. The nucleophile favors the attack at the imine carbon included in the seven-membered ring of compound 8 to generate an aza-quaternary stereocenter containing trifluoromethyl, pyrrole/indole, and benzoazepinoindole moieties

• for the functionalization of the C3–H bond in indoles 9 in the presence of BINOL-derived chiral phosphoric acid P6 as the catalytic agent. They utilized trifluoromethyl ester-substituted N-unprotected imine 15 as the potential electrophile to install an aza-quaternary stereocenter in the C3 position

• -derived chiral phosphoric acid catalysts P17 and P18. The electrophile was the α-trifluoromethyl-containing imine 52 which directed the C2 functionalization in the pyrrole moiety with catalyst P17 and a C3 substitution in indole derivatives using catalyst P18 forming the trifluoromethylated aza-quaternary

Synthesis, structure, and properties of switchable cross-conjugated 1,4-diaryl-1,3-butadiynes based on 1,8-bis(dimethylamino)naphthalene

• Semyon V. Tsybulin,
• Ekaterina A. Filatova,
• Alexander F. Pozharskii,
• Valery A. Ozeryanskii and
• Anna V. Gulevskaya

Beilstein J. Org. Chem. 2023, 19, 674–686, doi:10.3762/bjoc.19.49

• trifluoromethyl group of one independent molecule is disordered with an occupancy of fluorine atoms of 0.54/0.46, which makes the molecule asymmetric. The second independent molecule has an inversion center. Compared to the free bases 5 discussed above, the protonated form 11с demonstrates almost complete

• (Scheme 5). Presumably, when R = H or OMe, structure 17 contributes the most to the resonance hybride, while in cases of molecules 5d,e with π-acceptor substituents, a dication of type 18 better describes the electron density distribution. The only exception is the trifluoromethyl derivative 5с, which

• through a butadiyne linker and aryl–C≡C–DMAN conjugation paths. A comprehensive study by X-ray diffraction, NMR spectroscopy and cyclic voltammetry revealed that the “butadiyne pathway” is realized in cases where the aryl substituent is p-methoxyphenyl, phenyl or p-(trifluoromethyl)phenyl. Oligomers 5

Access to cyclopropanes with geminal trifluoromethyl and difluoromethylphosphonate groups

• Ita Hajdin,
• Romana Pajkert,
• Mira Keßler,
• Jianlin Han,
• Haibo Mei and
• Gerd-Volker Röschenthaler

Beilstein J. Org. Chem. 2023, 19, 541–549, doi:10.3762/bjoc.19.39

• -pentafluoropropylphosphonate, bearing a trifluoromethyl and a difluoromethyl group is reported for the first time. Its application in CuI-catalyzed cyclopropanation reactions with aromatic and aliphatic terminal alkenes under mild reaction conditions is demonstrated. In total, sixteen new cyclopropanes were synthesized in

• them, trifluoromethyl- and difluoromethyl-substituted cyclopropanes are of great interest in pharmaceutical, materials and agricultural chemistry [3]. Due to the unique properties of fluorine, such as highest electronegativity, small atomic radius, or low polarizability, the strategic placement of

• fluorinated moieties within cyclopropyl rings imparts useful properties to these molecules. Thus, it is not surprising that difluoromethyl- or trifluoromethyl-substituted cyclopropanes serve as important structural motifs in many biologically active molecules as well as in special materials [4][5][6

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• -trifluoromethyl substituent forming the ketone product in <10% yield. While substitution of the norbornene was tolerated, both EWGs and EDGs hindered the reaction. Upon several mechanistic studies, the authors proposed the catalytic cycle begins with the oxidative addition of the active Ni(0) catalyst to imide 27

Transition-metal-catalyzed C–H bond activation as a sustainable strategy for the synthesis of fluorinated molecules: an overview

• Louis Monsigny,
• Floriane Doche and
• Tatiana Besset

Beilstein J. Org. Chem. 2023, 19, 448–473, doi:10.3762/bjoc.19.35

• reaction was also tolerant to a large class of functional groups (halogens, cyano, trifluoromethyl), affording products 34c,d and 34e in high yields (86%, 89% and 81%, respectively). The α-methyl-substituted acrylamide 33j also underwent difluoromethylthiolation to give product 34j in 81% isolated yield

Group 13 exchange and transborylation in catalysis

• Dominic R. Willcox and
• Stephen P. Thomas

Beilstein J. Org. Chem. 2023, 19, 325–348, doi:10.3762/bjoc.19.28

• tris[3,5-bis(trifluoromethyl)phenyl]borane [59], tris(3,4,5-trifluorophenyl)borane [54], and BH3 [55][56] found to be competent catalysts of this transformation (Scheme 3a). The mechanism was proposed to be analogous to that of borane-catalysed alkyne hydroboration; alkene 4 hydroboration, followed by

Synthesis and characterisation of new antimalarial fluorinated triazolopyrazine compounds

• Kah Yean Lum,
• Jonathan M. White,
• Daniel J. G. Johnson,
• Vicky M. Avery and
• Rohan A. Davis

Beilstein J. Org. Chem. 2023, 19, 107–114, doi:10.3762/bjoc.19.11

• first 1 min, followed by a linear gradient to 80% MeOH/20% H2O (0.1% TFA) over 59 min, all at a flow rate of 9 mL/min. 3-(4-(Difluoromethoxy)phenyl)-5-phenethoxy-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine (10). White amorphous solid (6 mg, 12%); UV (MeOH) λmax (log ε): 243 (3.94), 324 (3.50) nm

• -phenethoxy-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine (13). White amorphous solid (3 mg, 6%); UV (MeOH) λmax (log ε): 244 (3.69), 286 (3.19), 322 (3.22) nm; 1H NMR (800 MHz, CDCl3) δH 2.98 (t, J = 6.6 Hz, 2H, H-17), 4.55 (t, J = 6.6 Hz, 2H, H-16), 6.88 (m, 2H, H-19, H-23), 7.24 (m, 1H, H-21), 7.25 (m

• ), 137.3 (t, J = 26.6 Hz, C-8), 144.5 (C-9), 145.2 (C-5), 147.0 (C-3); LRESIMS m/z: 401 [M + H]+, 823 [2M + Na]+; HRESIMS (m/z): [M + H]+ calcd for C20H16ClF2N4O, 401.0975; found, 401.0978. 4-(5-Phenethoxy-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)benzonitrile (16). White amorphous solid (5 mg

Practical synthesis of isocoumarins via Rh(III)-catalyzed C–H activation/annulation cascade

• Qian-Ci Gao,
• Yi-Fei Li,
• Jun Xuan and
• Xiao-Qiang Hu

Beilstein J. Org. Chem. 2023, 19, 100–106, doi:10.3762/bjoc.19.10

• , trifluoromethyl and nitro substituents, were retained unchanged in the final products (3ja, 3ka, 3ma, and 3na). Also the strongly coordinating thioether substituent proved to be suitable for this protocol, providing the desired product 3ea in 76% yield. Moreover, under the standard conditions, 3-thienyl and 2