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

• , the synthesis of difluoromethylcyclopropanes utilizing difluoromethyldiazo reagents remains rather unexplored. Nevertheless, some difluorocarbene reagents, including HCF2CH(N2) [32], Ph2S+CH2CF2H TfO− [33], and difluoroacetaldehyde N-triftosylhydrazone (DFHZTfs) [34], have been developed (Scheme 1B

Cathodic generation of reactive (phenylthio)difluoromethyl species and its reactions: mechanistic aspects and synthetic applications

• Sadanobu Iwase,
• Shinsuke Inagi and
• Toshio Fuchigami

Beilstein J. Org. Chem. 2022, 18, 872–880, doi:10.3762/bjoc.18.88

• seems to undergo elimination of difluorocarbene to generate a phenylthiolate anion which reacts with compound 1 to form product 3 as shown in Scheme 6. In order to confirm the proposed reaction pathway to product 3, the reaction of bromodifluoromethyl phenyl sulfide (1) with phenylthiolate anion was

• performed at room temperature. As expected, product 3 was formed in moderate yield of 67% as shown in Scheme 7. It is known that difluorocarbene has generally low reactivity towards olefins; however, it can be trapped with electron-rich olefins [32]. In order to trap difluorocarbene with an olefin, we tried

• to increase the amount of generated difluorocarbene by increasing the current density for the cathodic reduction of compound 1. Thus, the cathodic reduction of 1 was carried out completely at a high current density of 16 mA/cm2 in the presence of α-methylstyrene. As shown in Scheme 8, the expected

Catalyzed and uncatalyzed procedures for the syntheses of isomeric covalent multi-indolyl hetero non-metallides: an account

• Ranadeep Talukdar

Beilstein J. Org. Chem. 2021, 17, 2102–2122, doi:10.3762/bjoc.17.137

• . Here the base assisted the condensation of 2-(fluorosulfonyl)difluoroacetic acid (115) with 1 followed by decarboxylation to give difluorocarbene and sulfinate 119, that combine to produce sulfanol 121, which in the presence of acid and reaction with another molecule of indole affords 105. In 2018

Synthesis of bis(aryloxy)fluoromethanes using a heterodihalocarbene strategy

• Carl Recsei and
• Yaniv Barda

Beilstein J. Org. Chem. 2021, 17, 813–818, doi:10.3762/bjoc.17.70

• )fluoromethane synthesis is a 1973 report by Platonov of the reaction of a slight excess of dichlorofluoromethane with pentafluorophenol in the presence of base, presumably via chlorofluorocarbene as an intermediate (Scheme 2) [6]. Typically, phenoxides are known to react with difluorocarbene to form

• a screen of bases, reactant ratios, reactor pressure, addition rates and temperature. A compound with the requisite molecular formula was produced as a minor product by the reaction of 6 (Scheme 3) with difluorocarbene generated at elevated temperature via decarboxylation of chlorodifluoroacetate

• aldehydes were present, and that unreacted phenol comprised a further 26% of the mass balance. Thus, the reactivity of fluorobromocarbene in this case mirrored the tendency of difluorocarbene to react with phenoxides to form dihalomethyl phenyl ethers, rather than forming aldehydes as with dichlorocarbene

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

• ], has dramatically improved the prospects. One of the problems facing the treatment of HCF3 for nucleophilic trifluoromethylation reactions is the low stability of the directly generated CF3 anion (CF3−) for decomposing to difluorocarbene (:CF2) and fluoride (F−) (Scheme 1a). Due to the formation of

• highly stable fluoride salts (MF), the breakdown of CF3− into difluorocarbene in the presence of alkali (M+) and other metal cations is favored. In earlier studies, the solvent N,N-dimethylformamide (DMF), was essential for nucleophilic trifluoromethylation by HCF3 since DMF acts as a CF3 anion reservoir

• . Trifluoromethyl ketones. a) Hydrolysis of trifluoromethyl ketones. b) Selected examples of biologically active trifluoromethyl ketones. Chemistry of the CF3 anion generated from HCF3. a) Decomposition of the trifluoromethyl anion to difluorocarbene and fluoride. b) A hemiaminaloate adduct of CF3 anion to DMF. c

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

• Difluorocarbene methods with non-metal sources Difluorocarbene chemistry was first reported by Doering in 1954 [12]. The lone electron pairs on the fluorine substituents interact with the carbene center, making the structure stabilized [13]. Difluorocyclopropanes 4 were synthesized from the reaction of

• halodifluoromethanes and alkenes (Scheme 2). The elimination of hydrogen halide from the halodifluoromethane under basic conditions (metal alkoxide or alkyllithium) generated difluorocarbene [14][15]. The low yields of the product have been attributed to the facile addition of the strong bases to difluorocarbene. The

• yields were best in the reactions with electron-rich alkenes and when a low concentration of the base was used to minimize the destruction of difluorocarbene. The use of oxirane or epichlorohydrin as hydrogen halide scavengers avoided the need for a stoichiometric amount of the strong base [16][17]. The

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

• demonstrated the synthesis of aryl fluoroalkyl ethers as shown in Scheme 1 [32][33][34]. For example, the reactions of phenols with “gem-difluorocarbene precursors (route (a))” or “bromodifluoroalkyl compounds (route (b))” have been typically used to obtain a variety of aryl gem-difluoromethyl ethers

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

• caffeine, claimed in the patent literature [19][20] and 7-difluoromethyl caffeine, prepared by the insertion of difluorocarbene into the N–H bond of theophylline (7) [11][21][22]. Similar to the reaction of tetrakis(trifluoromethyl)-1,3-dithietane (1) and theophylline (7, Scheme 5), this process also led

• to the formation of two regioisomers, but interestingly, the ratio of the 7-CF2H- and 9-CF2H-isomers varied broadly from 1:2 [22] to 3:2, depending on the reaction conditions and the source of difluorocarbene [11]. Mechanism, regiochemistry, and rotation barriers of the CH(CF3)2 group The mechanism

Photoredox-catalyzed silyldifluoromethylation of silyl enol ethers

• Vyacheslav I. Supranovich,
• Vitalij V. Levin and
• Alexander D. Dilman

Beilstein J. Org. Chem. 2020, 16, 1550–1553, doi:10.3762/bjoc.16.126

• silane is very sensitive to Lewis bases and accordingly it was used as a precursor of difluorocarbene, which can react with enol ethers [19][20] (Scheme 1). We showed that this silane could be involved in the radical chain hydrofluoroalkylation of electron-deficient alkenes, using a boron hydride as a

• employed in photoredox reactions to scavenge acidic byproducts [28][29], could not be employed. Silane 1 is easily destroyed by bases (even by the amide group [30]) followed by the rapid addition of difluorocarbene to silyl enol ethers [19][20]. Disappointingly, we were unable to isolate ketone 3a using

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

• and a subsequent homologation step involving a putative copper difluorocarbene will allow the formation of the CuCF2CF3 species. With this tool in hand, a panel of aryl iodides was functionalized (Scheme 24). Conclusion This review aims at providing an overview of the recent advances made since 2014

Synthesis of organic liquid crystals containing selectively fluorinated cyclopropanes

• Zeguo Fang,
• Nawaf Al-Maharik,
• Peer Kirsch,
• Matthias Bremer,
• Alexandra M. Z. Slawin and
• David O’Hagan

Beilstein J. Org. Chem. 2020, 16, 674–680, doi:10.3762/bjoc.16.65

• used difluorocarbene additions to olefin precursors, an approach which proved straightforward such that these liquid crystal candidates could be efficiently prepared. Their physical and thermodynamic properties were evaluated and depending on individual structures, they either displayed positive or

• negative dielectric anisotropy. The study gives some guidance into effective structure–property relationships for the design of LCs containing selectively fluorinated cyclopropane motifs. Keywords: dielectric anisotropy; difluorocarbene; organic liquid crystals; selectively fluorinated cyclopropanes

• difluorocarbene addition to alpha-fluorostyrenes [13]. This used the extraordinary useful method for the generation of difluorocarbene from the Ruppert–Prakash (TMSCF3) reagent [14]. DFT analysis suggests the lowest energy conformer of aryl α,β,β-trifluorocyclopropane 7 orients the C–F bond perpendicular to the

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

• , which is in line with an SN2 mechanism. The authors proposed a mechanism where difluorocarbene is first generated upon thermal decomposition of the starting difluorophosphobetaine. The carbene then reacts with elemental selenium to yield difluoroselenophosgene, and in the presence of fluoride anions

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

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

• difluorocarbene but these compounds display poor stability in most cases and readily undergo hydrolysis into cyclopropenones which possess an aromatic character [66][67]. Gem-difluorocyclopropenylcarbinyl glycolates 65a–n were prepared by slow addition of an excess of trimethylsilyl fluorosulfonyldifluoroacetate

6’-Fluoro[4.3.0]bicyclo nucleic acid: synthesis, biophysical properties and molecular dynamics simulations

• Sibylle Frei,
• Andrei Istrate and
• Christian J. Leumann

Beilstein J. Org. Chem. 2018, 14, 3088–3097, doi:10.3762/bjoc.14.288

• unsaturated 6’-fluoro[4.3.0]bicyclo nucleotides (6’F-bc4,3-DNA). Two 6’F-bc4,3 phosphoramidite building blocks (T and C) were synthesized starting from a previously described [3.3.0]bicyclic sugar. The conversion of this sugar to a gem-difluorinated tricyclic intermediate via difluorocarbene addition followed

• improving the already existing protocol [50]. The sugars 2α/β were then individually treated with the Ruppert–Prakash reagent (TMSCF3) as difluorocarbene precursor and sodium iodide as initiator [52], furnishing the exo-tricyclic sugars 3α/β as major isomers. The closer evaluation of this reaction revealed

• to the hindrance of the difluorocarbene attack on the double bond. The stereochemistry around the cyclopropane ring (endo vs exo) could be assessed by the characteristic coupling pattern between the fluorine atom and the H-C(1) or C(7) in the endo-tricyclic sugars in the corresponding 1H and 13C NMR

Visible light-mediated difluoroalkylation of electron-deficient alkenes

• Vyacheslav I. Supranovich,
• Vitalij V. Levin,
• Marina I. Struchkova,
• Jinbo Hu and
• Alexander D. Dilman

Beilstein J. Org. Chem. 2018, 14, 1637–1641, doi:10.3762/bjoc.14.139

• availability issues [25][26][27][28][29]. Recently, we developed a general protocol for the synthesis of iodides 1 from organozinc reagents and a source of difluorocarbene [30][31][32] (Scheme 1). Moreover, it was shown that compounds bearing the CF2I group can be obtained from carbonyl compounds and

Progress in copper-catalyzed trifluoromethylation

• Guan-bao Li,
• Chao Zhang,
• Chun Song and
• Yu-dao Ma

Beilstein J. Org. Chem. 2018, 14, 155–181, doi:10.3762/bjoc.14.11

• . Trifluoromethylation of aryl halides using difluorocarbene precursors as the trifluoromethyl source The trifluoromethyl sources employed in the above-mentioned trifluoromethylations were mainly CF3-containing reagents. Besides, some examples employing difluorocarbene precursors as the trifluoromethylation reagents

• were reported recently. In 2015, the group of Lin, Zheng and Xiao [21] disclosed a trifluoromethylation reagent, the difluorocarbene precursor difluoromethyltriphenylphosphonium bromide (DFPB), which could be applied in the trifluoromethylation of aromatic iodides without addition of external fluoride

• (Scheme 9). It was found that DBU can promote the decomposition of difluorocarbene to give fluoride which then reacts with difluorocarbene to a trifluoromethyl anion. Both electron-rich and electron-deficient substrates were converted to the corresponding analogues in moderate to good yields, without

Photocatalytic formation of carbon–sulfur bonds

• Alexander Wimmer and
• Burkhard König

Beilstein J. Org. Chem. 2018, 14, 54–83, doi:10.3762/bjoc.14.4

• available difluorobromoacetic acid. The respective carbon-centred radical intermediate is then oxidized by the [Ir] catalyst to close the catalytic cycle and form a reactive difluorocarbene intermediate by releasing carbon dioxide. At the same time, the aryl thiol is deprotonated by Cs2CO3. Finally, the

• resulting aryl thiol anion reacts with the difluorocarbene to deliver the coupled difluoromethylated aryl sulfide. This method provides a facile synthetic procedure for the selective difluoromethylation of aryl thiols with different functional groups in excellent yields. A very different approach for the

Carbon–carbon bond cleavage for Cu-mediated aromatic trifluoromethylations and pentafluoroethylations

• Tsuyuka Sugiishi,
• Hideki Amii,
• Kohsuke Aikawa and
• Koichi Mikami

Beilstein J. Org. Chem. 2015, 11, 2661–2670, doi:10.3762/bjoc.11.286

• . This report suggests that TFA can act as a trifluoromethyl source in the reaction with inactivated aromatic compounds, while the control of regioselectivity is difficult. Trifluoromethylation with difluorocarbene and fluoride ions The reaction system with ClCF2CO2Me/KF/CuI also generates CF3Cu in situ

• [40][41] (Scheme 7). The demethylation of ClCF2CO2Me proceeds by iodide, followed by decarboxylation of the resulting chlorodifluoroacetate to provide difluorocarbene (:CF2), trapped by fluoride to give the CF3− species. This reacts with CuI leading to CF3Cu. The method described above for the

Coupling of α,α-difluoro-substituted organozinc reagents with 1-bromoalkynes

• Artem A. Zemtsov,
• Alexander D. Volodin,
• Vitalij V. Levin,
• Marina I. Struchkova and
• Alexander D. Dilman

Beilstein J. Org. Chem. 2015, 11, 2145–2149, doi:10.3762/bjoc.11.231

• Federation 10.3762/bjoc.11.231 Abstract α,α-Difluoro-substituted organozinc reagents generated from conventional organozinc compounds and difluorocarbene couple with 1-bromoalkynes affording gem-difluorinated alkynes. The cross-coupling proceeds in the presence of catalytic amounts of copper iodide in

• difluorocarbene addition to multiple bonds [15]. Recently, we proposed a general method for assembling gem-difluorinated structures from organozinc reagents 1, difluorocarbene, and a terminating electrophile [16][17][18][19][20][21] (Scheme 1). (Bromodifluoromethyl)trimethylsilane [16][17][18] or potassium

• bromodifluoroacetate [19] can be used as precursors of difluorocarbene. In this process, the use of C-electrophiles is particularly important since it allows for the formation of two C–C bonds within one experimental run. Previously, as C-electrophiles in this methodology, only allylic substrates [17] and

Organic chemistry on surfaces: Direct cyclopropanation by dihalocarbene addition to vinyl terminated self-assembled monolayers (SAMs)

• Malgorzata Adamkiewicz,
• David O’Hagan and
• Georg Hähner

Beilstein J. Org. Chem. 2014, 10, 2897–2902, doi:10.3762/bjoc.10.307

• -difluorocyclopropane-terminated SAMs by generating difluorocarbene, following the procedure of Wang et al. [22] for small molecule transformations. This involved stirring a solution of NaI (0.2 equiv) and TMSCF3 in THF (2 mL), and then immersing the silicon wafers (1 cm × 1.5 cm) into the reaction mixture at 65 °C for

• ; c) TMSCF3, RMS 79 pm. The experimental set-up for the dibromo-, dichloro- and difluorocarbene reactions performed on C11-vinyl SAMs. Model reactions of dec-1-ene (1) with dihalocarbenes in the liquid phase. a) and b) NaOH, BTEAC, CHX3, DCM, 8 h, 25 °C; c) TMSCF3, THF, NaI, 3 h, 65 °C. Assignment of

Deoxygenative gem-difluoroolefination of carbonyl compounds with (chlorodifluoromethyl)trimethylsilane and triphenylphosphine

• Fei Wang,
• Lingchun Li,
• Chuanfa Ni and
• Jinbo Hu

Beilstein J. Org. Chem. 2014, 10, 344–351, doi:10.3762/bjoc.10.32

• . Conclusion: Similar to many other Wittig-type gem-difluoroolefination reactions in the presence of PPh3, the reaction of TMSCF2Cl with aldehydes and activated ketones is effective. Keywords: (chlorodifluoromethyl)trimethylsilane; difluorocarbene; gem-difluoroolefin; organo-fluorine; Wittig reaction; ylide

• difluoromethylene phosphonium ylide, which can be generated in situ either by the transformation of a difluorinated phosphonium salt or by the reaction between difluorocarbene (:CF2) and a phosphine (Scheme 1) [19][20][21][22][23][24][25][26]. In 1964, Fuqua and co-workers first reported the difluoromethylenation

• (Ph3P+CF2CO2−) and its application in carbonyl gem-difluoroolefination by Xiao and co-workers [21] finally confirmed the mechanism proposed by Burton and others [19][20]. Burton and co-workers also developed another difluorocarbene-free approach using a 1:2 mixture of CF2Br2 and PPh3 or P(NMe2)3 to

Aromatic and heterocyclic perfluoroalkyl sulfides. Methods of preparation

• Vladimir N. Boiko

Beilstein J. Org. Chem. 2010, 6, 880–921, doi:10.3762/bjoc.6.88

• ) [94]. The compounds shown in Figure 6 have been synthesized by this method. An alternative approach for the generation of CF3SCu involves heating of methyl fluorosulfonyl difluoroacetate in polar aprotic solvents to generate difluorocarbene, which in the presence of CuI and sulfur, forms