Synthesis of 2-trifluoromethylpyrazolo[5,1-a]isoquinolines via silver triflate-catalyzed or electrophile-mediated one-pot tandem reaction

• Xiaoli Zhou,
• Meiling Liu,
• Puying Luo,
• Yingjun Lai,
• Tangtao Yang and
• Qiuping Ding

Beilstein J. Org. Chem. 2014, 10, 2286–2292, doi:10.3762/bjoc.10.238

• -alkynylbenzylidene)hydrazides 1, electrophiles (I2 or ICl), and ethyl 4,4,4-trifluorobut-2-ynoate (2) were carried out under mild conditions. The results are summarized in Table 3. For all cases, this tandem reaction worked well leading to the corresponding iodinated fluorine-containing pyrazolo[5,1-a]isoquinolines

Synthesis of trifluoromethyl-substituted pyrazolo[4,3-c]pyridines – sequential versus multicomponent reaction approach

• Barbara Palka,
• Angela Di Capua,
• Maurizio Anzini,
• Gyté Vilkauskaité,
• Algirdas Šačkus and
• Wolfgang Holzer

Beilstein J. Org. Chem. 2014, 10, 1759–1764, doi:10.3762/bjoc.10.183

• all obtained products. Keywords: microwave-assisted reactions; multicomponent reactions; NMR (1H; 13C; 15N; 19F); Sonogashira coupling; trifluoromethylpyrazoles; Introduction Fluorine-containing compounds play an important role in medicinal and pharmaceutical chemistry as well as in agrochemistry [1

• substituent, including important drug molecules in different pharmaceutical classes [5]. Keeping in mind the above facts, the synthesis of fluorinated heterocyclic compounds, which can act as building blocks for the construction of biologically active fluorine-containing molecules, is of eminent interest. In

Syntheses of fluorooxindole and 2-fluoro-2-arylacetic acid derivatives from diethyl 2-fluoromalonate ester

• Antal Harsanyi,
• Graham Sandford,
• Dmitri S. Yufit and
• Judith A.K. Howard

Beilstein J. Org. Chem. 2014, 10, 1213–1219, doi:10.3762/bjoc.10.119

• –fluorine bonds are ‘man-made’. Syntheses rely either on the construction of carbon–fluorine bonds using a fluorinating agent (‘late-stage’ fluorination) or the application of polyfunctional fluorine-containing small molecule building blocks (‘early stage’ fluorination) which may be employed in further

Flow microreactor synthesis in organo-fluorine chemistry

• Hideki Amii,
• Aiichiro Nagaki and
• Jun-ichi Yoshida

Beilstein J. Org. Chem. 2013, 9, 2793–2802, doi:10.3762/bjoc.9.314

• synthesis and reactions of fluorine-containing molecules by the use of flow microreactor systems to overcome long-standing problems in fluorine chemistry. Keywords: defluorination; fluorine; fluorination; flow microreactor; organo-fluorine; perfluoroalkylation; Review Fluorine is a key element in the

• stability of fluorine-containing intermediates and low selectivity (chemo-, regio-, and/or stereo-) of the reactions have disturbed the progress of synthesis of fluorochemicals. New methodologies that can cure the weak points in synthesizing fluoro-organic compounds would open up a new perspective for

• conducted in one flow by adding the reagents at different places in continuous-flow synthesis [18][19][20][21][22][23][24][25]. This review deals with the successful examples on synthesis and reactions of fluorine-containing molecules by the use of flow microreactor systems. Useful applications using flow

Stereoselectively fluorinated N-heterocycles: a brief survey

• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2013, 9, 2696–2708, doi:10.3762/bjoc.9.306

• from fluorine-containing organic building blocks. Such an approach benefits from the wide variety, and frequently the low cost, of today’s commercially available organofluorine molecules [63][64]. For example, the fluorinated aziridines 2 and 3 presented earlier (Figure 1) were synthesised through a

• enantioselectivity. 6.5 Radical reactions Examples of direct fluorination of C–H bonds with fluorine-containing radicals are rare in the literature, especially if stereoselective versions of such reactions are sought. However, this transformation can be a very effective and concise method for synthesising

Novel synthesis of pseudopeptides bearing a difluoromethyl group by Ugi reaction and desulfanylation

• Jingjing Wu,
• Hui Li and
• Song Cao

Beilstein J. Org. Chem. 2011, 7, 1070–1074, doi:10.3762/bjoc.7.123

• cleavage; Ugi reaction; Introduction Fluorinated amino acids and pseudopeptides have increasingly attracted attention in recent years [1][2][3][4][5]. The selective incorporation of fluorine-containing groups, such as trifluoromethyl, difluoromethyl and difluoromethylene, into peptides or peptidomimetics

• isosteric and isopolar to the hydroxyl group and can behave as a hydrogen donor through hydrogen bonding [13]. However, to date, most fluorine-containing peptide modifications involve the introduction of trifluoromethyl or difluoromethylene into molecules [14][15][16][17][18]. Only a few examples have been

Continuous gas/liquid–liquid/liquid flow synthesis of 4-fluoropyrazole derivatives by selective direct fluorination

• Jessica R. Breen,
• Graham Sandford,
• Dmitrii S. Yufit,
• Judith A. K. Howard,
• Jonathan Fray and
• Bhairavi Patel

Beilstein J. Org. Chem. 2011, 7, 1048–1054, doi:10.3762/bjoc.7.120

• appropriate nucleophilic or electrophilic fluorinating agent [6], or syntheses based on the reactions of appropriate fluorine containing building blocks [7]. Of course, whichever methodology is used for the synthesis of a specific fluorinated organic molecule, a carbon–fluorine bond must be formed at some

• fluorination in the first stage of a multi-step, telescoped, continuous flow process. Thus, continuous flow methodology was used for successful sequential carbon-fluorine bond formation and subsequent fluorine-containing building block reactions in a single continuous high yielding, efficient and

Synthesis, reactivity and biological activity of 5-alkoxymethyluracil analogues

• Lucie Brulikova and
• Jan Hlavac

Beilstein J. Org. Chem. 2011, 7, 678–698, doi:10.3762/bjoc.7.80

• all the compounds is divided into sections according to the nature of the furanose present. 2'-Deoxyuridine analogues: The earliest article describing 2'-deoxyuridine analogues was focused on uracil analogues modified at position 5 by a fluorine containing moiety [6]. Bases or nucleosides substituted

• efficient synthetic route for the preparation of ethoxy-substituted 5-(perfluoroalkyl)pyrimidines (Scheme 10) and investigated their regioselective transformations [18]. Some of these fluorine-containing pyrimidine analogues are potent antitumor and antiviral agents. The reported synthesis started with the

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

Shelf-stable electrophilic trifluoromethylating reagents: A brief historical perspective

• Norio Shibata,
• Andrej Matsnev and
• Dominique Cahard

Beilstein J. Org. Chem. 2010, 6, No. 65, doi:10.3762/bjoc.6.65

• , chemical and biological properties [3]. The specific physical and chemical properties of fluorine in fluorine containing compounds, especially its strong electronegativity, lipophilicity and reaction ability, differ dramatically from those of other halogens and thus lead to changes in the interaction

• ]. Among the increasingly powerful methods that have been developed for the direct introduction of fluorine into organic compounds, trifluoromethylation is one of the most direct and straightforward strategies in the synthesis of fluorine-containing organic compounds. Efficient transfer of the

The C–F bond as a conformational tool in organic and biological chemistry

• Luke Hunter

Beilstein J. Org. Chem. 2010, 6, No. 38, doi:10.3762/bjoc.6.38

• ) interactions. Such interactions can indeed be observed in an intermolecular sense, where, for example, fluorine-containing drug molecules can bind their receptor with the fluorine atom oriented towards a partial positive charge such as an amide carbon or an acidic hydrogen in a protein receptor (1 and 2

Synthesis of gem-difluoromethylenated analogues of boronolide

• Jing Lin,
• Xiao-Long Qiu and
• Feng-Ling Qing

Beilstein J. Org. Chem. 2010, 6, No. 37, doi:10.3762/bjoc.6.37

• aldehyde 9 with the fluorine-containing building block 11 and the efficient construction of α,β-unsaturated-δ-lactones 15a–b via BAIB/TEMPO-procedure. Keywords: boronolide; gem-difluoromethylenated analogues; gem-difluoropropargylation; α,β-unsaturated-δ-lactones; Introduction (+)-Boronolide (1

• could be obtained via an indium-mediated reaction of the fluorine-containing building block C and the protected aldehyde D, which in turn could be readily prepared by the reported procedure. Three chiral centres in our target molecules would be derived from D-glucono-δ-lactone, and the last one could be

• ). Conclusion In summary, we accomplished a concise synthesis of the gem-difluoromethylenated analogues of boronolide 4–7. Our approach featured the preparation of separable key diastereoisomers 12a–b from the indium-mediated gem-difluoropropargylation of aldehyde 9 with fluorine-containing building block 11

Enantioselective nucleophilic difluoromethylation of aromatic aldehydes with Me₃SiCF₂SO₂Ph and PhSO₂CF₂H reagents catalyzed by chiral quaternary ammonium salts

• Chuanfa Ni,
• Fang Wang and
• Jinbo Hu

Beilstein J. Org. Chem. 2008, 4, No. 21, doi:10.3762/bjoc.4.21

• this field. Background Because of the unique properties of fluorine, selective introduction of fluorine atom(s) or fluorine-containing moieties into organic molecules often dramatically alter their stability, lipophilicity, bioavailability, and biopotency. It is estimated that as many as 30–40% of

Understanding the mechanism of Pd-catalyzed allylic substitution of the cyclic difluorinated carbonates

• Jun Xu,
• Xiao-Long Qiu and
• Feng-Ling Qing

Beilstein J. Org. Chem. 2008, 4, No. 18, doi:10.3762/bjoc.4.18

• fluoroalkyl groups would alter the regioselectivities of acyclic allylic alkylation compared with their non-fluorinated counterparts [12][13][14][15][16][17], their reactions mostly concerned the Pd-catalyzed regio- and stereoselective formate reduction of fluorine-containing allylic mesylates. To the best of

Efficient 1,4-addition of α-substituted fluoro(phenylsulfonyl)methane derivatives to α,β-unsaturated compounds

• G. K. Surya Prakash,
• Xiaoming Zhao,
• Sujith Chacko,
• Fang Wang,
• Habiba Vaghoo and
• George A. Olah

Beilstein J. Org. Chem. 2008, 4, No. 17, doi:10.3762/bjoc.4.17

• ][10][11][12][13]. As part of our ongoing effort to extend the applications of fluorine-containing (phenylsulfonyl)methane derivatives, we envisaged that fluoro(phenylsulfonyl)methane, α-substituted by nitro, cyano, ester, or acetyl would be useful for the synthesis of functionalized

Trifluoromethyl ethers – synthesis and properties of an unusual substituent

• Frédéric R. Leroux,
• Baptiste Manteau,
• Jean-Pierre Vors and
• Sergiy Pazenok

Beilstein J. Org. Chem. 2008, 4, No. 13, doi:10.3762/bjoc.4.13

• . Introduction Nowadays, fluorine containing compounds are synthesized in pharmaceutical research on a routine basis and about 10% of all marketed pharmaceuticals contain a fluorine atom. There has been an enormous increase in the use of fluorine containing compounds for medicinal applications. For example, nine

A convenient catalyst system for microwave accelerated cross- coupling of a range of aryl boronic acids with aryl chlorides

• Matthew L. Clarke,
• Marcia B. France,
• Jose A. Fuentes,
• Edward J. Milton and
• Geoffrey J. Roff

Beilstein J. Org. Chem. 2007, 3, No. 18, doi:10.1186/1860-5397-3-18

• conditions yields only 1,2,5 trifluorobenzene as the only fluorine containing product. Protodeboronation is therefore the cause of the low reactivity observed here, and is a likely problem in other Suzuki couplings of highly fluorinated substrates. Finally, we stirred 2,3,6-trifluorophenyl boronic acid with

Stereoselective α-fluoroamide and α-fluoro- γ-lactone synthesis by an asymmetric zwitterionic aza-Claisen rearrangement

• Kenny Tenza,
• Julian S. Northen,
• David O'Hagan and
• Alexandra M. Z. Slawin

Beilstein J. Org. Chem. 2005, 1, No. 13, doi:10.1186/1860-5397-1-13

• with (S)-N-allyl-2(methoxymethyl)pyrrolidine 23. Product α-fluoroamides were prepared with very high diastereoselectivities (99%de) and the absolute stereochemistry of these products was determined by derivatisation and X-ray structure analysis. It is notable that with this auxilary the fluorine

• containing substrates gave higher diastereoselectivities relative to the non-fluorinated counterpart an observation which may have its origin in electronic stabilisation of one diastereoselective transition state as a consequence of the C-F bond. The aza-Claisen products where then subjected to