DOCSLIB.ORG

Magnesium Metal-Mediated Reductive Trifluoromethylation Of

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Magnesium Metal-Mediated Reductive Trifluoromethylation Of SPECIAL TOPIC 1899 Magnesium Metal-Mediated Reductive Trifluoromethylation of Aldehydes with Phenyl Trifluoromethyl Sulfone TrifluoromethylationYanchuan of Aldehydes Zhao, Jieming Zhu, Chuanfa Ni, Jinbo Hu* Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling-Ling Road, Shanghai 200032, P. R. of China E-mail: [email protected] Received 28 February 2010 der the reductive conditions appeared to be more chal- Abstract: An unprecedented reductive nucleophilic trifluorometh- 3b ylation of aldehydes by using phenyl trifluoromethyl sulfone is re- lenging. Although an alkoxide-induced nucleophilic ported. Mercury(II) chloride efficiently activates magnesium metal trifluoromethylation with 1 has been developed, the meth- to induce the desulfonylative trifluoromethylation process. The new od is only suitable for non-enolizable carbonyl com- reductive trifluoromethylation provides an alternative method for pounds.3f Because of the low cost and ready availability of efficient trifluoromethylation of non-enolizable or enolizable alde- phenyl trifluoromethyl sulfone (1) (Scheme 1), which is hydes with readily available phenyl trifluoromethyl sulfone reagent. also a precursor of trimethyl(trifluoromethane)silane,3b Key words: alkylations, aldehydes, alcohols, trifluoromethyla- further exploration of the synthetic applications of the sul- tions, phenyl trifluoromethyl sulfone fone under milder conditions is desirable. Here, we report a reductive nucleophilic trifluoromethylation of carbonyl compounds by using phenyl trifluoromethyl sulfone (1), The selective introduction of a trifluoromethyl (CF3) which is commercially available and can also be prepared group into an organic molecule is a strategy that is fre- from methyl phenyl sulfide (2) through chlorination, flu- quently used in drug design and agrochemical develop- orination, and oxidation (Scheme 1).5 ment because of the profound changes in bioactivity that O occur when a methyl group is replaced by a trifluoro- O H O Cl 2 2 HF 2 1 S PhSCF PhSCH PhSCCl 3 3 methyl group. As a result, a variety of nucleophilic, elec- 3 Ph CF AcOH 3 3 4 2 trophilic, and free-radical trifluoromethylation methods 1 have been developed,2 among which the nucleophilic tri- fluoromethylation reactions have been most extensively Scheme 1 Synthesis of phenyl trifluoromethyl sulfone (1) 2a–g – studied. Because the trifluoromethyl anion (CF3 ) is highly unstable, various compounds with the structure Reductive alkylation through desulfonylation remains a XCF3 [X = H, Br, I, SPh, TMS, SO2Ph, C(O)Y; relatively poorly studied reaction (especially when com- Y=NR1R2, OR, Ph]3 are normally used as synthons for pared with Barbier-type and Grignard-type reactions), the trifluoromethyl anion in nucleophilic trifluorometh- partly because of the greater dissociation energy of the C– 6 ylation reactions. The strategies for transferring the CF3 S bond compared with the C–X (X = Br, I) bond. As a re- group and breaking the X–C bond in XCF3 can be gener- sult, reductive desulfonylation generally requires harsher ally categorized into two types: a) electron transfer from a reaction conditions than do reductive dehalogenation re- suitable reducing agent to XCF3 (X = Br, I, SPh, actions. Indeed, the known desulfonylative alkylation re- 2h,3a,b SO2Ph), and b) nucleophilic attack of X in XCF3 actions usually employ relatively expensive samarium 1 2 7 8 [X = H, SPh, TMS, SO2Ph, C(O)Y (Y = NR R , OR, diiodide or lithium naphthalenide as a reducing agent, 3c–g Ph)] to cleave the X–C bond of XCF3. Because of the which hampered their widespread adoption. We envis- Downloaded by: Shanghai Institute of Organic Chemistry. Copyrighted material. relatively low bond-dissociation energy of XCF3 (X = I, aged that phenyl trifluoromethyl sulfone (1) might act as TMS) and the ease with which these undergo reduction or a good electron acceptor because of the high electron- nucleophilic attack, trifluoro(iodo)methane and trimeth- withdrawing ability of the trifluoromethyl group and that yl(trifluoromethane)silane (Ruppert–Prakash reagent) are the consequent reductive trifluoromethylation should pro- considered to be the most versatile reagents of types a) ceed smoothly. and b), respectively. Initial results were, however, quite discouraging. We Previously, we were interested in the exploration of syn- found that reducing agents such as magnesium, alumi- thetic applications of fluorinated sulfones.4 Although the num, zinc, or samarium diiodide in various solvents led to reductive trifluoromethylation of chlorosilanes by using recovery of phenyl trifluoromethyl sulfone (1). After phenyl trifluoromethyl sulfone (1) was successfully screening of several metal salts as additives for activating achieved in 2003, reactions with carbonyl compounds un- the reducing metals, we found that mercury(II) chloride efficiently activates magnesium to induce the required SYNTHESIS 2010, No. 11, pp 1899–1904xx.xx.2010 desulfonylation reaction (Table 1). The solvent also plays Advanced online publication: 23.04.2010 an important role in the desulfonylation reaction, as the re- DOI: 10.1055/s-0029-1218752; Art ID: C00810SS action only occurs in highly polar solvents such as N,N- © Georg Thieme Verlag Stuttgart · New York 1900 Y. Zhao et al. SPECIAL TOPIC dimethylformamide or dimethyl sulfoxide, which facili- of this new nucleophilic trifluoromethylation reaction be- tate the electron-transfer process and stabilize the anionic tween 1 and carbonyl compounds 5a–l. On treatment with intermediate. sulfone 1, various aldehydes reacted smoothly to the cor- responding trifluoromethyl carbinols 6 in moderate-to- Table 1 Effects of the Reaction Conditions on the Reductive good yields (Table 3; entries 1–8, 10–12). Aldehydes with a Desulfonylation of Phenyl Trifluoromethyl Sulfone (1) strong electron-withdrawing groups gave lower yields be- reducing metal (1 equiv) cause of the rapid reduction and pinacol coupling of these O O additive (5 mol%) S HCF substrates under the reductive conditions (entries 3, 5, 8, 3 Ph CF 3 solvent and 9). Moreover, under the reductive trifluoromethyla- 1 tion conditions, the enolizable aldehyde 5l gave an accept- Entry Reducing metal Solvent Additive Conv.b (%) able yield that was superior to that of the previously developed alkoxide-induced nucleophilic trifluorometh- 3f 1Mg DMFNiCl2 0 ylation. Note that the magnesium–mercury(II) chloride– 2Mg DMFPbCl 0 methanol system is used extensively in reductive desulfo- 2 nylation reactions,9 but, to the best of our knowledge, the 3 Mg DMF CuBr2 0 corresponding desulfonylative alkylation reaction in a nonprotic solvent has never been reported. 4Mg DMFHgCl2 >99 Note that, unlike fluoride-induced nucleophilic trifluo- 5 Mg THF HgCl2 0 romethylation with trimethyl(trifluoromethyl) silane, our – 6 Mg DMSO HgCl2 >99 method generates the CF3 species (or its synthetic equiv- alent) in the presence of a strong Lewis acid, so that sub- 7Zn DMFHgCl2 0 strates with a low electrophilicity (such as N,N- 8Al DMFHgCl2 0 O O OH 3 M HCl , BF OEt a Mg, HgCl S ⋅ 3 2 For all cases, PhSO2CF3 was added to a mixture of reducing metal, 2 CF 3 OH C F 3 15 °C to r.t. additive, and solvent at r.t. DMF, − b Determined by 19F NMR of the crude reaction mixture, and based on H the consumption of 1. 4 19 77% F NMR Next, we chose anisaldehyde (5a) as a model compound H N NH to optimize the reactant ratio and reaction temperature 2 (Table 2). We found that when the reactant ratio 1/5a/Mg/ O N NO H 2 2 H HgCl was 2:1:2:0.06 and the reaction temperature N 2 N 7 ranged between –15 °C and room temperature, the corre- CF 3 O N NO 2 sponding trifluoromethylated product 6a was obtained in 2 17% 88% yield (Table 2, entry 4). 8 Having determined the optimal reaction conditions Scheme 2 Synthesis and trapping of the hydrated form of the (Table 2, entry 4), we evaluated the scope and limitations trifluoroacetaldehyde (fluoral) Table 2 Effects of the Reaction Conditions for Reductive Desulfonylation Trifluoromethylation with Phenyl Trifluoromethyl Sulfone (1) OH CHO O O Mg, HgCl 2 CF 3 + S Downloaded by: Shanghai Institute of Organic Chemistry. Copyrighted material. solvent Ph CF 3 MeO MeO 1 5a 6a a b Entry Temp (°C) Molar ratio HgCl2 (mol%) Solvent Yield (%) 1/5a/Mg 1 –50 °C to r.t. 1:1:1 3 DMF 50 2 –50 °C to r.t. 2:1:2 3 DMF 80 3 0 °C to rt 1.5:1:1.5 6 DMF 79 4 –15 °C to r.t. 2:1:2 3 DMF 88 5 r.t. 1:1:2 2 DMSO 28c a Relative to the amount of Mg metal used. b Isolated yield. c Determined by 19F NMR spectroscopy. Synthesis 2010, No. 11, 1899–1904 © Thieme Stuttgart · New York SPECIAL TOPIC Trifluoromethylation of Aldehydes 1901 Table 3 Reductive Desulfonylation–Trifluoromethylation of Aldehydes with Phenyl Trifluoromethyl Sulfone (1) O OH Mg, HgCl (3 mol%) O O 2 S + 1 1 R H CF 15 °C to r.t. DMF, R − 3 Ph CF 3 H 1 5 6 Entrya Substrate Product Yield (%)b 1 6a R = 4-MeO 88 2 6b R = 3,4-(MeO)2 82 3 6c R = 2-Cl 60 CHO HO CF 4 3 6d R=4-Ph 72 5 6e R = 3-Cl 53 R 6 6f R=4-t-Bu 69 R 7 6g R = 4-BnO 78 i 5a– 8 6h R = 2,4-Cl2 45 9 6i R=4-O2N 28 OH CHO 10 6j 55 CF3 5j CHO HO CF3 11 6k 60 5k OH CHO 12c 6l 45 CF3 5l a In all cases, the molar ratio of reactants was 1/5/Mg/HgCl2 = 2.0:1.0:2.0:0.06. b Isolated yield. c MgCl2 was added to neutralize the basicity of the reaction system. O O O– O O Mg, HgCl2 R H S – (1) S – + CF3 Ph CF – Ph O R CF3 3 2 e H 9 1 6 Br O O O O Mg, HgCl2 S S (2) Ph CF3 DMF DMF, 60 °C Downloaded by: Shanghai Institute of Organic Chemistry.
Load more

Recommended publications
  • From Celebrex to a Novel Class of Phosphoinositide-Dependent Kinase 1 (Pdk-1) Inhibitors for Androgen-Independent Prostate Caner
    FROM CELEBREX TO A NOVEL CLASS OF PHOSPHOINOSITIDE-DEPENDENT KINASE 1 (PDK-1) INHIBITORS FOR ANDROGEN-INDEPENDENT PROSTATE CANER DISSERTATION Presented in Partial Fulfillment of the requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Jiuxiang Zhu, M.S. * * * * * The Ohio State University 2005 Dissertation Committee: Approved by Professor Ching-Shih Chen, Advisor Professor Robert Brueggemeier Advisor Professor Pui-Kai (Tom) Li Graduate Program in Pharmacy Professor Matthew D. Ringel ABSTRACT Celebrex, a nonsteroidal anti-inflammatory drug (NSAID, cyclooxygenase-2 inhibitor), was reported to induce apoptosis in the prostate cancer cell line PC-3 at 50µM. Early research from our laboratory demonstrated that this apoptotic inducing effect was independent of its COX-2 inhibitory activity. Further investigation showed that PDK-1 was a major protein targeted by celebrex in PC-3 cells to induce apoptosis. However, celebrex was very weak in inhibiting PDK-1 with IC50 of 48µM. To improve its potency, two series of analogs were designed and synthesized. In the first series of 24 compounds, the 5-position methylphenyl moiety of celebrex was replaced by various aromatic ring systems to explore the optimal hydrophobic group. OSU02067 (IC50=9µM) with phenanthrene at the 5-position was the best inhibitor among this series and was selected as the lead compound for further modification. Enzyme kinetics study of PDK-1 inhibition by celebrex indicated that it competed with ATP for binding. Docking of OSU02067 into the ATP binding domain of PDK-1 showed that the sulfonamide moiety hydrogen bonded to hinge region residue Ala162.
    [Show full text]
  • C'. Phsocfh (1C) OH
    US007087789B2 (12) United States Patent (10) Patent No.: US 7,087,789 B2 Prakash et al. (45) Date of Patent: Aug. 8, 2006 (54) METHODS FOR NUCLEOPHILC OTHER PUBLICATIONS FLUOROMETHYLATION Stahly, Nucleophilic Addition of Difluoromethyl Phenyl Sulfone to Aldehydes and Various Transformation of the (75) Inventors: issure Esthi, Resulting Alcohols, Journal of Fluorine Chemistry, 43, s s s 1989, 53-66.* E. i. 'S'srge A. Olah, Russell et al., Effective Nucleophilic Trifluoromethylation everly 1111s, with Fluoroform and Common Base, Tetrahedron, 54, 1998, Assignee: University of Southern California, 13771-13782.* - (73) Los Angeles, CA (US) Large et al., Nucleophilic Trifluoromethylation of Carbonyl s Compounds and Disulfides with Trifluoromethane and Sili (*) Notice: Subject to any disclaimer, the term of this con-Containing Bases with Fluoroform and Common Base, patent is extended or adjusted under 35 Snythesis, J. Org. Chem. 2000, 65, 8848-8856. U.S.C. 154(b) by 0 days. Prakash, G.K.S.; Krishnamurti, R.; Olah, G.A., J. Am. Chem. Soc. 1989, 111, 393-395. (21) Appl. No.: 10/755,902 (Continued) (22) Filed: Jan. 12, 2004 Primary Examiner Johann Richter O O Assistant Examiner Chukwuma Nwaonicha (65) P O PublicationDO Dat (74) Attorney, Agent, or Firm Winston & Strawn LLP US 2004/0230079 A1 Nov. 18, 2004 (57) ABSTRACT Related U.S. Application Data (60) Provisional application No. 60/440,011, filed on Jan. 13, 2003. A novel, convenient and efficient method for trifluoromethy s lation of substrate compounds is disclosed. Particularly, (51) Int. Cl. alkoxide and hydroxide induced nucleophilic trifluorom C07C 319/00 (2006.01) ethylation of carbonyl compounds, disulfides and other (52) U.S.
    [Show full text]
  • Chemistry of Trifluoroacetimidoyl Halides As Versatile Fluorine-Containing Building Bloks
    number 137 Contribution Chemistry of Trifluoroacetimidoyl Halides as Versatile Fluorine-containing Building Blocks Kenji Uneyama Professor of Emeritus, Department of Applied Chemistry, Okayama University Okayama 700-8530, Okayama, Japan 1. Outline of trifluoroacetimidoyl halides develop more sophisticated building blocks. They should be synthesized in high yields from easily available starting The trifluoromethyl group involved in organic compounds materials and should contain highly potential functional plays important roles as a key functional group in groups usable for further molecular modification. On this medicine, agricultural chemicals and electronic materials basis, trifluoroacetimidoyl halides are one of the unique and like liquid crystals. Common methods for introducing the valuable CF3-containing synthetic building blocks due to trifluoromethyl group (CF3 group) into organic compounds the following promising profiles; a) easy one-step are categorized into three; 1) the use of building blocks synthesis from a very available trifluoroacetic acid in containing CF3 group, 2) trifluoromethylation by the use of excellent yields, b) relatively stable to be stored, and c) trifluoromethylating agents such as CF3-TMS, FSO2CO2Me, containing highly potential functional groups such as CF3, CF3I, etc., and 3) the transformation of a functional group imino C=N double bond and halogen (Scheme 1). such as CCl3 and CO2H groups to CF3 group by the use of fluorinating agents such as F2 and HF. The method 3 is (Synthesis) conventionally used for the industrial mass production of Imidoyl halides 1 (X: Cl, Br) are synthesized from CF3-containing molecules, which are mostly structurally trifluoroacetic acid in excellent yields (85-95%) as shown 2) simple and stable molecules.
    [Show full text]
  • New Reagents for Fluoroalkylchalcogenations : Applications to Hot Chemistry Ermal Ismalaj
    New Reagents For Fluoroalkylchalcogenations : applications To Hot Chemistry Ermal Ismalaj To cite this version: Ermal Ismalaj. New Reagents For Fluoroalkylchalcogenations : applications To Hot Chemistry. Or- ganic chemistry. Université de Lyon, 2017. English. NNT : 2017LYSE1021. tel-01522960 HAL Id: tel-01522960 https://tel.archives-ouvertes.fr/tel-01522960 Submitted on 15 May 2017 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. N°d’ordre NNT : 2017LYSE1021 THESE de DOCTORAT DE L’UNIVERSITE DE LYON opérée au sein de l’Université Claude Bernard Lyon 1 Ecole Doctorale ED 206 (Ecole Doctorale de Chimie) Spécialité de doctorat : Chimie Discipline : Chimie Organique Soutenue publiquement 10/02/2017, par : (Ermal Ismalaj) New Reagents For Fluoroalkylchalcogenations. Applications To Hot Chemistry Devant le jury composé de : Popowycz Florence Professeur INSA Lyon Présidente Gouverneur Véronique Professeur University of Oxford Rapporteur Magnier Emmanuel, DR CNRS Université de Versailles-Saint-Quentin Rapporteur Zimmer Luc, Professeur, Université Claude Bernard Lyon-1, Examinateur Billard Thierry DR CNRS Université Lyon 1 Directeur de thèse Le Bars Didier, MCU-PH, Universite Lyon 1. Membre invite UNIVERSITE CLAUDE BERNARD - LYON 1 Président de l’Université M. le Professeur Frédéric FLEURY Président du Conseil Académique M.
    [Show full text]
  • Introduction of Fluorine and Fluorine- Containing Functional Groups
    Introduction of Fluorine and Fluorine- Containing Functional Groups The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Liang, Theresa, Constanze N. Neumann, and Tobias Ritter. 2013. Introduction of Fluorine and Fluorine-Containing Functional Groups. Angewandte Chemie International Edition 52, no. 32: 8214–8264. Published Version doi:10.1002/anie.201206566 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:12336403 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Open Access Policy Articles, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#OAP Fluorine DOI: 10.1002/anie.200((will be filled in by the editorial staff)) Introduction of Fluorine and Fluorine-Containing Functional Groups Theresa Liang, Constanze N. Neumann, and Tobias Ritter* Keywords: C–H functionalization fluorine catalysis trifluoromethylation transition metals 1 Theresa was born in 1985 in San Jose, A few decades ago, the development of several fluorinating California and received her undergraduate reagents such as Selectfluor®[11] and DAST (diethylaminosulfur education at University of California, [12] Berkeley pursuing research under the trifluoride) resulted in fast development of new fluorination mentorship of Prof. Richmond Sarpong in methods. Within the past ten years, a similar leap in fluorination total synthesis. After UC Berkeley, she chemistry has occurred, which we ascribe to increased efforts moved from sunny California to Harvard towards catalytic methods for fluorine incorporation. The merger of University and obtained her PhD in 2012 fluorination chemistry and synthetic organic chemistry––considered working with Prof.
    [Show full text]
  • Trifluoromethyl-Functionalized Poly(Lactic Acid): a Fluoropolyester Designed for Blood Contact Applications
    Biomaterials Science Trifluoromethyl-Functionalized Poly(lactic acid): A Fluoropolyester Designed for Blood Contact Applications Journal: Biomaterials Science Manuscript ID BM-ART-03-2019-000353.R2 Article Type: Paper Date Submitted by the 04-Jul-2019 Author: Complete List of Authors: Khalifehzadeh, Razieh; University of Washington, Chemical Engineering Ratner, Buddy; University of Washington, Department of Bioengineering Page 1 of 53 Biomaterials Science Trifluoromethyl-Functionalized Poly(lactic acid): A Fluoropolyester Designed for Blood Contact Applications Razieh Khalifehzadeh1, Buddy D. Ratner *,1, 2 1Department of Chemical Engineering, University of Washington, Seattle, USA 2Department of Bioengineering, University of Washington, Seattle, USA *Corresponding author: E-mail address: [email protected] Keywords: Fluoropolymer, Hemocompatibility, Protein adsorption, Poly(lactic acid), Biomaterials, organic synthesis 1 Biomaterials Science Page 2 of 53 Abstract Fluorinated polymers are strong candidates for development of new cardiovascular medical devices, due to their lower thrombogenicity as compared to other polymers used for cardiovascular implants. Few studies have reported the development of fluorinated polyesters and their potential in blood contact applications has never been examined. In this study, we developed a versatile method for preparing trifluoromethyl-functionalized poly(lactic acid) that can be potentially extended to prepare a new class of polyesters with various halogen or halocarbon substitutions. The resulting fluorinated
    [Show full text]
  • Metal-Catalyzed Synthesis of Heterocycles Bearing a Trifluoromethyl Group
    DOI 10.1515/pac-2013-1202 Pure Appl. Chem. 2014; 86(7): 1247–1256 Conference paper Mikiko Sodeoka* and Hiromichi Egami Metal-catalyzed synthesis of heterocycles bearing a trifluoromethyl group Abstract: The trifluoromethyl group has unique functional properties and is widely used not only in organic chemistry, but also in pharmaceutical and agrochemical science. Here we describe trifluoromethylation reactions of indoles and alkenes using Togni’s reagent. These reactions provide useful trifluoromethylated organic compounds, including heterocycles, with high efficiency. Keywords: alkenes; catalysis; copper; ICHC-24; indoles; trifluoromethylation. *Corresponding author: Mikiko Sodeoka, Synthetic Organic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan, e-mail: [email protected]; and RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; and Sodeoka Live Cell Chemistry Project, ERATO, Japan Science and Technology Agency, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan Hiromichi Egami: Synthetic Organic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Sodeoka Live Cell Chemistry Project, ERATO, Japan Science and Technology Agency, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; and School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan Article note: A collection of invited papers based on presentations at the 24th International Congress on Heterocyclic Chemistry (ICHC-24), Shanghai, China, 8–13 September 2013. Introduction Introduction of a trifluoromethyl group into organic frameworks is an important strategy for improving metabolic stability, lipophilicity and selectivity of bioactive compounds in pharmaceutical and agrochemi- cal research [1]. The trifluoromethyl group can be introduced not only on sp2 carbon, but also on sp3 carbon [2, 3].
    [Show full text]
  • Synthesis of Aromatic Trifluoromethyl Compounds: the Potential for Large Scale Application
    FUORINE CHEMISTRY HEINZ STEINER Solvias AG, Römerpark 2, 4303 Kaiseraugst, Switzerland Heinz Steiner Synthesis of aromatic trifluoromethyl compounds: The potential for large scale application KEYWORDS: trifluoromethylation, trifluoromethylating reagents, trifluoromethyl aromatics, deoxofluorination. This article provides an overview on reagents and protocols for the synthesis of aromatic trifluoromethyl Abstract compounds. The generation of trifluoromethylated aromatic building blocks, the deoxoflurination of carboxylic acids, and the trifluoromethylation of aromatic precursors are covered by this review. Issues that favor or hinder the large scale application of particular reagents and protocols are presented. Remarkably, only one out of more than 10 protocols covered by this review is currently applied on large production scale, a few others have been applied on a 5 kg to 100 kg scale. INTRODUCTION THE TERM “POTENTIAL FOR LARGE SCALE APPLICATION” (2) Trifluoromethylated aromatic rings are common motifs in When discussing the terms ‘potential for large scale pharmaceutical and agrochemical active compounds as application’ or ‘viability for industrial application’ aspects well as in performance materials (1). For many decades, such as cost of goods, processing cost, hazard potential, or formation of aryl-CF3 compounds has been limited to a few process safety are of increasing importance. Similar aspects traditional technologies, especially the perchlorination of are also discussed with respect to “green chemistry”. aromatic methyl-groups followed by exhaustive chlorine- fluorine exchange using anhydrous HF (AHF) or SbF5, or the In the current article the ‘potential for large scale application’ deoxofluorination of carboxylic acids using sulfur tetrafluoride. will be qualitatively assessed, regarding: In recent years, a plethora of new reagents and protocols - cost of starting materials, reagents, solvents, catalysts, have been developed at various universities, resulting in a auxiliaries tremendously expanded synthetic toolkit for R&D chemists.
    [Show full text]
  • Organo-Fluorine Chemical Science Inventing the Fluorine Future 2012 Helmut Martin Hugel¨ (Ed.)
    Special Issue Organo-Fluorine Chemical Science Inventing the Fluorine Future 2012 Helmut Martin Hugel¨ (Ed.) MDPI OPEN ACCESS External Editors Editorial Office Editor-in-Chief MDPI AG Prof. Dr. Takayoshi Kobayashi Kandererstrasse 25 Advanced Ultrafast Laser Research Center Basel, Switzerland The University of Electro-Communications Phone: +41 61 683 77 34 1-5-1, Chofugaoka, Chofu Website: http://www.mdpi.com/journal/applsci/ Tokyo 182-8585, Japan E-Mail: [email protected] Phone: +81 42 443 5845 Website: http://femto.pc.uec.ac.jp Publisher E-Mail: [email protected] Dr. Shu-Kun Lin Guest Editor Production Editor Dr. Helmut Martin Hugel¨ Dr. Brietta Pike School of Applied Sciences (Chemistry) RMIT University Managing Editor Melbourne VIC 3001 Dr. Ophelia Han PO Box 2476V, Australia Phone: +61 3 99252626 E-Mail: [email protected] Cover picture: Available online at: www.emsl.pnl.gov/upload/1337721062386/ buildingItBetter web.jpg Image credit to: EMSL ISBN 3-906980-33-2 Summary Dear Colleagues, The unique properties imparted on molecules by fluorine substitution, continues to be the subject of intense research as the products have widespread application in all areas of science. Incorporation of fluorine can productively and unpredictably modulate several properties that interest medicinal chemists. Selected drugs for the treatment of high cholesterol such as Lipitor R by Pfizer, Crestor R by AstraZeneca, Zetia R by Merck/Schering-Plough and Lescol R by Novartis all of which contain one or more fluorine atoms that increase metabolic stability, rank amongst the highest selling prescription drugs ever developed. Without doubt every current drug discovery and development program includes and evaluates fluorine-containing drug candidates.
    [Show full text]
  • Progress in Copper-Catalyzed Trifluoromethylation
    Progress in copper-catalyzed trifluoromethylation Guan-bao Li1, Chao Zhang1, Chun Song*1 and Yu-dao Ma*2 Review Open Access Address: Beilstein J. Org. Chem. 2018, 14, 155–181. 1School of Pharmaceutical sciences, Shandong University, 44 West doi:10.3762/bjoc.14.11 Culture Road, Jinan 250012, PR China and 2Department of chemistry, Shandong University, 27 Shanda South Road, Jinan Received: 19 October 2017 250100, PR China Accepted: 04 January 2018 Published: 17 January 2018 Email: Chun Song* - [email protected]; Yu-dao Ma* - This article is part of the Thematic Series "Organo-fluorine chemistry IV". [email protected] Guest Editor: D. O'Hagan * Corresponding author © 2018 Li et al.; licensee Beilstein-Institut. Keywords: License and terms: see end of document. copper; fluorine; trifluoromethylation Abstract The introduction of trifluoromethyl groups into organic molecules has attracted great attention in the past five years. In this review, we describe the recent efforts in the development of trifluoromethylation via copper catalysis using nucleophilic, electrophilic or radical trifluoromethylation reagents. Introduction The fluorine atom has a strong electronegativity and a small romethylation has gained enormous interest due to its high effi- atomic radius, and the incorporation of fluoroalkyl groups into ciency and cheapness. molecules imparts a variety of features. The trifluoromethyl group, as the most significant common used fluoroalkyl group, Recently, several reviews on trifluoromethylation were could improve molecular properties such as metabolic stability, disclosed. Xu, Dai [5] and Shen [6] mainly discussed progress lipophilicity and permeability [1-4]. Therefore, organic mole- in copper-mediated trifluoromethylation before 2013. Other cules bearing trifluoromethyl groups are widely used in pharma- works focus on the trifluoromethylation of alkynes [7] or on the 3 2 ceuticals and agrochemicals, such as the antidepressant fluoxe- C(sp )−CF3, C(sp )−CF3, and C(sp)−CF3 bond construction tine, the anti-ulcer drug lansoprazole and so on (Figure 1).
    [Show full text]
  • Functional Group Characteristics and Roles
    2 Functional Group Characteristics and Roles INTRODUCTION This chapter is written with the assumption that the reader has a basic knowledge of organic chemistry and is at least familiar with the terminology used to describe the parts of an organic molecule. The goals of this chapter are to define the term functional group, review the major chemical properties or characteristics inherent to any given functional group, relate these chemical properties or characteristics to the discipline of medicinal chemistry, and to provide some initial examples of how these properties or characteristics are important for drug action. Subsequent chapters provide detailed information with regard to the ionization of acidic and basic functional groups, the roles of water and lipid soluble functional groups, the types of chemical interactions possible between functional groups and their biological targets, the specific routes of metabolism associated with specific functional groups, and how functional groups can be altered to provide a therapeutic benefit. LEARNING OBJECTIVES After completing this chapter, students will be able to: 1. Identify the individual functional groups that comprise the structure of a given drug molecule. 2. Explain the general purpose of functional groups and provide specific examples of how functional groups affect drug activity. 3. Analyze the electronic, solubility, and steric effects that an individual functional group can impart to a specific drug molecule. 1 2 Basic Concepts in Medicinal Chemistry 4. Explain how a specific functional group can serve different purposes on differ- ent drug molecules and how the importance of a specific functional group can vary among different drug molecules based on the influence of the adjacent functional groups.
    [Show full text]
  • The Unique Fluorine Effects in Organic Reactions: Recent Facts and Insights Into Fluoroalkylations Chem Soc Rev
    Volume 45 Number 20 21 October 2016 Pages 5435–5796 Chem Soc Rev Chemical Society Reviews www.rsc.org/chemsocrev ISSN 0306-0012 TUTORIAL REVIEW Chuanfa Ni and Jinbo Hu The unique fluorine effects in organic reactions: recent facts and insights into fluoroalkylations Chem Soc Rev View Article Online TUTORIAL REVIEW View Journal | View Issue The unique fluorine effects in organic reactions: recent facts and insights into fluoroalkylations Cite this: Chem. Soc. Rev., 2016, 45, 5441 Chuanfa Ni and Jinbo Hu* Fluoroalkylation reaction, featuring the transfer of a fluoroalkyl group to a substrate, is a straightforward and efficient method for the synthesis of organofluorine compounds. In fluoroalkylation reactions, fluorine substitution can dramatically influence the chemical outcome. On the one hand, the chemistry of alkylation with non-fluorinated reagents may not be applicable to fluoroalkylations, so it is necessary to tackle the fluorine effects to achieve efficient fluoroalkylation reactions. On the other hand, fluorine substitution may bring about new reactivities and transformations that cannot be realized in alkylation with non-fluorinated reagents; thus, fluorine substitution can be used to explore new synthetic Received 30th April 2016 methods. This tutorial review provides a brief overview of the unique fluorine effects in recently DOI: 10.1039/c6cs00351f developed nucleophilic, electrophilic, radical, and transition metal-mediated fluoroalkylation reactions by Creative Commons Attribution 3.0 Unported Licence. comparing with either their non-fluorinated counterparts or fluorinated counterparts with different www.rsc.org/chemsocrev numbers of fluorine substituents. Key learning points (1) Fluorine substitution can dramatically influence the chemical outcome of fluoroalkylation reactions. (2) The chemistry of alkylation with non-fluorinated reagents may not be applicable to fluoroalkylation chemistry.
    [Show full text]