A Continuous-Flow Approach to 3,3,3-Trifluoromethylpropenes: Bringing Together Grignard Addition, Peterson Elimination, Inline Extraction, and Solvent Switching

被引：30
作者：
Hamlin, Trevor A. [1 ]
Lazarus, Gillian M. L. [1 ]
Kelly, Christopher B. [1 ]
Leadbeater, Nicholas E. [1 ,2 ]
机构：
[1] Univ Connecticut, Dept Chem, Storrs, CT 06269 USA
[2] Univ Connecticut, Ctr Hlth, Dept Community Med & Hlth Care, Farmington, CT 06030 USA
来源：
ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2014年 / 18卷 / 10期
基金：
美国国家科学基金会;
关键词：
TRIFLUOROMETHYL KETONES; MEDICINAL CHEMISTRY; DIPEPTIDE ISOSTERES; EFFICIENT SYNTHESIS; PEPTIDE ISOSTERES; FLUORINE; OLEFINATION; REACTOR; SEPARATION; REAGENTS;
D O I：
10.1021/op500190j
中图分类号：
O69 [应用化学];
学科分类号：
081704 ;
摘要：
A continuous-flow approach to the synthesis of 3,3,3-trifluoromethylpropenes involving Grignard addition of, (trimethylsilyl)methylmagnesium chloride to a trifluoromethyl ketone followed by dehydrative desilylation of the alpha-trifluoromethyl-beta-hydroxysilyl alcohol using trimethylsilyl trifluoromethanesulfonate is reported. An inline aqueous/organic extraction and a concomitant solvent switch were key to the success of the methodology. Transition from batch to continuous flow conditions allows for higher yields, shorter reaction times, and facile scale out.
引用
收藏
页码：1253 / 1258
页数：6
相关论文
共 49 条
  • [1] Membrane-Based, Liquid-Liquid Separator with Integrated Pressure Control
    Adamo, Andrea
    Heider, Patrick L.
    Weeranoppanant, Nopphon
    Jensen, Klavs F.
    [J]. INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH, 2013, 52 (31) : 10802 - 10808
  • [2] [Anonymous], 2012, [No title captured], Patent No. [20120238517, 20120238517 A1]
  • [3] Continuous multi-injection reactor for multipurpose production - Part I
    Barthe, Philippe
    Guermeur, Celine
    Lobet, Olivier
    Moreno, Maxime
    Woehl, Pierre
    Roberge, Dominique M.
    Bieler, Nikolaus
    Zimmermann, Bertin
    [J]. CHEMICAL ENGINEERING & TECHNOLOGY, 2008, 31 (08) : 1146 - 1154
  • [4] Synthesis of Polyfluoro Ketones for Selective Inhibition of Human Phospholipase A2 Enzymes
    Baskakis, Constantinos
    Magrioti, Victoria
    Cotton, Naomi
    Stephens, Daren
    Constantinou-Kokotou, Violetta
    Dennis, Edward A.
    Kokotos, George
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (24) : 8027 - 8037
  • [5] Cassayre J. Y., 2012, U.S. Patent, Patent No. [EP 2199287 A1, 2010, 2199287, 2012/0238517 A1]
  • [6] Continuous Hydrolysis and Liquid-Liquid Phase Separation of an Active Pharmaceutical Ingredient Intermediate Using a Miniscale Hydrophobic Membrane Separator
    Cervera-Padrell, Albert E.
    Morthensen, Sofie T.
    Lewandowski, Daniel J.
    Skovby, Tommy
    Kiil, Soren
    Gernaey, Krist V.
    [J]. ORGANIC PROCESS RESEARCH & DEVELOPMENT, 2012, 16 (05) : 888 - 900
  • [7] New Fluorinated Peptidomimetics through Tandem Aza-Michael Addition to α-Trifluoromethyl Acrylamide Acceptors: Synthesis and Conformational Study in Solid State and Solution
    Fustero, Santos
    Chiva, Gema
    Piera, Julio
    Sanz-Cervera, Juan F.
    Volonterio, Alessandro
    Zanda, Matteo
    de Arellano, Carmen Ramirez
    [J]. JOURNAL OF ORGANIC CHEMISTRY, 2009, 74 (08) : 3122 - 3132
  • [8] Anhydrodihydroartemisinin and its 10-trifluoromethyl analogue:: Access to novel D-ring-contracted artemisinin trifluoromethyl ketones
    Grellepois, F
    Chorki, F
    Crousse, B
    Ourévitch, M
    Bonnet-Delpon, D
    Bégué, JP
    [J]. JOURNAL OF ORGANIC CHEMISTRY, 2002, 67 (04) : 1253 - 1260
  • [9] The many roles for fluorine in medicinal chemistry
    Hagmann, William K.
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (15) : 4359 - 4369
  • [10] Methylenation of Perfluoroalkyl Ketones using a Peterson Olefination Approach
    Hamlin, Trevor A.
    Kelly, Christopher B.
    Cywar, Robin M.
    Leadbeater, Nicholas E.
    [J]. JOURNAL OF ORGANIC CHEMISTRY, 2014, 79 (03) : 1145 - 1155
12345