Communication pubs.acs.org/OPRD
Multigram Laboratory Scale Synthesis of α‑Trifluoromethoxy Carbonyl Compounds Julien Barbion,† Sergii Pazenok,‡ Jean-Pierre Vors,§ Bernard R. Langlois,† and Thierry Billard*,† †
Université de Lyon, Université Lyon 1, CNRS, ICBMS (UMR CNRS 5246), 43 Bd du 11 novembre 1918, Bat Raulin, 69622 Lyon, France ‡ Bayer CropScience AG, Product Technology, Process Research, Alfred-Nobel-Str. 50, 40789 Monheim am Rhein, Germany § Bayer CropScience SAS, Centre R&D de La Dargoire, 14-20 rue Pierre Baizet, 69009 Lyon, France Scheme 1. Synthesis of α-trifluoromethoxy carbonyl compounds (1)
ABSTRACT: α-trifluoromethoxy carbonyl compounds are valuable building blocks for the synthesis of various trifluoromethoxylated compounds. The best way to easily obtain them is the direct trifluoromethoxylation with the CF3O− anion, generated in situ from trifluoromethyl triflate. However, the necessary autogenous pressure generated during this reaction constitutes a main drawback for a multigram scale extrapolation. A specific procedure using adapted glassware has allowed a laboratory largescale production (up to 50 g) of such building blocks with good yields.
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INTRODUCTION The intrinsic properties of a fluorine atom (small size, high electronegativity, formation of strong C−F bonds) induce dramatic changes in the electronic, steric, and hydrophobic parameters of the molecules which bear fluorinated moieties.1−4 Thus, their pharmacodynamic and pharmacokinetic properties are deeply modified.5,6 This is the reason why fluorine chemistry is now so popular in the life sciences. Among the fluorinated moieties currently used, the trifluoromethoxy group (OCF3) becomes more and more prominent.7−9 Until now, the major trifluoromethoxylated compounds described in the literature are essentially aromatic ones. In contrast, trifluoromethoxy-substituted heterocycles are still rare in the literature.9,10 However, because of the importance of heterocyclic molecules in pharmaceutical and agrochemical chemistry, the synthesis of trifluoromethoxylated heterocycles could be of great interest for the development of novel original molecules for various applications in the life sciences.
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Among all of these strategies, the TFMT pathway remains the more rapid and efficient method to obtain easily the targeting compounds 1. However, the generated CF3O− anion (3) is instable and collapses rapidly into difluorophosgene and fluoride (Scheme 2). Scheme 2. Decomposition of the trifluoromethoxide anion (3)
Consequently, this degradation requires that the reactions were conducted into closed vessels to conserve a sufficient pressure of gaseous difluorophosgene to displace the previous equilibrium in favor of the CF3O− anion (3) formation. Because of this necessary precaution the additions of TFMT and 4 were generally performed with syringes, without vent. Nevertheless, if such additions under pressure were possible with small quantities, this reaction appeared very difficult to extrapolate, in the laboratory, to larger quantities in safe and efficient conditions.
RESULTS AND DISCUSSION
Simple accesses to such fluorinated heterocycles have been previously described starting from α-trifluoromethoxy carbonyl compounds (1).11−14 Nevertheless, the syntheses of such starting material are relatively restricted.14−18 The first one is a multistep synthesis via a de novo building of the OCF3 moiety by using a HF−pyridine complex (Scheme 1).18 The other way of access consists to a direct introduction of the OCF3 group by a nucleophilic substitution with the trifluoromethoxide anion (3), generated from the trifluoromethyl triflate (CF3SO2OCF3, TFMT)14−16 or from the 2,4-dinitro(trifluoromethoxy)benzene (2) (Scheme 1).17 © XXXX American Chemical Society
Special Issue: Fluorine Chemistry 14 Received: April 9, 2014
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dx.doi.org/10.1021/op500118r | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Communication
Since the control of pressure seemed to be crucial, a pressure checking has been added onto the reactor to follow the pressure and to adapt the dropwise to maintain a low internal pressure (
