Article pubs.acs.org/joc
Cite This: J. Org. Chem. 2018, 83, 723−732
Cu(OTf)2‑Catalyzed Pummerer Coupling of β‑Ketosulfoxides Regev Parnes, Hagai Reiss, and Doron Pappo* Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel S Supporting Information *
ABSTRACT: The copper(II) trifluoromethanesulfonate-catalyzed Pummerer reaction of β-ketosulfoxides with 1,3dicarbonyl compounds or π-nucleophiles such as phenols, arenes, and tetraallylsilane is reported. The mild conditions provide an efficient entry to a novel class of polysubstituted 3alkylthiofuran and polysubstituted 3-thiobenzofuran heterocycles from readily available materials.
■
INTRODUCTION The Pummerer reaction1 is an attractive method for assembling complex heterocycles from simple organosulfur compounds in a single synthetic operation.2,3 The mechanistic scheme involves generating a powerful electrophilic thionium ion intermediate that reacts with a nucleophilic coupling partner, producing one or more new carbon−carbon or carbon−heteroatom bonds (Scheme 1A). In general, the generation of thionium ions from sulfoxides,4 dithioacetal5, or hemithioacteal (connective Pummerer)6 requires stoichiometric amounts of an activator (such as Ac2O, Tf2O, or TMSCl) and/or strong Lewis acids or Brønsted acids (such as TiCl4, SnCl2, Hg(OAc)2, BF3·OEt2, or p-toluenesulfonic acid (pTSA)) in a moisture-free environment at reduced temperatures.1 Under these kinetically controlled conditions, only substrates and nucleophiles that survive the harsh acidic conditions are applicable.7 Therefore, the development of a catalytic system for promoting the Pummerer reaction under mild and sustainable conditions is an important objective that needs to be addressed.8 Recently, a catalytic system for performing the Pummerer reaction based on copper(II) trifluoromethanesulfonate [Cu(OTf)2 (2.5−5 mol %)] in polar solvents, such as nitromethane and 2,2,2-trifluoroethanol (TFE), was developed by our group. These conditions were found to be exceptionally efficient for generating thionium ion species directly from aldehydes and thiols (Scheme 1B). The powerful electrophilic species was reactive toward nucleophilic arenes (Pummerer/ Friedel−Crafts)9 and vinyl sulfides (Pummerer/aldol addition), which are formed from ketones and thiols under the reaction conditions.10 To extend the application of our novel conditions, we turned to study the Lewis acid-catalyzed Pummerer reaction of β-ketosulfoxides (Scheme 1C). Furans and benzofurans are among the most important heterocycles11 with biologically active characteristics12 that are used as building blocks in the synthesis of a variety of heterocyclic and acyclic organic compounds.13 Condensation of dicarbonyl compounds and cycloisomerization of alkyne© 2018 American Chemical Society
Scheme 1. Cu(OTf)2-Catalyzed Pummerer Reactions
and allene-containing molecules are the most studied strategies for their preparation.11f,14 The development of synthetic Received: October 25, 2017 Published: January 2, 2018 723
DOI: 10.1021/acs.joc.7b02708 J. Org. Chem. 2018, 83, 723−732
Article
The Journal of Organic Chemistry methods for assembling multisubstituted furans15 and benzofurans with unique substituent patterns under simple conditions remains an important synthetic goal.16 Over the years, various methods for preparing 2- or 3-(alkyl or arylthio)furans by utilizing thionium ion chemistry have been developed.17 In a typical example, the Satoh group applied classical Pummerer conditions (trifluoroacetic anhydride (TFAA, 5 equiv), sodium iodide (5 equiv), Scheme 2)
Table 1. Optimization Conditions for the Synthesis of Furan 5aa
entry
Scheme 2. Satoh’s Synthesis of 2-Furan Thioether b by Pummerer Cyclization
1 2 3 4 5 6 7 8 9 10 11 12 13
for activating sulfoxide a to afford substituted 2-arylthiofuran derivatives (b). Alkyl and arylthio groups in furans and benzofurans18 serve as useful means for synthetic manipulations (e.g., compound c) and are commonly used as key intermediates in the synthesis of more advanced materials,17a,19 including drug derivatives.20 Herein, we report on the Cu(OTf)2 (10 mol %)/MeNO2 catalytic system that activates β-ketosulfoxides, forming electrophilic thionium ions that couple with different nucleophiles such as 1,3-dicarbonyl compounds and phenols, thus offering an entry to obtaining complex heterocycles in a single synthetic step (Scheme 1C). The mild conditions can be applied in preparing novel polysubstituted furan-3-thioethers and polysubstituted benzofuran-3-thioethers directly from simple and readily available starting materials.
catalyst b
TFAA Cu(OTf)2c Cu(OTf)2 Cu(OTf)2d BF3·OEt2 CuBr FeCl3 Sc(OTf)3 Co(OAc)2·4H2O pTSA (10 mol %) Cu(OTf)2 Cu(OTf)2 Cu(OTf)2
solvent
3a (%)
4 (%)
5a (%)
CH2Cl2 CH3NO2 CH3NO2 CH3NO2 CH3NO2 CH3NO2 CH3NO2 CH3NO2 CH3NO2 CH3NO2 DCE CH3CN DMF
− 19 21 − 17 7 22 7
