An Efficient and General Approach to β-Functionalized Ketones

Abstract

The oxidation of selected anions (N 3 − , SCN − , I − and Br − ) by ceric ammonium nitrate (CAN) in the presence of substituted cyclopropyl alcohols provides a novel approach to β-functionalized ketones.The protocol has a number of advantages including short reaction times, ease of reagent handling and mild, neutral reaction conditions. Overall, this method provides an alternative pathway to important starting materials and intermediates in organic synthesis.Ketones substituted in the β position are important starting materials in organic chemistry. Among this group, β-haloketones are extremely useful intermediates in organic synthesis and act as precursors to enones, annulated compounds, heterocyclic derivatives, and dicarbonyl products. 1 In spite of their importance as precursors to a large range of important intermediates, 2 only a few of methods have been developed to synthesize β-substituted ketones. 3 The synthesis of β-substituted ketones by 1,4-addition of HX (X = Cl, Br, I) or trimethylsilyl iodide to the corresponding enone are sometimes experimentally inconvenient since the use of reactive or moisture sensitive reagents are required. 3b, 3d More recent approaches to β-substituted ketones, while useful, provide access to a limited range of compounds. 4,5 As a consequence, the development of new synthetic methods offering a general approach for the introduction of diverse functionality to the beta position of a carbonyl group still constitutes a challenge in organic chemistry.Cerium(IV) ammonium nitrate (CAN) has found wide applications in carbon-heteroatom bond forming reactions in organic synthesis. 6 The reported carbon-heteroatom bond formations mediated with CAN include C-Br, C-I, C-S, C-N, and C-Se bonds. These reactions usually involve the generation of heteroatom-centered radicals from the oxidation of anions and addition of the heteroatom radicals to alkenes or alkynes.Based on this precedent, we reasoned that Ce(IV) oxidation of an anion in the presence of a cyclopropyl alcohol would provide a route to β-substituted ketones as shown in Scheme 1. Since cyclopropyl units are readily accessible via the Kulinkovich reaction, 7 the ring opening of cyclopropanols and the carbon-heteroatom bond formation mediated with CAN could provide a novel, efficient, and general approach to a variety of β-substituted ketones.The synthesis of substituted cyclopropyl alcohols 1-4 shown in Table 1 were carried out using the Kulinkovich reaction and provided good isolated yields in the range of 63-82%. In an initial experiment, sodium azide was chosen as the first anion to react with a cyclopropyl alcohol since oxidation of this anion with CAN has been previously reported. 8 Reaction of 1 with NaN 3 in the presence of 2 equivalents of CAN in methanol produced a moderate yield (50%) of the 3-azido-1-phenyl propanone along with dimer and nitrated products as side products.rof2@lehigh.edu. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptSince solvent is known to play...

Silver-Catalyzed Tandem Radical Cyclization for the Synthesis of 3,3'-Disubstituted Oxindoles

“…环丙醇可以用来合成多种化合物, 比如 β-取代的 酮 [10] 、烯丙基氯 [11] 、氮杂环 [12] 以及通过三元环开环的其 它化合物, 环丙醇可以被一些单电子氧化剂, 比如过硫 酸根和 Ag(I) [13] 、CAN [10] 、锰盐 [12] 等, 氧化开环形成 β-羰基碳自由基. 2013 年 Ilangovan 课题组 [14] 报道了一种 Ref.…”

Recent advances in CAN mediated reactions in organic synthesis

“…173 Recently, Flowers et al have shown that the selective oxidation of an inorganic anion in the presence of 1-substituted cyclopropanol and 1-substituted cyclobutanol led to the formation of b-and g-substituted ketones, respectively (Scheme 33). 174,175 The formation of b-substituted ketones was achieved using anions like SCN(À), N 3 (À) and halide while g-substituted ketones were obtained using halide ion. 175 The inorganic radical generated from the anion added to cyclopropanol leading to a radical intermediate, which on subsequent oxidation followed by deprotonation afforded the final product.…”

Synthesis of γ-halogenated ketones via the Ce(IV)-mediated oxidative coupling of cyclobutanols and inorganic halides

“…CAN has proven to be a cost-effective, versatile reagent that is capable of mediating novel carbon–carbon and carbon–heteroatom bonds 7,8. Previous research from our group has shown that β-substituted ketones are accessible through the use of CAN 9. By selectively oxidizing an inorganic anion in the presence of a 1-substituted cyclopropanol with CAN, the generated inorganic radical was added to the cyclopropanol resulting in ring opening.…”