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...

The Ce(IV)-initiated oxidation of synthetically relevant beta-diketones and beta-keto silyl enol ethers was explored in three solvents: acetonitrile, methylene chloride, and methanol. The studies presented herein show that the rate of reaction between Ce(IV) and the substrates is dependent upon the polarity of the solvent. Thermochemical studies and analysis are interpreted to be consistent with transition state stabilization by solvent being primarily responsible for the rate of substrate oxidation. Kinetic investigation of radical cations obtained from oxidations of beta-diketones reveals that a more ordered transition state for the radical cation decay is achieved through the direct involvement of methanol in the deprotonation of the intermediate. In the case of radical cations derived from beta-keto silyl enol ethers, experimental data support a mechanism involving unimolecular decay of the intermediate. Remarkably, radical cations derived from beta-diketones and beta-keto silyl enol ethers are surprisingly stable in methylene chloride.

A mild protocol for the conversion of β-ketoesters and β-diketones to carboxylic acids using CAN in CH 3 CN is described. The method is compatible with a number of functional groups, and can generate carboxylic acids under neutral conditions at room temperature. The reaction is fast and general, providing an alternative method to the commonly used malonic ester acid preparation. Initial mechanistic studies show that initial oxidation of the enol form of the β-dicarbonyl initiates the reaction. The presence of nitrate as an oxidant ligand or as an additive is critical for success of the reaction.

This report describes the scope and mechanism of the solvent-dependent, chemoselective oxidative coupling of 1-aryl-1,3-dicarbonyls with styrene using Ce(IV) reagents. Dihydrofuran derivatives are obtained when reactions are performed in methanol whereas α-tetralones can be selectively synthesized in acetonitrile and methylene chloride. Mechanistic studies are consistent with the rate of solvent-assisted deprotonation of a radical cation intermediate playing an integral role in the selective formation of products.

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2006 Carboxylic acids P 0250 Mild Conversion of β-Diketones and β-Ketoesters to Carboxylic Acids. -In the presence of CAN α-unsubstituted β-diketones and β-ketoesters efficiently and rapidly undergo oxidation to carboxylic acids. -(ZHANG, Y.; JIAO, J.; FLOWERS*, R. A. I.; J. Org. Chem. 71 (2006) 12, 4516-4520; Dep. Chem., Lehigh Univ., Bethlehem, PA 18015, USA; Eng.) -Jannicke 41-054

This report describes the scope and mechanism of the solvent-dependent, chemoselective oxidative coupling of 1-aryl-1,3-dicarbonyls with styrene using Ce(IV) reagents. Dihydrofuran derivatives are obtained when reactions are performed in methanol whereas nitrate esters can be selectively synthesized in acetonitrile and methylene chloride. Mechanistic studies are consistent with the rate of solvent-assisted deprotonation of a radical cation intermediate playing an integral role in the selective formation of products.

A convenient one-pot approach for the synthesis of spirocyclic pyrido[1,2-a]indole derivatives is described. The method involves treatment of 1,3-diketones and 1,3-ketoesters with base to generate dianions, which react with 3-(2-bromoethyl)indole to construct a spirocyclopropyl ring and an N-heterocyclic ring sequentially in moderate to very good yields.The indole unit represents a key structure among natural products and pharmaceutically important compounds. 1 The synthesis of pyrido[1,2-a]indole derivatives, a class of tricyclic compounds 1, has drawn considerable attention due to their biological activity and synthetic interest. 2 Although a variety of strategies has been developed to generate these heterocyclic derivatives, 3,4 the popular methods mainly involve the cyclization catalyzed by metal compounds such as Pd(II), 3b,5 Sm(II), 3a and Ni(II) complexes. 3d Solid-phase synthesis has also been used to construct the pyrido[1,2-a]indole derivatives via radical cyclization. 6 Spiroindolenine (2) first synthesized by Closson also contains an indole subunit. 7 Compound 2 can be readily accessed from 3-(2-bromoethyl)indole 8 and was recently used as a electron-deficient adduct to synthesize pyrrole derivatives. 9While numerous approaches to 1 and 2 ( Figure 1) are available, there are no reports describing easy access to the related spiropyrido[1,2-a]indole 3 (Figure 1), in spite of the fact that such a protocol would provide important approaches to a range of natural product precursors. 10 Inspired by the protocol originally described by Closson, we reasoned that the dianions generated from 1,3-diketones and 1,3-ketoesters 11 would be good candidates to undergo reaction with 3-(2-bromoethyl)indole to simultaneously construct the spiro ring in 2 and the N-heterocyclic sixmembered ring in compound 1 to produce 3. A convenient one-pot approach to spirocyclic pyrido[1,2-a]indole derivatives is reported herein.To initially examine this approach, 2,4-pentadione (4a) was treated with two equivalents of sodium hydride in tetrahydrofuran at 0 °C and then two equivalents of n-butyllithium followed by the addition of 3-(2-bromoethyl)indole (Scheme 1). 12The reaction worked well to afford a novel spirocyclic pyrido[1,2-a]indole compound 5a in 85% isolated yield. The success of this reaction encouraged us to investigate its generality and scope. Two other 1,3-diketones (4b,c) and a 1,3-ketoester (4d) were reacted with 3-(2-bromoethyl)indole using the same procedure. The data for these reactions is summarized in Table 1. The data in Table 1 shows the reaction proceeds to produce spirocyclic pyrido[1,2-a]indole derivatives for all four 1,3-diketones and 1,3-ketoesters (4a-d). Moderate to good yields (66-85%) were achieved and all products were purified and characterized by NMR, and HRMS. 13 Figure 1 N N1 2 N R 1 R 2 3 pyrido[1,2-a] indole skeleton spiroindolenine spiropyrido[1,2-a] indole skeleton Scheme 1 One-pot transformation from 3-(2-bromoethyl)indole to spirocyclic pyrido[1,2-a]indole derivatives R 1 O O R 2 N H ...