Andrey A. Tabolin

Rearrangement of N-Oxyenamines and Related Reactions

ion from either the RCH2 or the R CH2 group. However, some selective cases have been reported. The products 294 and 296 can be converted to imidazoles and oxazoles, respectively. Reaction of the oximes 297 with dimethyl carbonate in the presence of potassium carbonate under heating in an autoclave afforded N-methyloxazolones 299 in moderate yields (Scheme 93). The primary O-methoxycarbonylation of the initial oximes 297 has been established as leading to the target products. The intermediates 298 are further subjected to Nmethylation and thus give rise to the oxyenamines A. Subsequently, these undergo [3,3]-rearrangement with ultimate ring closure. Reaction is facile only for α-CH2-ketone-derived oximes. Tautomerization leading to A proceeds exclusively through abstraction of the more mobile proton. Recently, a similar transformation was reported for the O-perfluorobenzoyl oxime 300 (Scheme 94). In this case the reaction proceeds under milder conditions than those for dimethyl carbonate. An older multistep approach to the mentioned transformation consists of oxime O-acylation, followed by Nmethylation with a Meerwein salt and subsequent proton abstraction (Scheme 95). This method is the predecessor for the direct α-oxygenation methodology discussed in the next section. Acid-catalyzed conversion of conjugated cyclohexenone oximes into aniline derivatives has been known since the end of the 19th century. This reaction is often referred as “Semmler−Wolff aromatization”. Typical conditions consist of treating the oximes with acetic anhydride in the presence of a strong acid such as hydrogen chloride. The reaction was used in the syntheses of substituted anilines, quinolines, and other heteroaromatics as well as in the total syntheses of miltirone, sanguinarine, and chelerythrine. It also proved successful for more complex targets such as pseudopteroxazole, penitrem D, and HKI 0231B. Ketene and 1-ethoxyvinyl acetate were found to be useful reagents for the transformation (Scheme 96, eq 1). Other mild reaction conditions involve treatment of 303 with acetyl chloride in toluene at 80 °C. One of the mechanisms proposed includes a N,O-bis(acetylation) of the starting oximes, leading to the oxy-enamines A and/or B. Although alternative ways involving dienimine 307 or azirine 308 are also possible, acetic acid elimination from A or B affords the anilides 304. Another way for generation of the initial enoxime is the in situ enolization of the monooximes 305, which allows synthesis of the acetylated m-aminophenols 306 (eq 2). A substituent shift can be observed if the initial cyclohexenone oxime possesses quaternary carbon atoms. In certain cases a Beckmann rearrangement is a side process in the rearrangement. However, judicious choice of reaction conditions may allow selective transformations. Due to the acidic medium there is a high probability for formation of cationic species that can be trapped onto aromatics. In contrast, sometimes basic media may be preferable for aromatization, for example, if the cyclohexenone oxime ring possesses electron-withdrawing substituents. Scheme 94 Scheme 95 Chemical Reviews Review dx.doi.org/10.1021/cr400196x | Chem. Rev. 2014, 114, 5426−5476 5456 4.6. Direct α-Oxygenation of Carbonyl Compounds Reaction of carbonyl compounds with secondary amines is a classical method for enamine synthesis. The enamines formed can be involved in [3,3]-rearrangements with subsequent hydrolysis, affording functionalized carbonyl compound. Thus, it seems somewhat amazing that only recently has the reaction of aldehydes and ketones 309 with N-alkyl-O-acylhydroxylamines been applied for reliable introduction of the α-hydroxyl moiety (Scheme 97, Table 1). The bulky reagent 310 (X = C, R = t-Bu, R = Ph) reacts selectively with aldehydes but is, however, unactive toward ketones. The less sterically demanding derivative 310 (X = C, R = Me, R = Ph) reacts with cyclic ketones at room temperature and with acyclic and aromatic ones under mild heating (50 °C). This synthesis methodology tolerates different functionalities, such as esters, acetals, or phenols. Unsymmetrical ketones give selective rise to CH2-group oxygenation in the presence of a CH3 group. Note that methyl ketones (acetone, acetophenone) fail to react. A similar reaction is applicable for synthesis of carbonates (X = C, R = Me, R = OR′) and carbamate derivatives (X = C, R = Me, R = NR′2) 311. Use of N-methyl-O-tosylhydroxylamine in the presence of methanesulfonic acid converts aldehydes to the corresponding 2-tosyloxy derivatives 311 (X = SO, R = Me, R = n-Tol). In such a manner the functionalization of methyl ketones 309 (R = H) is possible but with only moderate regioselectivity (functionalization of the secondary site/primary site ≈ 2.6− 4.2:1). More electron-accepting substituents at the sulfur, such as p-nitrophenyl, lead to Beckmann-like rearrangements. The applicability of asymmetric reagents such as 310 was also studied. Substituents on both the nitrogen and the oxygen atoms, reaction temperature, solvent, and counteranion were all found to have a dramatic effect on both the yield and the asymmetric induction. After thorough screening the best Scheme 96

Six-Membered Cyclic Nitronates as 1,3-Dipoles in Formal [3 + 3]-Cycloaddition with Donor–Acceptor Cyclopropanes. Synthesis of New Type of Bicyclic Nitrosoacetals

The first formal [3 + 3]-cycloaddition of nitronates with donor-acceptor cyclopropanes is reported. The reaction is catalyzed by ytterbium trifluoromethanesulfonate and leads to hitherto unknown bicyclic nitrosoacetals, possessing two annelated six-membered rings.

Radical Nitration-Debromination of α-Bromo-α-fluoroalkenes as a Stereoselective Route to Aromatic α-Fluoronitroalkenes—Functionalized Fluorinated Building Blocks for Organic Synthesis

A new highly efficient method for the synthesis of 2-fluoro-2-nitrostyrenes was described. Radical nitration of readily available 2-bromo-2-fluorostyrenes with Fe(NO3)3·9H2O resulted in the formation of the corresponding α-fluoro-nitroalkenes in isolated yields up to 92%. The reaction proceeded as a nitration-debromination sequence to highly stereoselectively give α-fluoro-nitroalkenes as Z-isomers only. The broad scope of this method was demonstrated. Prepared monofluorinated alkenes were shown to be versatile building blocks for the synthesis of various fluorinated products.

Synthesis and chemical transformations of six/six-membered bicyclic nitroso acetals

A synthesis of hitherto unknown bicyclic nitroso acetals possessing two annulated six-membered rings is accomplished. The synthesis comprises formal [3+3] cycloaddition of six-membered cyclic nitronates with donor-acceptor cyclopropanes. Some chemical transformations and conformational preferability of the obtained nitroso acetals are discussed.

Fluoronitroalkenes in tandem [4 + 1]/[3 + 2]-cycloaddition: one-pot three-component assembly of fluorinated bicyclic nitroso acetals

A one-pot three-component route towards fluorinated five/five-annulated nitroso acetals bearing two fused isoxazolidine rings is described. Target nitroso acetals were obtained with complete regioselectivity and high stereoselectivity. The mechanism of this tandem [4 + 1]/[3 + 2] cycloaddition was proposed to include the intermediate formation of elusive 3-fluoro-isoxazoline-N-oxides as key intermediates. This method is applicable for the synthesis of a broad scope of nitroso acetals starting from various fluoronitroalkenes, halogenated dicarbonyl compounds and dipolarophiles of different electronic nature.

Acylation of Nitronates: [3,3]-Sigmatropic Rearrangement of in Situ Generated N-Acyloxy,N-oxyenamines

Acylation of nitronates affords α-acyloxyoxime derivatives via an umpolung functionalization of the α-position. This transformation involves generation of hitherto unknown N-acyloxy, N-oxyenamines and their fast [3,3]-sigmatropic rearrangement driven by the cleavage of the weak N-O bond. The reaction has a broad scope, and it is regioselective in the case of nitronates possessing nonsymmetrically substituted α-positions. Application to the formal total synthesis of clausenamide and cis-clausenamide is presented.