Cyclohexanone 2-nitro

Cyclohexanones may serve as precursors to aromatic amines in a reductive alkylation, the source of hydrogen being aromatization of the cyclohexanone (66). In a variation, an aromatic nitro compound acts as both an amine precursor and a hydrogen acceptor (64). 

In contrast, the tin(Il) enolates of cyclohexanone undergo addition to (2f)-(2-nitroethenyl)ben-zene to give 2-(2-nitro-l-phenylethyl)cyclohexanones with high anti diastereoselection5. The analogous reactions with cyclopentanone and 4-tert-butylcyclohexanone were less diastereose-lective with anti/syn ratios of 70 30 and 62 38. respectively. Modest to excellent diastereoselec-tivity was observed with acyclic ketones (d.r. 75 25 to 90 10) however the precise stereochemical details were not provided. 

The lithium enolates of cyclopentanone and cyclohexanone undergo addition-elimination to the 2,2-dimethylpropanoic acid ester of ( )-2-nitro-2-hepten-l-ol to give 2-(l-butyl-2-nitro-2-propenyl)cycloalkanones with modest diastereoselection. An analogous reaction of the enolate ion of cyclohexanone with the 2,2-dimethylpropanoic acid ester of (Z)-2-nitro-3-phenyl-2-propenol to give 2-(2-nitro-l-phenyl-2-propenyl)cyclohexanones was also reported. The relative configuration of these products was not however determined6. 

The initial addition step is reversible allowing isomerization of the ( )- and (Z)-nitroalkenes and equilibration between the initially formed syn- and ann -imminium ion adducts. The spn-ad-duct is identical to that obtained from the lithium enolate of cyclohexanone and ( >(2-nitro-cthenyl)benzenc. The preference for the. yyu-adduct can be rationalized by inferring the transition state 1 which is similar to that proposed for the reaction of (-E)-nitroalkcnes with ( )-eno-lates11, l2. 

Primary aliphatic nitro compounds can be reduced to nitriles with sodium dihydro(trithio)borate " or with f-BuN=C/BuN=C=0. Secondary compounds give mostly ketones (e.g., nitrocyclohexane gave 45% cyclohexanone, 30% cyclohexanone oxime, and 19% A-cyclohexylhydroxylamine). Tertiary aliphatic nitro compounds do not react with this reagent. See also 19-41. 

These oxidants are generally too feeble to attack monofunctional compounds except thiols, carbonyl- and nitro-compounds in their enolic forms, phenols and aromatic amines. However, ferric rWj-o-phenanthroline readily oxidises cyclohexanone. 

Nitration of ketones or enol ethers provides a useful method for the preparation of a-nitro ketones. Direct nitration of ketones with HN03 suffers from the formation of a variety of oxidative by-products. Alternatively, the conversion of ketones into their enolates, enol acetates, or enol ethers, followed by nitration with conventional nitrating agents such as acyl nitrates, gives a-nitro ketones (see Ref. 79, a 1980 review). The nitration of enol acetates of alkylated cyclohexanones with concentrated nitric acid in acetic anhydride at 15-22 °C leads to mixtures of cis- and rrans-substituted 2-nitrocyclohexanones in 75-92% yield. 4-Monoalkylated acetoxy-cyclohexanes give mainly m-compounds, and 3-monoalkylated ones yield fra/w-compounds (Eq. 2.40).80... 

However, 3- or4-methylcyclohexanone is less reactive to nitromethane than cyclohexanone. Although 2-methylcyclohexanone does not react with nitromethane under the conventional conditions, under high pressure and a fluoride ion catalysis the reaction proceeds to give the P-nitro alcohol in moderate yields (Eq. 3.18).29... 

The stereoselective intramolecular Henry reactions have been reported by Seebach. The Michael addition of doubly deprotonated acetyl acetaldehyde to l-methylenedioxyphenyl-2-nitroethene followed by subsequent intramolecular nitro-aldol cyclization leads to the diastereomerically pure cyclohexanone derivative, where the nitro and OH groups are cis as shown in Eq. 3.73.114 This reaction is applied to the synthesis of l-desoxy-2-lycorinone as shown in Eq. 3.74.115... 

Ono and coworkers have extended the radical elimination of v/c-dinitro compounds to P-nitro sulfones151 and P-nitro sulfides.138,152 As P-nitro sulfides are readily prepared by the Michael addition of thiols to nitroalkenes, radical elimination of P-nitrosulfides provides a useful method for olefin synthesis. For example, cyclohexanone is converted into allyl alcohol by the reaction shown in Eq. 7.110. Treatment of cyclohexanone with a mixture of nitromethane, PhSH, 35%-HCHO, TMG (0.1 equiv) in acetonitrile gives ahydroxymethylated-P-nitro sulfide in 68% yield, which is converted into the corresponding allyl alcohol in 86% yield by the reaction with Bu3SnH.138 Nitro-aldol and the Michael addition reactions take place sequentially to give the required P-nitro sulfides in one pot. 

In order to clarify the reaction mechanism, 6-deuterio-labeled 3,5-dinitro-l-methyl-2-pyridone (87, 1 mmol) was prepared and heated with cyclohexanone (2 mmol) and ammonia (10 mmol). A mixture of 2-deuterio- (88) and 4-deuterio-3-nitro-5,6,7,8-tetrahydroquinoline (89) was obtained in the ratio 58 42 (Scheme III.49). 

The potential application of this catalytic system was illustrated by Takemoto in the application to a tandem conjugate addition towards the asymmetric synthesis of (-)-epibatidine, a biologically active natural product [100, 101], The authors designed an enantioselective double Michael addition of an unsaturated functionalized P-ketoester to a p-aryl nitro-olefm. The asymmetric synthesis of the 4-nitro-cyclohexanones was achieved in both high diastereoselectivity and enantioselectivity, with the natural product precursor synthesized in 90% yield and 87.5 12.5 er (Scheme 49). The target (-)-epibatidine was subsequently achieved in six steps. 

Palladium-charcoal has also been used in the presence of cinnamic acid as a hydrogen acceptor. Raney nickel alone and in the presence of hydrogen acceptors, the best being cyclohexanone, has also been utilized, although dehydrogenation did not occur with 6-chloro- and 6-nitro-l,2,3,4-tetrahydrocarbazoles." Selenium has also been used. ... 

Dianions of a-nitro cyclohexanone imines are prepared by metalation under optimized conditions with 1 equivalent of LDA, followed by 2 equivalents of. sef-butyllithium in TIIF at — 78 to — 90"C using tetrahydro-l,3-dimcthyl-2(1//)-pyrimidinone (DMPU) as additive22. 

Die Umsctzung gelingt am besten mit einer Mischung aus Cyclohexanon 2-Chlor-2-nitro-propan Li-thiumdiisopropylamid im Verhiiltnis 1 1 1 (bei 2S°/1 h)1. 

In related asymmetric Michael-additions of enamine (206) and 2-aryl- 1-nitro-ethylenes, only one of the four possible enantiomerically pure diastereomers was formed 204). Hydrolysis of the crude primary products furnished a-alkylated cyclohexanones of > 90 % enantiomeric excess 204). 

An example of the usefulness of the methodology was the new industrial route to cyclohexanone oxime developed by Corma and Serna, a process which is based on the selective hydrogenation of 1-nitro-l -cyclohexene by gold nanoparticles supported on Ti02 or Fe203 [220]. 

Asymmetric Michael addition to to-nitrostyrenes,2 The enamine (2) formed from cyclohexanone and this prolinol derivative reacts with 2-aryl-1-nitroethylenes (3) to form, after acid hydrolysis of the primary adduct, essentially only one (4) of the four possible y-nitro ketones. 

Cyclohexanones. The ability of tri-n-butyltin hydride to effect denitration (10, 413) permits use of a-nitroalkenes for construction of cyclohexanones by a Diels-Alder reaction. Only one regioisomer (as a mixture of stereoisomers) is formed in the example cited, owing to the reinforcing effect of the nitro group in control of the direction of Ihc cycloaddition.1 ... 

A pyrrolidine-thiourea organocatalyst (69) facilitates Michael addition of cyclohexanone to both aryl and alkyl nitroalkenes with up to 98% de and ee 202 The bifunctional catalyst (69) can doubly hydrogen bond to the nitro group, leaving the chiral heterocycles positioned for cyclohexyl enamine formation over one face of the alkene. 

Another concise route to 107 featured the facile construction of the cyclohexanone derivative 109 via the Michael addition of triply deprotonated methyl dioxohexanoate to the nitrostyrene (108 (Scheme 9) (115). Ketalization of 109 followed by hydrogenation of the nitro function and then cyclization of the resulting amino ester by thermolysis in refluxing xylene furnished the lactam 110, which was reduced LiAlH4 to the amine 111. All attempts to cyclize 111 via a Pictet-Spengler reaction led to complex mixtures of products. However, when the unstable enone 112, which was obtained by acid-catalyzed hydrolysis of 111,... 

Unsaturated nitro compound and nitriles do not usually suffer nucleophilic attack by enols or enolates and both are good at conjugate addition. The addition of the morpholine enamine 57 of cyclohexanone to 58 demonstrates that the nitro group is more effective than the ester at promoting conjugate addition.7... 

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