Aromaticity, oxime ethers

Leclerc, G., Mann, A., Wermuth, C. G., Bieth, N., Schwartz, J. Synthesis and (3-adrenergic blocking activity of a novel class of aromatic oxime ethers. J. Med. Chem. 1977, 20, 1657-1662. 

The Ponzio reaction provides a useful route to gem-dinitro compounds and involves treating oximes with a solution of nitrogen dioxide or its dimer in diethyl ether or a chlorinated solvent. The Ponzio reaction works best for aromatic oximes where the synthesis of many substituted aryldinitromethanes have been reported. Compound (56), an isomer of TNT, is formed from the reaction of dinitrogen tetroxide with the oxime of benzaldehyde (55) followed by mononitration of the aromatic ring with mixed acid. Yields are usually much lower for aliphatic aldoximes and ketoximes. " The parent carbonyl compound of the oxime is usually the major by-product in these reactions. 

Wordy Over the past few years, we have encountered numerous examples of water as the perfect solvent. We observed this first in osmium-catalyzed dihydroxylation reactions and also in nucleophilic ring-opening reactions of epoxides. We also observed this in cycloaddition reactions and in most oxime ether, hydrazone, and aromatic heterocycle condensation processes.Finally, we observed it in formation reactions of an amide from a primary amine and an acid chloride using aqueous Schotten-Baumann conditions. ... 

The 3-nitroisoxazoline has gas and liquid phase values available. Given the absence of knowledge about isoxazolines, we accept these data and use them in what follows. We are told that the dehydration reaction of 3-phenyl-A -isoxazoline-5-ol (an oxime ether) to form 3-phenylisoxazole (equation 42) is exothermic by 16 kJmol. The gas phase enthalpy of formation of the latter species is 139.5 6.2 kJmoG. (As the isoxazoles are nominally aromatic, they are not included here as unsaturated oxime ethers.)... 

Now where does the discrepancy lie An acyclic paradigm was used for the oxi-mate/imidate interconversion. Had we used the plausibly aromatic paradigm of isoxa-zole/oxazole, the isomerization enthalpy would have been 95 kJ moR where the requisite enthalpies of formation are from References 76 and 1, respectively. This difference is meaningfully distinct from that of the acyclic paradigm but still does not particularly ameliorate the difference. Is it possible that the N—O bond in aryl and alkyl oxime ethers are profoundly different Could it be that we have neglected any antiaromaticity in the 8 n... 

Enantioselective reduction of ketoxime ethers with chiral boron hydrides produces chiral 0-alkylhydroxylamines with variable ee. Reduction of oxime ethers of type 94 (equation 65) with norephedrine-derived oxazoborolidine 95 proceeds with very high ee. However, an analogous reduction of acyclic aromatic oximes with chiral oxab-orazolidines produced a mixture of amine and hydroxylamine . 

The endothermicity of this reaction is 40 kJ mol1 and so we deduce benzisoxazole has significant aromaticity. No direct measurements of the enthalpy of formation of any acyclic oxime ethers appear in the literature. However, from the calculational literature [69] we find a value for the enthalpy of formation of CH3CH=NOCH3 of -7 kJ mol1, Unmeasured by combustion calorimetry because of experimental complications, the enthalpy of formation of benzisoxazole was recently suggested [70] to be 139 kJ mol-1. 

Aromatic oximes, for example, can be converted back to carbonyl compounds with only 2 equiv. of PDC in 1 h at rotmi temperature. PDC will also cleave enol ethers. ... 

In addition to the reduction of ketones (e.g., aromatic and aliphatic ketones, a-halo ketones, hydroxyketones, enones, and ketoesters), oximes can be reduced to the corresponding amine with this reagent. In general, ketone oxime ethers, such as 39, can give rise to amines 40 in excellent chemical yield with good to excellent optical purity.5d... 

Among a number of oxime ether derivatives of 1 with aromatic and aliphatic substitutions, the compounds bearing heteroatoms in substituents, such as nitrogen, oxygen, and sulfur, exhibited a significant increase in activity in vivo. Based on their in vitro and in vivo activities against staphylococci and streptococci as well as their pharmacokinetics, five compounds 18 and 23 through 26 have been selected (Table I) [6]. 

Isonitrile 19 was detected in ultraviolet (UV) and infrared (IR) studies at low temperatures. They speculated that azirine intermediate 21 may precede the formation of 19 and, indeed, LFP studies on 18 performed by Richard and co-workers allowed observation of an intermediate which was assigned to 21 on the basis of the similarity of its UV absorption spectra to that of the cyclohexadienone chro-mophore. The reaction was not quenchable by piperylene and is presumed to occur via the singlet manifold. The authors did not put forward a mechanism for the formation of 21, although it may be formed by initial ESIPT from the phenol to the cyano group to give tautomer 22, which can then rearrange to give 21. Similar products (substituted benzoxazoles) were observed via presumed initial ESIPT in structurally related o-hydroxy substituted aromatic oximes and oxime ethers. ... 

Haley, M. E and Yates, K., The photochemistry of carbon-nitrogen multiple bonds in aqueous solution. 2. o-Hydroxy-substituted aromatic oximes and oxime ethers, /. Org. Chem., 52, 1825, 1987. 

Since the 1960s, numerous investigations have been carried out on the nature of the CN and NN double bond photoisomerization and the competitive nature of the ,Z-isomerization with other processes, such as photocychzation, photoreduction and photorearrangement. The variety of substrates studied included oxime, oxime ethers, aliphatic and aromatic azo compounds, azoxy compounds, hydra-zones, and Schiff bases. The accumulated results were the subjects of several comprehensive and thorough review articles by Wettermark, Padwa, Pratt, Griffiths, Engel, Diirr, and Taylor. ... 

Oximes, hydrazines and semicarbazones. The hydrolysis products of these compounds, t.e., aldehydes and ketones, may be sensitive to alkali (this is particularly so for aldehydes) it is best, therefore, to conduct the hydrolysis with strong mineral acid. After hydrolysis the aldehyde or ketone may be isolated by distillation with steam, extraction with ether or, if a solid, by filtration, and then identified. The acid solution may be examined for hydroxylamine or hydrazine or semicarbazide substituted hydrazines of the aromatic series are precipitated as oils or solids upon the addition of alkali. 

Sheradsky has found that the hydroxyl function of a ketoxime such as acetophenone oxime can be made to react with DMAD when the reaction is carried out in methanol with a basic catalyst, to give mixture of the fumarate and maleate isomers (164) in the ratio 2 1. This mixture on heating undergoes a hetero-Cope rearrangement followed by cyclization and dehydration to give dimethyl 5-phenylpyrrole-2,3-dicarboxylate (168) (Scheme 25). Similarly, Heindel and Chun have reported that vinyl ether adducts (171), obtained by the condensation of arylamide oximes with DMAD, get thermally converted into oxa-diazolines (172) or imidazolinones (174), depending on the reaction conditions. A similar reaction occurs with aromatic amidoxime-methyl propiolate adducts to give imidazoles (170) (Scheme 26). 1,2,4-Dioxazoles have been reported to be formed in the reaction of hydrox-amic acids with DMAD. - ... 

SSRI activity is interestingly maintained even in the absence of one of the aromatic rings. Attaching the oxygen atom to an oxime leads to the antidepressant fluvoxamine. The requisite oxime (25-2) is obtained by reaction of the starting ketone (25-1) with hydroxylamine. Treatment of that intermediate with ethylene oxide adds the ether-linked side chain that will carry the amine. The hydroxyethyl product (25-3) is thus converted to its mesylate by means of methanesulfonyl chloride. This leaving group is then displaced by any one of several methods to afford the primary amine and thus fluvoxamine (25-4) [25]. 

An imine moiety can, interestingly, be interposed in the ether linkage used to connect the two halogenated aromatic rings. The requisite oxime (55-1) is obtained in a straightforward fashion by reaction of imidazo acetophenone (54-2) with hydroxyl-amine alkylation with a,2,3-trichlorotoluene leads to oxiconazole (55-2) [60]. 

The lower members of the homologous series of 1. Alcohols 2. Aldehydes 3. Ketones 4. Acids 5. Esters 6. Phenols 7. Anhydrides 8. Amines 9. Nitriles 10. Polyhydroxy phenols 1. Polybasic acids and hydro-oxy acids. 2. Glycols, poly-hydric alcohols, polyhydroxy aldehydes and ketones (sugars) 3. Some amides, ammo acids, di-and polyamino compounds, amino alcohols 4. Sulphonic acids 5. Sulphinic acids 6. Salts 1. Acids 2. Phenols 3. Imides 4. Some primary and secondary nitro compounds oximes 5. Mercaptans and thiophenols 6. Sulphonic acids, sulphinic acids, sulphuric acids, and sul-phonamides 7. Some diketones and (3-keto esters 1. Primary amines 2. Secondary aliphatic and aryl-alkyl amines 3. Aliphatic and some aryl-alkyl tertiary amines 4. Hydrazines 1. Unsaturated hydrocarbons 2. Some poly-alkylated aromatic hydrocarbons 3. Alcohols 4. Aldehydes 5. Ketones 6. Esters 7. Anhydrides 8. Ethers and acetals 9. Lactones 10. Acyl halides 1. Saturated aliphatic hydrocarbons Cyclic paraffin hydrocarbons 3. Aromatic hydrocarbons 4. Halogen derivatives of 1, 2 and 3 5. Diaryl ethers 1. Nitro compounds (tertiary) 2. Amides and derivatives of aldehydes and ketones 3. Nitriles 4. Negatively substituted amines 5. Nitroso, azo, hy-drazo, and other intermediate reduction products of nitro com-pounds 6. Sulphones, sul-phonamides of secondary amines, sulphides, sulphates and other Sulphur compounds... 

Many compounds have been tested as ignition quality improvers—additives which shorten the ignition delay to a desirable duration. An extensive review in 1944 (6, 43) listed 303 references, 92 dealing with alkyl nitrates and nitrites 61 with aldehydes, ketones, esters, and ethers 49 with peroxides 42 with aromatic nitro compounds 29, with metal derivatives 28 with oxidation and oxidation products 22 with polysulfides 16 with aromatic hydrocarbons nine with nitration and four with oximes and nitroso compounds. In 1950, tests at the U. S. Naval Engineering Experiment Station (48) showed that a concentration of 1.5% of certain peroxides, alkyl nitrates, nitroaikanes, and nitrocarbamates increased cetane number 20 or more units. 

According to that author, such a typical aromatic nitro compound as 4-nitro-1-naphthol (VII) when reacted with diazomethane, formed not only methyl ether (VIII) but also quinone oxime (IX) in lower yield (16%) ... 

---