Beckmann-rearrangement

Rearrangement of oximes to give TV-substituted carboxylic amides 

The rearrangement of oximes 1 under the influence of acidic reagents to yield A -substituted carboxylic amides 2, is called the Beckmann rearrangement. The reaction is usually applied to ketoximes aldoximes often are less reactive. 

Upon treatment with a protic acid, the hydroxy group of the oxime 1 initially is protonated to give an oxonium derivative 3 which can easily lose a water molecule. The migration of the substituent R (together with the bonding electrons) and loss of water proceed simultaneously  

The cationic species 4 thus formed reacts with water to give the iminol 5, which tautomerizes to a more stable amide tautomer, the N-substituted carboxylic amide 2. Those steps correspond to the formation of amides by the Schmidt reaction. A side reaction can give rise to the formation of nitriles. 

As reagents concentrated sulfuric acid, hydrochloric acid, liquid sulfur dioxide, thionyl chloride, phosphorus pentachloride, zinc oxide and even silica gel can be used. Reagents like phosphorus pentachloride (as well as thionyl chloride and others) first convert the hydroxy group of the oxime 1 into a good leaving group  

Among numerous other studies, Ferrier rearrangement is notable since it proceeds well (72-83%) upon irradiation of neat reactants [93], 

According to Horning and Stromberg,132 the Beckmann rearrangement gives particularly good results when carried out by means of polyphosphoric acid  

A mixture of 4,4 -dimethoxybenzophenone oxime (2 g) and polyphosphoric acid (60 g) is heated, with stirring, to 130° and kept at that temperature for 10 min, then poured into water and extracted with 1 1 ether-ethyl acetate. After being washed with water and then saturated salt solution and dried over sodium sulfate, the organic phase affords A-p-anisoylanisidine, m.p. 199-203°, in 91 % yield. 

An industrially important application is the ring expansion of cyclohexanone oxime to 6-hexanolactam 133 

The following details have been given by Ziegenbein, Schaffler, and Kauf-hold134 for the rearrangement of 4-ethylcyclohexanone to 4-ethyl-6-hexano-lactam  

4-Ethylcyclohexanone oxime (19 g) is dropped with stirring into concentrated sulfuric acid (30 g), the temperature not being raised above 125°. The mixture is then allowed to cool to 90° and further amounts (150 g each) of the oxime and 25 % oleum are slowly added. The rearrangement is complete in 45-60 min but the mixture is finally briefly heated at 130°. In the working up, the mixture is dropped into dilute ammonia for neutralization, and the product is taken up in much methylene dichloride and distilled in a vacuum. A 90% yield of crude 4-ethyl-6-hexanolactam, b.p. 160—165°/15 mm, is obtained. 

Mani and co-workers utilized the organoaluminum promoted modified Beckmann rearrangement during their efficient synthetic route to chiral 4-alkyl-1,2,3,4-tetrahydroquinoline. (4R)-4-Ethyl-1,2,3,4-tetrahydroquinoline was obtained by rearrangement of the ketoxime sulfonate of (3R)-3-ethylindan-1-one. The resulting six-membered lactam product was reduced to the corresponding cyclic secondary amine with diisobutylaluminum hydride. 

In the laboratory of J.D. White, the asymmetric total synthesis of the non-natural (+)-codelne was accomplished via intramolecular carbenoid insertion In the late stages of the total synthesis It was necessary to Install a 6-membered piperidine moiety. This transformation was accomplished utilizing a Beckmann rearrangement of the cyclopentanone oxime portion of one of the intermediates. Later the 6-membered lactam was reduced to the corresponding amine with LAH. To this end, an oxime brosylate (Bs) was prepared, which underwent a smooth Beckmann rearrangement in acetic acid to provide a 69% yield of two isomeric lactams in an 11 1 ratio in favor of the desired isomer. 

White et al. reported the total synthesis of ( )-ibogamine via the catalytic asymmetric Diels-Alder reaction of benzoquinone. The azatricyclic framework of the molecule was established by converting the bicyclic ketone to the anti oxime and then subjecting it to a Beckmann rearrangement in the presence of p-toluenesulfonyl chloride to afford the 7-membered lactam. Elaboration of this lactam into the azatricyclic core of ibogamine and later to the natural product itself was accomplished in a few additional steps. 

A novel variant of the photo-Beckmann rearrangement was utilized bv I a u  

The benziiic acid rearrangement is an irreversible process. The first step of the mechanism is the addition of the nucleophile (HO , alkoxide, or amide Ion) across the C=0 bond to give a tetrahedral intermediate. The next step is aryl or alkyl migration to form the corresponding a-hydroxy acid salt. 

Another transformation that has received considerable interest is the Beckmann rearrangement. Traditionally, this process requires the presence of a strong acid with heating at high temperatures over extended periods of times. It therefore represents an 

Although many solid-acid catalysts have been reported for the vapor-phase Beckmann rearrangement [2], their performance has been less than satisfactory from an industrial standpoint and the heterogeneously catalyzed Beckmann rearrangement has not yet been commercialized. In this chapter heterogeneous catalysis of the Beckmann rearrangement, its mechanism, and acid properties and reaction conditions suitable for the reaction will be reviewed. 

Beckmann, E. Chem. Ber. 1886, 89, 988. Ernst Otto Beckmann (1853—1923) was bom in Solingen, Germany. He studied chemistry and pharmacy at Leipzig. In addition to the Beckmann rearrangement of oximes to amides, his name is associated with the Beckmann thermometer, used to measure freezing and hoihng point depressions. Mazur, R. H. J. Org. Chem. 1961,26, 1289. 

Torisawa, Y. Nishi, T. Minamikawa, J.-i. Bioorg. Med. Chem. Lett. 2002,12, 387. Sharghi, H. Hosseini, M. Synthesis 2002, 1057. 

Raju Ranjith Kumar, K. Angaiyarkanni Vanitha and Marudai Balasubramanian 

The acid-catalyzed rearrangement of an oxime 2 to an amide 3 is named after 

Fresenius, passing his pharmacy examination in 1877. He then joined Kolbe, and his assistant, Ernst von Meyer, and started work on the oxidation of dialkyl sulfides. For this research Beckmann received his PhD in July 1878. Beckmann tried to apply an already-known reaction to discriminate between aldehydes and ketones. This reaction involved the use of hydroxylamine to convert benzophenone into an oxime. Treating this oxime with phosphorus pentachloride he converted it into a substance already characterized by Wallach. This reaction is now known as the Beckmann rearrangement. 

Benzophenone oxime 15 underwent the Beckmam rearrangement to afford amide 16 under microwave irradiation in the presence of bismuth trichloride within 8 min. Aluminum trichloride afforded the product 16 in 15 min. under the same condition. 

The one pot synthesis of amide 18 was accomplished within 2 min. by P205/Si02 catalyzed Beckmann rearrangement of the ketone 17 under microwave irradiation. Other ketones such as cyclohexanone, benzophenone, acetophenone and benzil furnished the rearranged products in excellent yields. 

the substituent tram to the leaving group migrates 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 16, Springer-Verlag Berlin Heidelberg 2009 

Acid-mediated isomerization of oximes to amides. In protic acid  

Name Reactions A Collection ofDaailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 19, Springer International Publishing Switzerland 2014 

However, conventional heating gives only 17% yield. 

1 1 inclusion compound of (-)-l, 6-bis(o-chlorophenyl)-1,6-diphenylhexa-2,4-diyne-l, 6-diol and 4-methyl cyclohexanone oxime 

Example 8.1 Propose the retrosynthetic analysis and synthesis of the analsetic paracetamol TM 8.1. 

The cited conditions for the preparation and rearrangement of oxime have been selected among many others reported in the literature and patents. For specific oximes, the Beckmann rearrangement is catalyzed by zeolites or nanoporous materials in ionic liquids in the presence of Co(III), Mn(III) or Fe(III) salts [4]. 

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Beckmann rearrangement of cvc7ohexanone oxime. M.p. 68-70 C, b.p. I39 C/12 mm. On healing it gives polyamides. Used in the manufacture of Nylon[6]. Cyclohexanone oxime is formed from cyclohexane and niirosyl chloride. U.S. production 1978 410 000 tonnes, capryl alcohol See 2-octanol. caiH Uc acid See oclanoic acid. 

When treated with certain reagents, the ketoximes in particular undergo the Beckmann rearrangement to isomeric acid amides (p. 227). 

Beckmann Rearrangement. Prepare the 85% sulphuric acid by adding 50 ml. of the concentrated acid cautiously to 10 ml. of water, stirring the mixture meanwhile, and then cool the diluted acid in ice-water. Place 16 ml. of the cold acid in a 500 ml. beaker, add 8 g, of the pure oxime, and warm the mixture cautiously until effervescence begins, and then at once remove the heat. A vigorous reaction occurs, and is soon complete. Repeat this operation with another 8 g. of the oxime in a second beaker the reaction is too vigorous to be carried out with larger quantities. 

By treatment of this oxime with phosphorus pentachloride or thionyl fhloride in ether solution, smooth conversion into benzanilide, m.p. 163°, results. The change of any oxime into a substituted amide under the conditions mentioned is usually termed the Beckmann rearrangement. The above example may be represented ... 

Beckmann rearrangement of benzophenone oxime to benz-anilide. Dissolve 2 g. of benzophenone oxime in 20 ml. of anhydrous ether in a small conical flask and add 3 g. of powdered phosphorus pentachloride (or 3 ml. of pure tbionyl chloride). Distil off the solvent and other volatile products on a water bath CAUTION ether), add 25 ml. of water, boil for several minutes and break up any lumps which may be formed. Decant the supernatant liquid, and recrystallise, in the same vessel, from boiling alcohol. The product is benzanilide, m.p. 163° confirm this by a mixed m.p. determination with an authentic specimen. 

The oximes of ketones undergo the Beckmann rearrangement on treatment with phosphorus pentachloride (118). 

Ingredients. Nylon-6 is produced commercially from caprolactam [105-60-2] which is the most important lactam industrially. AH industrial production processes for caprolactam are multistep and produce ammonium sulfate [7783-20-2] or other by-products. Approximately 95% of the world s caprolactam is produced from cyclohexanone oxime [100-64-1] via the Beckmann rearrangement (144). The starting material for cyclohexanone can be... 

Cyclohexanone oxime is converted quantitatively to caprolactam by Beckmann rearrangement in the presence of oleum, which is of sufficient strength to consume the several percent water in the molten oxime. The reaction mass is neutralized with aqueous ammonia to a cmde caprolactam layer and a saturated solution of ammonium sulfate. Approximately 1.5 kg of the total 4.4 kg ammonium sulfate per kilogram of caprolactam is produced in this step. Purification is by multistage vacuum crystallization from aqueous solution in neatly quantitative yield. 

The oxime is converted to caprolactam by Beckmann rearrangement neutralization with ammonia gives ca 1.8 kg ammonium sulfate per kilogram of caprolactam. Purification is by vacuum distillation. A no-sulfate, extraction process has been described, but incineration of the ammonium bisulfate recovers only sulfur values and it is not practiced commercially (14). 

Toray. The photonitrosation of cyclohexane or PNC process results in the direct conversion of cyclohexane to cyclohexanone oxime hydrochloride by reaction with nitrosyl chloride in the presence of uv light (15) (see Photochemical technology). Beckmann rearrangement of the cyclohexanone oxime hydrochloride in oleum results in the evolution of HCl, which is recycled to form NOCl by reaction with nitrosylsulfuric acid. The latter is produced by conventional absorption of NO from ammonia oxidation in oleum. Neutralization of the rearrangement mass with ammonia yields 1.7 kg ammonium sulfate per kilogram of caprolactam. Purification is by vacuum distillation. The novel chemistry is as follows ... 

The course of the reaction is dependent on the configuration of the oxime. The (Z)-oxime gave 1,2-benzisoxazoles as the primary product while the (E)-oxime generally produced a Beckmann rearrangement product with or without subsequent cyclization to a benzisoxazole (Scheme 167) (67AHC(8)277). Bunnett conducted a kinetic study on the reaction shown in Scheme 167 and determined that cyclization to intermediate (551) was the rate determining step (61JA3805). 

BAY 94337 — see l,2,4rTriazin-5-one, 4-amino-6-t-butyl-3-methylthio- Bay region epoxides, 7, 189 Beckmann rearrangement, 7, 34 Beirut reaction, 3, 181-184 6, 407, 425 Bemegride... 

Beckmann rearrangement, 4, 292 pyrolysis, 4, 202 synthesis, 4, 223 Wittig reaction, 4, 294 Wolff-Kishner reduction, 4, 291 Indole, 1-acyl-2,3-disubstituted photoisomerization, 4, 204 photo-Fries rearrangement, 4, 204 photoisomerization, 4, 42 synthesis, 4, 82 Indole, 2-acyl acidity, 4, 297 synthesis, 4, 337, 360 Indole, 3-acyl-acidity, 4, 297 cleavage, 4, 289 reduction, 4, 289 synthesis, 4, 360 Indole, 7-acyl-synthesis, 4, 246... 

H-Indole, 3,3-dichloro-synthesis, 4, 369 3H-Indole, 3,3-dimethyl-synthesis, 4, 224 3H-Indole, 3-hydroperoxy-autoxidation, 4, 247 rearrangement, 4, 249 3H-Indole, 3-oximino-synthesis, 4, 209, 210 3H-Indole, 3-oximino-2-phenyl Beckmann rearrangement, 4, 210 Indoleacetic acid synthesis, 4, 337 Indole-3-acetic acid as growth regulator, 4, 372 synthesis, 4, 346 Indole alkaloids, 4, 373 synthesis, 4, 276... 

Beckmann rearrangement, 6, 156 Isothiazole, 3-alkoxy-tautomerism, 6, 145 Isothiazole, alkyl-bromination, 5, 58 Isothiazole, 3-alkyl-5-amino-synthesis, 6, 166 Isothiazole, alkylthio-mass spectra, 6, 142 Isothiazole, amino-azo dyes from, 1, 330 tautomerism, 6, 157 Isothiazole, 3-amino-synthesis, 5, 135 tautomerism, 6, 146 Isothiazole, 4-amino-azo dyes from, 6, 175 diazotization, 6, 158 methylation, 5, 95 quaternization, 6, 158 reactions... 

Beckmann rearrangement, 3, 710 Pyran-4-carbaldehyde, 2,2-dimethyl-tetrahydro-Reformatsky reaction, 3, 732 4H-Pyran-4-carbaldehydes synthesis, 3, 760-761 Pyran-2-carbonitrile, 5,6-dihydro-reactions, 3, 732... 

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