Several superior promoters for the Lossen reaction have been described (Scheme 43). N-Benzenesulfonyloxysuccinimide (196) also undergoes the Lossen reaction with amines to give β-ureidopropionamides (197).118, Although the Lossen reaction of O-acylated derivatives of the amide oxime (198) has failed, its mesylate (199) easily gives the Lossen product (200) under alkaline conditions (equation 52).119, J. Aubé, ... H.F. Motiwala, in Comprehensive Organic Synthesis II (Second Edition), 2014, The Lossen reaction is driven by the expulsion of a carboxylate group from a bis-acylated hydroxylamine. Cycloaddition Reactions of Aliphatic and Aromatic Acyl Isocyanates, An Efficient Process for the Manufacture of Carmegliptin§, A Solid-Phase Synthesis of N,N‘-Disubstituted Ureas and Perhydroimidazo[1,5-a]pyrazines via the Curtius Rearrangement, Novel Approach to Lactams via (Triisopropylsilyl)azidohydrin Formation and Photoinduced Schmidt Rearrangement, TiCl4-mediated reactions of alkyl azides with cyclic ketones, The Influence of Substituents on the Rates of Decomposition of the Potassium Salts of Dihydroxamic Acids. All result in the production of amides and/or amines involving nitrogen insertion via concerted rearrangement of a nitrenoid intermediate. Bonding of a nucleophile to the nitrogen atom would require expanding its valence shell to include ten electrons, or formation of an unstable dipolar species. After a rearrangement and extrusion of N 2, amines, nitriles, amides or imines are produced. In this case, the substrate is defined as a hydroxamic acid or derivative thereof.97 The formation of a univalent, six-electron nitrogen center had been proposed in the years after the reaction was discovered,99,100 but all attempts to capture a nitrene intermediate have failed.96 A concerted mechanism based on the stereospecific nature6 of the reaction replaced the nitrene theory in the early twentieth century. If the hydroxyl group of a ketoxime is removed by the action of strong acid or phosphorous pentachloride, followed by hydrolysis, an amide is formed. The first example is similar to a Wagner-Meerwein rearrangement, and the second to a pinacol rearrangement. Especially, rearrangements of the Beckmann type are commonly used to make large nitrogen-containing rings, such as azepinones (Section 23.6 Hofmann-Bromamide Reaction or Hofman Rearrangement . Monomer Syntheses and Model Reactions for the Dendritic Poly(amide-urea)s Synthesis, Photolysis of some unsymmetrical phosphinic azides in methanol, Curtius Rearrangement Using Ultrasonication: Isolation of Isocyanates of Fmoc-Amino Acids and Their Utility for the Synthesis of Dipeptidyl Ureas, One-Pot Synthesis of Ureido Peptides and Urea-Tethered Glycosylated Amino Acids Employing Deoxo-Fluor and TMSN3, The Chemistry of Hydroxamic Acids andN-Hydroxyimides, Synthesis of Urethanes by a Modified Curtius Reaction with Alcohols. Hydroxamic acid - Isocyanate - Ester - Curtius rearrangement - Hofmann rearrangement - Schmidt reaction - 4-Toluenesulfonyl chloride - Amine - Carbon dioxide - Decarboxylation - Gabapentin - Myrosinase - List of organic reactions - Wilhelm Lossen - RXNO Ontology - Rearrangement reaction - 1,2-rearrangement - Arndt–Eistert reaction The oxime from cyclohexanone has identical carbonyl substituents. Doubtless a key factor in this reaction, considered to proceed via a radical cage mechanism, is the intramolecular nature of the carbon–nitrogen bond formation. Two such cations are shown on the left (in the blue box) below. Alkylcarboxamides can be converted to the respective amines by Hofmann rearrangement using hypervalent iodine species generated in situ from PhI and Oxone in aqueous acetonitrile. The Lossen reaction of peptide carboxylic acids has been investigated in order to determine the carboxy terminal amino acid residue of peptides.117 The procedure first involves the formation of O-pivaloylhydroxamic acids (187) by condensation of peptide carboxylic acids (184) with O-pivaloylhydroxylamine (185) using a water soluble carbodimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (186). In the Lossen rearrangement (# 7) butyl amine adds to the isocyanate to give a substituted urea (urea is NH2CONH2). By continuing you agree to the use of cookies. The Lossen rearrangement (Equation (17)) in which hydroxamic acids are O-activated to create a suitable leaving group for subsequent rearrangement belongs to the category of named classical carboxyl degradation reactions that provide useful isocyanate intermediates from carboxylic acid derivatives. The Lossen rearrangement of (187) occurs at pH 8.5 and 50 °C to give a mixture of isocyanates (188) and their reaction products, which, on acidic hydrolysis, afford the aldehydes (189), ammonia and amino acids, as shown in Scheme 30.117 Identification of aldehydes determines the C-terminal amino acids of the original peptides. These reagents allow the more efficient use of free hydroxamic acids without prior acylation, and by providing a facile and complete activation of the hydroxamic acid, they eliminate the propensity for self-dimerization.105 All three reagents – carbonyldiimidazole106 (91), cyanuric chloride107 (92), and bromodimethylsulfonium bromide108 (93) – can be used in a ‘one-pot’ sequence for further synthetic convenience. Mild Replacement for Bromine R NH 2 O R H NBS, DBU N O MeOH, O reflux 45 min R Yield, % 3,4-(MeO) 2C 6H 3-p-MeC 6H 4-89 84 C H-95 p-ClC 6H 4-p-NO 2-C 6H 4-94 6 5 70 K ill JW H XOSth2004 C ll V l … C. Schmidt reaction. ChemInform Abstract: Synthesis of (-)-Oseltamivir by Using a Microreactor in the Curtius Rearrangement. In this instance the initially formed thiocyanate (134) rearranges easily at 80 °C in butanone, although strongly electron-withdrawing groups lower the rate of isomerisation. 23.5 Schmidt Reaction . Synthetic methods based on the mechanistically related Hofmann, Curtius, and, Five-membered Rings (One Oxygen or Sulfur and At Least One Nitrogen Atom) Fused with Six-membered Rings (At Least One Nitrogen Atom), Synthesis: Carbon with Two Heteroatoms, Each Attached by a Single Bond. To address the availability of hydroxylamine-starting materials, several ‘reagent-based’ modifications have been developed (Scheme 45). This sole example of a chiral Lossen reaction has been demonstrated on N-acylhydroxyimide 99.113, This variant of the Lossen reaction was implicated in the mechanism of action for a series of serine protease inhibitors (Scheme 48). A variation to obtain the corresponding O-acylhydroxamic acid consists of the reaction of aromatic hydroxamic acids with triphenylphosphine, ethanol, and diethyl azodicarboxylate which gives rise to the formation of O-(N-phenylcarbamyl) hydroxamates through a Lossen rearrangement, which involves the formation of a nonisolated isocyanate intermediate <74TL1965>. Each one of the initial steps has its particular merit: (i) because TMS-ONH-TMS is prepared directly from TMS-Cl and hydroxylamine; (ii) it is useful for low-boiling acid chlorides; (iii) it is attractive in that the whole sequence (acid chloride to isocyanate) can be carried out in homogeneous solution without isolation of intermediates. A substantial number of molecular rearrangements lead to the incorporation of heteroatoms into carbon–carbon chains. This has been called an abnormal Beckmann reaction.