If the heteroatom in these conversions is attached to a carbocyclic ring, and rearrangement of one ring segment to the heteroatom is effected, a heterocyclus of n + 1 members is formed (Scheme 5). Finally, the last example illustrates a selective Hofmann rearrangement of a bromo-imide. Typically, various t-butoxy-carbonyl (t-BOC) or Cbz protected amino acid azides and their analogues readily lose nitrogen on heating to 80 °C in toluene to form the corresponding isocyanates in high yield (Equation (90)) <83JMC129, 83MI 409-01, 83MI 409-02>. Although the, Recent Advances in the Synthesis of Benzimidazol-2-ones via Rearrangements, Vakhid A. Mamedov, Nataliya A. Zhukova, in, Unlike the Curtius, Schmidt, and Hofmann rearrangements, the, (Aube, Fehl, Liu, McLeod, and Motiwala) Hofmann, Curtius, Schmidt, Lossen, and Related Reactions. W. Lwowski, in Comprehensive Heterocyclic Chemistry, 1984. 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. Because of the carbon chain joining the oxime function to the ortho-carbon of the benzene ring, the phenonium ion that normally facilitates phenyl migration may be unable to assume its preferred structure (three-membered ring orthogonal to the phenyl ring). Trapping of the isocyanate by the hydroxamic acid results in dimerization (Scheme 11b) <1989S61>. A series of disubstituted pyridine derivatives was synthesized from the corresponding acryloyl azides by acetic acid-promoted cycloaddition. 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. Unacylated aryl hydroxamic acids such as 96 have also been found to efficiently undergo Lossen reaction when heated with basic metal salts as catalysts. The 1,2-shift of the ortho-phenol substituent is faster than that of the unsubstituted phenyl group, and the hydroxyl is ideally located to bond to the electrophilic carbon of the intermediate. 23.5 Schmidt Reaction . Several superior promoters for the Lossen reaction have been described (Scheme 43). For cases where steric, lone pair-cation, and cation-π effects have been invoked previously as regiocontrol elements, the origins and magnitudes of these effects have been examined theoretically. A facile isocyanate synthesis. ChemInform Abstract: Chiral Broensted Acid Promoted Enantioselective Desymmetrization in an Intramolecular Schmidt Reaction of Symmetric Azido 1,3-Hexanediones: Asymmetric Synthesis of Azaquaternary Pyrroloazepine Skeletons. Early activating agents for free hydroxamic acids were plagued by a self-dimerization side reaction (Scheme 42). This lactam serves as an important industrial precursor to nylon 6. The rigid configuration of the phenonium cation shown above imposes a structural constraint that is nicely demonstrated by the rates of rearrangement of some fused ring bicyclic compounds. A third problem traditionally associated with the rearrangement is the undesired dimerization of any starting hydroxamic acids with the highly reactive isocyanate formed.98, Like other members of this class, the Lossen reaction has been established as a thermal, ionic, concerted decomposition process. Example # 5 shows a Schmidt reaction in which an optically active carboxylic acid is the substrate. The acid-catalysed reaction of hydrogen azide with electrophiles, such as carbonyl compounds, tertiary alcohols or alkenes. We also explored the comprehensive mechanism by the acid-promoted cycloaddition of (13)C-labeled cinnamoyl azide. Such modifications have frequently involved trapping intermediate isocyanates formed as a result of Curtius, Lossen or Hofmann rearrangements of N-protected amino acid derivatives <83MI 409-01>, but the Curtius acyl azide rearrangement is the most commonly used of these three. It is usually conducted under alkaline conditions. An alternative Curtius approach to the amine product of example # 2 is also shown. However, a survey of the chemical literature reveals that the Lossen rearrangement receives little attention as a general and practical synthetic method. They found that a short-term heating of anthranilohydroxamic acids 145 in formamide at 130–140°C converts them into corresponding benzimidazol-2-ones 146 almost quantitatively (Scheme 52). Using this methodology, both enantiomers of 4-chloro-3-hydroxybutanamide were prepared and converted into pyrrolidin-3-ol and 5-(chloromethyl)-1,3-oxazolidin-2-one by simple processes consisting of a reduction reaction and a Hofmann rearrangement, respectively. Synthetic methods based on the mechanistically related Hofmann, Curtius, and Lossen rearrangements and the Schmidt reaction are surveyed. The Lossen reaction14,15 is the rearrangement of hydroxamic acids, which are prepared from acids, acyl chlorides and esters. Both single-pot and two-stage variations of this process were examined, with particular attention to the stereochemical outcome of the processes. As the isocyanate is formed, it is extracted into the organic layer. Also, a patent claims that mono- and diisocyanates can be prepared by thermal decomposition of acetates of hydroxamic acids when they are heated under nitrogen to 150 °C <69USP3465024>. Efficient preparative sequences involving radical decarboxylation followed by carbon–nitrogen bond formation are rare. On the basis of this reaction, a convenient experimental procedure for the preparation of alkylcarbamates using Oxone as the oxidant in the presence of iodobenzene in methanol has been developed. Schmidt reaction. Clicking on the diagram will show the results of such a study. The former reaction is much faster than the latter, presumably because it proceeds by way of a relatively stable phenonium ion intermediate (structure in shaded box). A noteworthy exception44 is found in the thermal or photochemical decarboxylation of tetrahydro-1,2-oxazine 3,6-diones leading to β-lactams (equation 47). 23.6 Hofmann-Bromamide Reaction or Hofman Rearrangement . For example, either N-(tert-butyloxycarbonyl)-O-methanesulfonyl-hydroxamic acid110 (94) or N,O-bis-(ethoxycarbonyl)hydroxylamine105 (95) has been used to generate activated hydroxamic acid species directly from the acid chloride or carboxylic acid, respectively. The mechanism of the acid-catalyzed intramolecular Schmidt reaction of 2-azidopropylcyclohexanones was studied using density functional theory (primarily M06-2X). Derek R. Buckle, Ivan L. Pinto, in Comprehensive Organic Functional Group Transformations, 1995. The approach which is used for the preparation of title compound (I) may also be suitable for the synthesis of analogues. An alternative method involving the displacement of chloride from the aryl isocyanates (133) by simply stirring with triethylamine and a secondary amide in benzene for 2 h at room temperature has been reported, and provides 64–75% yields of readily isolable product <92ZOR2119>. Watch the recordings here on Youtube! Note that the structure drawn for this intermediate is the more favored of two resonance contributors, inasmuch as all heavy atoms have filled valence shell octets. Chapter 24 Polymers. This has been called an abnormal Beckmann reaction. Unless otherwise noted, LibreTexts content is licensed by CC BY-NC-SA 3.0. Subsequent studies confirmed that benzyl groups could also migrate,117 expanding the scope beyond aryl groups, and also showed this transformation to be stereospecific.118, P. Molina, ... A. Arques, in Comprehensive Organic Functional Group Transformations II, 2005. An attempt to combine the preparation of hydroxamic acids, their silylation, and their subsequent thermolysis to isocyanate into one process gave good results only in the aromatic series (Equation (60)) <84ZOB878>. The general applicability of this reaction remains to be established since it is possible that the trifluoromethyl substituent may be necessary to enhance halogen displacement. 3 -iodane as a Reagent for the Synthesis of Methyl Carbamates via Hofmann Rearrangement of Aromatic and Aliphatic Carboxamides. Synthesis of Methyl-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylate via a Hofmann Rearrangement Utilizing Trichloroisocyanuric Acid as an Oxidant, Temporary Restraints To Overcome Steric Obstacles: An Efficient Strategy for the Synthesis of Mycalamide B. ChemInform Abstract: Hofmann Rearrangement of Carboxamides Mediated by Hypervalent Iodine Species Generated in situ from Iodobenzene and Oxone: Reaction Scope and Limitations. By continuing you agree to the use of cookies. N-mesyloxysuccinimide compounds were shown to be activated by α-chymotrypsin to inhibit the enzyme covalently.114 Similarly, a crystal structure of a serine protease clearly indicated in situ trapping of an isocyanate formed by a Lossen reaction occurring in the active site.115, Finally, the Lossen reaction has been extended to systems beyond carbonyl centers. The second example involves an oxime derivative with different carbonyl substituents, which exists as a pair of stereoisomers (syn & anti). water) at the electrophilic carbon atom adjacent to the "onium" nitrogen. Beckmann type rearrangements may also be carried out by treating hydrazones with nitrous acid, as shown on the right.