Activation parameters for the interconversion of conformers IA and IB of neopentylbenzylnitrosamine and of rotamers IIA and IIB of N,2,4,6-tetramethyl-N-benzylbenzamide were determined by two techniques: Equilibration of pure IB (or IIA, respectively) and subsequent measurement of 1H-NMR line shapes with the same sample. Ea- and k0-values obtained by the two methods agree well within error limits, thus confirming the accuracy of rate determinations using NMR line shapes. Chemical shifts Δν, line widths bE, and equilibrium constants K were extrapolated to those temperatures at which they could not be measured directly. Line shape parameters were used for the evaluation of spectra. This method is shown to be preferable to the complete line shape analysis if the line broadening by field inhomogeneities is not taken into account by a convolution.

Protonenresonanz-Untersuchungen zur inneren Rotation 6: The conformers of a nitrosamine and a carboxamide: Comparison of NMR line shape and equilibration methods

4.16 – Isoxazoles and their Benzo Derivatives

Early researchers studying the condensation product of carbonyl compounds with N-substituted hydroxylamines elected to coin the term “nitrone” as a combination of the words “nitrogen” and “ketone.” This was done to emphasize the parallel between this newly discovered functionality and the already rich chemistry of the carbonyl group.



For example, nitrones are capable of reacting with carbanions of various types, a consequence of the iminium species embedded in the nitrone that renders the functionality susceptible to nucleophilic attack. Thus C-phenyl-N-methylnitrone undergoes a Reformatsky reaction with ethyl bromoacetate in complete analogy with benzaldehyde. The intermediate zinc alkoxide cyclizes to 2-methyl-3-phenylisoxazolidin-5-one, a type of compound that can also be prepared by the related nucleophilic addition of dialkyl malonates to nitrones.



This chapter deals with a unique property of nitrones not shared by the corresponding carbonyl compounds, namely, a marked ability to undergo a [3 + 2] cycloaddition reaction in the presence of a dipolarophile. The reactions of nitrones with substituted olefins, both intermolecular and intramolecular are addressed. This process yields isoxazolidines directly, affording products related to those obtained in the Reformatsky reaction but arising by a different reaction mode.



The intent of the review presented in this chapter is to provide a thorough understanding of the nitrone–olefin [3 + 2] cycloaddition reaction and to illustrate its power by describing some significant applications to complex synthetic problems. Various aspects have been reviewed. This documentation of the nitrone–olefin cycloaddition reaction begins with the preparation and stability of the nitrone component and is followed by mechanistic considerations. A presentation of the dipolarophile syntheses is beyond the scope of this chapter; however, the tabular survey provides leading references to specific examples. The important concepts of regio- and stereo-selectivities are introduced next. Since the general rules of regiochemistry that apply in the intermolecular version of the reaction are often reversed in the intramolecular version, the latter are dealt with separately. Finally, important applications to the total synthesis of natural products are presented. The versatile utility of the nitrone–olefin cycloaddition reaction in the synthesis of natural products has been the major driving force in the development of this long-neglected chemistry. An in-depth understanding of the key transformations of the isoxazolidines afforded by the reaction will place this chemistry firmly within the arsenal of organic reactions.


Keywords:

cycloaddition reactions;
[3 + 2] reaction;
nitrone;
olefins;
nitrone stability;
mechanism;
regioselectivity;
intermolecular reaction;
intramolecular reaction;
C-alkenylnitrones;
N-alkenylnitrones;
natural products;
alkaloids;
biotin;
aldehyde-derived nitrones;
ketone-derived nitrones;
endocyclic nitrones;
exocyclic nitrones;
amino glycosides;
adaline;
nitrogen-free systems;
experimental procedures

The [3 + 2] Nitrone–Olefin Cycloaddition Reaction

3.03 – Isoxazoles

Reaction of the nitrone 1 with α-chloroacrylonitrile (4) as ketene equivalent yields the 5-isoxazolidinone 2a and the α-chloroimine 5. The mechanism of the reaction is discussed. The compound 2a is useful for the synthesis of hindered pyrrolidines 3.

Sterisch gehinderte Pyrrolidine. Umsetzung von 2,5,5-Trimethyl-1-pyrrolin-1-oxid mit α-Chloracrylnitril

Nitrone, 6. Mitt.: Isoxazolidin-Verbindungen, 6. Mitt.: Malonester-Addition an Nitrone mit größerem N-Substituenten

Die Ketonitrone 1a–c werden durch Reformatzky-Reaktion mit Bromessigsaureathylester und Zink in siedendem Tetrahydrofuran zu den 5-Isoxazolidinonen 3a–c umgesetzt. Im 3-spiro-Isoxazolidinon 3b ist die N-Inversion langsam auf der NMR-Zeitskala mit einer Koaleszenztemperatur von 32° fur die beiden 4-standigen Protonen. Die freie Aktivierungsenthalpie betragt 14.7 Kcal/mol (61 600 J/mol). Die entsprechenden Werte fur das Isoxazolidinon 3a sind: −3° und 13.9 Kcal/mol (54 800 J/mol). Das Invertomerengleichgewicht des in 3-Stellung unsymmetrisch substituierten Isoxazolidinons 3c hat bei −50° einen von 1 verschiedenen Wert der Gleichgewichtskonstanten: das Z-Invertomere liegt nur zu 16–22% der gesamten Mischung vor.



Nitrones, VIII. Isoxazolidine-Compounds, VII: Reformatzky Reaction with Ketonitrones. Slow N-Inversion in the 5-Isoxazolidinone Ring



The ketonitrones 1a–c are transformed to the 5-isoxazolidinones 3a–c by Reformatzky reaction with ethyl bromoacetate and zinc in boiling tetrahydrofuran. In the 3-spiroisoxazolidinone 3b N-inversion is slow on the NMR time scale with a coalescence temperature of 32°C for the two protons at position 4: the free enthalpy of activation is 14.7 kcal/mole (61 600 J/mole). The corresponding values for the isoxazolidinone 3a are: −3°C and 13.9 kcal/mole (54 800 J/mole). For the isoxazolidinone 3c, which is unsymmetrically substituted at position 3, the equilibrium constant of the inversion reaction is different from 1 at −50°C, i. e. the Z-invertomer accounts for 16 to 22% of the total mixture.

Nitrone, 8. Mitt. Isoxazolidin‐Verbindungen, 7. Mitt. Reformatzky‐Reaktion mit Ketonitronen Langsame N‐Inversion im 5‐Isoxazolidinon‐Ring

Nitrone, 7. Mitt.: Ein Isoxazolin durch Dimerisation eines C‐Methylnitrons

Etude de la redention par le bromure de methyl-magnesium, par LiAlH 4 et H 2 /Pd, C, des aryl-3 trimethyl-2,4,4 isoxazolidone-5. Dans les 2 derniers cas il y a scission et formation respectivement de derives d'hydroxyamino-3 propanols et d'ammoniopivalate

Isoxazolidin‐Verbindungen, 10. Mitt. Reduktive Reaktionen mit 5‐Isoxazolidinonen

Die 2-Methyl-3-aryl-5-oxoisoxazolidine 1 werden mit “magic methyl” bzw. Triethyloxoniumtetrafluoroborat quaternisiert. Die sehr empfindlichen cyclischen Kationen 2 bzw. 3 solvolysieren leicht in Methanol ohne erkennbare Polonovski-Umlagerung.



Isoxazolidine Compounds, XI: 2, 2-Dialkyl-3-aryl-5-oxoisoxazolidinium Salts: Cyclic Analogues of Polonovski Intermediates



The 2-methyl-3-aryl-5-oxoisoxazolidines 1 are quaternized with “magic methyl” or triethyloxonium tetrafluoroborate, respectively. The very sensitive cations 2 and 3, respectively, undergo easily solvolysis in methanol without recognizable Polonovski rearrangement.

Harald Steudle

Papers

Nitrone, 6. Mitt.: Isoxazolidin-Verbindungen, 6. Mitt.: Malonester-Addition an Nitrone mit größerem N-Substituenten

Nitrone, 8. Mitt. Isoxazolidin‐Verbindungen, 7. Mitt. Reformatzky‐Reaktion mit Ketonitronen Langsame N‐Inversion im 5‐Isoxazolidinon‐Ring

Nitrone, 7. Mitt.: Ein Isoxazolin durch Dimerisation eines C‐Methylnitrons

Isoxazolidin‐Verbindungen, 10. Mitt. Reduktive Reaktionen mit 5‐Isoxazolidinonen

Isoxazolidin‐Verbindungen, 11. Mitt.: 2, 2‐Dialkyl‐3‐aryl‐4‐oxoisoxazolidinium‐Salze: Cyclische Analoga von Polonovski‐Intermediaten