Elimination Cope, reverse

The action of iV-methylhydroxylamine on enantiopure 4-formylazetidin-2-ones bearing an N-tethered alkynyl group 89 has been studied and products formed by 1,3-dipolar cycloaddition and reverse Cope elimination isolated, e.g. 90 <00TL1647>. 

In order to study the mechanism of reverse Cope elimination reactions in the condensation of pentenal and hexenal with iV-methylhydroxylamine. it seemed reasonable to synthesize unsaturated nitrones (226). 

Another approach is based on the condensation of lithiated sulfones to unsaturated nitrones (387). Good yields of single stereoisomers of unsaturated hydrox-ylamines (388) are obtained. They undergo a reverse-Cope elimination leading to a single enantiomer of pyrrol idine-/V -oxide (389) (Scheme 2.169) (626). 

In 1998, an uncatalyzed cydization of N-2,3-dienylhydroxylamine affording bicyc-lic products was also observed. The reaction was believed to proceed via a reverse Cope elimination [171]. 

Alcaide et al. (68,69) recently published their smdies of the intramolecular 1,3-dipolar cycloaddition reactions of alkynyl-p-lactams in which they found that the desired cycloaddition was in competition with a reverse-Cope elimination. The reaction of alkynyl aldehydes 37a-c with Al-methylhydroxylamine afforded a mixture of products depending on the reaction conditions and the chain length separating the alkyne and the lactam (Scheme 1.8). Thus, up to three separate... 

Perhydropyrido[l,2-fl]pyrazin-l-one N-oxide 167 was formed from 1-hydroxypipecolic acid amide 261 by reverse Cope elimination by heating in CHCI3. Similar reaction of 1-hydroxypipecolinate 262 resulted an 1 5 30 equilibrium mixture of 262, 263, and 264 (07TL1683). 

The intramolecular nitrone-alkene cycloaddition reaction of monocyclic 2-azetidinone-tethered alkenyl(alkynyl) aldehydes 211, 214, and 216 with Ar-aIkylhydroxylamincs has been developed as an efficient route to prepare carbacepham derivatives 212, 215, and 217, respectively (Scheme 40). Bridged cycloadducts 212 were further transformed into l-amino-3-hydroxy carbacephams 213 by treatment with Zn in aqueous acetic acid at 75 °C. The aziridine carbaldehyde 217 may arise from thermal sigmatropic rearrangement. However, formation of compound 215 should be explained as the result of a formal reverse-Cope elimination reaction of the intermediate ct-hydroxy-hydroxylamine C1999TL5391, 2000TL1647, 2005EJ01680>. 

Ciganek, E. Reverse Cope elimination reactions. 2. Application to synthesis. J. Org. Chem. 1995, 60, 5803-5807. 

Gallagher, B. M., Pearson, W. H. Thermal cyclization of N-hydroxylamines with alkenes the reverse Cope elimination. Chemtracts Org. Chem. 1996, 9, 126-130. 

Komaromi, I., Tronchet, J. M. J. Quantum Chemical Reaction Path and Transition State fora Model Cope (and Reverse Cope) Elimination. J. Phys. Chem. A 1997, 101, 3554-3560. 

As the name suggests, the reverse Cope elimination reaction involves formation of a tertiary amine oxide from a hydroxylamine and olefin.17,18 For example, reaction of N-methylhydroxylamine (49) with 2,2-diphenyl-4-pentenal (50) in ethanol at room temperature gave amine oxide 51 in 51% yield, together with the expected nitrone 52. It has been suggested the mechanism of the reverse Cope reaction could be a radical chain reaction19,20 however, more recent studies have confirmed the mechanism is analogous to the concerted Cope elimination.17... 

Allyl amines 30 react with aldehyde-derived nitrones 31 to give oxadiazinanes 32 in excellent yield. The reaction proceeds via initial nucleophilic attack on the nitrone by the amine, followed by a reverse-Cope elimination and subsequent Meisenheimer rearrangement to give the observed products as shown in Figure 4 <2000J(P1)3292>. 

The Cope eUmination is reversible and the intramolecular reverse Cope elimination, involving the addition of a tethered hydroxylamine to an alkene, has found recent application for the stereocontrolled preparation of cyclic amines."... 

Hanrahan, J. R. and Knight, D. W. 1998. A new strategy for the elaboration of pyrrolidine n-oxides using the reverse-cope elimination. Chem. Commun. 20 2231-2232. 

Bis-homoallylic hydroxylamines (29) (R = Me or H) undergo an intramolecular hydroamination (formally a reversed Cope elimination) in the presence of a thiourea... 

Nucleophilic addition of lithiated sulfones to nitrones made it possible to develop new stereoselective approaches to the synthesis of pyrrolidine-N -oxides based on a reverse-Cope-type elimination. One method is based on the reaction of lithiated sulfones with nitrones (386) (Scheme 2.168) (625). 

The reaction with the siloxy derivative 29 is an interesting example because the product 30 is a 1,5-dicarbonyl derivative (Equation (36)).96 1,5-Dicarbonyls are classically prepared by a Michael addition, but the synthesis of 30 by a Michael addition is not possible because it would require addition to the keto form of 1-naphthol. The acetoxy derivative 31 resulted in a different outcome, leading to the direct synthesis of the naphthalene derivative 32 (Equation (37)).96 In this case, the combined C-H activation/Cope rearrangement intermediate was aromatized by elimination of acetic acid before undergoing a reverse Cope rearrangement. 

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