Cope rearrangement reaction with aldehydes

Abstract The photoinduced reactions of metal carbene complexes, particularly Group 6 Fischer carbenes, are comprehensively presented in this chapter with a complete listing of published examples. A majority of these processes involve CO insertion to produce species that have ketene-like reactivity. Cyclo addition reactions presented include reaction with imines to form /1-lactams, with alkenes to form cyclobutanones, with aldehydes to form /1-lactones, and with azoarenes to form diazetidinones. Photoinduced benzannulation processes are included. Reactions involving nucleophilic attack to form esters, amino acids, peptides, allenes, acylated arenes, and aza-Cope rearrangement products are detailed. A number of photoinduced reactions of carbenes do not involve CO insertion. These include reactions with sulfur ylides and sulfilimines, cyclopropanation, 1,3-dipolar cycloadditions, and acyl migrations. 

MgS04, the tetracycles 2-648 were obtained with excellent diastereoselectivity in reasonable yield. The reaction presumably starts with a condensation of the aldehydes 2-645 with the benzyl-protected amine moiety of 2-644 to give an iminium ion which can subsequently cyclize to afford the spirocyclic intermediates 2-646. A [3,3] sigmatropic Cope rearrangement then forms the nine-membered cyclic enamines 2-647 which, after protonation, act as the starting point for another indole iminium cyclization to provide the tetracycles 2-648 via 2-647. 

An earlier example of this type of domino reaction was reported by Greeves and coworkers (Scheme 2.194) [443]. Treatment of either the ( )- or (Z)- allyl vinyl ether 2-870 with NaH initiates the [2,3]-Wittig rearrangement to afford 2-872 via 2-871. The subsequent oxy-Cope rearrangement led to the aldehyde 2-873, which was reduced with NaBH4 to give the alcohols 2-874. Both isomers of 2-870 predominantly generated the (/ )-xyu-product 2-874 in comparable ratios as the main product. 

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>. 

The aldol reaction is an addition of metal enolates to aldehydes or ketones to form P-hydroxy carbonyl compounds.1 The simplest aldol reaction would be the reaction of acetaldehyde lithium enolate with formaldehyde (Scheme 2.1). As the transition state of this reaction involves six atoms, the aldol reaction is another example where a six-membered transition state is presumed to be operating. The transition state of the aldol reaction is very similar to those of Claisen and Cope rearrangements, and therefore the remarkable facility of the lithium enolate reaction is attributed to the stability of an aromatic transition state.2... 

That the rearrangement occurs with the enammonium salt has been confirmed by the fact that N-allyl-A methylisobutenylamine (154), which is stable under the reaction conditions, affords aldehyde 155 by treatment with methyl tosylate followed by hydrolysis (equation 33)103. MeOTs acts as a promoting reagent which facilitates the rearrangement. Other electrophilic reagents110-112 have also been employed to create a quaternary nitrogen center in order to accelerate the 3-aza-Cope rearrangement. 

The readily available aldehyde (118) has served as a suitable precursor for a number of 6-endo-( al-kenyl)bicyclo[3.1,0]hex-2-enes. For example, treatment of (118) with PhsP —CHC02Me gives a mixture of die bicyclic diene esters (121)-(123) (Scheme 18). In view of the stereospecific nature of the Cope rearrangement process (vide supra), it is highly likely that (121) and (122) are derived by bond reorganization of the initially formed Wittig products (119) and (120), respectively. The ratio of (121) (122) is, therefore, a reflection of the (expected) fact that the Wittig reaction produces primarily the rrans-a,P-un-saturated ester (119). The diene ester (123) is, presumably, formed by partial isomerization of (121) and (or) (122). 

Therefore, a Cope rearrangement can be detected only when the diene is not symmetrical about this bond. Any 1,5-diene gives the rearrangement for example, 3-methyl-l,5-hexadiene heated to 300°C gives 1,5-heptadiene. However, the reaction takes place more easily (lower temperature required) when there is a group on the 3- or 4-carbon with leads to the new double bond being substimted. The reaction is obviously reversible and produces an equilibrium mixture of the two 1,5-dienes, which is richer in the thermodynamically more stable isomer. However, the equilibrium can be shifted to the right for 3-hydroxy-1,5-dienes, because the product tautomerizes to the ketone or aldehyde ... 

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