Cycloaddition of enamines

Two-step 1,4 cycloaddition of enamines, such as was observed with methyl vinyl ketone, is not possible with acrylate or maleate esters. This is due to the fact that, following the initial simple substitution, no side-chain carbanion is available for nueleophilic attack on the a carbon of the iminium ion. Likewise two-step 1,3 eycloaddition, such as that found when alicyclic enamines were treated with acrolein, is impossible with acrylate or maleate esters because transfer of the amine moiety from the original enamine to the side chain to form a new enamine just prior to the final cyclization step is not possible. That is, the reaction between a seeondary amine and an ester does not produce an enamine. 

It appears, however, that the most used strategy for the preparation of thietane dioxides is the [2 + 2] cycloaddition of enamines (202) with in situ-generated sulfenes (220)74,143,186 188,202,242 to give /(-aminothietane sulfones (equation 85). 

The rather complex reactivity exhibited by cyclopropenones on interaction with enamines (see p. 74) is not re-found in the reactions of triafulvenes with enamines and ketene acetals. Instead of a (3 + 3) cycloaddition of enamine C=C—N sequence to the CI(2)/C3 bond of triafulvene (as represented by ylide 51 J) the addition of the enamine double bond to triafulvene C /C2 bond (operating with cyclopropenones only as a minor side-reaction) predominates in all reactions hitherto investigated. 

Pyrimidobenzomorphane 119, has been obtained by [4+2] cycloaddition of enamine 118, produced from the bicyclic ketone 117 and pyrrolidine, to 1,3,5-triazine (82TL4559 Scheme 33). 

Asymmetric induction in the [2 + 2] cycloaddition of enamines, e.g. 42, with methyl ( )-4-oxo-4-(2-oxo-l,3-oxazolidin-3-yl)-2-butenoate (41) has been reported (equation 7)35. The reaction is promoted by a chiral titanium reagent generated in situ from dichlorodiisopropoxytitanium and a tartrate-derived chiral 1,4-diol (43). In the presence of excess amounts of the titanium reagent, 77% ee of cycloadduct 44 was achieved together with 45. The reaction also works with only a catalytic amount of the chiral reagent. 

Dihydro- 1,3-oxazines (398) are cyclic intermediates in the synthesis of a-amino-y-oxo acid esters by reaction of acyliminoacetates with enamines derived from six-membered ketones240. Sulfur-containing heterocycloadducts 399 and 400 have been prepared by [4 + 2] cycloaddition of enamines to heterocumulenes like thioacyl isocyanates and acyl isothiocyanates241. 

The two-carbon ring expansion which involves the [2 + 2] cycloaddition of enamines of cyclic ketones with electron-deficient acetylenes followed by thermal rearrangement of the resulting fused cyclobutenes (see Section II.E) has been successfully used in the synthesis of medium-size heterocycles. Examples include the preparation of compounds 407246, 408247 and 409248. 

The intramolecular Diels-Alder reaction promises to become widely used in the synthesis of natural products from reports of recent research (142-144). In natural alkaloid synthesis by a Diels-Alder reaction, an enamide was utilized as either a suitable dienophile or diene group. There exist numerous examples of bimolecular and intramolecular Diels-Alder reactions of enamides with various dienophiles as well as bimolecular (4 + 2) cycloadditions of enamines with electron-deficient dienes. On the other hand, there appear to be only few reports of the (4 + 2) cycloaddition reactions of enamides with unactivated dienes. 

Ruder, S.M., and Norwood, B.K., Cycloaddition of enamines with alkynylphosphonates. A route to functionalized medium sized rings. Tetrahedron Lett., 35, 3473, 1994. 

We will review first the influence of the organic residue R of the azides used for the reactions in Scheme 2-67. Fusco et al. (1961 a, 1961 b, 1962) studied the formation of triazolines by cycloaddition of enamines and aromatic azides (2-68). 5-Amino-... 

Stereochemistry, substituent effects and activation parameters of most ketene reactions are consistent with a one-step cycloaddition polar effects of substituents and solvents, as well as the isotope effect, often require, however, that a fair amount of charge separation (that is, unequal bond formation) characterises the transition state. It has been kinetically proved that cycloadditions of enamines to ketenes can also proceed through a dipolar intermediate this is so for the reaction between dimethylketene and N-isobutenylpyrrolidine . In the latter case, the rate coefficient for the formation of the intermediate strongly depends on solvent polarity itacetonuriie/ cyclohexane = 560. Use of the Same criteria used for ketenes (as far as experimental data allow it) in the case of the 1,2-cycloadditions of fluorinated olefins results, instead, in the conclusion that a two-step biradical mechanism is operating. Results for 1,2-cycloaddition of sulfonyl isocyanates to olefins, cases (g) and (h) in Table 17, give indications of dipolar intermediates during the course of these reactions. 

Eq. 20). A more generally employed process involves the cycloaddition of enamines followed by cleavage of the cycloadduct (Eq. 21). ... 

Quinolines and Related Compounds.— The Erythrina alkaloids have an interesting molecular architecture, and new routes to the skeleton and to the alkaloids themselves have been described recently. One approach requires the synthesis of the dibenzazonine system, which is now readily available by nickel-promoted coupling of a bis(iodophenyl)ethylamine (Scheme 90). An attempt to utilize an intramolecular [4 + 2] cycloaddition of enamines and enamides for the construction of the Erythrina carbon skeleton failed, but nevertheless provided an interesting synthesis of bridged bicyclotetrahydroisoquinolines (Scheme 91). ... 

Direction of cycloaddition [2+2]- versus [2+4]-Cycloaddition of enamines to 3-alkylideneoxindoles... 

In the early 1960s, Brannock et al. reported a thermal [2+2] cycloaddition of enamines. Enamines react with a variety of electron-deficient alkenes such as acrylates, nitro-olefines, acetonitriles, vinylsulfones, fumarates, and malei-mides to give aminocyclobutanes [4]. The reaction generally does not require the assistance of an acid catalyst. Narasaka et al. exploited asymmetric thermal [2+2] cycloaddition of vinyl and aUenyl sulfides with electron-deficient alkenes catalyzed by Lewis acid [5]. Yamazaki et al. have reported that a stoichiometric amount of Lewis acid activates [2+2] cycloaddition of vinylselenides with highly electron-deficient olefins [6]. These reactions proceed via a stepwise annulation to give mercapto- and seleno-cyclobutanes, respectively. However, cyclobutane formation from silyl enol ethers, which are one of the most easily prepared ketone... 

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