Enamines cycloaddition, stepwise

The reactions of electrophilic alkenes (alkenes attached to electron-withdrawing groups) with enamines produce one or more of the following products simple alkylation (2), 1,2 cycloaddition (3), and 1,4 cycloaddition (4). Competition with C alkylation by N alkylation is inconsequential and therefore will be largely ignored (5,7). A stepwise ionic mechanism leading to these products necessarily involves the formation of a zwitterion intermediate (1) as the first step, which is then followed either by one of the... 

The synthetic potential of such transformations for the preparation of medium-size heterocycles172 has been discussed elsewhere2. It is generally accepted that the reaction between thiirene dioxides and enamines is a stepwise (nonconcerted) thermal [2 -I- 2] cycloaddition. However, a concerted [4 + 2] cycloaddition, in which the lone pair of the enamine nitrogen atom participates, cannot be excluded. 

Cycl[3.2.2]azines may also be obtained by the cycloaddition of a bifunctional three-carbon unit to a 3//-pyrrolizine. Vinamidinium salts have been used for this purpose <1984CB1649>, although the reactions require the use of a strong base (sodium hydride) and extended reaction times. They appear to proceed via a stepwise mechanism, since intermediates (the conjugated enamines 354 and 355) have been isolated in certain cases (Scheme 94). 

Derivatives of o-quinones react with enamines to form oxazines. In this reaction, o-quinones themselves form dioxanes [88JCS(P1)151]. The authors assume that the reaction proceeds by a stepwise [4 + 2]-cycloaddition with the formation of intermediates 242. Dioxanes are also formed by... 

Nitro-3-phenylisoxazole-5-carboxylates (290) act as heterocyclic 1-azadiene components in [4 + 2] cycloaddition reaction with some enamines affording bicyclo derivatives 295 probably via a stepwise ionic cycloaddition involving the Michael adducts 292 as primary intermediates. Further intramolecular attack by the isoxazole nitrogen on the immonium carbon followed by elimination of the amine and aromatization of dihydropyridine 293 afforded 294, which was transformed into pyridine 295 by simple reduction164 (equation 63). 

Inevitably there is some overlap between the present chapter and that on Cycloaddition reactions of enamines because many such reactions result in the formation of heterocycles. The criterion for inclusion in this chapter is isolation of, or evidence for, discrete acyclic intermediates. Often the mechanism of the reaction is not known the mere suspicion that the cycloaddition proceeds in a stepwise manner was thought sufficient justification for mentioning it here. 

There is evidence indicating that the [2+2] cycloadditions of sulfene (75) to enamines (101) to give the cycloadducts (102) are stepwise rather than concerted processes, as indicated in Scheme 68. 

Chen and coworkers have reported a new domino Michael-Michael addition reaction between a,a-dicyanoalkene [26] derived from cyclohexanone and benzyli-deneacetone, resulting in a stepwise [4 + 2]-type cycloaddition to afford almost enantiopure bicyclic adduct 15. In contrast to the completely inert function of secondary ammonium salt, a primary amine, 9-amino-9-deoxyepiquinine lo [27], in combination with trifluoroacetic acid, was found to be highly efficient in the activation of the a, 3-unsaturated ketone by tandem iminium-enamine catalysis (Scheme 10.21) [28],... 

Olefinic, acetylenic, and typical electron-deficient dienophiles participate in apparent concerted [4 + 2] cycloadditions with the thioacylketene thioacetals (Scheme 8-V), while enamines provide modest yields of [4 + 2] cycloadducts via a polar, stepwise addition-cyclization.22c... 

Another synthetically useful carbon bond-forming reaction involves reaction of diiron nonacarbonyl with halo-carbonyl compounds. Noyori found that a,a -dibromoketones (498) react with diiron nonacarbonyl [Fe2(CO)9] to give an iron stabilized alkoxy zwitterion (499). The intermediate Jt-allyl iron species reacts with alkenes in a stepwise manner (initially producing 500) to give cyclic ketones such as 501, 23 and the product is equivalent to the product of a [3-t2]-cycloaddition with an alkene (sec. 11.11). This cyclization method is now known as Noyori annulation. This reaction is related to the Nazarov cyclization previously discussed in Section 12.3.C. Enamines can react with 498, but the initially formed enamino ketone product eliminates the amino group to form cyclopentanone derivatives. Intermediates such as 499 may actually exist as cations hound to a metal rather than as the alkoxide-iron structures shown.323b-d noted that Zn/B(OEt)3 is... 

The reaction of benzyne with enamines has been reinvestigated In the original study it was proposed that the two observed products from the reaction of benzyne with 1-pyrrolidinocyclohexene 362, (i.e. 364 and, after hydrolysis, 366) arose from a common dipolar intermediate 363 as shown. An alternative explanation is that 364 arises from a stepwise [2 + 2] cycloaddition as shown, but that 365 arises independently from a concerted ene reaction. If this hypothesis is correct, then there should in fact be two possible ene products, 367 and 368. Careful product analysis showed the presence of about 1% of previously unobserved 368, together with 15-25% of 367 and 15-25% of [2 + 2] product... 

Keteniminium cations and imines can undergo a formal 2-1-2 thermal cycloaddition to yield 2-azetidinones [j8-lactams (8)] see Scheme 2. A computational study suggests the cycloaddition occurs via a stepwise mechanism, with N—C bond formation occurring first. Stereochemistry is determined in the second step, by torquoelec-tronic effects. However, the nature of the anion can affect the stereochemistry, which appears to explain the change in stereochemistry found when X = Cl, i.e. when chloro-enamines are used as precursors of keteniminium ions. 

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... 

The reaction of a,(3-unsaturated Fischer carbene complexes 42 with cyclic enamines 43 gives cyclopentannulation products 46 with complete regioselectivity by a formal [3-1-2] cycloaddition (Scheme 5.11) [20]. The formal [3-1-2] cycloaddition is assumed to occur in a stepwise manner via the 1,4-addition of cyclic enamines 43 to the alkynyl carbene complexes 42 (formation of iminium intermediate 44), the intramolecular cyclization to the formed iminium moiety from the carbene carbon (formation of intermediate 45), and the hydrolysis reaction. When (—)-8-phenylmenthyl derivatives of Fischer carbene complexes 42 are reacted with indoles 43, the corresponding indolinones 46 are obtained with >97% ee. 

For the reviews on stepwise [3+3] formal cycloadditions leading to bridged carbocycles, pyridines, or pyridones using enamines, enaminones, enol ethers, or a-ketoesters, see ... 

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