Intermolecular cycloadditions 1,3-addition reactions

In Corey and Chaykovsky s initial investigation, a cyclic ylide 79 was observed from the reaction of ethyl cinnamate with ylide 1 in addition to 32% of cyclopropane 53. In a similar fashion, an intermolecular cycloaddition between 2-acyl-3,3-bis(methylthio)acrylnitrile 80 and 1 furnished 1-methylthiabenzene 1-oxide 81. Similar cases are found in transformations of ynone 82 to 1-arylthiabenzene 1-oxide 83 and N-cyanoimidate 84 to adduct ylide 85, which was subsequently transformed to 1-methyl-lX -4-thiazin-l-oxide 86. ... 

Introduction of an additional methyl group on the donor atom of TMM moiety gives a low 33% yield of the perhydroindans (49, X=H2) and (50, X=H2) with substantial production of the diene by-products [24]. However, it is still remarkable that the reaction works at all since the corresponding intermolecular cycloaddition failed. Incorporation of a carbonyl moiety adjacent to the donor carbon atom doubles the yield of the cycloadducts to 66% (Scheme 2.15). This so-called acyl effect works by making the donor carbon of the TMM unit "softer," thus facilitating the initial step of the conjugate addition, as well as inhibiting base-induced side reactions [22]. 

Jug and co-workers investigated the mechanism of cycloaddition reactions of indolizines to give substituted cycl[3,2,2]azines <1998JPO201>. Intermediates in this reaction are not isolated, giving evidence for a concerted [8+2] cycloaddition, which was consistent with results of previous theoretical calculations <1984CHEC(4)443>. Calculations were performed for a number of substituted ethenes <1998JPO201>. For methyl acrylate, acrylonitrile, and ethene, the concerted [8+2] mechanism seems favored. However, from both ab initio and semi-empirical calculations of transition states they concluded that reaction with nitroethene proceeded via a two-step intermolecular electrophilic addition/cyclization route, and dimethylaminoethene via an unprecedented two-step nucleophilic addition/cyclization mechanism (Equation 1). 

Intermolecular Cycloaddition at the C=C Double Bond Addition at the C=C double bond is the main type of 1,3-cycloaddition reactions of nitrile oxides. The topic was treated in detail in Reference 157. Several reviews appeared, which are devoted to problems of regio- and stereoselectivity of cycloaddition reactions of nitrile oxides with alkenes. Two of them deal with both inter- and intramolecular reactions (158, 159). Important information on regio-and stereochemistry of intermolecular 1,3-dipolar cycloaddition of nitrile oxides to alkenes was summarized in Reference 160. 

Based on the number of n electrons in polyenes, we can predict which type of intermolecular cycloadditions will be symmetry allowed. The close in energy the frontier orbitals are, the stronger will be the interaction between them and therefore the more easily the reaction will occur. The orbital coefficients at the interacting centres can also influence the rate and the direction of addition. 

Subsequently to the intermolecular Diels-Alder reaction, a new diene is produced which can then be utilized in a second cycloaddition process. The feasibility of the second Diels-Alder process was demonstrated by the thermal cycloaddition of 44 with a variety of dienophiles to afford the cycloadducts 47 in high yields, albeit with moderate diastereoselectivity (Scheme 8.8). Additional investigations will be necessary to delineate further the scope and limitations of this rapid increase in molecular complexity. 

Intermolecular cycloadditions involving pyridinones are well known (80H(14)1793). 4-Cyano-l-methylpyridin-2-one undergoes Diels-Alder reaction with a suitable diene (equation 195) (79H(12)l). The pyridinone (307) forms 1 1 and 1 3 adducts on reaction with DMAD under pressure (Scheme 225) (82H(19)499). 2-Azabarrelenone (308) may be prepared by a sequence (Scheme 225), the first step of which is the addition of maleic anhydride to l-benzylpyridin-2-one (80AG(E)463). 

Muthusamy et al. (82) prepared a number of oxacyclic ether compounds from the tandem ylide formation-dipolar cycloaddition methodology. Their approach provides a synthetic tactic to compounds such as ambrosic acid, smitopsin, and linearol. Starting with either cyclopentane or cyclohexane templates, they prepared ylide sizes of five or six, which are trapped in an intermolecular cycloaddition reaction by the addition of DMAD. The products are isolated in good overall yield. In a second system, 2,5-disubstituted cyclohexenyl derivatives are utilized to generate the pendent ylide, then, A-phenylmaleimide is added in an intermolecular reaction, accessing highly substituted oxatricyclic derivatives such as 182 (Scheme 4.43). 

The intermolecular [4+2] cycloaddition of cyclopentadiene and iV-acetyl-2-azetine 23 occurs when they are heated in toluene in a sealed tube to give a good yield (83%) of the Diels-Alder adduct 317 (Equation 35). Similar high-yielding addition reactions occur with substituted cyclopentadienes and 1,3-diphenylisobenzofuran to give endo-adducts <1999TL443>. 

In contrast to the hydrazones mentioned above, a,/ -unsaturated N -sulfonyl imines react as electron-deficient diene component in aza Diels-Alder reactions. In addition to several investigations dealing with their intermolecular cycloadditions under thermal and under high pressure conditions [231-234], Boger s... 

The palladium-catalyzed [3 + 2] cycloaddition of vinylic oxirane 20a [42] and aziridine 20b [39] with the activated olefin 4a for the formation of five membered cyclic ether 21a and pyrrolidine derivative 21b has also been reported in our laboratories. The mechanistic issue is very much similar to that discussed in Scheme 9. Pd(0) catalyst added oxidatively to 20 to produce the 7r-allylpalladium complex 22. The Michael addition of a hetero nucleophile in 22 to the activated olefin 4a gives 23 which undergoes intramolecular nucleophilic attack on the inner 7r-allylic carbon atom to give the cy-clized products 21 and Pd(0) species is generated (Scheme 10). Similarly, the palladium-catalyzed [3 + 2] cycloaddition of vinylic oxirane 20a with the N-losylimincs 24 is also known (Scheme 11) [43]. Intermolecular cycloaddition of vinyl epoxides and aziridines with the heterocumulenes such as isocyanates, carbodiimides and isothiocyanates is also known [44,45]. Alper et al. reported the regio- and enatioselective formation of the thiaolidine, oxathiolane, and dithiolane derivatives by the palladium-catalyzed cyclization reaction of 2-vinylthiirane with heterocumulenes [46]. 

This coupling reaction can be formally viewed as a metal-assisted intramolecular retrocarbene addition of bicyclobutanes, followed by intermolecular cycloaddition of the resulting allylcarbene-nickel complexes to alkenes. 

As with intermolecular D-A reactions, the diastereoselectivity of intramolecular cycloadditions can be improved by the addition of Lewis acids. 

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