Isomiinchnone 1,3-dipolar cycloaddition

The reader was given a taste of the power of isomiinchnone dipolar cycloaddition chemistry in Section 10.2.1. As discussed by Potts (1) and Gingrich and Baum (10), the isomiinchnone ring system—a masked carbonyl dipole—is exceptionally reactive as a 1,3-dipole in 1,3-dipolar cycloaddition reactions. In the intervening years since these two excellent reviews the major research efforts in isomiinchnone chemistry have entailed synthetic applications to specific targets such as alkaloids and other natural and unnatural products. 

The first successful generation and trapping of isomiinchnones using this strategy was described independently by Maier et al. (36,37) and Padwa et al. (38,39). Maier and Evertz (36) were the first workers to report the intramolecular dipolar cycloaddition of isomiinchnones to alkenes, the reaction that Padwa would later exploit so spectacularly. Thus, diazo imide 62 was readily prepared from... 

In the full account of this work, Padwa et al. (41) demonstrated that the 1,3-dipolar cycloaddition is an endo cycloaddition and the regiochemistry is consistent with that of a HOMO-dipole controlled process as judged from the products 91 and 92 that arise from the reaction between isomiinchnone 90 and methyl propiolate and phenyl vinyl sulfone, respectively (Scheme 10.15). Iso-miinchnone 90 is also trapped with DMAD to give the expected furan in 41% yield. 

Kato et al. (113) have had much better success in performing 1,3-dipolar cycloadditions with isomiinchnones than with miinchnones (see above). Thus, the room temperature union of isomiinchnone 51a with benzocyclopropene (249) leads to a syn-cycloadduct 250. The latter is remarkably stable and is recovered unchanged upon heating to 300°C. It is also impervious to the action of tributylpho-sphine, in Kato s abortive attempt to excise the bridging oxygen, which would have led to a methanooxonine. 

The dipolar cycloaddition chemistry of isomiinchnones is a powerful and concise route to polycyclic azaheterocycles, and Padwa has been the pioneer in this effort. Sheehan and Padwa (159) employed the rhodium-catalyzed isomiinchnone generation and subsequent trapping to a synthesis of 2-pyridones and the alkaloid... 

Gowravaram and Gallop (169) adapted the rhodium-catalyzed generation of isomiinchnones from diazo imides to the solid-phase synthesis of furans, following a 1,3-dipolar cycloaddition reaction with alkynes. A variety of furans were prepared in this fashion. With unsymmetrical electron-deficient alkynes (e.g., methyl... 

Padwa et al. (187,188) concisely summarized his domino cycloaddition/ A -acyliminium ion cyclization cascade process, which involves sequentially the generation of an isomiinchnone 1,3-dipole, intramolecular 1,3-dipolar cycloaddition reaction, 77-acyliminium ion formation, and, hnally, Mannich cyclization. Kappe and co-workers (189) utilized Padwa s cyclization-cycloaddition cascade methodology to construct several rigid compounds that mimic the putative receptor-bound conformation of dihydropyridine-type calcium channel modulators. 

Padwa and Prein (105,106) applied chiral, but racemic, isomiinchnone dipoles in diastereoselective 1,3-dipolar cycloadditions. The carbonyl ylide related isomiinch-none derivative rac-70 was obtained from the rhodium-catalyzed cyclization of diazo-derivative rac-69 (Scheme 12.24) (105). The reactions of the in situ formed dipole with a series of alkenes was described and in particular the reaction with maleic acid derivatives 71a-c gave rise to reaction with high selectivities. The tetracyclic products 72a-c were all obtained in good yield with high endo/ exo and diastereofacial selectivities. In another paper by the same authors, the reactions of racemic isomilnchnones having an exo-cyclic chirality was described (106). 

Ibata was the first to show that the masked carbonyl ylide embedded within the isomiinchnone framework would readily undergo 1,3-dipolar cycloaddition with various dipolarophiles [34], The isolable isomiinchnone 4 was observed to react with dimethyl fumarate to produce cycloadduct 7 which possesses the 7-oxa-2-azabicyclo[2.2.1]heptane skeleton. When the reaction of 1 was carried out using catalytic amounts of Cu(acac)2 in the presence of various dipolarophiles, smooth dipolar cycloaddition was observed to occur giving mixtures of endo and exo isomers. In most cases, the exo isomers were favored. All of Ibata s isomiinchnone cycloadditions contain aromatic substituent groups, presumably selected to facilitate dipole formation. The synthetic utility of the cycloaddition reaction is diminished, however, because of the low reactivity of the aromatic substituents toward further manipulation. 

The cycloaddition of isomiinchnones with acetylenic dipolarophiles followed by the extrusion of an alkyl or aryl isocyanate (RNCO) has proven to be an effective method for the synthesis of substituted furans. The Ibata group investigated the bimolecular 1,3-dipolar-cycloaddition of aryl-substituted isomiinchnones with a number of acetylenic dipolarophiles [50]. Aryl diazoimides of type 1 were heated in the presence of a catalytic amount of Cu(acac)2 and the appropriate acetylenic dipolarophile. Formation of the substituted furan was found to be temperature-dependent higher temperatures (ca. 120°C) were needed for complete conversion to the furan. It was reasoned that the extrusion of methyl isocyanate was not as facile as the loss of carbon dioxide from sydnones and miinchnones [50]. 

Prompted by our earlier work dealing with the internal dipolar cycloaddition reaction of mesoionic oxazolium ylides of type 74, we subsequently studied the rhodium(II) catalyzed reactions of the related a-diazo ketoamide system 154 <97JOC2001 04OL3241 05JOC2206>. Attack of the amido oxygen at the rhodium carbenoid produces a push-pull carbonyl ylide dipole (i.e., 155) that is isomeric with the isomiinchnone class of mesoionic betaines. 

A Pummerer-initiated cascade reaction has also been used as a method for generating isomiinchnones for further use in cycloaddition chemistry. For example, treatment of sulfoxide 23 with acetic anhydride first resulted in the formation of a reactive thionium ion that reacted with the distal amide carbonyl group to produce isomunchnone 24 (Scheme 6) (99JOC2038). Exposure of 24 to a dipolarophile, such as iV-phenylmaleimide, resulted in 1,3-dipolar cycloaddition to give 25 as a single diastereomer in 85% yield. 

The decomposition of suitably crafted diazoimides 181, in the presence of a transition metal catalyst, affords the metallo-carbenoids 182 that undergo intramolecular cycUzation onto the neighboring amide carbonyl oxygen to form the five-membered ring carbonyl yUdes (isomiinchnones) 183 (Scheme 58). Early examples of inter- and intramolecular 1,3-dipolar cycloaddition of the mesoionic ylides 183 have mainly emanated from the research groups of Ibata [149], Maier [150] and Padwa [151]. These reactive species (isomimchnones) can be trapped by various electron-rich and electron-deficient dipolarophiles [152] to furnish the cycloadducts in high yield. Much work has been reported in this area and for clarity of presentation is described here under various subheadings. 

Kappe and co-workers have extended their intermolecular isomiinch-none cycloaddition reaction (see Scheme 26) to an intramolecular version to obtain the conformationally rigid polyheterocycles 206, which mimic the putative receptor-bound conformation of dihydropyrimidine-type calcium channel modulators [159]. The key step in the synthesis involves the regio- and diastereoselective intramolecular 1,3-dipolar cycloaddition reaction of a dihydropyrimidine-fused isomiinchnone dipole. The diazoimides... 

Asymmetric versions of the intermolecular cycloaddition of isomiinch-none dipoles, further enhancing the synthetic appeal of this cyclo addition protocol, have been developed. Austin and co-workers have reported [161] the optimization of a chiral auxiliary for the diastereofacially selective 1,3-dipolar cycloaddition of isomiinchnones in the presence of a variety of vinyl... 

Mesoionic oxazolium ylides (isomiinchnones) correspond to the cyclic equivalent of a carbonyl ylide embedded in a heteroaromatic ring, and these reactive intermediates readily undergo 1,3-dipolar cycloaddition with suitable chpolarophiles. Isomiinchnones are readily obtained through the transition metal—catalyzed cyclization of a suitable a-diazoimide precursor... 

The intramolecular 1,3-dipolar cycloaddition of isomiinchnones with alkyl vinyl ethers has been shown to proceed with complete diastereoselectivity. The cyclodehydration of cyclic A-acyl-a-amino acids yields bicyclic mesoionic compounds which react with A-(phenylmethylene)benzenesulfonamides to produce a new class of spiro-cyclic -lactams possessing biological activity. 

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