Isomiinchnone

Padwa and co-workers employed a rhodium-catalyzed [3+2] cycloaddition reaction to generate a number of 3-hydroxy-2-pyridones, including the tricyclic 146, obtained using fV-phenylmaleimide 145 as the dipolarophile. The rhodium-catalyzed cyclization of 143 generates an isomiinchnone intermediate 144, which undergoes the cycloaddition (Scheme 11) <1997JOC438>. 

When l-[diazo(methoxycarbonyl)acetyl]-2-oxopyrrolidine derivative 231 was treated with Rh2(pfm)4 (pfm = per-fluorobutyro amidate) in the presence of W-phenylmaleimide, none of the desired dipolar cycloadduct was formed but instead the acidic proton at C-3 in the isomiinchnone intermediate 232 was transferred, and the fused oxazoli-dinone 3-oxo-2,3,5,6-tetrahydropyrrolo[2,l- ]oxazole-2,7-dicarboxylic acid dimethyl ester 233 was isolated in 77% yield (Scheme 33) <1997JOC6842>. 

Many different types of 1,3-dipoles have been described [Ij however, those most commonly formed using transition metal catalysis are the carbonyl ylides and associated mesoionic species such as isomiinchnones. Additional examples include the thiocar-bonyl, azomethine, oxonium, ammonium, and nitrile ylides, which have also been generated using rhodium(II) catalysis [8]. The mechanism of dipole formation most often involves the interaction of an electrophilic metal carbenoid with a heteroatom lone pair. In some cases, however, dipoles can be generated via the rearrangement of a reactive species, such as another dipole [40], or the thermolysis of a three-membered het-erocycHc ring [41]. 

One of the earliest uses for rhodium(II)-catalyzed dipoles was demonstrated in Davies furan synthesis [22]. Isomiinchnones were also shown to produce substituted furans [115]. Additional furan syntheses have been described using silylacetates [116], unsaturated esters [117], and fluoroalkyl diazo acetates [118]. The synthesis of furofuranones and indenofuranones 35 from a-diazo ketones having pendant alkynes has also been reported (Eq. 6) [119]. Other fused heterocyclic systems include furo[3,4-c]furans [120, 121] furo[2,3-b]furans [122] as well as thiobenzofurans [123], and benzoxazoles[124] have also been synthesized with this methodology. 

Additional heterocyclic ring systems, such as benzofurans [125], dihydropyrroles and dihydroazepines [41], piperidines and dihydropyrimidines 36 [126], and fused oxazole derivatives [127], have been described (Eq. 7). The formation of epoxides and aziri-dines, formally emanating from ylides, was recently reported by Doyle et al. [77]. Rho-dium(II)-catalyzed isomiinchnone cycioaddition followed by Lewis acid-mediated ring opening has been used as an entry into the protoberberine azapolycyclic ring structure [128]. 

A number of bridged heterocyclic compounds have been prepared using the intramolecular cycloaddition of rhodium( 11)-generated isomiinchnones [51-53, 84, 129], as exemplified by the complex structure 37 [49, 53] and the tricyclic derivatives 38 and 39 (Scheme... 

Maier and Evertz (90) synthesized an isomiinchnone intermediate to generate simple annulated piperidine substrates 193. The reaction was extended to several ring sizes and substitution patterns about the olefinic tether. The yields were routinely good and produced compounds of known stereochemical integrity (Scheme 4.48). 

Kappe et al. (103,104) approached dihydropyrimidines, a potent group of calcium channel modulators, through the use of an isomiinchnone-type cyclization. Kappe prepared the cyclization precursor 195 in the course of a three component Biginelli condensation process (Scheme 4.49). 

Although the mesoionic l,3-oxazolium-4-olates, isomiinchnones , occupied only a few pages in the reviews by Potts (1) and Gingrich and Baum (10), in the intervening years this ring system has exploded in popularity, largely due to the efforts of Padwa and co-workers. Padwa has summarized his isomtinchnone work in several reviews (22-27). While isomiinchnones are rarely isolable, these carbonyl... 

Mathias and Moore (30-33) described a new synthesis of isomiinchnones 55 via the thermal cyclization of A-(chloroacetyl)lactams (54) (Scheme 10.7). These isomiinchnones can be captured by NPM to give fused 2-pyridones in moderate yields. Cycloadducts from the reaction with DMAD are produced in much lower yields (<17%), and other olefinic dipolarophiles (fumarate, maleate, acrylate, and dicyanocyclobutene) are unreactive. Reaction of 7/-(chloroacetyl)benzamide (57) in the presence of NPM gave 58 in low yield. 

Doyle et al. (34) were the first group to generate isomiinchnones from diazo imides using Rh(II) catalysis. For example, isomiinchnone 60 was produced from diazo imide 59, but attempts to trap this species with ethyl acrylate were unsuccessful. The only material identified was the isomiinchnone hydrolysis product. This use of Rh(II) to generate a rhodium-carbenoid species from an a-diazo carbonyl compound is reminiscent of the first successful synthesis of... 

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... 

Maier and Schoffling (37) extended this intramolecular isomiinchnone cycloaddition to a synthesis of fused furans by employing an alkyne dipolarophile (Scheme 10.9). Thus, the diazo acetylenes (66) are smoothly converted to furans (69) via isomtinchnones (67) with catalytic rhodium acetate. 

Trapping isomiinchnone 77 with DMAD led to furan isocyanate 78, after a retro-Diels-Alder reaction (Scheme 10.11) (38). 

Doyle et al. (39) expanded the rhodium-catalyzed generation of isomiinchnones from diazoacetacetamides and subsequent trapping with dipolarophiles (38). As shown in Scheme 10.12, in the case of diazoacetoacetyl urea (79) the derived isomtinchnone 80 reacts with methyl propiolate to give a 2 1 mixture of cycloadducts 81. The resulting regiochemistry is successfully rationalized using frontier molecular orbital (FMO) theory as being isomiinchnone-HOMO controlled. This result represents one of the few reactions in which the cycloadducts from isomiinchnones and alkynes are stable. 

The newest method for generating isomiinchnones was reported by Padwa and co-workers (40,41). Thus, Kuethe and Padwa developed an exciting new application of the venerable Pummerer reaction of imidosulfoxides to generate and trap isomiinchnones with alkenes. For example, the readily prepared imidosulfoxide 82... 

This strategy is a powerful route to bicyclic pyridones and their transformation products. Thus, these workers (40,41) applied this methodology to formal syntheses of the lupinine alkaloids ( )-lupinine and ( )-anagyrine (89) (Scheme 10.14). Imidosulfoxide (82) is converted to the corresponding isomiinchnone that is trapped with methyl acrylate to give 85. Oxidation, ring opening, and triflate formation... 

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. 

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. 

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. 

Kato et al. (151,152) explored the chemistry of 2-ferf-butylMvenes with isomiinchnones, as well as with several other mesoionic compounds, in a novel approach to pseudo-hetero-azulenes. Thus, isomtinchnone 51a, generated as before in situ from A-benzoylphenylglyoxyanilide 253 with triethylphosphite, reacts with 2-ferf-butyl-6-(dimethylamino)fulvene to give the [47i+6ti] adduct diphenylcyclo-penta[c]pyran in low yield. Likewise, reaction of 51a with dimethylfulvene gave a mixture of two adducts, one of which arises from a [47i+2ti] cycloaddition. 

Regitz and co-workers (143) found that 2,3,4-tri-tert-butylazete reacts with isomiinchnones to give relatively labile cycloadducts. This group (153) has employed the cycloaddition of isomiinchnones 256 with phosphaalkynes 257 to prepare 1,3-oxaphospholes 258 (Scheme 10.35). This sequence is clearly the method of choice for the synthesis of the relatively little investigated 1,3-oxaphosp-holes. The presumed bicyclic intermediates could not be detected by NMR. 

Whereas 260 does not react with electron-rich dipolarophiles, the more delocalized isomiinchnone 261 does react with both electron-rich and -deficient dipolarophiles (154). A detailed FMO analysis is consistent with these observations and with the regiochemistry exhibited by diethyl ketene acetal and methyl vinyl ketone as shown in Scheme 10.36. The reaction of 261 with the ketene acetal to give 262 is LUMO-dipole HOMO-dipolarophile controlled (so-called lype III process). In contrast, the reaction of 261 with methyl vinyl ketone to give 263 is HOMO-dipole LUMO-dipolarophile controlled (so-called lype I process). In competition experiments using a mixture of A-phenylmaleimide and ketene acetal only a cycloadduct from the former was isolated. This result is consistent with a smaller energy gap for... 

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... 

Padwa and Prein (162) generated several chiral isomiinchnones, using the rhodium catalyzed deamination of chiral ot-diazo unides, and trapped them with various dipolarophiles. 

Kappe et al. (166) employed an isomilnchnone generation-trapping sequence to access conformationally restricted dihydropyrimidine derivatives as novel calcium channel modulators. For example, the conformationally restricted analogues 269 were prepared via intramolecular cycloadditions from the isomiinchnones generated from a-diazo imides 268. The structures of these cycloadducts were established by X-ray crystallography. 

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). 

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