Dipolar isomunchnones

A novel type of heterocyclisation reaction involving the dipolar cycloaddition of jV,A-dialkylamino substituted thioisomunchnones and azodicarboxylates giving 1,2,4-triazine derivatives has been reported. The cycloadduct 26 is initially formed from the isomunchnone 24 and the azodicarboxylate 25, it then undergoes a selective fragmentation to give the 1,2,4-triazine 27 <99TL8675>. 

The 3 + 2-cycloaddition of ring-fused isomunchnones with various dipolarophiles produces predominantly die exo-dipolar adduct exo selectivity could be enhanced by the inclusion of substituents on any position of the fused five-membered ring.112 Dihydropyrimidine-fused isothiomunchnones and isomunchnones (80) undergo intramolecular 1,3-dipolar cycloadditions to form cycloadducts (81) with high regio-and stereo-selectivity (Scheme 28).113 The tandem 1,3-dipolar cycloadditions of 1,3-... 

The first example of a bimolecular 1,3-dipolar cycloaddition between an isomtinchnone and an electron-rich dipolarophile was reported by our group several years ago [27]. The reaction of diethyl ketene acetal and isomtinchnone 9 gave cycloadduct 29 in high yield. Again, only one regioisomer was obtained and the regiochemistry encountered is consistent with cycloaddition involving the HOMO of diethyl ketene acetal and the LUMO of isomunchnone 12 (n = 1). 

Wudl, Padwa, and co-workers found that the Rh(II)-catalyzed 1,3-dipolar cycloaddition of several isomunchnone precursors with C6o readily affords the [3 + 2] cycloadducts, such as ( )-213 (Scheme 1.17).364 On thermolysis, the adducts cleanly regenerated the mesoionic heterocycles, for which they may be used as a repository (Scheme 1.17). When a chiral, racemic isomunchnone precursor was used as starting material, the diastereoisomeric adducts with C60 were formed in unequal amounts which, in the absence of significant steric effects, points toward subtle electronic interactions between the reaction partners.364... 

An interesting example of an intramolecular 1,3-dipolar cycloaddition of an isomunchnone with an unactivated alkene to produce a complex polycyclic compound in one step has been reported <89TL4077 89CB1081>. The isomunchnones derived from the Rh2(OAc)4 catalyzed reaction of acyclic diazoimides 92-96 were found to undergo facile cycloaddition onto the tethered it-bond to provide polycyclic adducts 97-101. A notable feature of this cycloaddition is that only one diastereomer is formed. The relative... 

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. 

A solution phase chiral auxiliary for 1,3-dipolar cycloaddition of isomunchnones with vinyl ethers has been adapted for solid phase synthesis by attaching both enantiomers of the precursor a-hydroxyvaline to benzhydrylamine resin (Scheme 12.12) [13,19]. The auxiliary 22 was then functionalized by acylation and diazotiza-tion to provide diazoimide resin 23. Rhodium(II)-catalyzed nitrogen extrusion and cycloaddition in the presence of different vinyl ethers afforded, after detachment from the polymer, various bicydic molecules (24) in 49-65% yield and provided high degrees of selectivity (93-95% ee). 

Rhodium(II) acetate in benzene catalyzes the decomposition of the diazoamide containing a tethered Tc-system (227) to form the 1,3-dipole of an isomunchnone which subsequently undergoes intramolecular dipolar cycloaddition to afford the cycloadduct (228) in high yield <92TU73l>. 

Although several resonance structures can be imagined for munchnones (1,3-oxazolium 5-oxides or 1,3-oxazolium 5-olates) and isomunchnones (1,3-oxazolium 4-oxides or 1,3-oxazolium 4-olates), I will draw those forms depicted in 1 and 2, respectively, which capture the flavor of the 1,3-dipolar reactivity of these heterocycles. In addition, this chapter covers the relatively few new developments involving munchnone imines and isomunchnone rmines. The format follows that used by Gingrich and Baum. 

Only one new example of the isolation and spectral data of isomunchnones has been reported since the cases presented by Gingrich and Baum. Regitz and co-workers prepared a series of remarkably stable isomunchnones 426 (Fig. 4.135). These yellow solids can often be obtained in analytical purity and have melting points in the range of 153°-207°C. Their synthesis and 1,3-dipolar cycloaddition reactions are described in Section 4.4.3.2. 

The limited number of molecular orbital calculations, which deal with the regioselectivities of isomunchnone 1,3-dipolar cycloaddition reactions, are covered in Section 4.4.3.2. 

The only significant reaction of isomunchnones with nucleophiles is hydrolysis. However, because this is normally observed only as a side reaction during 1,3-dipolar cycloaddition reactions, the few examples of isomunchnone hydrolysis are covered in the next section. 

As presented by Gingrich and Baum, the isomunchnone ring system—a masked carbonyl dipole—is exceptionally reactive as a 1,3-dipole in 1,3-dipolar cycloaddition reactions. In the intervening years, the major research efforts in isomunchnone chemistry have entailed synthetic applications to specific targets such as alkaloids. 

Kato and co-workers had much better success in performing unusual 1,3-dipolar cycloadditions with isomunchnones than with munchnones (vide supra). Thus the room temperature union of isomunchnone 383a with benzocyclopropene 271 leads to a syn cycloadduct (Fig. 4.136). The latter is remarkably stable, is recovered unchanged on heating to 300°C, and is impervious to the action of tributylphosphine, in an abortive attempt to excise the bridging oxygen, which would have led to a methanooxonine. 

Padwa and Prein presented an extensive experimental and theoretical study of the 1,3-dipolar cycloaddition reactions of isomunchnones with olefinic dipolaro-philes. The a-diazo carbonyl isomunchnone precursors were synthesized in the usual fashion from amides and diazoethylmalonyl chloride. For example, isomunchnone 457 was readily generated from 456 using rhodium catalysis to form... 

The dipolar cycloaddition chemistry of isomunchnones is a powerful and concise route to polycyclic azaheterocycles, and Padwa has been the pioneer in this effort. Sheehan and Padwa employed the rhodium-catalyzed isomunchnone generation and subsequent trapping to a synthesis of 2-pyridones and the alkaloid ( )-ipalbidine (465) (Fig. 4.144). Thus ot-diazo imide 462 was readily constructed from 2-pyrrolidinone and allowed to react with rhodium acetate in the presence of c/i-l-(phenylsulfonyl)-l-propene to afford 2-pyridone 464 after loss of phenylsul-finic acid. Further manipulation, featuring a Stille coupling, gave ( )-ipalbidine 465. 

Independently, Harwood also demonstrated the role of chiral-templated isomunchnones in 1,3-dipolar cycloaddition reactions. Thus using the rhodium(II)-catalyzed decomposition of diazo carbonyl compounds, Harwood and co-workers explored cycloadditions of isomunchnone derivatives of (5R)- and (55)-phenyloxazin-2,3-dione. Along with the work of Padwa (vide supra), these reactions appear to represent the first examples of chiraUy templated isomunctmone 1,3-dipolar cycloadditions. For example, reaction of 471 under standard rhodium acetate conditions in the presence of NPM affords a mixture of endo-472 and exo-473 adducts (Fig. 4.146). A-Methylmaleimide and DMAD react with 471 similarly. 

Gowravaram and Gallop adapted the rhodium-catalyzed generation of isomunchnones from diazo imides to the solid-phase synthesis of furans, following a 1,3-dipolar cycloaddition reaction with alkynes. A variety of furans 492 were prepared in this fashion (Fig. 4.150). With unsymmetrical electron-deficient alkynes (e.g., methyl propiolate), the anticipated regiochemistry is observed, e.g., HOMO-dipole LUMO-dipolarophile, as seen previously. 

A competition experim Qt involving isomunchnone 502 and ethyl acrylate and ethyl vinyl ether afforded both cycloadducts, 505 and 506, although the former predominated (Fig. 4.153)- The authors concluded that similar FMO energetics are operating for both electron-rich and electron-deficient dipolarophiles in their 1,3-dipolar cycloaddition reactions with isomunchnones. 

Although Maier achieved the first intramolecular 1,3-dipolar cycloaddition reaction of an isomunchnone, it was Padwa who unleashed the synthetic utility of this reaction. Thus Padwa and co-workers also found that isolated 7t-bonds can successfully and efficiently capture the in situ-generated isomunchnones, as shown by the examples 518 519 (Fig. 4.156). The alkene can also be tethered adjacent to the nitrogen atom (not shown). The indole double bond in 520 intercepts an isomunchnone 1,3-dipole to give the single diastereomer 521, the stmcture of which is supported by X-ray crystallography. 

Padwa and co-workers effected intramolecular 1,3-dipolar cycloaddition reactions of isomunchnones tethered with other examples of Ji-systems. Several substrates with tethers of varying lengths were examined in this study. For example, reaction of diazo imide 527, readily assembled from the appropriate >-alkenyl... 

In the full account of this rhodium-catalyzed isomunchnone generation and intramolecular 1,3-dipolar cycloaddition reaction, followed by a terminal Mannich... 

Padwa ° has concisely summarized his domino cycloaddition/iV-acyliminium ion cyclization cascade process—a tactic akin to a two-move chess combination— involving the generation of an isomunchnone 1,3-dipole, intramolecular 1,3-dipolar cycloaddition reaction, A -acyliminium ion formation, and Mannich cyclization. 

Carbonyl ylides, most often in the form of isomunchnones (formed by decomposition of diketo diazo compounds in the presence of rhodium (II) acetate, and subsequent cyclization of the intermediate rhodium carbenoid species) are by far the most studied 1,3-dipolar cycloaddition partners for indole derivatives. These cycloadditions have been employed in elegant examples of complex ring construction en route to a number of polycyclic indole-containing natural products. Preliminary work by Pirrung [54, 55] (Scheme 23) on simple intermolecular cycloadditions was followed shortly by the utilization of intramolecular examples by Padwa, Boger and others. 

A formal synthesis of ( )-vallesamidine (218) has been achieved [167] based on an intramolecular dipolar cycloaddition reaction of isomunchnone. Following a study of a range of model substrates, the reaction of the cychc diazoimide 215 with Rh2(pfb)4 was carried out to obtain the desired cycloadduct 216 as a single diastereomer (Scheme 68). A series of functional group maneuvers on 216 afforded the enamide 217, which can be readily elaborated to ( )-vallesamidine (218) using a known methodology [168]. 

Gowl997 Gowravaram, M.R. and Gallop, M.A., Traceless Solid Phase Synthesis of Furans via 1,3-Dipolar Cycloaddition Reactions of Isomunchnones, Tetrahedron Lett., 38 (1997) 6973-b976. 

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