1,3-dipoles carbonyl ylides

Interesting structures can be formed by combinations of ring and side-chain substituents in special relative orientations. As indicated above, structures (28) contain the elements of azomethine or carbonyl ylides, which are 1,3-dipoles. Charge-separated species formed by attachment of an anionic group to an azonia-nitrogen also are 1,3-dipoles pyridine 1-oxide (32) is perhaps the simplest example of these the ylide (33) is another. More complex combinations lead to 1,4-dipoles , for instance the pyrimidine derivative (34), and the cross-conjugated ylide (35). Compounds of this type have been reviewed by Ramsden (80AHCl26)l). 

Azomethine ylides are also frequently obtained by ring opening of aziridines, and the analogous carbonyl ylides from oxiranes. These aspects are dealt with in Section 3.03.5.1. A variety of five-membered heterocycles can also function as masked 1,3-dipoles and this aspect is considered in Section 3.03.5.2. 

For the reactions of other 1,3-dipoles, the catalyst-induced control of the enantio-selectivity is achieved by other principles. Both for the metal-catalyzed reactions of azomethine ylides, carbonyl ylides and nitrile oxides the catalyst is crucial for the in situ formation of the 1,3-dipole from a precursor. After formation the 1,3-di-pole is coordinated to the catalyst because of a favored chelation and/or stabiliza-... 

For azomethine ylides and carbonyl ylides, the diastereoselectivity is more complex as the presence of an additional chiral center in the product allows for the formation of four diastereomers. Since the few reactions that are described in this chapter of these dipoles give rise to only one diastereomer, this topic will not be mentioned further here [10]. 

The application of 1,3-dipolar cycloaddition processes to the synthesis of substituted tetrahydrofurans has been investigated, starting from epoxides and alkenes under microwave irradiation. The epoxide 85 was rapidly converted into carbonyl ylide 86 that behaved as a 1,3-dipole toward various alkenes, leading to quantitative yields of tetrahydrofuran derivatives 87 (Scheme 30). The reactions were performed in toluene within 40 min instead of 40 h under classical conditions, without significantly altering the selectivi-ties [64]. 

In an alternative approach to annulation across the indole 2,3-tt system, Padwa and coworkers have reported approaches to the pentacyclic and hexacyclic frameworks of the aspidosperma and kopsifoline alkaloids respectively that involve as the key step a Rh(II)-promoted cyclization-cycloaddition cascade <06OL3275, 06OL5141>. As illustrated in their approach to ( )-aspidophytine 150, Rh2(OAc)4-catalyzed cyclization of a diazo ketoester 148 affords a carbonyl ylide dipole that undergoes [3+2]-cycloaddition across the indole 2,3-tt bond to generate 149 <06OL3275>. 

Tetracyano ethylene oxide, however, which represents a potential 1,3-dipole of the carbonyl ylide type, reacts with diphenyl cyclopropenone to give a cycloadduct of probable structure 415/417263, which may arise from insertion into the cyclopropenone C1(2)/C3 bond. 

Mejla-Oneto and Padwa have explored intramolecular [3+2] cycloaddition reactions of push-pull dipoles across heteroaromatic jr-systems induced by microwave irradiation [465]. The push-pull dipoles were generated from the rhodium(II)-cata-lyzed reaction of a diazo imide precursor containing a tethered heteroaromatic ring. In the example shown in Scheme 6.276, microwave heating of a solution of the diazo imide precursor in dry benzene in the presence of a catalytic amount of rhodium I) pivalate and 4 A molecular sieves for 2 h at 70 °C produced a transient cyclic carbonyl ylide dipole, which spontaneously underwent cydoaddition across the tethered benzofuran Jt-system to form a pentacyclic structure related to alkaloids of the vindoline type. 

A number of benzo- or dibenzo-fused seven membered phosphorus heterocyclic systems have also been studied. These include the benzo-fused oxa-bridged phosphaalkene 76 prepared by thermolysis of 2,3-diphenylindenone 23-epoxide (as a source of the carbonyl ylide 1,3-dipole intermediate) in the presence of /-butylphosphaalkyne. This bridged phosphaalkene is unusually stable even without inert gas blanketing . Reaction of 76 with sulfur or grey selenium stereoselectively affords the thia- or selenaphosphiranes 77 (X = S, Se respectively). <00T6259>... 

C6 and C9 are at opposite ends of a four-carbon unit, but since one of these atoms (C7) is saturated and quaternary, a Diels-Alder reaction is unlikely (can t make diene). The combination of a diazo compound with Rh(II) generates a carbenoid at C9. The nucleophile 06 can add to the empty orbital at C9, generating the 06-C9 bond and a carbonyl ylide at C6-06-C9. Carbonyl ylides are 1,3-dipoles (negative charge on C9, formal positive charge on 06, electron deficiency at C6), so a 1,3-dipolar cycloaddition can now occur to join C2 to C6 and Cl to C9, giving the product. Note how a relatively simple tricyclic starting material is transformed into a complex hexacyclic product in just one step ... 

Despite this promising beginning, and its growing use for the generation of electrophilic carbenes [5, 6], it was not until many years later that rhodium(II) was used generally for the formation of 1,3-dipoles. Padwa and Stull reported the use of rhodium(II) acetate [Rh2(OAc)4] in the successful formation of a six-membered ring carbonyl ylide (Scheme 19.2) [21]. This work was quickly followed by the use of rhodium(II) for the generation of... 

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]. 

Dipoles can also be generated from rearrangements that take place after the formation of an initial rhodium carbenoid product ]40, 70, 71]. One example of this type of transmutation, also known as a dipole cascade process, involves the formation of an azomethine ylide via the initial formation of a carbonyl ylide [72]. This process was... 

Carbonyl ylides (1) are highly reactive dipoles that have been proposed as key intermediates in a variety of reactions since the 1960s (Fig. 4.1). Since these early reports, there has been a virtual explosion in the study of these unstable intermediates both at the theoretical level and more recently in their application to organic synthesis. This chapter will focus on the structure, generation, and chemical reactions of carbonyl ylides and will review the literature since 1984. 

After completing his initial intramolecular cycloaddition, Hodgson utilized conditions that had been optimized for the intermolecular cycloaddition of DMAD with simple cyclic carbonyl ylides used by Hashimoto and co-workers (139). Hodgson et al. (140) found that the reaction indeed gave excellent overall chemical yield, but the enantioselectivity dropped to 1%, giving essentially a racemic mixture. It appeared that ee ratios were sensitive to the electronic nature of the dipole. Hodgson chose to screen several binaphthol derived rhodium catalysts of the type developed by McKervey and Pirrung, due in part to the reports of... 

Suga et al. (197) reported the first stereocontrolled 1,3-dipolar cycloaddition reactions of carbonyl ylides with electron-deficient alkenes using a Lewis acid catalyst. Carbonyl ylides are highly reactive 1,3-dipoles and cannot be isolated. They are mainly generated through transition metal carbenoid intermediates derived in situ from diazo precursors by treatment with a transition metal catalyst. When methyl o-(diazoacetyl)benzoate is treated with A-methylmaleimide at reflux... 

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). 

The last comprehensive survey of this area dates back to 1984, when the two-volume set edited by Padwa, 1,3-Dipolar Cycloaddition Chemistry, appeared. Since then, substantial gains in the synthetic aspects of this chemistry have dominated the area, including both methodology development and a body of creative and conceptually new applications of these [3+ 2]-cycloadditions in organic synthesis. The focus of this volume centers on the utility of this cycloaddition reaction in synthesis, and deals primarily with information that has appeared in the literature since 1984. Consequently, only a selected number of dipoles are reviewed, with a major emphasis on synthetic applications. Both carbonyl ylides and nitronates, important members of the 1,3-dipole family that were not reviewed previously, are now included. Discussion of the theoretical, mechanistic, and kinetic aspects of the dipolar-cycloaddition reaction have been kept to a minimum, but references to important new work in these areas are given throughout the 12 chapters. 

Mechanistic and theoretical investigation has been carried out on the carbonyl ylide formation and the subsequent 1,3-dipole addition, Ghemo- and stereoselectivity have been found to be affected by the ligands of the Rh(ii) catalysts.These results imply that in the cycloaddition process, the Rh(ii) catalyst may be associated with the 1,3-dipole. Theoretical calculation indicates that the Rh(ii) catalyst-associated ylide has the lowest energy in the catalytic cycle.The suggestion that metal complex-associated ylide may be involved in the cycloaddition has great implication for the asymmetric catalysis in this type of reaction. 

Asymmetric catalysis of 1,3-dipole addition of carbonyl ylides... 

Imine ylides 7 and carbonyl ylides 8 are not stable but may be generated in situ by pyrolysis of suitably substituted aziridines and oxiranes. The energy of the HOMO, and therefore the nucleophilicity of the parent 18-electron dipoles, decreases from very high to very low across the series 7-18. In the same series, the electrophilicity increases from moderate to high, being consistently higher when the central atom is oxygen. 

Treatment of bis(chloromethylether) 54 with a mixed-manganese/lead system generated a reactive intermediate equivalent to the carbonyl ylide depicted in 55. Intermediate 55 behaved as a 1,3-dipole undergoing cycloaddition with a variety of dipolarophiles including /V-tosylaldimines such as 56, resulting in the formation of oxazolidine 57 in 73% yield. 

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