Cyclo-addition reactions 1,3-dipolar

Abstract The photoinduced reactions of metal carbene complexes, particularly Group 6 Fischer carbenes, are comprehensively presented in this chapter with a complete listing of published examples. A majority of these processes involve CO insertion to produce species that have ketene-like reactivity. Cyclo addition reactions presented include reaction with imines to form /1-lactams, with alkenes to form cyclobutanones, with aldehydes to form /1-lactones, and with azoarenes to form diazetidinones. Photoinduced benzannulation processes are included. Reactions involving nucleophilic attack to form esters, amino acids, peptides, allenes, acylated arenes, and aza-Cope rearrangement products are detailed. A number of photoinduced reactions of carbenes do not involve CO insertion. These include reactions with sulfur ylides and sulfilimines, cyclopropanation, 1,3-dipolar cycloadditions, and acyl migrations. 

Starting material which, upon oxidation with PSP, gave aldehydes. These were in turn condensed with primary hydroxylamines, promoted by polymer-bound acetate, to produce nitrones. The nitrones assembled using either method then underwent 1,3-dipolar cyclo-addition reactions with various alkenes to give the corresponding isoxazolidines (Scheme 2.46 and 2.47). 

An efficient approach to synthesize spiroheterocycles 67 (Scheme 19) with various ring sizes via rhodium(II)-catalyzed tandem cyclization-l,3-dipolar cyclo addition reaction was developed that features a rapid construction of... 

The 1,3-dipolar cycloadditions are a powerful kind of reaction for the preparation of functionalised five-membered heterocycles [42]. In the field of Fischer carbene complexes, the a,/ -unsaturated derivatives have been scarcely used in cyclo additions with 1,3-dipoles in contrast with other types of cyclo additions [43]. These complexes have low energy LUMOs, due to the electron-acceptor character of the pentacarbonyl metal fragment, and hence, they react with electron-rich dipoles with high energy HOMOs. 

Microwave-induced 1,3-dipolar cycloadditions involving azomethine ylides have been widely reported in the literature. Bazureau showed that imidates derived from a-amino esters 120, as potential azomethine ylides, undergo 1,3-dipolar cyclo-additions with imino-alcohols 121 in the absence of solvent under microwave irradiation. This reaction leads to polyfunctionalized 4-yliden-2-imidazolin-5-ones 122 (Scheme 9.36) [87]. 

Cyclo-addition (Criegee mechanism) — As a result of its dipolar structure, an ozone molecule may lead to three dipolar cyclo-additions on unsaturated bonds, with the formation of primary ozonide (I) corresponding to the reaction shown in Figure 4.8. In a protonic solvent such as water, this primary ozonide decomposes into a carbonyl compound (aldehyde or ketone) and a zwitterion (II) that quickly leads to a hydroxy-hyperoxide (III) stage that, in turn, decomposes into a carbonyl compound and hydrogen peroxide (see Figure 4.9). 

Azine approach. 4,5-Dihydro-6//- 1,2-oxazine 2-oxides undergo 1,3-dipolar cyclo-addition reacting with appropriately substituted alkenes and alkynes to form isoxazolo-[2,3-Z>][l,2]oxazines. With styrene as the dipolarophile in the reaction with the oxazine (87), the product (88) with cis methyl and phenyl groups is formed. With acrylonitrile and methyl acrylate, some trans isomer is formed, but the cis isomer is predominant. The rings are always c/s-fused (77IZV211). 

The selective synthesis of the 2-allyltetrazoles 55 by the three-component coupling reaction of the cyano compounds 54, allyl methyl carbonate 5b, and trimethylsilyl azide 42 was accomplished in the presence of Pd2(dba)3.CHCl3 and P(2-furyl)3 (Scheme 19) [55,56]. Most probably, the formation of rj -allyl)(77 -tetrazoyl)-palladium complex 56 took place through [3 + 2] dipolar cyclo addition of 7r-allylpalladium azide 44 with the nitrile 54. The complex 56 thus formed would undergo reductive elimination to form the products 55. 

A review of such additions reactions can be found in the recent very interesting publications of Huisgen and co-workers (see Centenary lecture on 1,3-dipolar cyclo-additions) (775),... 

The reaction of carbon disulfide with sodium azide may also be considered as a t,3-dipolar cyclo-addition. Libber 235, 238) has shown that the product of this reaction is 2l2"l,2,3.4-thiatriazoIine-5-thione (CLVIIIb) rather than an azidodithiocarbonate (CLVI) as was thought earlier (72). c... 

Bixchler Napiralski, Dieckmann cyclization [15], Suzuki reaction [48], Wittig reaction, ozonolysis, condensation, esterification, nucleophilic substitution [49], Henry reaction, 1.3-dipolar cyclo-addition, electrophilic addition [50], oxidation chloride -> aldehyde [50], sulfide —> sulfone [51], alcohol —> ketone, Arbuzov reaction (phosphine-phosphorox-ide) [52], reduction hydration [45], ester -> alcohol [49, 53]... 

Cyclo-addition [76] (nitriloxide - isoxazole alkene —> isoxazoline), 1,3-dipolar cyclo-addition (pyrrole), Ugi 4-components reaction [75], Aza-Wittig reaction, N-alkylation [77], Stille reaction [78], Heck reaction [74], Pd-cata yzed amina-tion with primary and secondary alkyl- or aryl- ... 

Dipolar cyclo-addition, Diels Alder reaction [233], metalorganic alkylation (Pd, Mn) [234], Mitsunobu reaction (57[. 

The final option is to convert both functional groups in one reaction step. During the synthesis of isoxazolines [24] via a 1,3-dipolar cyclo-addition with nitrile oxides [25], the hydroxy function reacts with phenylisocyanate which is used to dehydrate the nitroalkane to form a carbamate. 

In the following section we focus our attention on library analysis, and especially on libraries which are not related to oligomers. To demonstrate the possibilities and limits of this analysis, two typical compound libraries were chosen. The first group of libraries contains an aromatic scaffold, pyrroles, which were synthesized by the Hantzsch pyrrole synthesis. The second class of compounds are heterocyclic isoxazolines synthesized via a 1,3-dipolar cyclo-addition. In both cases the reaction conditions were first established on single compounds. Supporting mass spectrometric data are presented in Section 17.7 (Appendix). 

Synthesis of the isoxazoline library [59] was performed on 2-chlorotritylchloride resin. The resin was loaded with diethylphosphonoacetic acid and the polymer-bound phospho-nate reacted with aldehydes to yield substituted E-cinnamic esters or substituted E-acrylic esters. This was followed by a 1,3-dipolar cyclo-addition with nitrileoxides, synthesized via the method of Mukaiyama and Floshinoc [60] (Fig. 17.18). In this reaction, two regioi-somers are formed, each of which exist in two enantiomeric forms. Table 17.4 shows the building blocks used in the library synthesis. 

Some examples are known of 1,3-dipolar cycloaddition reactions of trifluoromethyl-substituted alkenes and alkynes with other dipoles (see Table 12), such as diazomethane.103 108 nitrile imines, )<> u,9J 1(1 nitronates,111 and munchones.112 Depending on reaction conditions, cyclo-additions may occur via a two-step process. 

Isoxazoles and isoxazolidines fused with sugar systems are found to show biological activity. In a continuation of our studies on the utilization of a variety of protocols on the sugar-derived chirons we embarked onto the 1,3-dipolar cycloaddition reactions. Accordingly, intramolecular oxime olefin cyclo-addition (lOOC) reactions on the chiron (91 X=NOH) gave an isoxazolidine-fused saccharide (92) (Scheme 22.21). 

Recently, other groups have also examined the chemistry of trifluoromethylated alkynes, such as 1,3-dipolar cyclo-addition, the reaction of Cp3-containing titanacycle with various electrophiles, Ru3(CO)/PPh3-catalyzed addition of carboxylic acids, and Ru3(CO)i2/2-DPPBN-catalyzed... 

The formation of the two new tr-bonds is unlikely to be equally advanced in the transition states of 1,3-dipolar cyclo-additions because of the highly unsymmetrical nature of the cyclic array of participating atoms. Nevertheless, in most cases these reactions appear to be concerted, and they have proven valuable in heterocyclic synthesis. A few examples are shown in Equations 6.59)-(6.64). Reaction (6.63) marks one of the earliest proofs not only of... 

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