Cycloaddition three-component 1,3-dipolar

Gong and coworkers have described the first enantioselective synthesis of spiropyrrolidine oxindoles 240 using a three-component dipolar cycloaddition (Scheme 6.34) [67]. 

A microwave-assisted three-component reaction has been used to prepare a series of 1,4-disubstituted-1,2,3-triazoles with complete control of regiose-lectivity by click chemistry , a fast and efficient approach to novel functionalized compounds using near perfect reactions [76]. In this user-friendly procedure for the copper(l) catalyzed 1,3-dipolar cycloaddition of azides and alkynes, irradiation of an alkyl halide, sodium azide, an alkyne and the Cu(l) catalyst, produced by the comproportionation of Cu(0) and Cu(ll), at 125 °C for 10-15 min, or at 75 °C for certain substrates, generated the organic azide in situ and gave the 1,4-disubstituted regioisomer 43 in 81-93% yield, with no contamination by the 1,5-regioisomer (Scheme 18). 

A spiro[pyrrolidine-2,3 -oxindole] library <1998TL2235> has been synthesized via a three-component 1,3-dipolar cycloaddition in the solution phase. Isatins 432 were treated with L-proline or L-thiaproline and chalcone 433 in a MeOH-H20, CH3CN-H20, or dioxane-H20 solution. Spiropyrrolidines 49 (Scheme 96) were obtained as the sole products in good yield and high purity (Table 15). 

The three-component reaction between isatin 432a, a-aminoacids 433 (proline and thioproline) and dipolarophiles in methanol/water medium was carried out by heating at 90 °C to afford the pyrrolidine-2-spiro-3 -(2-oxindoles) 51. The first step of the reaction is the formation of oxazlidinones 448. Loss of carbon dioxide from oxazolidinone proceeds via a stereospecific 1,3-cycloreversion to produce the formation of oxazolidinones almost exclusively with /razw-stereoselectivity. This /f-azomethine ylide undergo 1,3-dipolar cycloaddition with dipolarophiles to yield the pyrrohdinc-2-r/ V -3-(2-oxindolcs) 51. (Scheme 101) <2004EJ0413>. 

A 1,3-dipolar cycloaddition of the nonstabilized azomethine ylide 6 is the key step in a three-component reaction. The azomethine ylides were generated from (2-azaallyl)stannanes or (2-azaallyl)silanes 5 through an intramolecular iV-alkylation/demetallation cascade. The ylides underwent cycloaddition reactions with dipolarophiles yielding indolizidine derivatives 7-9 <2004JOC1919> (Scheme 1). 

In 2008, Gong and coworkers introduced a new chiral bisphosphoric acid 19 (Fig. 4) that consists of two BINOL phosphates linked by an oxygen atom for a three-component 1,3-dipolar cycloaddition (Scheme 42) [66]. Aldehydes 40 reacted with a-amino esters 105 and maleates 106 in the presence of Brpnsted acid 19 (10 mol%) to afford pyrrolidines 107 as endo-diastereomers in high yields (67-97%) and enantioselectivities (76-99% ee). This protocol tolerated aromatic, a,P-unsaturated, and aliphatic aldehydes. Aminomalonates as well as phenylglycine esters could be employed as dipolarophiles. 

Bora and co-workers44 have developed a microwave-assisted three-component synthesis of indolizines. The reaction involves a 1,3-dipolar cycloaddition reaction between the in situ generated dipole (from the bromoacetophenone and pyridine) and acetylene, Scheme 5.26. The developed method provides fast access to cycloadducts, which otherwise are accessible only through multi-step synthesis. 

The synthesis of proline-fused heterocyclic systems by 1,3-dipolar cycloaddition has been well-established in solution-phase synthesis (Scheme 14) [42]. It is usually performed as a one-pot, three-component reaction of a dipo-larophile with an in situ prepared azomethine ylide. Perfluoroalkanesulfonyl protected hydroxybenzaldehydes [43] or fluorous alcohol protected amino esters [44] have been developed as two different fluorous components for the synthesis of proline derivatives 11 and 12. 

Fluorous aminoesters have also been used in DOS of three unique triaza tricyclic and tetracyclic ring systems (Scheme 22) [44], Bicyclic pyrrolidines 12 generated from one-pot, three-component 1,3-dipolar cycloaddition of azomethine ylides were further converted to hydantoin-, piperazinedione-, and benzodiazepine-fused compounds 31-33, respectively. Each of these three heterocyclic scaffolds has four stereocenters on the central pyrrolidine ring and up to four points of diversity (R1 to R4). The structure of compound... 

In the context of a coupling-1,3-dipolar cycloaddition sequence, Muller and coworkers [89] developed a consecutive one-pot, three-component process to indolizines. Starting from (hetero)arenecarbonyl chlorides 88 and terminal alkynes 89 under Sonogashira conditions, the expected alkynones were formed (Scheme... 

Scheme 5.20 One-pot, three-component coupling-1,3-dipolar cycloaddition synthesis of indolizines.

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 (r)3-allyl)( ]5-tetrazoyl)-palladium complex 56 took place through [3 + 2] dipolar cycloaddition of 7r-allylpalladium azide 44 with the nitrile 54. The complex 56 thus formed would undergo reductive elimination to form the products 55. 

Rotaru AV, Dmta ID, Oeser T, Muller TJJ (2005) A novel coupling 1,3-dipolar cycloaddition sequence as a three-component approach to highly fluorescent indolizines. Helv Chim Acta 88 1798-1812... 

In this three-component reactions, the SiMea group has a multiple function. Due to its Ji-acceptor character, it suppresses the direct 1,3-dipolar-cycloaddition of the intact diazoester to the added dipolarophile (a competition reaction that is observed when methyl diazoacetate is employed) and it probably stabilizes the dipolar carbonyl ylide intermediate. Furthermore, the diastereospecific formation of 23-25 suggests that the SiMe3 group occupies the exo-position in the W-shaped, planar carbonyl ylide 21 and that this configuration is intercepted in a stereospecific [3+2] cycloaddition reaction. 

The 1,3-dipolar cycloaddition of nitrones to alkenes is a useful route to isoxazolidine derivatives, the reductive cleavage of which furnishes a range of compounds such as fi-hydroxy ketones, /S-amino alcohols, etc. [29]. Although Lewis acids are known to promote the cycloaddition [29,30], some nitrones, especially aliphatic nitrones, are unstable under these conditions and lower yields are sometimes obtained. The three-component coupling reaction of benzaldehyde, A/-benzylhydroxylamine, and A-phe-nylmaleimide proceeded smoothly in the presence of a catalytic amount of Sc(OTf)3, to afford the corresponding isoxazolidine derivative in a good yield with high diaster-eoselectivity (Eq. 12) [31]. 

Kobayashi et al. found that lanthanide triflates were excellent catalysts for activation of C-N double bonds —activation by other Lewis acids required more than stoichiometric amounts of the acids. Examples were aza Diels-Alder reactions, the Man-nich-type reaction of A-(a-aminoalkyl)benzotriazoles with silyl enol ethers, the 1,3-dipolar cycloaddition of nitrones to alkenes, the 1,2-cycloaddition of diazoesters to imines, and the nucleophilic addition reactions to imines [24], These reactions are efficiently catalyzed by Yb(OTf)3. The arylimines reacted with Danishefsky s diene to give the dihydropyridones (Eq. 14) [25,26], The arylimines acted as the azadienes when reacted with cyclopentadiene, vinyl ethers or vinyl thioethers, providing the tet-rahydroquinolines (Eq. 15). Silyl enol ethers derived from esters, ketones, and thio-esters reacted with N-(a-aminoalkyl)benzotriazoles to give the /5-amino carbonyl compounds (Eq. 16) [27]. The diastereoselectivity was independent of the geometry of the silyl enol ethers, and favored the anti products. Nitrones, prepared in situ from aldehydes and N-substituted hydroxylamines, added to alkenes to afford isoxazoli-dines (Eq. 17) [28]. Addition of diazoesters to imines afforded CK-aziridines as the major products (Eq. 18) [29]. In all the reactions the imines could be generated in situ and the three-component coupling reactions proceeded smoothly in one pot. 

The one-pot three-component reaction of polyethylene glycol-supported acrylate 623 with aldehydes 621 and hydrazines 622 in the presence of chloramine-T followed by methanolysis afforded pyrazolines 624 in good yields and high purities (Scheme 77) <2003SL1467>. 1,3-Dipolar cycloaddition of resin-supported acrylic acid 625 with the nitrilimines generated in situ by oxidation of the aldehyde phenylhydrazones with (diacetoxy)iodobenzene under microwave irradiation gave 626, which was converted into l-phenyl-3-substituted-2-pyrazolinyl-5-carboxylates 627 (Scheme 78) <2004SC3521>. 

Dipolar cycloaddition methodology has also been utilized in a one-pot three-component system to generate oxazolidines 292 <2005T6088>. Reactions between sulfonyl azides and vinyl ethers, for example 289, generated aziridine intermediates 290, which then reacted via ring-opened zwitterionic intermediate 291 with aldehydes to generate the oxazolidines in good yields (Scheme 82). 

The cyclic a,/ -unsattirated ketone cyclohex-2-en-l-one (50) was used as building block in the one-pot domino cycloaddition of enol ether 14 and nitrostyrene 15a. At 15 kbar and 50 "C, nitroso acetal 51 was formed in 67 % yield, whereas nitroso acetal 54a was formed as a side product (Scheme 9.18). This result indicated that the 1,3-dipolar cycloaddition is still faster with the electron-poor substituted cyclohexenone 50 than with the electron-rich mono-substituted enol ether 14. The one-pot reaction of 52 with enol ether 14 and nitrostyrene 15a merely resulted in formation of nitroso acetal 54a instead of nitroso acetal 53. The unwanted side reaction was not observed in the one-pot three-component reaction with 14 and methyl-substituted nitrostyrene 15b and 52 (Scheme 9.19). The large difference in reactivity between the three components in both the Diels-Alder and the [3 + 2] cycloaddition resulted in the formation of 55 as the main product. The side reaction of 16b with 14 to form 54b was prevented, since 14 was completely consumed in the reaction with 15b to give nitronate 16b (15 kbar, 50 °C, 16 h). However, heating (50 °C) the reaction mixture for 76 h at 15 kbar was necessary to produce nitroso acetal 55, which was formed as a mixture of two major diastereomers (ratio 3 1) in 69 % yield. 

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