Intramolecular cycloaddition 1,3-dipolar

When the chain between the azirine ring and the alkene end is extended to three carbon atoms, the normal mode of 1,3-intramolecular dipolar cycloaddition occurs. For example, irradiation of azirine (73) gives A -pyrroline (74) in quantitative yield 77JA1871). In this case the methylene chain is sufficiently long to allow the dipole and alkenic portions to approach each other in parallel planes. 

The reaction of the a-bromo aldoxime 52e (R = R = Me) with unsaturated alcohols has been extended to the heterocyclic systems furfuryl alcohols and 2-thiophene methanol [29b]. The furanyl and thiophenyl oximes 63a-c were treated with NaOCl and the resulting heterocyclic nitrile oxides were found to undergo spontaneous intramolecular dipolar cycloaddition to produce the unsaturated tricyclic isoxazolines 64a-c in high yield (Eq. 5). In these cases, the heterocyclic ring acts as the dipolarophile with one of the double bonds adding to the nitrile oxide [30]. 

Synthetic work commenced with evaluation of an azomethine ylide dipole for the proposed intramolecular dipolar cycloaddition. A number of methods exist for the preparation of azomethine ylides, including, inter alia, transformations based on fluoride-mediated desilylation of a-silyliminium species, electrocyclic ring opening of aziridines, and tautomerization of a-amino acid ester imines [37]. In particular, the fluoride-mediated desilylation of a-silyliminium species, first reported by Vedejs in 1979 [38], is among the most widely used methods for the generation of non-stabilized azomethine ylides (Scheme 1.6). 

The feasibility of azomethine ylide generation from 7 and intramolecular dipolar cycloaddition was examined under a variety of conditions. For example, activation of vinylogous amide 71 with BzOTf [41] followed by desilylation with TBAT led to complex mixtures of products. Likewise, using MeOTf as the activating agent yielded similar results. Significantly, none of these protocols furnished the desired pyrrolidine 73. Only decomposition of the silylpyridinone to form unidentified products was observed, despite the fact that quantitative O-methylation of the... 

To investigate the feasibility of employing 3-oxidopyridinium betaines as stabilized 1,3-dipoles in an intramolecular dipolar cycloaddition to construct the hetisine alkaloid core (Scheme 1.8, 77 78), a series of model cycloaddition substrates were prepared. In the first (Scheme 1.9a), an ene-nitrile substrate (i.e., 83) was selected as an activated dipolarophile functionality. Nitrile 66 was subjected to reduction with DIBAL-H, affording aldehyde 79 in 79 % yield. This was followed by reductive amination of aldehyde x with furfurylamine (80) to afford the furan amine 81 in 80 % yield. The ene-nitrile was then readily accessed via palladium-catalyzed cyanation of the enol triflate with KCN, 18-crown-6, and Pd(PPh3)4 in refluxing benzene to provide ene-nitrile 82 in 75 % yield. Finally, bromine-mediated aza-Achmatowicz reaction [44] of 82 then delivered oxidopyridinium betaine 83 in 65 % yield. 

Scheme 1.10 Evaluation of intramolecular dipolar cycloadditions of model substrates...

Each of the 3-oxidopyridinium betaine substrates 83, 91, and 98 were extensively investigated for their potential to engage in intramolecular dipolar cycloaddition (Scheme 1.10). Heating a solution of ene-nitrile 83 in variety of solvents failed to effect the desired intramolecular [3+2] dipolar cycloaddition to form the bridged pyrrolidine 100, as tricyclic oxidopyridinium betaine 103 was the only... 

Scheme 1.13 Intramolecular dipolar cycloaddition of nitroalkene oxidoisoquinolinium betaine 123...

Scheme 1.15 Intramolecular dipolar cycloaddition of ene-nitrile oxidoisoquinolinium betaine 131...

Substituent effects on intramolecular dipolar cycloadditions can be illustrated by the gem-dicarboalkoxy effect (404). This effect (rel. rate >20) has been... 

The sequential intramolecular conjugate addition of the oxime followed by intramolecular dipolar cycloaddition of the intermediate nitrone affords a... 

An elegant one-pot bicycloannulation method for the synthesis of tetrahydroisoquinoline systems has been disclosed by Pawda et al. <1998TL4757, 2000JOC2684>. This method generates a transient thioisomilnchnone 423 that undergoes an intramolecular dipolar cycloaddition. The thus obtained cycloadduct 424 is next reduced with Raney-Ni, followed by LAH to furnish ( )-alloyohimbane 425 in 31% overall yield from 421 (Scheme 109). 

Several routes to the pyrrolo[l,2-f][l,2,3]triazole skeleton have been described. Intramolecular dipolar cycloaddition of azido-alkenes or alkynes seems to be the most convenient process, although the cyclization efficiency seems to be highly substrate dependent (Scheme 16) <2002JA2134, 2003T1477, 2005SL2187, 2005TL8639>. The formation of this bicyclic system by an intramolecular Heck reaction is an attractive alternative. The recent syntheses of sulfamides by intramolecular cyclization of alkenes or allenes offer a complementary route to the classical... 

The intramolecular dipolar cycloaddition of a nitrone with an unactivated allene was also studied [76], Treatment of 5,6-heptadien-2-one with N-methylhydroxyl-amine in refluxing ethanol yielded allenyl nitrone 78, which cyclized with the terminal allenic C=C bond to give an unsaturated bicyclic isoxazolidine. On the other hand, the site selectivity decreased with an allenic ketone having a trimethylene tether. 

Diazoacetamides undergo intramolecular cyclopropanation with similarly high enantios-electivities (Eq. 4) [33, 36, 37]. In these cases, however, competition from intramolecular dipolar cycloaddition can compHcate the reaction process. Therefore, the use of R = Me or Bu has been required to achieve good yields of reaction products. Representative examples of applications of chiral dirhodium(II) carboxamidates for enantioselective intramolecular cyclopropanation of diazoacetamides are compiled in Scheme 15.2. 

Trimethyl-2-azidobiphenyl thermolyzed in n-hexadecane gave only 4% 2,4,9-trimethylcarbazole, that is, the product of nitrene insertion into the ortho C-methyl bond the main products were 2 -amino-2,4,6-trimethyl-biphenyl and 250 (R = Me). An intramolecular dipolar cycloaddition com-... 

An impressive enantiopure synthesis of Amaryllidaceae alkaloids has been achieved through the formation of sugar-derived homochiral alkenyl nitrone 265 (Fig. 1.7).[280] While this reagent required lengthy preparation, it underwent an intramolecular dipolar cycloaddition to establish the required stereochemistry of the polycyclic pyrrolidine skeleton of (—)-haemanthidine (266), which was converted to (+)-pretazettine and (+)-tazettine by established procedures (281). 

TABLE 2.39. INTRAMOLECULAR DIPOLAR CYCLOADDITION OF SILYL NITRONATES... 

The intramolecular dipolar cycloaddition of nitronates has remained relatively underexplored in comparison to the intermolecular variant. In the case of acyclic nitronates, there are only a few reports of an intramolecular nitronate cycloaddition (36,176,177). However, the intermediate nitroso acetal decomposes to the isoxazo-line due to the presence of HCl in the reaction mixture (Scheme 2.19). 

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... 

Scott Denmark of the University of Illinois reports (J. Org. Chem. 68 8015,2003) a hetero intramolecular Diel-Alder reaction of a nitro alkene 5, followed by intramolecular dipolar cycloaddition of the resulting nitronate 6, to give the tricycle 7. Raney nickel reduction effected cleavage of the N-0 bonds and reductive amination of the liberated aldehyde, to give, after acetylation, the angularly substituted cis-decalin 8. 

The application of intramolecular dipolar cycloaddition reactions to the synthesis of complex natural products has recently come to be recognized as a very powerful synthetic tool, one equally akin to the intramolecular Diels-Alder reaction in its potential scope of application.69 This is particularly the case with nitrile oxides and the 1NOC reaction has been extensively utilized in total synthesis.70 The intramolecular nitrile oxide cycloaddition (INOC) generally displays exceptional regio- and stereo-chemical control which undoubtedly accounts for the popularity of this reaction. Internal cycloadditions of nitrile oxides have been found to offer a powerful solution to many problems in complex natural product synthesis.48 For example, Confalone and coworkers have utilized the INOC reaction for the stereospecific synthesis of the key amino alcohol (60), which was converted in five subsequent steps to ( )-biotin (61 Scheme 14).71... 

There is an excellent recent review on intramolecular dipolar cycloadditions.1 Reviews on mechanistic aspects of intermolecular 1,3-dipolar cycloadditions abound2 and a treatise on intramolecular Diels-Alder cycloadditions is available.3... 

Jung, M. E. Vu, B. T. Substituent effects on intramolecular dipolar cycloadditions the gem-dicarboalkoxy effect. Tetrahedron Lett. 1996, 37, 451-454. 

The enolate ion derived from the nitrone 15 undergoes an unusual intramolecular dipolar cycloaddition reaction involving the enol double bond to yield 16 (95T6285). 

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