1.3- Dipoles, cycloaddition

In Scheme 2.210, possible variants of intramolecular 1,3-dipole cycloaddition of norbomadiene derivatives with 2-substituted norbomadiene-tethered nitrones are presented. 

An alternative approach in the asymmetric catalysis in 1,3-dipole cycloaddition has been developed by Suga and coworkers. The achiral 1,3-dipole 106 was generated by intramolecular reaction of an Rh(ii) carbene complex with an ester carbonyl oxygen in the Rh2(OAc)4-catalyzed diazo decomposition of <9-methoxycarbonyl-o -diazoacetophenone 105 (Scheme 12). The asymmetric induction in the subsequent cycloaddition to G=G and G=N bond was achieved by chiral Lewis acid Sc(iii)-Pybox-/-Pr or Yb(iii)-Pybox-Ph, which can activate the dipolarophile through complexation. With this approach, up to 95% ee for G=0 bond addition and 96% ee for G=G bond addition have been obtained, respectively. ... 

In the past 10 years, studies on the reaction of ylides generated from metal carbene complexes have witnessed tremendous progress. In particular, synthetic applications of the three most common reactions of ylides, namely [2,3]-sigmatropic rearrangement, [l,2]-shift, and 1,3-dipole cycloaddition, have gained considerable success to demonstrate... 

The 3 + 2-cycloaddition of nitrile oxides to 2-crotyl-l,3-dithiane 1-oxides produces exclusively 5-acyldihydroisoxazoles.92 Lewis acid addition to 1,3-dipole cycloaddition reactions of mesityl nitrile oxide with a, /i-unsaturated 2-acyl-1,3-dithiane 1-oxides can reverse the sense of induced stereoselectivity.93 The 1,3-dipolar cycloaddition of 4-t-butylbenzonitrile oxide with 6A-acrylainido-6A-deoxy-/i-cyclodextrin (68) in aqueous solution favours the formation of the 4-substituted isoxazoline (69) rather than the 5-substituted regioisomer (Scheme 24).94 Tandem intramolecular cycloadditions of silyl nitronate, synthons of nitrile oxides, yield functionalized hydrofurans.95... 

Nucleophiles attack C-6, since this is the site of highest LUMO coefficient. Similarly, nucleophilic 4 n addends should cycloadd across the 2 and 6 positions, with the more nucleophilic end of the 4 rr addend attacking C-6. By contrast, electrophiles attack C-2, the site of highest HOMO coefficient, and electrophilic 4 n addends can only add across C-2 and C-3, due to the node at C-6. The presence of the second highest occupied MO (SHOMO) of the fulvene complicates this simple picture, and substituents may drastically change the HOMO shape, as described below. Nevertheless, this picture does help explain, at least qualitatively, the varying periselec-tivity of diene and 1,3-dipole cycloadditions to fulvenes. 

In the absence of dipolarophiles, dimerization occurs, and yellow crystals of the hexahydrotetrazine derivative 107 precipitate in a few seconds (58CB1495). Solutions of 107 exhibit, reversible thermochromism above 60°C, due to dissociation to the monomeric azomethinimine 106. Likewise, the alcohol adduct 108 also serves as a stable, convenient, neutral source of the dipole at moderate temperature (Scheme 36) (62AG491 84MI1). Most cycloadditions are usually carried out in an inert solvent at reflux temperature the end of the reaction can often be recognized by the disappearance of the typical deep color associated with the dipole. Cycloadditions of azomethinimines are distinguished by the mild reaction conditions and the absence of side products (84MI1). 

Dipole cycloaddition of diazomethane to 2-bromo-3,3,3-trifluoropropene 48 (Scheme 12.6) followed by dehydrobromination affords 41, quantitatively. A copper-catalyzed A-phenylation reaction of 41 with phenyl bromide or iodide under mild conditions provides A-phenyl-3-trifluoromethylpyrazole 47 in excellent yields. 

Keywords Cyclization Dipole cycloaddition Cross-coupling Axially biaryls Radical-mediated coupling Planar chirality... 

As a further extension of push-pull dipole cycloaddition chemistry, the Rh (I I)-catalyzed cycHzation/cycloaddition cascade was applied toward the hexacyclic framework of the kopsifoline alkaloids. The kopsifolines 14 are structurally intriguing compounds, related to and possibly derived from an aspidosperma-type alkaloid precursor 12. A possible biogenetic pathway to the kopsifolines from 12 could involve an intramolecular epoxide-ring opening followed by loss of H2O as shown in Scheme 4. The interesting biological activity of these compounds, combined with their... 

The chemistry of the 1,3-dipole cycloaddition reaction, so elegantly elucidated by Professor Huisgen by the early 1960 s, appeared to be especially suited for the synthesis of aromatic polymers since the monomers could be recdily synthesized, and many of the dipolar additions gave high yields of 5-membered heterocyclic aromatic compounds. An inspection of the literature revealed that nitrili-mines, sydnones and nitrile oxide dipoles were especially suited. 

A novel and efficient approach to 4-sulfonamidoquinolines catalyzed by Cul via a cascade reaction of sulfonyl azides with alkynyl imines has been developed by Cheng and Cui (Scheme 8.87). The reaction process includes 1,3-dipole cycloaddition/ketenimine formation/6 r-electrocyclization/[l,3]-H shift. Various 4-sulfonamidoquinolines were afforded in moderate to good yields under this mild copper catalytic system [157]. 

Allene insertion/nucleophile incorporation can also be combined with 1,3-dipole cycloaddition as an efficient protocol for the synthesis of various fused polycycles. In 2005, Dondas et al. used this strategy to synthesize various nitrogen- or oxygen-containing fused polycycles such as 323 through intermediate azomethine ylides, azomethine imines, and nitrones [112] (Scheme 6.85). 

Although the most general cycloaddition reaction of diazo compounds is that they react as 1,3-dipoles, recently some reactions have been reported in which they react as 1,2-dipoles,... 

The reaction is illustrated by the intramolecular cycloaddition of the nitrilimine (374) with the alkenic double bond separated from the dipole by three methylene units. The nitrilimine (374) was generated photochemically from the corresponding tetrazole (373) and the pyrrolidino[l,2-6]pyrazoline (375) was obtained in high yield 82JOC4256). Applications of a variety of these reactions will be found in Chapter 4.36. Other aspects of intramolecular 1,3-dipolar cycloadditions leading to complex, fused systems, especially when the 1,3-dipole and the dipolarophile are substituted into a benzene ring in the ortho positions, have been described (76AG(E)123). 

As the sp nitrogen atom in many heterocycles can be alkylated and aminated, the construction of an azomethine ylide or azomethine imine dipole is readily attainable as shown in Scheme 13. These ylides are very reactive and undergo cycloaddition with a... 

Heterocyclics of all sizes, as long as they are unsaturated, can serve as dipolarophiles and add to external 1,3-dipoles. Examples involving small rings are not numerous. Thiirene oxides add 1,3-dipoles, such as di azomethane, with subsequent loss of the sulfur moiety (Section 5.06.3.8). As one would expect, unsaturated large heterocyclics readily provide the two-atom component for 1,3-dipolar cycloadditions. Examples are found in the monograph chapters, such as those on azepines and thiepines (Sections 5.16.3.8.1 and 5.17.2.4.4). 

Frontier molecular orbital theory correctly rationalizes the regioselectivity of most 1,3-dipolar cycloadditions (73JA7287). When nitrile ylides are used as 1,3-dipoles, the dipole... 

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. 

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