Inverse electron demand 1,3-dipolar

As for boron catalysts, the aluminum catalysts have exclusively been applied for the inverse electron-demand 1,3-dipolar cycloaddition between alkenes and nitrones. The first contribution to this field was published by j0rgensen et al. in... 

A quite different type of titanium catalyst has been used in an inverse electron-demand 1,3-dipolar cycloaddition. Bosnich et al. applied the chiral titanocene-(OTf)2 complex 32 for the 1,3-dipolar cycloaddition between the cyclic nitrone 14a and the ketene acetal 2c (Scheme 6.25). The reaction only proceeded in the presence of the catalyst and a good cis/trans ratio of 8 92 was obtained using catalyst 32, however, only 14% ee was observed for the major isomer [70]. 

The enantioselective inverse electron-demand 1,3-dipolar cycloaddition reactions of nitrones with alkenes described so far were catalyzed by metal complexes that favor a monodentate coordination of the nitrone, such as boron and aluminum complexes. However, the glyoxylate-derived nitrone 36 favors a bidentate coordination to the catalyst. This nitrone is a very interesting substrate, since the products that are obtained from the reaction with alkenes are masked a-amino acids. One of the characteristics of nitrones such as 36, having an ester moiety in the a position, is the swift E/Z equilibrium at room temperature (Scheme 6.28). In the crystalline form nitrone 36 exists as the pure Z isomer, however, in solution nitrone 36 have been shown to exists as a mixture of the E and Z isomers. This equilibrium could however be shifted to the Z isomer in the presence of a Lewis acid [74]. 

Furukawa et al. also applied the above described palladium catalyst to the inverse electron-demand 1,3-dipolar cycloaddition of nitrones with vinyl ethers. However, all products obtained in this manner were racemic [81]. 

The reactions of nitrones constitute the absolute majority of metal-catalyzed asymmetric 1,3-dipolar cycloaddition reactions. Boron, aluminum, titanium, copper and palladium catalysts have been tested for the inverse electron-demand 1,3-dipolar cycloaddition reaction of nitrones with electron-rich alkenes. Fair enantioselectivities of up to 79% ee were obtained with oxazaborolidinone catalysts. However, the AlMe-3,3 -Ar-BINOL complexes proved to be superior for reactions of both acyclic and cyclic nitrones and more than >99% ee was obtained in some reactions. The Cu(OTf)2-BOX catalyst was efficient for reactions of the glyoxylate-derived nitrones with vinyl ethers and enantioselectivities of up to 93% ee were obtained. 

Fig. 8.17 An FMO diagram of the normal and inverse electron-demand 1,3-dipolar cy-...

Inverse electron-demand 1,3-dipolar cycloaddition reaction... 

Chiral aluminium complexes have been used as catalysts for inverse electron-demand 1,3-dipolar cycloadditions of alkenes with nitrones, and the first contribution to this field was pubhshed in 1999 (344). The chiral AlMe-BEMOL (BINOL = 2,2 -bis(diphenylphosphino)-l,l -binaphthyl) complexes 235 were excellent catalysts for the reaction between nitrone 225a and vinyl ethers 232 (Scheme 12.68). The diastereo- and enantioselectivities are highly dependent on the chiral ligand. An exo/endo ratio of 73 27 was observed, and the exo-product was... 

The inverse-electron demand 1,3-dipolar cycloaddition has also been pursued with other Ti(IV) complexes (364). The cycloaddition reaction of C,Al-diphenyl nitrone to ferf-butyl vinyl ether catalyzed by different bidentate C2-symmetrical ligands gave moderate to good diastereoselectivity, and up to 41% ee was achieved. 

The enantioselective inverse electron-demand 1,3-dipolar cycloadditions of nitrones with alkenes described so far are catalyzed by metal complexes that favor a monodentate coordination of the nitrone, such as boron and aluminium complexes. However, the glyoxylate-derived nitrone 256 favors abidentate coordination to the catalyst, and this nitrone is an interesting substrate, since the products that are obtained from the reaction with alkenes are masked ot-amino acids (Scheme 12.81). 

The anionic inverse electron-demand 1,3-dipolar cycloaddition of nitrones 95 with lithium ynolates (equation 41) proceeds at 0°C to afford the substituted isoxazolidinones 97. The relative configuration is determined during the protonation step of the initial isoxazolidinone enolate adduct 96. With a thermodynamically controlled protonation, the trans products are mainly produced. The in situ alkylation of the resulting enolate adduct 96 furnishes the trisubstituted isoxazolidinone 98 with high diastereoselectivity. The isoxazolidinones are easily converted into /3-amino acids (99, 100) in good yield . 

The anionic inverse electron demand 1,3-dipolar cycloaddition of ynolates with chiral nitrones followed by quenching of the initially generated enolate was applied to the synthesis of 5-isoxazolidinones with high yields and good diastereoselectivity. The primary adducts could also be alkylated to obtain 4,4-disubstituted isoxazolidinones (Scheme 133) <200381441, 2005TA2821>. 

In 2011 the same research group described another efficient application of dicarbo Q lic acids 63 in the asymmetric inverse-electron-demand 1,3-dipolar cycloaddition (lED 1,3-DC) of C//-cyclic azomethine imines with t-butyl vinyl ether or vinylogous aza-enamines (synthesized from enals) (Scheme 24.23). This latter reaction, carried out without exclusion of moisture and air, gave cycloadducts regioisomeric to the products observed in the normal-electron-demand 1,3-dipolar cycloaddition (NED 1,3-DC) catalysed by Ti/binolate starting from the enals and for this reason the authors introduced the concept of lED umpolung 1,3-DC. 

Asymmetric inverse-electron-demand 1,3-dipolar cycloaddition of C,A-cyclic azomethine imines with c-rich dipolarophiles was accomplished with a high stereo-selectivity by using an axially chiral dicarboxylic catalyst (40)." The metal-free silicon Lewis-acid-catalysed 3-1-2-cycloadditions of A-acylhydrazones with cyclopentadiene provides a mild access to pyrazolidine derivatives in excellent... 

In 2010, Suga et al. reported high enantioselectivities of up to 97% ee for the inverse electron-demand 1,3-dipolar cycloaddition between cyclohe)yl or bulyl vinyl ethers and carbonyl ylides in situ generated via rhodium-catalysed... 

Nitrones activated by chiral 2,2 -dihydroxy-l,P-bisnaphthol (BINOL)-AlMe complexes undergo enantioselective inverse-electron-demand 1,3-dipolar cycloaddition reactions with electron-rich alkenes to produce exo-diastereoisomers of isoxazolidines. The diastereoselectivity of the 1,3-dipolar cycloaddition between diphenyl nitrone and 4-(5 )-benzyl-( )-but-2 -enoyl)-l,3-oxazolidin-2-one can be controlled by inorganic salts whose cations behave like Lewis acids.The Cu(OTf)2-bisoxazoline-catalysed asymmetric 1,3-dipolar cycloaddition of nitrones with electron-rich alkenes at room temperature gave isoxazolidines in good yields and diastereoselectivity and with high enantioselectivities of up to 94% ee. ° Kinetic studies have shown that the reaction rate of the 1,3-dipolar cycloaddition of C,tV-diphenyl nitrone with dibutyl fumarate increases dramatically in aqueous solutions... 

Simonsen KB, Bayon P, Hazell RG, Gothelf KV, Jprgensen KA (1999) Catalytic enantioselective inverse-electron demand 1,3-dipolar cycloaddition reactions of nitrones with alkenes. J Am Chem Soc 121 3845-3853... 

The use of 27f, with bis(2-naphthyl)methyl groups at the 3,3 -positions, as a catalyst enabled the employment of C,N-cyclic azomethine imines as a dipole for the asymmetric inverse-electron-demand 1,3-dipolar cycloaddition with vinyl ethers as exemplified in Scheme 7.52 [79],... 

Recently, Maruoka and coworkers have also developed an asymmetric inverse electron demand 1,3-dipolar cycloaddition of C,A -cyclic azomethine imines with fort-butyl vinyl ether catalyzed by a newly developed axially chiral dicarboxylic acid having diarylmethyl groups at the 3,3 -positions (Scheme 7.7) [18]. Based on this finding, the concept of the inverse electron demand umpolung 1,3-dipolar cycloaddition was introduced as a strategy for switching the regioselectivity of the cycloaddition from that of the titanium BINOLate-catalyzed normal electron demand 1,3-dipolar cycloaddition with enals (Table 7.3) by... 

CARBAMOYLNITRILE OXIDE AND INVERSE ELECTRON-DEMAND 1,3-DIPOLAR CYCLOADDmON... 

As mentioned previously, highly electron-deficient keto ester 34h is an inactive dipolarophile. This disadvantage is overcome by converting keto ester 34h to electron-rich sodium enolate 32h beforehand, which undergoes an inverse electron-demand 1,3-dipolar cycloaddition [64] with nitrile oxide 6 even at room temperature leading to 5-trifluorome-thylisoxazole 33h with 57% yield (Scheme 9.16). 

As mentioned so far, methylnitroisoxazolone 10 serves as a precursor of carbamoylnitrile oxide 6 upon treatment with only water under mild conditions, in which any special reagents, conditions, and manipulations are not necessary. The nitrile oxide 6 reacts with alkynes 15, alkenes 17, nitriles 29, and 1,3-dicarbonyl compounds 34 to afford corresponding carbamoyl-substituted isoxazoles 16, isoxazolines 18, 1,2,4-oxadiazoles 28, and isoxazoles 33, respectively (Scheme 9.17). The electron-withdrawing carbamoyl group realizes the cycloaddition with electron-rich dipolarophiles, which is inverse electron-demand 1,3-dipolar cycloaddition. Furthermore, the carbamoyl group also plays a role of an activator of the dipolarophile. This mefliodology will be useful for the construction of a new library of functionalized compounds. 

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