1.3- dipolar cycloaddition reactions electron-rich alkenes

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

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. 

Copper(II)-bisoxazoline also catalyzes asymmetric 1,3-dipolar cycloaddition reactions of nitrones with electron-rich alkenes (Eq. 8.57).90... 

Hetero Diels-Alder reactions using nitroalkenes followed by 1,3-dipolar cycloadditions provide a useful strategy for the construction of polycyclic heterocycles, which are found in natural products. Denmark has coined the term tandem [4+2]/[3+2] cycloaddition of nitroalkenes for this type of reaction. The tandem [4+2]/[3+2] cycloaddition can be classified into four families as shown in Scheme 8.31, where A and D mean an electron acceptor and electron donor, respectively.149 In general, electron-rich alkenes are favored as dienophiles in [4+2] cycloadditions, whereas electron-deficient alkenes are preferred as dipolarophiles in [3+2] cycloadditions. 

Cycloaddition of 3-methylenephthalide with ot./V-diphenylnitrone gave two diastereoisomers of 2,3-diphenyl-2,3-dihydrospiro 1,3-oxazole-5(47/ )l (3 H)-2-benzoluran]-3 -one (805). The 1,3-dipolar cycloaddition reaction of /V-benzyl-C-(2-furyl)nitrones with electron-rich alkenes gave preferentially trans-3,5-disubstituted isoxazolidines (endo approach). These experimental results are in good qualitative agreement with those predicted from semiempirical (AMI and PM3) and ab initio (HF/3-21G) calculations (806). 

In behaviour that is typical of a 1,3-dipolar cycloaddition reaction, 0s04 reacts almost as well with electron-poor as with electron-rich alkenes. 0s04 simply chooses to attack the alkene HOMO... 

Since [4 + 2]cycloaddition and ene reactions are generally assumed to proceed in a concerted manner via isopolar activated complexes, they should exhibit virtually the same small, often negligible, response to changes in solvent polarity. This is what, in fact, has been found cf. for example [138, 682, 683]. However, two-step [2 + 2]-cycloaddition reactions of singlet oxygen to suitably substituted electron-rich alkenes proceed via dipolar activated complexes to zwitterionic intermediates (1,4-dipoles or perepoxides). In this case, the relative amounts of 1,2-dioxetane and allylic hydroperoxides or e do-peroxides should vary markedly with solvent polarity if two or even all three of the reaction pathways shown in Eq. (5-145) are operative [681, 683, 684]. 

Cycloaddition Reactions. Bis(oxazoline) copper complex 2 catalyzes the dipolar cycloaddition reaction between electron deficient nitrones and electron rich alkenes. While exo.endo selectivities are marginal, products can be obtained in as high as 94% enantiomeric excess (eq 19). Based on the stereochemical outcome of the reaction, a five-coordinate intermediate has been postulated in which both the nitrone (as a bidentate ligand) andl alkene are coordinated to the Cu center. 

With isoxazole derivatives, carbene reactions are of virtually no synthetic value. The only exception affords A -isoxazoline N-oxide 533 in moderate yields by thermal decomposition of the silver salt of aryldinitromethanes in the presence of electron-rich alkenes. This synthesis involves 1,3-dipolar cycloaddition of the intermediate arylnitrocarbenes to the olefins (80JOC4158). 

Electron-rich alkenes (e.g. enol ethers) react with electron-deficient dienophiles in [2-1-2] cycloaddition reactions giving four-membered rings. According to the Woodward-Hoffmann rules the reactions are forbidden in a 25-1-25 pathway and thus have to proceed stepwise via dipolar or diradical intermediates. The thermochemically allowed 25-I-25 attack is sterically hindered and thus probably extremely rare." Photochemically, however, 25-1-25 additions are allowed and are of preparative interest. 

Cyclopropanes exhibit similar modes of reactivity. [2Dipolar additions with electron-deficient alkenes and electron-donor-substituted cyclopropanes, additions of electron-rich alkenes to electron-deficient cyclopropanes, a number of radicaloid reactions and intramolecular photochemical cycloadditions are known, which may be described by the general scheme H-2 3. 

According to Nishida ° the [27t-l-27r] cycloadditions proceed via dipolar intermediates, whereas the [2n + 2(7] cycloadditions start with a single-electron-transfer process. In [27i-l-27t] additions a deeply colored charge-transfer complex is initially formed and the reaction is favored by polar solvents (as is usually the case with [2jt-l-2jt] additions of TCNE to electron-rich alkenes). Vinylcyclopropanes with a very low ionization potential afford the [2 t-f 2(t] product they do not form a charge-transfer complex with TCNE and the reactions have to be performed under oxygen-free conditions (Table 5). 

The reactions of p-nitrostyrene (81a) with both acyclic and cyclic enol-ethers have been studied. In general, when electron-rich alkenes interact at 1.5 GPa with p-nitrostyrene (81a), mixtures of bicyclic or tricyclic regioisomers are obtained. For example, the reaction of 81a with enol ether 86 (Scheme 7.21) led to a 7 3 mixture of compounds 87 and 88. p-Nitrostyrene (81a) first reacts as an electron-poor diene in an inverse electron demand Diels-Alder reaction with the enol ether, and then as an electron-poor dipolarophile with the formed monoadduct in a 1,3-dipolar cycloaddition. 

The domino [4 + 2]/[3 - - 2] cycloaddition of an enol ether, a nitroalkene and a third alkene is a representative example of a multicomponent reaction in which a polycyclic N-containing system is formed in a single transformation [10, 11]. In this domino reaction, a nitroalkene reacts as a heterodiene with an electron-rich alkene such as an enol ether, in an inverse electron-demand Diels-Alder reaction, to form a cyclic nitronate, which then reacts with another alkene in a 1,3-dipolar cycloaddition to produce a nitroso acetal (Scheme 9.4). 

A major advantage of the non-Lewis acid catalyzed cycloaddition is the possibility of carrying out the domino [4 + 2]/[3 + 2] cycloaddition in a one-pot fashion, since electron-poor alkenes react much faster with the nitronate formed in situ than electron-rich alkenes [14c, 20, 21[. This multicomponent reaction then provides the nitroso acetals in a single transformation, without the need to isolate the nitronate which was formed first, prior to the 1,3-dipolar cycloaddition. 

Scheme 14). The regiochemical outcome of the 1,3-dipolar cycloaddition reactions of the cyclic five-membered ring carbonyl yUde 48 with a variety of acycUc and cycHc alkenes having activated or inactivated r-bonds can be ra-tionaUzed [78,79] on the basis of frontier molecular orbital considerations, with the HOMO and LUMO of the carbonyl ylides dominating the reactions with electron-deficient and electron-rich dipolarophiles, respectively (Scheme 14). 

Jorgensen and coworkers reported a chiral Cu(ll)-catalyzed 1,3-dipolar cycloaddition reaction between electrophilic nitrones (304) and electron-rich alkenes (305) (Scheme 17.68) [99]. In contrast with the more widely studied cycloaddition of nitrones to electron-deficient alkenes in which Lewis acid coordination results in lowering of the alkene LUMO, this methodology utilizes Lewis acid coordination to electron-deficient nitrones (304) to lower the nitrone LUMO. The result is a change from a HOMOnitrone-LUMO controlled reaction path to a HOMOaikene-LUMOnitrone Controlled reaction path. Cu(OTf)2/t-Bu-BOX (13)-catalyzed cycloadditions proceed in moderate to good yields and selectivi-ties with a pentacoordinated complex (308) proposed to account for the observed stereoselectivity. 

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... 

Cyclic alkyl nitronates may be used in tandem [4+2]/[3+2] cycloadditions of nitroalkanes, and this reaction has been extensively studied by Denmark et al. (64,333-335). In recent work, they developed the silicon-tethered heterodiene-alkene 219 (Scheme 12.63). Steric hindrance and the fact that both the nitroalkene and the a,p-unsaturated ester in 219 are electron deficient renders the possibility of self-condensation. Instead, 219 reacts with the electron-rich chiral vinyl ether 220 in the presence of the catalyst 224 to form the intermediate chiral nitronate 221. The tandem reaction proceeds from 221 with an intramolecular 1,3-dipolar cycloaddition to form 222 with 93% de. Further synthetic steps led to the formation of ( )-detoxinine 223 (333). A similar type of tandem reaction has also been applied by Chattopadhyaya and co-workers (336), using 2, 3 -dideoxy-3 -nitro-2, 3 -didehydrothymidine as the starting material (336). 

For [2 + 2] cycloadditions of electron-poor and electron-rich pairs of alkenes, configuration interaction is not just marginally helpful it is of dominant importance. Without it, activation energies would ordinarily be not just a bit higher, but drastically higher. Interestingly, the nucleophilicities of the cyanoethylenes as two-bond nucleophiles in Diels-Alder reactions and as one-bond nucleophiles in [2 + 2] cycloadditions going by way of 1,4-dipolar intermediates are projected to be i proximately the same. ... 

Nitroalkenes have found some use as dienes in the Diels-Alder reaction. The nitroalkene is electron-dehcient and therefore reacts best with electron-rich dienophiles such as enol ethers. Good yields of the cycloadduct can be obtained by using a Lewis acid catalyst such as SnCU or TiCl2(0 Pr)2 at low temperature. For example, cycloaddition with cyclopentene gave the nitronate 69 in high yield (3.56). ° The nitronate cycloadducts can undergo a variety of different transformations, such as a subsequent 1,3-dipolar cycloaddition with an alkene (see Section 3.4). 

Enantioselective 1,3-dipolar cycloaddition of imino esters to electron-deficient alkenes is one of the most powerful and atom-economical C-C bond-forming reaction that facilitates the synthesis of a range of structurally and stereochemically rich pyrrolidines [35]. Wang developed the asymmetric 1,3-dipolar cycloaddition of naphthalene-1,4-dione (116) with imino esters 117 catalyzed by the Cu(I) complex of ferrocenyl ligand 115, followed by silica-gel-promoted aromatization [39]. 

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