Cycloaddition of styrenes

Certain olefinic substrates undergo thermally-forbidden [2 + 2] type cycloaddition in the presence of Lewis acid catalysts through coordination to the acceptor molecules. Scheme 111 illustrates the enantiose-lective version of this reaction (271). Some thio acetylenes can also be used. Substantial asymmetric induction has been observed in cycloadditions of styrenes and 1,4-benzoquinones using a stoichiometric amount of a chiral Ti(IV) complex (272). The [2 + 2] cycloadducts are readily rearranged to 2-ary 1-2,3-dihydrobenzofirrans. 

A review of photo-cycloadditions of dienones and quinones has been published.41 The first example of a Lewis acid-catalysed 2 + 2-cycloaddition of styrene with naphthoquinone has been reported.42 FMO methods have been used to investigate the effect of substituents on the regiochemistry of the 2 + 2-photo-cycloaddition of a, fi-unsaturated carbonyl compounds with substituted alkenes.43 Evidence has been presented for the presence of a triplet exciplex intermediate in the photo-cycloaddition of 4,4-dimethylcyclohexenone to 1,1-diphenylethylene.44 The intramolecular 2-1-2-photo-cycloaddition of 2-acyloxy-3-hexenoylcyclohexenones (26) is highly diastereo-selective yielding the tricyclic adduct (27) (Scheme 10).45... 

A formal iron-catalyzed [3 + 2]-cycloaddition of styrene derivatives with benzoqui-none was reported by Itoh s group [96]. The process is believed to proceed via electron-transfer reactions mediated by a proposed Fe3+/Fe2+ couple, which generates a styrene radical cation and a semiquinone. These intermediates undergo stepwise addition to yield the benzofuran product 51 (Scheme 9.38). The reaction seems to be limited to electron-rich alkoxy-functionalized styrenes, as the Fe3+/Fe2+ redox couple is otherwise unable to transfer the electrons from the styrene to the quinone. 

Cycloaddition of styrene with p-quinone methides.2 In the presence of this Lewis acid, p-quinone methides and styrenes undergo a formal [3 +2]cycloaddi-tion to form dihydro-lff-indenes. The reaction shows some stereoselectivity. Thus the geometry of the (E)-styrene is largely retained (17 1) and only two of the four possible products are formed. Presumably, any electron-rich alkene could participate in this cycloaddition. 

Steric enhancement of reaction rate has been reported in cycloaddition of styrene to acridinium ion (74JOC1172) and of 2(lH)-pyridone to dimethyl butynedioate (79CC501) when methyl groups are either ortho or peri (Scheme 45). 

The meso-ionic 1,3-dithiolium 4-olate (283 R = SMe) exists in equilibrium with the dimer (284 R = SMe). Complete regiospecificity is observed in the 1,3-dipolar cycloaddition of styrene to the diphenyl-derivative (283 R = Ph), which gives only compound (285 R = H,R = Ph) in contrast, methyl acrylate yields a mixture of (285 R = C02Me, R = H) and the isomeric adduct (285 R = H, R = C02Me)/ Irradiation of the diphenyl-compound (283 R = Ph) yields a mixture of 4,5-diphenyl-l,2-dithiole-3-thione (286) via the bridged intermediate shown), sulphur, diphenylacetylene, tetraphenylthiophen, and the latter s precursor, the dithiin (287). The dithiin is thought to arise from the dimeric compound (284 R = Ph) by loss of carbon oxysulphide. ... 

For the preparation of 2,3-dihydrobenzo[6]furans, several strategies have been developed. The acid-catalyzed cycloaddition of styrenes (e.g., (135)) with quinone monoketals is suitable for the synthesis of both 2,3-dihydrobenzofurans and the quinonoid derivatives (Scheme 93) <77JA8073,... 

Adduct 100 is formed from the 1,4 cycloaddition of o-quinone (99) with the morpholine enamine of cyclohexanone (125). Treatment of styrene oxide with cyclic enamines at elevated temperatures (about 230°C) produces O.N-ketals possessing a furan nucleus (125a). 

N, -Diphenylmtrone, by condensation of N-phenylhydroxylamine with bcnzaldchyde, 46,127 1,3-dipolar cycloaddition to styrene, 46,128... 

The comparison of rates of cycloaddition of maleic anhydride, tetracyanoethylene, and styrene to PPA shows that the latter, irrespective of the presence of electronegative groups, behaves in these reactions not as an electron-poor diene system. This fact, together with the composition of side products (giving evidence of PPA decarboxylation), allows the assumption to be made that the cycloaddition of dienophiles involves mainly decarboxylated polyene sections of cis-transoid structure213, 266. This is in agreement with the fact that PPA with predominant trans-transoid configuration interacts with these dienophiles at a substantially lower rate. The ultimate amounts of the dienophile combined with PPA of this structure is also considerably smaller. 

Phenanthrene-l,4-diones have been prepared [52] by cycloaddition of a-substituted styrenes with an excess of 1,4-benzoquinone (Equation 2.18). Initial cycloadducts are oxidized by 1,4-benzoquinone. 

When strong electron-withdrawing substituents were introduced at the a-or )S-carbon of the vinyl group, the styrenes acted as dienophiles. Thus cycloaddition of a-trifluoromethyl styrene (58) with Danishefsky s diene 59 afforded regioselectively a 1 1 mixture of cycloadducts which were then converted (Equation 2.20) into 4-phenyl-4-trifluoromethyl-2-cyclohexen-l-one [54]. 

Harano and colleagues [48] found that the reactivity of the Diels-Alder reaction of cyclopentadienones with unactivated olefins is enhanced in phenolic solvents. Scheme 6.28 gives some examples of the cycloadditions of 2,5-bis-(methoxycar-bonyl)-3,4-diphenylcyclopentadienone 45 with styrene and cyclohexene in p-chlorophenol (PCP). Notice the result of the cycloaddition of cyclohexene which is known to be a very unreactive dienophile in PCP at 80 °C the reaction works, while no Diels-Alder adduct was obtained in benzene. PCP also favors the decarbonylation of the adduct, generating a new conjugated dienic system, and therefore a subsequent Diels-Alder reaction is possible. Thus, the thermolysis at 170 °C for 10 h of Diels-Alder adduct 47, which comes from the cycloaddition of 45 with 1,5-octadiene 46 (Scheme 6.29), gives the multiple Diels-Alder adduct 49 via decarbonylated adduct 48. In PCP, the reaction occurs at a temperature about 50 °C lower than when performed without solvent, and product 49 is obtained by a one-pot procedure in good yield. 

The Pettus group has also developed three methods (F-H, Fig. 4.26) enabling low-temperature, inverse demand cycloadditions of o-QM intermediates. Jones and Selenski began by investigating the reactions of styrenes with o-OBoc benzalcohols... 

FIGURE 4.27 Some examples of low-temperature cycloadditions with styrene. 

The hetero-Diels-Alder reaction can also employ dienes containing heteroatoms. Cycloaddition of substituted styrenes with di-(2-pyridyl)-1,2,4,5-tetrazine was investigated by Engberts (Eq. 12.56).127 Again, the rate of the reaction increased dramatically in water-rich media. Through kinetic studies, they showed that the solvent effects on the... 

Engler and coworkers [76] developed a new domino process which consists of a [5+3] cycloaddition of a p-quinone monoimide with a styrene derivative followed by a [3+2] or [3+3] cycloaddition. The reaction allows the formation of two additional rings and up to eight stereogenic centers, with high selectivity. The best results, with 58% yield of4-230, were obtained in the transformation of 4-227 and 4-228 in the presence of BF3 Et20 at -20 °C (Scheme 4.49). In addition, the diastereomer 4-231 was obtained in 16 % yield. It can be assumed that the cation 4-229 functions as an intermediate. The process also functions with quinones, though much less efficiently. 

A 1,2-diazetidine has been proposed as an intermediate in the reaction of pyridazine-3,6-dione (12) with styrene.87 The observed product was thought to arise from addition of water to the 1,2-diazetidine, although the alternative more likely explanation involving a dipolar intermediate (cf. Scheme 5) was apparently not considered. In the photochemical reaction of styrene with DEAZD, a 1,2-diazetidine structure was tentatively assigned to a minor product.88 Attempted photochemical [2 + 2] cycloaddition of DEAZD to other olefins failed to give any 1,2-diazetidines.88... 

Pyrazoles can be synthesized by thermal cycloreversion of adducts formed in the 1,3-dipolar cycloaddition of alkyldiazoacetates with norbornadiene. The rate of the primary process of cycloaddition is accelerated by iron pentacarbonyl (Scheme 88)155 a similar catalytic effect has been observed during the formation of ethyl 5-phenyl-A2-pyrazoline-3-carboxylate from cycloaddition of ethyl diazoacetate and styrene.155 Reactions of this type are catalyzed presumably because of coordination of one or both reactants to the transition metal, and a wider study of the effect of a variety of complexes on 1,3-dipolar cycloaddition processes would be valuable. 

An example of asymmetric synthesis involving cycloaddition of an azide to dimethyl acetylenedicarboxylate is depicted in Scheme 172. Thus, asymmetric auxiliary 1042 reacts with styrene and sodium azide to generate azide 1043 in 90% yield and 94% diastereomeric purity. The following reaction (Scheme 172) with dimethyl acetylenedicarboxylate converts azide 1043 into triazole 1044 in 75% yield. Finally, the bond with selenium is cleaved by treatment with triphenyltin hydride and AIBN to furnish triazole 1045 in 80% yield and preserved optical purity (94%) <2003AGE3131>. 

When dimethylgermylene is formed by the decomposition of 8 in the presence of excess styrene, cis- and fraws-l,l-dimethyl-3,4-diphenylgermacyclopentane forms from the apparent cycloaddition of dimethylgermylene to two alkene molecules. This is thought to occur by a stepwise mechanism where dimethylgermylene adds in a concerted fashion to styrene to yield a phenyl-substituted germacyclopropane, in the first step. In a second step, concerted addition of the germacyclopropane to a second styrene molecule has been proposed (Scheme 6). 

The cycloaddition of 3,5-dichloro-2,4,6-trimethylbenzonitrile oxide to tricar-bonylchromium complexed styrenes proceeds with high stereoselectivity (Scheme 1.17), thus offering a new synthetic route to optically active 3,5-di-substituted 4,5-dihydroisoxazoles (213). The preferred formation of cycloadducts 44 rather than 45 shows that nitrile oxide attacks the it face opposite to Cr(CO)3 and the reactive rotamer of the dipolarophile is transoid (213). 

Dipolarophiles D1 and D2. In the study of steric and electronic factors on regioselectivity and stereoselectivity of 1,3-cycloaddition of nitrones to olefins, 1-decene (734) and styrene derivatives (735) have been used. By comparative analyses of the kinetic and thermodynamic parameters in the 1,3-cycloadditions... 

To study asymmetric induction from the nitrone part in 1,3-dipolar cycloaddition to styrene, D-erythrose derived nitrones (479 a-c) have been used. Cycloaddition of nitrones (479 a-c) to styrene, in boiling toluene for 10 h, affords a mixture of four diastereomeric 3,5-disubstituted isoxazolidines (481 a-c-484 a-c) in high yields (82%-94%) (Scheme 2.237) (208). 

Table 2.17 1,3-Dipolar cycloaddition of C-a-alkoxyalkyl-substituted nitrones to styrene...

Let us remember the rule of orientation of substituents in viz. disubstituted olefins directed to the C-4 atom of the cycloadduct H > Si > C > O (162) (the atom of the substituent in olefin bound to C-4 in the resulting adduct). As in the previous case, many reactions proceed at high temperature. It should be emphasized that unsubstituted 5,6-dihydro-[47/]-oxazine A-oxides were successfully involved in [3 + 2] -cycloaddition. Professor Chlenov was the first to perform this reaction with the use of styrene (the yield was 21%) (337). More recently, the... 

Isoxazolines are partially unsaturated isoxazoles. In most cases these compounds are precursors to the isoxazoles, and as a result, the synthesis can also be found in Sect. 3.2.1b. Kaffy et al., used a 1,3-dipolar cycloaddition of a nitrile oxide (186) with the respective styrene (201a or b) to generate isoxazolines (202a or b, respectively). Depending on the substitution of the vinyl portion of the styrene molecule, either 3- or 4-substituted isoxazolines could be formed (Scheme 55) [94], Simoni et al. employed similar chemistry to produce isoxazolines [60]. Kidwai and Misra emplyed microwave technology to treat chalcones with hydroxylamine and basic alumina [99]. The isoxazoles synthesized by Simoni et al. possess anti-proliferative and apoptotic activity in the micromolar range [60]. 

Mukai et al.85 reported an asymmetric 1,3-dipolar cycloaddition of chromium(0)-complexed benzaldehyde derivatives. As shown in Scheme 5 52, heating chiral nitrone 171a, derived from Cr(CO)3-complexed benzaldehyde, with electron-rich olefins such as styrene (173a) or ethyl vinyl ether (173b) generates the corresponding chiral a.v-3,5-disubstitutcd isoxazolidine adduct 174 or... 

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