Styrenes cycloaddition

The nontethered styrene cycloadditions initially reported by Dauben [16] have been further studied by Caldwell [14b]. The 1-phenylcyclohexene... 

In Caldwell s styrene study (see Sch. 8) [14b], the regioselectivity is completely head-to-head. Only 1,2-diarylcyclobutane was observed upon irradiation at 355 nm. The stereoselectivity is approximately 11 1 in favor of the trans isomer in the / -acylstyrcnc to styrene cycloaddition. 

With 1,1-disubstituted trifluoromethylated alkenes, such as a-(trifluoromethyl)styrene, cycloaddition w ith nitrone 1 is regioselective, and a 50 50 mixture of the ais/ /ranj-isomers is obtained, as observed in Diels-Alder cycloaddition reactions (see Section 2.1.1.6.2.1.1.).5 When the reaction is performed solvent-free under microwave irradiation, instead of under thermal conditions (boiling toluene), the yield is improved from 65% to 98% and the reaction time decreases from 48 hours to 4 minutes, however, stereoselectivity is not improved.79... 

Endo adducts are usually favored by iateractions between the double bonds of the diene and the carbonyl groups of the dienophile. As was mentioned ia the section on alkylation, the reaction of pyrrole compounds and maleic anhydride results ia a substitution at the 2-position of the pyrrole ring (34,44). Thiophene [110-02-1] forms a cycloaddition adduct with maleic anhydride but only under severe pressures and around 100°C (45). Addition of electron-withdrawiag substituents about the double bond of maleic anhydride increases rates of cycloaddition. Both a-(carbomethoxy)maleic anhydride [69327-00-0] and a-(phenylsulfonyl) maleic anhydride [120789-76-6] react with 1,3-dienes, styrenes, and vinyl ethers much faster than tetracyanoethylene [670-54-2] (46). 

A large number of pyridazines are synthetically available from [44-2] cycloaddition reactions. In one general method, azo or diazo compounds are used as dienophiles, and a second approach is based on the reaction between 1,2,4,5-tetrazines and various unsaturated compounds. The most useful azo dienophile is a dialkyl azodicarboxylate which reacts with appropriate dienes to give reduced pyridazines and cinnolines (Scheme 89). With highly substituted dienes the normal cycloaddition reaction is prevented, and, if the ethylenic group in styrenes is substituted with aryl groups, indoles are formed preferentially. The cycloadduct with 2,3-pentadienal acetal is a tetrahydropyridazine derivative which has been used for the preparation of 2,5-diamino-2,5-dideoxyribose (80LA1307). 

Bis(trifluoromethyl)-l,l-dicyanoethylene is a very reactive dienophile. It undergoes facile and high-yield [2+4] cycloadditions with 1,3-dienes, cyclopen-tadiene, and anthracene [707] (equation 86). It is reactive enough in a Diels-Alder reaction with styrene [702] (equation 86). 

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... 

We have also used poly(propynoic acid) in our studies of the photochemical interaction of PCSs with dienophiles, such as maleic anhydride, tetracyanoethylene, and styrene. This photochemical reaction of Diels-Alder type is accompanied by the breakdown of the conjugation system and the formation of slightly colored adducts266. Together with the cycloaddition reaction, photodegradation of PPA and its adducts takes place. A cycloaddition reaction is always preceded by the formation of a donor-acceptor complex of a PCS with a dienophile. 

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]. 

Aminodienylesters. I the cycloaddition reactions of ferf-aminodienylester with a,p-unsaturated carbonyl compounds, styrenes and quinones [148]... 

Arylethenes are inner-outer-ring dienes in which the vinyl group is linked to an aromatic system. These dienes are poorly or moderately reactive the presence of electron-donating substituents in the diene moiety markedly increases their reactivity. Their cycloadditions are usually accelerated in order to be carried out under mild conditions. 1-Vinylnaphthalene is more reactive than 2-vinyl-naphthalene and styrenes. 

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. 

An interesting parallel was found while the microwave-enhanced Heck reaction was explored on the C-3 position of the pyrazinone system [29]. The additional problem here was caused by the capability of the alkene to undergo Diels-Alder reaction with the 2-azadiene system of the pyrazinone. An interesting competition between the Heck reaction and the Diels-Alder reaction has been noticed, while the outcome solely depended on the substrates and the catalyst system. Microwave irradiation of a mixture of pyrazinone (Re = H), ethyl acrylate (Y = COOEt) and Pd(dppf)Cl2 resulted in the formation of a mixture of the starting material together with the cycloaddition product in a 3 1 ratio (Scheme 15). On the contrary, when Pd(OAc)2 was used in combination with the bulky phosphine ligand 2-(di-t-butylphosphino)biphenyl [41-44], the Heck reaction product was obtained as the sole product. When a mixture of the pyrazinone (Re = Ar) with ethyl acrylate or styrene and Pd(dppf)Cl2 was irradiated at 150 °C for 15 min, both catalytic systems favored the Heck reaction product with no trace of Diels-Alder adduct. 

Both ( )-l-phenylsulfonyl and (5)-(+)-3-p-tolylsulfmyl -alk-3-en-2-ones can exhibit high diastereoselectivity in their reactions with vinyl ethers and styrenes, with the dienophile having a dominant influence on the stereochemical outcome <96T1205,96TL3687>. Indol-2-ylideneacetic acid esters can act as both dienophile and heterodiene in cycloaddition reactions in the latter case pyrano[3,2-h]indoles are formed <96SYN519>. 

The reactivity of the prototype o-QM as heterodiene in Diels-Alder cycloaddition reactions with several substituted alkenes such as methyl vinyl ether (MVE), styrene,... 

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 low yields, which are observed among styrenyl adducts, reflect a combination of the poor reactivity of the styrene at the low temperature of the reaction. For example, the combination of t-butyl Grignard with the 2,4-bis-OBoc-benzyl alcohol 15 affords the corresponding benzopyran 50 in only 50% yield even when carried out in the presence of 5-10 equivalents of the styrene (method H, Fig. 4.27).27 Yields for substituted benzopyran styrene adducts are still lower (method G, Fig. 4.27). For example, addition of methyl lithium to 2,4-bis-OBoc-benzylaldehyde 5 followed by the addition of the dienophile and magnesium bromide affords benzopyran 51 in a paltry 27% yield. Method F is entirely ineffective in these cases, because the methyl Grignard reagent competes with the enol ether and with styrene 1,4-addition of methyl supercedes cycloaddition. 

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... 

Hofmann degradation of the nonnatural protoberberine 454 afforded the 10-membered ring base 455 (65%) in addition to the styrene-type compound (13%) (Scheme 92). Dihydroxylation of the former with N-bromosuccinimide in the presence of a large excess of hydrochloric acid and subsequent oxidation of the product diol 456 with periodic acid afforded the dialdehyde 457. On irradiation in tert-butyl alcohol 457 provided ( )-cis-alpinigenine (445) along with ( )-alpinigenine (441) as a result of endo and exo intramolecular cycloaddition, respectively, of the intermediate photodienol (221,222). 

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. 

The substitution of the exo-methylene hydrogen atoms of MCP with halogens seems to favor the [2 + 2] cycloaddition reaction by stabilizing the intermediate diradical. Indeed, chloromethylenecyclopropane (96) reacts with acrylonitrile (519) to give a diastereomeric mixture of spirohexanes in good yield (Table 41, entry 2) [27], but was unreactive towards styrene and ds-stilbene. Anyway, it reacted with dienes (2,3-dimethylbutadiene, cyclopentadiene, cyc-lohexadiene, furan) exclusively in a [4 + 2] fashion (see Sect. 2.1.1) [27], while its... 

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