Quinodimethanes cycloaddition

Scheme 6. Vollhardt s tandem alkyne cyclotrimerization/o-quinodimethane cycloaddition strategy for polycycle synthesis.

The total synthesis of ( )-estrone [( )-1 ] by Vollhardt et al. is a novel extension of transition metal mediated alkyne cyclotrimeriza-tion technology. This remarkable total synthesis is achieved in only five steps from 2-methylcyclopentenone (19) in an overall yield of 22%. The most striking maneuver in this synthesis is, of course, the construction of tetracycle 13 from the comparatively simple diyne 16 by combining cobalt-mediated and ort/io-quinodimethane cycloaddition reactions. This achievement bodes well for future applications of this chemistry to the total synthesis of other natural products. 

Following earlier application of o-quinodimethane cycloaddition methodology to the alkaloid field, Oppolzer s initially described approach to steroids involved the reaction 93 94, which apparently has not been described in detail. ... 

Finally, both Oppolzer and Kametani and their respective collaborators have adapted their steroidal syntheses based upon intramolecular o -quinodimethane cycloaddition to achieve asymmetric induction by incorporation of an optically active cyclopentane moiety in the cyclization precursor. 

Malpass, 1977). Diels-Alder type [2 + 4]-cycloadditions are possible with certain hetero-"ene components (J.R. Malpass, 1977 S.F. Martin, 1980) or with highly reactive o-quinodimethanes as diene components (W. Oppoizer, I978A). 

CATEGORY llegf CYCLIZATIONS - CYCLOADDITIONS INVOLVING PYRROLE-2,3-QUINODIMETHANE INTERMEDIATES AND EQUIVALENTS... 

This category corresponds to the construction of the carbocyclic ring by 2 + 4 cycloaddition with pyrrole-2,3-quinodimethane intermediates. Such reactions can be particularly useful in the synthesis of 5,6-disubstituted indoles. Although there are a few cases where a pyrrolequinodimethane intermediate is generated, the most useful procedures involve more stable surrogates. Both 1,5-di-hydropyrano[3,4-b]pyrrol-5(lf/)-ones[l] and l,6-dihyropyrano[4,3-b]pyrrol-6-(in)-ones[2] can serve as pyrrole-2,3-quinodimethane equivalents. The adducts undergo elimination of CO2. 

Indoles by cycloaddition with pyrrole-2,3-quinodimethane equivalents... 

Aminomethylindoles are particularly important synthetic intermediates. 3-Dimethyl-aminomethylindole (gramine) (153) and especially its quaternary salts readily undergo displacement reactions with nucleophiles (Scheme 60). Indole-2,3-quinodimethanes, generated from 2-methylgramine as shown in Scheme 61, undergo intermolecular cycloaddition reactions with dienophiles to yield carbazole derivatives (82T2745). 

The synthetic utility of o-quinodimethane generated by cheletropic elimination of S02 has been amply demonstrated by Oppolzer and Nicolaou, who have conducted an intramolecular cycloaddition coupled with the alkylation of 1,3-dihydrobenzo[c]thiophene 2,2-dioxide122. When 1,3-dihydro-l-(4-pentenyl)benzo[c]thiophene 2,2-dioxide (201) prepared from 1,3-dihydrobenzo[c]thiophene 2,2-dioxide and 4-pentenyl bromide is heated in di-n-butyl... 

Bis-o-quinodimethanes have also been used to functionalize [60]-fullerene by Diels Alder reaction. An example is the preparation of main-chain polymers with incorporated [60]-fullerene units [48] illustrated in Scheme 2.20. Cycloaddition of bis-diene 50 generated in situ from bis-sulfone 49 with [60]-fullerene leads to an oligomer mixture 51. Another type of functionalization is based on the... 

The o-quinodimethanes are very reactive, unstable dienes, which are usually prepared in situ. The cycloaddition under high pressure of the dibromo-o-quinodimethane 91, generated in situ from a,a,a, a -tetrabromo-o-xylene. 

Dell C. P. Cycloaddition in Synthesis Contemporary Organic Synthesis 1997 4 87 Keywords natural products, metal catalyzed, asymmetric reactions, Ionic reactions, transannular reactions, tethered reactions, tandem reactions, benzo-qulnones, quinodimethanes, hefero-Dlels-Alder reactions... 

The synthetic utility of o-quinodimethane generated by cheletropic elimination of SO2 has been amply demonstrated by Oppolzer and Nicolaou, who have conducted an intramolecular cycloaddition coupled with the alkylation... 

The forerunner in the Co-catalyzed [2+2+2] cycloaddition domino processes was that identified by Vollhardt and colleagues [273], with their excellent synthesis of steroids. Reaction of 6/4-1 with [CpCo(CO)2] gave compound 6/4-3 with an aromatic ring B via the intermediate 6/4-2. In this process, trimerization of the three alkyne moieties first takes place, and this is followed by an electrocyclic ring opening of the formed cyclobutene to give o-quinodimethane. This then undergoes a Diels-Alder reaction to provide the steroid 6/4-3 (Scheme 6/4.1). 

Scheme 6.2S9 Diels-Alder cycloadditions of pyrazine ortho-quinodimethane with dienophiles.

Cycloadditions selectively afford the adducts on the 6,6-ring junctions [65], and the products occasionally undergo a facile retro-Diels-Alder reaction as a consequence of the low thermodynamic stability of the adduct. Very stable Diels-Alder cycloadducts have, however, been prepared by use of different substituted o-quinodimethanes, probably because of stabilization by aromatization of the resulting adducts [66],... 

The thiophene ring system can be utilized as a synthetic scaffold for the preparation of nonthiophene materials as the sulfur moiety can be removed by reduction (desulfurization) or extrusion (loss of SO2). The extrusion of sulfur dioxide from 3-sulfolenes (2,5-dihydrothiophene 1,1-dioxides) give dienes (butadienes or o-quinodimethanes) that can be utilized to prepare six-membered rings by cycloaddition chemistry. For example, thermolysis of 3-sulfolene 120 provided tricyclic pyrazole 122 via an intramolecular cycloaddition of the o-quinodimethane 121 that results by extrusion of sulfur dioxide <00JOC5760>. Syntheses of 3-sulfolenes 123 and 124 <00S507> have recently been reported. 

A [2.2]paracydophane was prepared by dimerization of p-quinodimethane 232, which was obtained by a [4+ 2]-cycloaddition reaction of bisallene with DMAD [184], This sequence represents one of the most general approaches to functionalized para-cyclophanes. 

Copolymers of [60] fullerene and in situ generated bis-o-quinodimethanes were prepared by Gtigel and colleagues114. In order to get soluble polymers, it proved necessary to introduce flexible groups on the bis-o-quinodimethanes. A maximum of 10 [60]fullerene units were incorporated into oligomers when [60]fullerene was reacted with a 7 3 mixture of 157 and 158 (i.e. with o-quinodimethanes 159 and 160). Monosulfone 158 was added to induce the formation of triple cycloadducts of [60]fullerene. This prevented polymerization of the oligomer (quadruple cycloadditions to [60]fullerene are hard to accomplish) and enhanced its solubility. 

Unstable dienes can also be generated in situ in the presence of a dienophile. Among the most useful examples of this type of diene are the quinodimethanes. These compounds are exceedingly reactive as dienes because the cycloaddition reestablishes a benzenoid ring and results in aromatic stabilization.37 38 39... 

These cycloadditions with o-quinodimethanes provide a broad variety of useful fullerene functionalizations, since o-quinodimethanes can be prepared using several routes and the resulting cycloadducts are thermally stable [42], There exist several alternatives to the iodide-induced bromine 1,4-elimination of 1,2-bis (bromomethyl)-benzenes [44-47]. o-Quinodimethanes have been prepared by thermolysis of 3-isochromanone (42) [43], benzocyclobutenes (43) [48-50], isobenzothiophene 2,2-dioxides (44) [42] and sultines [51,52] or by photolysis of o-alkylphenones such as 45 [53-55] and could be added to Cjq in good yields (Scheme 4.7). Indene, thermally rearranged to isoindene, also adds to Cjq in similar fashion to quinodimethanes [56]. 

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