Diels-Alder reaction quinodimethanes

Two approaches to convergent steroid syntheses are based on the thermal opening of benzocyclobutenes to the o-quinodimethane derivatives (see p. 80 W. Oppolzer, 1978 A) and their stereoselective intramolecular Diels-Alder cyclizations. T, Kametani (1977 B, 1978) obtained (+ )-estradiol in a six-step synthesis. The final Diels-Alder reaction occurred regio- and stereoselectively in almost quantitative yield, presumably because the exo transition state given below is highly favored over the endo state in which rings A and D would stcrically inter-... 

The Diels-Alder reaction of o-quinodimethanes (from benzocyclobutenes) with nitrogen-ubstituted enes has also been applied to alkaloids synthesis (see p. 280f. T. Kametani, 1972, 1973, 1974 W. Oppolzer, 1978 A). 

A highly efficient construction of the steroidal skeleton 166 is reported by Kametani and coworkers111 in the intramolecular Diels-Alder reaction of the a, jS-unsaturated sulfone moiety of 165 (equation 117). Thus, when the sulfone 165 is heated in 1,2-dichlorobenzene for 6h, the steroidal compound 166 can be obtained in 62% yield. The compound 166 produces estrone (167) by elimination of benzenesulfinic acid and subsequent hydrogenation of the formed double bond. The stereoselectivity of the addition reflects a transition state in which the p-tosyl group occupies the exo position to minimize the steric repulsion between methyl and t-butoxy groups and the o-quinodimethane group as shown in equation 117. 

Various o-quinodimethanes, generated in situ from o-alkenylbenzyltributyl-stannane precursors, have been used to synthesize functionalized polycycles by Diels Alder reaction with maleic anhydride, methylacrylate, dimethylfumarate and N-phenyl maleimide in the presence of electrophiles [37] (Scheme 2.16). 

Pyrano-[4,2-b]-pyrrol-5-ones (40) and pyrano-[4,3-b]-pyrrol-6-ones (41) (Figure 2.4) are stable cyclic analogs of pyrrole 2,3-quinodimethane and undergo Diels Alder reaction [40, 41] with various dienophiles to afford indole derivatives after loss of carbon dioxide. 

Indole-2,3-quinodimethanes [44] 44 are bicyclic outer-ring dienes that are widely used to prepare a variety of heterocyclic polycyclic compounds. These dienes, generated by extrusion of CO2 from lactones, are then trapped by dienophiles. Some examples of Diels Alder reactions of the dienes 44 are reported in Scheme 2.19. 

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... 

Utley et al. were able to perform Diels-Alder reactions in aqueous solution via electrogenerated or//zo-quinodimcthancs.34 They cathod-ically generated the or// o-quinodimethanes in aqueous electrolyte in the presence of /V-mcthylmaleimide, which is both the redox mediator and the dienophile. Competition from the electrohydrodimerization of /V-mcthy Irrialci midc is suppressed, allowing for the efficient formation of the endo-adduct (Scheme 12.1). 

A traceless linker for solid-phase homo- and hetero-Diels-Alder reactions was based upon resin bound quinodimethane precursors... 

Craig D, Robson MJ, Shaw SJ. Traceless linkers for solid-phase synthesis. Homo- and hetero Diels-Alder reactions of ortho-quinodimethanes. Synlett 1998 12 1381-1383. 

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). 

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],... 

An efficient method for the generation of oquinodimethanes via desilylation reaction involves treatment of a 2-[(trimethylsilylmethyl)benzyl]trimethylarmnonium iodide with fluoride ion (equation 31)64. This reaction was applied by Saegusa and coworkers for the synthesis of estrone in which an intramolecular Diels-Alder reaction of an o-quinodimethane, generated in situ, served as the key reaction (equation 32)65. 

Isochromones lose carbon dioxide on heating via retro-Diels-Alder pathway to result in o-quinodimethanes (equation 81)1241,129. An isochromone route to podophyllotoxin derivative has been described (equation 82)130. Diels-Alder adducts of a-pyrone readily extrude carbon dioxide on thermal activation to furnish cyclohexadienes, which are useful substrates in tandem Diels-Alder reactions (equation 83)131. 

Retro-Diels-Alder reactions can be used to regenerate dienes or alkenes from Diels-Alder protected cyclohexene derivatives under pyrolytic conditions144. Most of the synthetic utility of this reaction comes from releasing the alkene by diene-deprotection. However, tetralin undergoes cycloreversion via the retro-Diels-Alder pathway to generate o-quinodimethane under laser photolysis (equation 89)145. A precursor of lysergic acid has been obtained by deprotection of the conjugated double bond and intramolecular Diels Alder reaction (equation 90)146. 

Dienes can also be generated under the conditions of Diels-Alder reaction from precursors. An example of exceeding reactive diene is quinodimethane which has been synthesized from the pyrolysis of benzocyclobutene. 

The presence of a 5-hexenyl substituent in 28i allowed the o-quinodimethane 229b to be captured in an intramolecular Diels-Alder reaction, producing 230, having a tetracyclic steroidal skeleton, in a single operation (Scheme 20.47) [33, 34], The fused tetracyclic 5,6,6,5-ring system was likewise produced from 34f and 34g. 

One problem associated with An + 2n cyclizations of carbon nanotubes is the reversibility of the process, and for this reason Diels-Alder reactions have been a less used synthetic route. One of the most representative examples of Diels Alder functionalization was reported by Langa and co-workers, who performed MW-assisted addition of o-quinodimethane on pentanol-ester functionalized SWCNTs [34]. 

A review of Diels-Alder reactions of fullerenes with acyclic and cyclic dienes has been presented. The addition of substituted pyrimidine o-quinodimethanes (75) to [60]fullerenes yields novel organofullerenes (76) bearing a pyrimidine nucleus covalently attached to the Ceo cage (Scheme 26). The Diels-Alder dimerization of cyclopenta[/]phenanthrene (77) with isobenzindene (78) yields the dimer (79) in 85% yield (Scheme 27). Further evidence has been supplied to support an early reorganization of the r-network in the dimerization of 2-methoxycarbonylbuta-1,3-diene. The Lewis acid-catalysed Diels-Alder reactions of acrylate derivatives of new carbohydrate-based chiral auxiliaries with cyclohexadiene show excellent endo. exo... 

The application of indolo-2,3-quinodimethanes and their cyclic analogs in the synthesis of carbazole alkaloids has attracted wide interest since they could undergo Diels-Alder reactions with a wide variety of dienophiles to afford functionalized carbazole derivatives. This represents the shortest and most elegant method for the preparation of selectively functionalized carbazole derivatives (514). 

Miki and Hachiken reported a total synthesis of murrayaquinone A (107) using 4-benzyl-l-ferf-butyldimethylsiloxy-4fT-furo[3,4-f>]indole (854) as an indolo-2,3-quinodimethane equivalent for the Diels-Alder reaction with methyl acrylate (624). 4-Benzyl-3,4-dihydro-lfT-furo[3,4-f>]indol-l-one (853), the precursor for the 4H-furo[3,4-f>]indole (854), was prepared in five steps and 30% overall yield starting from dimethyl indole-2,3-dicarboxylate (851). Alkaline hydrolysis of 851 followed by N-benzylation of the dicarboxylic acid with benzyl bromide and sodium hydride in DMF, and treatment of the corresponding l-benzylindole-2,3-dicarboxylic acid with trifluoroacetic anhydride (TFAA) gave the anhydride 852. Reduction of 852 with sodium borohydride, followed by lactonization of the intermediate 2-hydroxy-methylindole-3-carboxylic acid with l-methyl-2-chloropyridinium iodide, led to the lactone 853. The lactone 853 was transformed to 4-benzyl-l-ferf-butyldimethylsiloxy-4H-furo[3,4- 7]indole 854 by a base-induced silylation. Without isolation, the... 

Three years later, the same authors also reported a modified Moody approach for the total synthesis of ellipticine (228). In this route, an indolopyrone is used as a stable equivalent of indolo-2,3-quinodimethane in a Diels-Alder reaction with 2-chloro-3,4-pyridyne (1267) (723). 

Quinodimethanes have been especially useful in intramolecular Diels-Alder reactions, as will be illustrated in Section 6.1.5. 

The generation and Diels Alder reaction of 4,5-bis(bromomethylene)-4,5-dihydrothiazole 39 has been investigated. 39 is a heterocyclic analogue of ortho-quinodimethanes and is generated by treating 4,5-bis(dibromomethyl)thiazole 38 with sodium iodide in dimethylformamide. 39 can be trapped in situ with symmetrical dienophiles to give substituted benzothiazoles such as 40 <98EJOC2047>. 

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