Quinodimethanes. generation

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... 

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). 

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... 

Mandelate and lactate esters have been found to generate diastereoselectivity in reactions of hydroxy-substituted quinodimethanes generated by thermolysis of benzo-cyclobutenols.88 The reactions are thought to proceed by an exo TS with a crucial hydrogen bond between the hydroxy group and a dienophile carbonyl. The phenyl (or methyl in the case of lactate) group promotes facial selectivity. 

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. 

Indole-2,3-quinodimethanes, generated from 2-methylgramine, undergo intermolecular cycloaddition reactions with dienophiles similar to that of (325) (82T2745). 

Alternatively, the o-benzoquinodimethane may be generated by fluoride-induced 1,4-elimination from trimethyl[2-(trimethylsilylmethyl)benzyl]ammonium iodide (13a). Interception with l-bromo-2-chlorocyclopropene gave the adduct 15a in 38% yield.Tetrahalocy-clopropenes were, however, unreactive. This method of o-quinodimethane generation has also been applied to pyridine derivatives, and provided a short route to l//-cyclopropa[g]quino-linc (16b).The interception was unsuccessful when the approach was applied to cyclo-propaisoquinoline. ... 

The cycloaddition of acrylate 28a to 2-quinodimethanes, generated thermally from cyclobutane 53 or the sulfone 54 gives a single product 51a, and in the same manner 50b (90%) is produced by the thermal reaction of the fumarate 38b with cyclobutane 5312. Thermal cycloaddition of 38b to z-hydroxy-T-phenyl-o-quinodimethane (56) (generated from sulfone 55) yields adduct 57 and its isomer of an unknown structure in a d.r. 95 5. The major adduct has been converted into a podophyllotoxin analog12. 

In an analogous system, it was found that a phenanthrene o-quinodimethane, generated by a reductive process, acted as a diene in [4 + 2] cycloadditions with two neutral imines to give pentacyclic adducts, although yields were rather low [Eq. (17)].68... 

Langa et al. [16] described the microwave-induced Diels-Alder reaction of o-quinodimethane, generated in situ from 4,5-benzo-3,6-dihydro-l,2-oxathiin-2-oxide (2) (sultine) [17], which led to cycloadduct 3 (Scheme 21.3). This reaction was the first application of microwave irradiation in the preparation of a functionalized Ceo [16]. 

Reductive Dehalogenation This was the first method used to produce an o-quinodimethane and has been widely applied to the formation of both 5- and 6-membered heterocyclic analogues as can be seen from the Table and from the examples in Scheme 3. The nonnal procedure uses Nal in DMF at temperatures ranging from ambient to 150 C. Activated zinc has been used extensively for non-heterocyclic o-quinodimethanes but has found little application with heterocyclic systems <91SC1055>. Yields of Diels-Alder adducts from 5-membered heterocyclic o-quinodimethanes generated by this method tend to be low to moderate and are accompanied by polymers. However, use of molecular sieves has been shown to give improved yields <92TL4499>. The elimination is most commonly carried out on the dibromo compounds but the dichloro compounds can also be used both most likely proceed via the diiodo derivative. 

Scheme 8. First example of cheletropic elimination of SO2 for o-quinodimethane generation (a), and application of the strategy as the key step in Nicolaou s total synthesis of estra-1,3,5(10)-trien-17-one (b).

Steroids.—Intramolecular Diels-Alder reactions of o-quinodimethanes, generated by thermolysis of the corresponding benzocyclobutanes, continue to form the basis of many steroid syntheses, " including estradiol derivatives, 18-hydroxyestrone, (+)-chenodeoxycholic acid, and des-A-ring steroids. Two alternative ways to obtain o-quinodimethanes, by photoenolization of o-methylphenyl ketones or by a fluoride-ion-induced elimination reaction [(191)- (192)1, have been utilized in syntheses of 19-nor-steroids and O-methyl estrone (193), respectively. 

Next, we investigated an asymmetric Diels-Alder reaction of o-quinodimethanes generated in situ from benzocyclobutenols utilizing a tartaric acid ester as a chiral auxiliary. The Diels-Alder reaction of o-quinodimethane with olefins is a useful method to construct tetrahydronaph-thalene frameworks bearing up to four stereocenters, which are key intermediates for the synthesis of polycyclic... 

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