Diels-Alder reaction of o-quinodimethanes

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). 

Several reviews have dealt with Diels-Alder reactions of o-quinodimethanes, 2" emphasizing the more powerful, selective and thus extensively used intramolecular versions (cf. Scheme 135) introduced in 1971. 2 The most recent survey also tackled the issue of asymmetric induction by means of a chiral auxiliary group attached to the o-quinodimethane precursor.This section aims at a complementary coverage of intermolecular Diels-Alder reactions of o-quinodimethanes, underlining synthetically relevant aspects. 

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]. 

Eru, E., Hawkes, G.E., Utley, J.H.P. and Wyatt, P.B. (1995) Diels-Alder reactions of o-quinodimethanes from the cathodic reduction of a,a-dibromo-l,2-dialkylbenzenes. Tetrahedron, 51, 3033-3044. 

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... 

R. L. Funk and K. P. C. Vollhardt, Thermal, Photochemical and Transition-metal Mediated Routes to Steroids by Intramolecular Diels-Alder Reactions of o-Xylylenes(o-Quinodimethanes) , Chem. Soc. Rev., 1980,9, 41. 

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. 

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. 

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... 

In another series of related experiments Errede and coworkers prepared o-quinodimethane itself by the flash pyrolysis of o-methylbenzyltrimethylam-monium hydroxide 23 [72, 73], The conditions of this experiment were such that the o-quinodimethane was quenched soon after it was formed by cooling to - 78 °C. The product trapped out under these conditions was an approximately 25 75 mixture of 1,2,5,6-dibenzocyclooctadiene 20 and the spiro o-quinodimethane dimer 24 (Fig. 14). Dimer 24 can readily be seen to be the result of the Diels-Alder reaction of one o-quinodimethane bis-exo-methylene diene unit across one of the exo-methylene groups of another o-quinodimethane. The spirodimer... 

The synthetic strategies used for the preparation of pyrans on insoluble supports have mainly been hetero-Diels-Alder reactions of enones with enol ethers and ringclosing olefin metathesis (Table 15.33). Benzopyrans have been prepared by hetero-Diels-Alder reactions of polystyrene-bound o-quinodimethanes with aldehydes. The required quinodimethanes were generated by thermolysis of benzocyclobutanes, which were prepared in solution [308]. Other solid-phase procedures for the preparation of benzopyrans are the palladium-mediated reaction of support-bound 2-iodo-phenols with 1,4-dienes (Entry 5, Table 15.33) and the intramolecular Knoevenagel... 

Table 33 Reduction of a,a -Dibiomo-o-xylenes and Diels-Alder Reactions of the Resulting o-Quinodimethane...

Several stereochemical facets show up on Diels-Alder reactions of 7,8-disubstituted o-quinodimeth-anes. A seminal study of addition reactions of 7,S-diphenylbenzocyclobutenes provided strong evidence for a conrotatory opening of the four-membered ring, followed by a supra-supra-facial endo-selective Diels-Alder reaction with TV-phenylmaleimide, as exemplified by the transformation (607) - (609) (Scheme 137). Based on this result, it is now generally agreed that the trans relation of substituents at C-7 and C-8 in benzocyclobutenes translates, via the transient ( , )-o-quinodimethanes, e.g. (608), into the cis disposition in the corresponding cycloadducts. 

As thiazoles have significant aromatic character, they display poor reactivity in cycloaddition reactions. However, a theoretical study of the Diels-Alder reactions of a thiazole o-quinodimethane 83 with 2- and 3-bromo-5-hydroxy-naphthoquinones 84 and 85 has been carried out (Scheme 24) <2000T1701>. The findings from the PM3, molecular hardness, and ab initio (3-2 Gp) calculations of this study agree with the experimental results and support the statement that hydrogen bonding plays a crucial role on the regiocontrol of the cycloadditions. 

According to the activation volume data the Diels-Alder dimerization of 1,3-butadiene [39] and o-quinodimethane (Table 2.5, entries (3) and (4), respectively) fall into the same class of concerted processes as those discussed for 1 and 7, while the Diels-Alder dimerization of hexamethylbis(methylene)cyclopentane seems to occur in stepwise fashion. According to the activation volume data summarized in Table 2.6 only the Diels-Alder reaction of 1,3-butadiene with a-acetoxyacrylonitrile seems to proceed concertedly while all other Diels-Alder and homo-Diels-Alder adducts are probably formed in stepwise processes comparable to the corresponding competitive [2 + 2] cycloadditions. Stereochemical investigations of the chloroprene and 1,3-butadiene dimerization using specifically deuterated derivatives confirm the conclusions drawn from activation volume data. In the dimerization of ( )-l-deuteriochloroprene (17) the diastereomeric Diels-Alder adducts ISa-Dz and... 

Ring aromatic steroids (72) have been constructed by sequential cobalt-catalysed cyclisation of enetriynes (69), and intramolecular Diels-Alder reaction of the resulting o-quinodimethanes (71) derived... 

The exclusive formation of a single diastereomer with a trans ring fusion in the intramolecular Diels-Alder reaction of the o-quinone methide is consistent with the cycloaddition reaction proceeding through a preferred exo transition state from a chair conformation possessing an equatorial methyl substituent. The similar preference for a chair-exo transition state in the intramolecular [4 -t- 2] cycloadditions of substituted a,/3-unsatu-rated carbonyl compounds and substituted o-quinodimethane has been observed. A variant of these observations utilizes the room temperature fluoride-induced 1,4-elimination of trimethylsilynol for the in situ generation of an o-quinone methide enroute to the total synthesis of (+)-or (-)-hexahydrocannabinols [Eq. (48)]. ... 

Intramolecular Diels-Alder reactions of orr/jo-quinodimethanes have been used widely in the synthesis of natural products, particularly in the steroid and alkaloid fields. orr/ o-Quinodimethanes are reactive dienes and evenunreactive dienophiles can be used to form cycloadducts. The diene is prepared in situ, using one of a number of procedures (see Section 3.1.2) such as the thermal ring-opening of benzocyclobutenes. One method makes use of the ready loss of sulfur dioxide from a sulfone such as 103 (3.83). Thus, heating the sulfone 103 gave the intermediate orr/jo-quinodimethane 104, which cyclized to the tetracycle 105. This product can be converted readily into the steroid (-f)-estradiol. 

Kametani et al. [10] and Oppolzer et aL [11] reported the Diels-Alder reaction of benzocyclobutane by heating. In this reaction, the benzocy-clobutanes produced o-quinodimethane intermediates, which readily reacted with acetylenic compounds to afford cycloadduct aromatic compoimds. Furthermore, Noland et aL reported the Diels-Alder reaction of the o-quino-dimethane intermediate obtained by heating indene [12]. 

The Diels-Alder reaction with ortho-quinodimethane and the gadolinium based metallofuUerene Gd3N Cgo was achieved in 2005 (Stevenson et al. 2005). The latter compound is of significant interest because of its potential applications as MRI contrast agent (Agnoli et al. 1987). It was shown that two o-quinodimethane molecules were attached to the Gd3N Cgo surface (i.e. the formation of a bisadduct). The yield of the reaction was modest as only 0.5-1 mg of bisadduct was obtained from 5 mg of Gd3N Cgo (10-20%). For comparison, the yield of the... 

Diels-Alder reactions of the o-quinodimethanes (167) and (168) with cyclopentene, cJ5-but-2-ene, norbornadiene, and benzonorbornadiene gave mainly endo-adducts similar behaviour was noted for benzo[c]furan except that the exo-adduct predominated for addition to norbornadiene. " Since it is thought that steric effects for endo- or exo-addition to (167) and (168) are similar, an attractive interaction between endo-alkyl groups and the diene systems is proposed to explain the predominant endo-addition pathway. In contrast to the preference for endo-addition to (167)—(169) by various dienophiles, reaction of l,4-diphenyl-2-benzopyran-3-one (170) leads mainly to the production of exo-adducts. Since 1,3-diphenylinden-2-one also reacted by endo-addition, the exo-selectivity in additions to (170) is explained as resulting from inhibition of attractive endo secondary interactions by non-coplanarity of the phenyl substituents. Related to these results is the finding that isodicyclopentadiene (171) reacts with methyl acrylate under kinetic control to give the syn-adduct (172) a similar result was observed in the addition of methyl... 

Other examples of the use of intramolecular Diels-Alder reactions in preparative chemistry have appeared the o-quinodimethane (186), produced as a transient intermediate in the pyrolysis of the analogous benzocyclobutene, cyclizes to give (187 65%), the desulphurization of which (Raney nickel) affords a potential intermediate for the preparation of tetracyclic diterpenes. Elevated temperatures result in the isomerization of (188) into the internal [4 -I- 2] adduct (189) in which it is clear that a cyano-group has acted as a dienophile (189) is the result of a subsequent double-bond shift, and the structure was validated by crystallographic structure analysis. Bridged y-lactams have been successfully prepared by the intramolecular Diels-Alder reactions of NN-diallyl- and iV-(l,l-dimethylprop-2-yn-l-yl)amides of various penta-2,4-diene carboxylic acids. Thus, pyrolysis of (190) gave an 80%... 

Kamatami et have investigated the reaction of unsymmetrical benzocyclo-butenes (473) with an unsymmetrical dienophile, methyl acrylate. Thermolysis of (473) in presence of methyl acrylate in refluxing toluene gave a 1 1 mixture of the tetralin derivatives (474) and (475). The Diels-Alder reaction of the intermediate o-quinodimethane is regiospeciflc. The stereoselectivity of the reaction can be affected by conducting the reaction in presence of toluenesulphonic acid. 

The Diels-Alder reaction of meso-tetraarylporphyrins with the pyrazine o-quinodimethane mainly affords the oxidized 49a-c instead of the expected chlorin adducts. The bisaddition is site specific, occurring in opposite pyr-rolic rings and leads to 51 and 52. The novel polycyclic 50a-c, 52a, and 52b result from the coupling between the P-fused quinoxaline ring and one adjacent meso-aryl group. In contrast to compounds 49a and 51a, there... 

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