Dienophiles benzyne

A Diels-Alder reaction is the formation of a cyclic compound from a diene and an electron-deficient alkene (a dienophile). Benzyne acts as the dienophile. 

Let us now explore the reactivity of these compounds as dienes (furan, pyrrole, thiophene) with a dienophile (benzyne) in Diels-Alder reactions. One approach that, for a long time, has been widely employed by chemists, is the use of Frontier Molecular Orbital (FMO) [19] energy gap between two of the reactants. According to this theory, the most reactive reactant pair will be the one that has a lower FMO energy gap. The reaction is predicted to be HOMO diene-controlled. If... 

Reactivity with benzyne even with the good dienophile benzyne Cgo does not react as diene but rather forms a [2 + 2] cycloadduct (Scheme 5) [110-112]. One reason for this type of reactivity is certainly due to the fact that in a hypothetical [4+ 2]-adduct one unfavorable [5,6]-double bond in the lowest energy VB structure is required. 

Its Strained triple bond makes benzyne a relatively good dienophile and when benzyne IS generated in the presence of a conjugated diene Diels-Alder cycloaddition occurs... 

Benzyne is a reactive dienophile and gives Diels-Alder products when generated m the presence of dienes In these cases it is convenient to form benzyne by dissociation of the Grignard reagent of o bromofluoro benzene... 

The reactions of pyrroles with dienophiles generally follow two different pathways involving either a [4 + 2] cycloaddition or a Michael-type addition to a free a-position of the pyrrole ring. Pyrrole itself gives a complex mixture of products with maleic anhydride or maleic acid and with benzyne reacts to give 2-phenylpyrrole rather than a product of cycloaddition (Scheme 47). 

Tetrafluorobenzyne, generally generated by the treatment of pentafluoro-benzene with butyllithium at -78 °C in ether in the presence of the substrate diene, is a versatile dienophile [9, 103, 104], In an interesting study of the use of substituted benzynes to synthesize isoindoles, tetrafluorobenzyne, 4-fluorobenzyne, and 4-(tntIuoromethyl)benzyne were shown to react in moderate yields with A7-(trimethylsiIyl)pyrroles, with the adducts being easily converted to the respective fluorinated isoindoles [705] (equation 87). 

Pyridyne is formed and reacts as a dienophile in reactions analogous to those described by Wittig and Pohmer and by Stiles and Miller in benzyne chemistry. ... 

Because of their strong aromatic character, benzene and naphthalene are very unreactive as dienes however anthracene 19 reacts with highly reactive dienophiles, such as dehydrobenzene (benzyne) 20 ... 

When benzyne is generated in the absence of another reactive molecule it dimerizes to biphenylene.132 In the presence of dienes, benzyne is a very reactive dienophile and [4+2] cycloaddition products are formed. The adducts with furans can be converted to polycyclic aromatic compounds by elimination of water. Similarly, cyclopentadienones can give a new aromatic ring by loss of carbon monoxide. Pyrones give adducts that can aromatize by loss of C02, as illustrated by Entry 7 in Scheme 11.9. 

It had been reported that, for example, 5.7.9(ll)-cholestatrienyl acetate shows a greater reactivity towards dienophiles than the corresponding 5,7-dienes 153>. We therefore investigated reactions with tetra-fluoro- and tetrachloro-benzyne 152>. The two isomeric adducts (115) and (116) were obtained in only modest yields with tetrafluorobenzyne, while with tetrachlorobenzyne no adducts or ene products were isolated. 

These reactions are found to be promoted by electron-donating substituents in the diene, and by electron-withdrawing substituents in the alkene, the dienophile. Reactions are normally poor with simple, unsubstituted alkenes thus butadiene (63) reacts with ethene only at 200° under pressure, and even then to the extent of but 18 %, compared with 100% yield with maleic anhydride (79) in benzene at 15°. Other common dienophiles include cyclohexadiene-l,4-dione (p-benzoquinone, 83), propenal (acrolein, 84), tetracyanoethene (85), benzyne (86, cf. p. 175), and also suitably substituted alkynes, e.g. diethyl butyne-l,4-dioate ( acetylenedicarboxylic ester , 87) ... 

The [2+4] cycloaddition proceeds with retention of dienophile configuration, as was clearly demonstrated by carrying out the reaction with /ra .r-l, 2-dicyanocthync leading to 148 (Scheme 58). When benzyne generated in situ was utilized, reactions gave rise to 1-borabenzobarrelene derivatives 149 and 150 (Scheme 59). 

Whenever benzyne is expected to undergo a [2+2] cycloaddition as with ketones,109 it behaves as a dienophile with aromatic thioketones. Reaction of thiobenzophenones with benzyne yields the [4+2] cycloadducts and 1H-2-benzothiopyrans.110,111 Sterically congested thiones,111 thiopivalophenones and 2, react with benzyne to give the [2+2] adducts, 2H-l-benzothietes. 

Transient intermediates like benzynes or cyclobutadiene are extremely reactive dienophile. 

Finally, it should be pointed out that the diaryne reactions of 1,2,4,5-tetrabromobenzene are stepwise. Thus the procedure described here, but using half the amounts of furan and butyllithium, can be used to prepare 6,7-dibromonaphthalene 1,4-endoxide (mp 115-117°C) in 70% yield.17 This versatile intermediate can then be used as a benzyne precursor, to make unsymmetric adducts 7 13 17 it also can be used as a dienophile.15 18... 

When benzyne is generated in the absence of another reactive molecule, it dimerizes to biphenylene.123 124 125 126 In the presence of dienes, benzyne is a very reactive dienophile, and [4 + 2] cycloaddition products are formed. 

Photooxygenations of 1,4-dioxins and their benzo- and naphtho derivatives as well as the ozonolyses of 1,4-benzo-dioxins and the cycloaddition of dithiins and 1,4-benzodithiins have been reported <1996CHEC-II(6)447>. In more recent reports, 2-chloro-l,4-benzodithiin-l,l,4,4-tetraoxide 67 was employed as a very reactive dienophile <19970393, 2005JOC5221> and was suggested as a mild alternative to the use of benzyne in [4-1-2] cycloaddition reactions (Scheme 7) <1996T14247>. 

L in Scheme 11.3) departs. Nucleophilic addition to the intermediate benzyne (step D) is readily explained by perturbative MO arguments. The extra and orbitals of benzyne are compared to those of ethylene in Figure 11.7. The aromatic n system is not involved in the special properties of benzyne. The third benzyne n bond is due to the overlap in fashion of the two sp2 hybrid orbitals which lie in the nodal plane of the intact 6 electron system. Two factors contribute to a very low LUMO for benzyne. First, the sp2 hybrid orbitals are lower in energy than the 2p orbitals from which the ethylene orbitals are constructed. Second, the intrinsic interaction between the two sp2 orbitals is less than the normal / cc since the orbitals have less p character and are tipped away from each other. The low LUMO of benzyne makes the molecule a strong Lewis acid, susceptible to attack by bases, and a reactive dienophile in Diels-Alder reactions, as we shall see later. 

Use orbital interaction diagrams to explain why benzyne is an excellent dienophile in Diels-Alder reactions. 

For a review of benzynes as dienophiles, see Hoffmann Dehydrobenzene and Cycloalkynes, Academic Press New York, 1967, pp. 200-239. For a review of the reactions of benzynes with heterocyclic compounds see Bryce Vernon Adv. Helerocycl. Chem. 1981,2, 183-229. 

Aromatic compounds can also behave as dienes.858 Benzene is very unreactive toward dienophiles very few dienophiles (one of them is benzyne) have been reported to give Diels-Alder adducts with it.859 Naphthalene and phenanthrene are also quite resistant, though naphthalene has given Diels-Alder addition at high pressures.860 However, anthracene and other compounds with at least three linear benzene rings give Diels-Alder reactions readily. The interesting compound triptycene can be prepared by a Diels-Alder reaction between benzyne and anthracene 861... 

The [,4 + 2] cycloaddition of dienophiles with 1-substituted pyrroles is also a reversible reaction, which has been utilized in the synthesis of 3,4-disubstituted pyrroles (b-77MI305oq) and, via the initial reaction of the pyrrole with benzyne, for the synthesis of isoindoles (81 AHC(29>341). The retro-reaction can be controlled and aided by a 1,3-dipolar cycloaddition of the intermediate adduct with benzonitrile oxide (74TL2163, 76RTC67) (Scheme 61). 

Incidentally, a 1,3-cycloaddition of benzyne to thiophene has been postulated (81CC124) to account for the small, but reproducible amount of benzo[ >]thiophene formed in this reaction (Scheme 79). Reactive alkynes have been successfully used as dienophiles to cycloadd with thiophenes benzene derivatives are obtained after extrusion of sulfur from the adduct (Scheme 80) (72TL605, 72TL1909, 73CB674). 

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