Cation Radical Diels-Alder Cycloadditions

The cation radical Diels-Alder cycloadditions of cis- and franx-prop-1-enyl aryl ethers to cyclopenta-1,3-diene catalysed by tris(4-bromophenyl)aminium hexachloroantimonate are stepwise processes involving an intermediate distonic cation radical in which the carbocationic site is stabilized by the electron-donating functionality (Scheme 9). " ... 

Harirchian, B. and Bauld, N.L. (1989) Cation radical Diels-Alder cycloadditions in organic synthesis a formal total synthesis of (—)-(S-selrnene. Journal American Chemical Society, 111, 1826-1828. 

Cation Radical Diels-Alder Cycloadditions Historical... 

With respect to the matter of steric sensitivity, the reaction of 2,5-dimethyl-2,4-hexadiene with 1,3-cyclohexadiene is instructive [39]. Apparently, no Diels-Alder additions of this sterically hindered acyclic diene, either as the dienophilic or dienic component, have ever been reported. However, the cation radical Diels-Alder cycloaddition referred to above (Scheme 20) occurs smoothly, the readily ionizable acyclic diene serving as the dienophilic component. 

From this perspective, it emerges that the kinetic driving force for the cation radical cycloaddition relative to the corresponding neutral one can be expressed as the difference in the ionizabilities of the reactant and the transition state. As a specific example, we may consider a highly non-synchronous TS for cation radical Diels-Alder cycloaddition—which is supported by theoretical calculations (vide infra). This transition state is essentially a distonic cation radical, the radical site of which is easily ionized because the odd electron is in a non-bonding MO. In contrast, the... 

Bauld, N. L., and Yang, J. "Stereospecificity and Mechanism in Cation Radical Diels-Alder and Cyclobutanation Reactions." Org. Lett, X 773-774 (1999). Gao, D., and Bauld, N. L. Mechanistic Implications of the Stereochemistry of the Cation Radical Diels-Alder Cycloaddition of 4-(cis-2-Deuteriovinyl)anisole to 1,3-Cyclopentadiene." /. Org. Chem., 65,6276-6277 (2000). Saettel, N. J., Oxsgaard, J., and Wiesl, O. "Pericyclic Reactions of Radical Cations." Eur. /. Cftem., 1429-1439 (2001). 

The first studies on cation-radical Diels-Alder reactions were undertaken by Bauld in 1981 who showed [33a] the powerful catalytic effect of aminium cation radical salts on certain Diels-Alder cycloadditions. For example, the reaction of 1,3-cyclohexadiene with trans, iraw5-2,4-hexadiene in the presence of Ar3N is complete in 1 h and gives only the endo adduct (Equation 1.14) [33]. 

A number of electrocyclic reactions under PET conditions have been reported. In this way, A-benzyl-2.3-diphcnylaziridinc (40) underwent a 3 + 2-cycloaddition with alkene and alkyne dipolarophiles to afford substituted pyrrole cycloadducts (41) via the radical cation intermediate (42) see Scheme 7.80 Elsewhere, novel arylallenes have been used as dienophiles in a radical cation-catalysed Diels-Alder cycloaddition reaction with 1,2,3,4,5-pentafluromethylcyclopentadiene, which often occurred with peri-, chemo-, facial- and stereo-selectivity.81... 

The uncatalyzed Diels-Alder reaction is well known to be highly stereospecific, preferentially occurring via syn addition to both the diene and dienophilic components. Stereochemical studies of the cation radical Diels-Alder reaction have confirmed an analogous stereospecificity in two distinctly different systems. The initial study was carried out using the cycloaddition of the three geometric isomers of 2,4-hexadiene as dienophilic components and 1,3-cyclohexadiene as the diene component [39]. Each of the three isomers of the acyclic diene was found to add stereo-specifically to cyclohexadiene. In a more recent study, the cis and trans isomers of 1,2-diaryloxyethenes were found to add stereospecifically to 1,3-cyclopentadiene (Scheme 17) and also to 2,3-dimethyl-l,3-butadiene [46]. 

Although neutral Diels-Alder reactions of stilbene as a dienophile are unknown, the cation radical Diels-Alder reaction cited above occurs smoothly [51]. Trans stilbenes yields only trans adducts, while cw-stilbenes yield primarily, but not exclusively, cis adducts. The stereospecificity of the cycloaddition step in the latter reaction system was, however, not readily evaluated because of the occurrence of competing cis to trans isomerization of the starting material. It was established, however, that at low conversions, the reaction tends toward stereospecificity. Since cw-stilbene is much less readily ionizable than tran -stilbene, the Diels-Alder cycloadditions in the cw-stilbene system were studied using the p,p -6. vciQ hy derivative. 

It should also be born in mind that electron rich alkenes are also especially reactive neutral components of cation radical cycloaddition reactions, since they are also highly nucleophilic. Consequently, in appropriate instances, either role sense of the cation radical Diels-Alder reaction may be operative, i.e. either the diene or the electron rich alkene could be reacting as the cation radical. 

In view of the demonstrated stereospecificity of at least some cation radical Diels-Alder reactions, it is at least possible that these reactions, like the neutral Diels-Alder, are true pericyclic reactions, i.e., they may occur via a concerted cycloaddition. The results of a variety of calculations, however, make clear that the cydoadditions must at least be highly non-synchronous, so that the extent of the formation of the second bond, which completes the cyclic transition state, is no more than slight [55, 56]. If the cation radical Diels-Alder reaction is nevertheless interpreted as pericyclic and the concept of orbital correlation diagrams is applied to them, it emerges that the cycloaddition is symmetry allowed if the ionized (cation radical) component is the dienophile, but forbidden if it is the diene [39, 55], The former mode of reaction has been referred to as the [4-1-1] mode, and the latter as the [3 -t- 2] mode. Interestingly, the great majority of cation radical Diels-Alder reactions thus far observed seem to represent the formally allowed [4-1-1] mode. An interesting case in point is the reaction of l,l -dicyclohexenyl with 2,3-dimethylbutadiene (Scheme 24) [57]. 

The cation-radical Diels-Alder reactions of cis- and fran5 -l,2-(diaryloxy)ethenes with butadienes are stereospecific, in agreement with a concerted cycloaddition mechanism. " Tris(4-bromophenyl)aminium hexachloroantimonate catalyses the two-step, non-stereospecific cation-radical Diels-Alder reaction of cis- and traui-prop-l-enyl aryl ethers with cyclopenta-1,3-diene in CH2CI2 solution. 

Electron transfer to or from a conjugated tr-system can also induce pericyclic reactions leading to skeletal rearrangements. A typical example is the Diels-Alder cycloaddition occurring after radical-cation formation from either the diene or the dienophile [295-297], The radical cation formation is in most cases achieved via photochemically induced electron transfer to an acceptor. The main structural aspect is that the cycloaddition product (s Scheme 9) contains a smaller n-system which is less efficient in charge stabilization than the starting material. Also, the original radical cations can enter uncontrollable polymerization reactions next to the desired cycloaddition, which feature limits the preparative scope of radical-type cycloaddition. 

Bauld and coworkers, especially, developed the analogous Diels-Alder (4 + 2) cycloaddition reactions. These reactions are conveniently catalyzed by tris(4-bromophenyl)aminium hexachloroantimonate (78) or by photosensitization with aromatic nitriles. The radical cation-catalyzed Diels-Alder reaction is far faster than the uncatalyzed one, and leads to some selectivity for attack at the least substituted double bond for the monoene component (Scheme 18, 79 —> 80), but only modest endo selectivity (e- and x-80) [105]. Cross reactions with two dienes proved to be notably less sensitive to inhibition by steric hindrance of alkyl groups substituted on the double bonds than the uncatalyzed reactions, as cyclohexadiene adds detectably even to the trisubstituted double bond of 2-methylhexadiene (82), producing both 83 and 84. Dienes such as 85 react with donor-substituted olefins (86) to principally give the vinylcyclobutene products 87, but they may be thermally rearranged to the cyclohexene product 88 in good yield [105]. Schmittel and coworkers have studied the cation radical catalyzed Diels-Alder addition of both... 

Since their original discovery [362] pericyclic radical cation reactions have been developed for various synthetic formats. The methodology nowadays is most advanced for intra- [363] and intermolecular Diels-Alder cycloadditions [364], and... 

Scheme 33. Only two out of 32 possible isomers of 32 are formed in this highly peri-, chemo-, regio-and stereoselective radical cation Diels-Alder cycloaddition [365b, cj.

An intriguing competition arises in the context of cation radical cycloadditions (as in the context of Diels-Alder cycloadditions) which involve at least one conjugated diene component. Since both cyclobutanation and Diels-Alder addition are extremely facile reactions on the cation radical potential energy surface, it would not be surprising to find a mixture of cyclobutane (CB) and Diels-Alder (DA) addition to the diene component in such cases. Even in the cyclodimerization of 1,3-cyclohexadiene, syn and anti cyclobutadimers are observed as 1 % of the total dimeric product. Incidentally, the DA dimers have been shown not to arise indirectly via the CB dimers in this case [58]. The cross addition of tw 5-anethole to 1,3-cyclohexadiene also proceeds directly and essentially exclusively to the Diels-Alder adducts [endo > exo). Similarly, additions to 1,3-cyclopentadiene yield essentially only Diels-Alder adducts. However, additions to acyclic dienes, which typically exist predominantly in the s-trans conformation which is inherently unsuitable for Diels Alder cycloaddition, can yield either exclusively CB adducts, a mixture of CB and DA adducts or essentially exclusively DA adducts (Scheme 26) [59]. 

Evidence for the operation of cation radical mechanisms for cycloaddition has often been provided by means of a comparison of the results obtained for various methods of generating cation radicals. For example, in the Diels-Alder cycloaddition of phenyl vinyl sulfide to 1,3-cyclopentadiene (Scheme 36) the same adducts are formed whether the cation radicals are generated by chemical ionization (aminium salt), photochemical ionization (the PET method), or electrochemical ionization (anodic oxidation) [65]. 

Scheme 62. Cation radical vs. carbocationic Diels-Alder cycloaddition reactions.

A tris(4-bromophenyl)ammonium hexachloroantimonate catalyst has been utilized to promote a cation radical mechanism in the Diels-Alder cycloaddition polymerization of a bis(diene) with an ionizable bis(dienophile) (Scheme 2). The polymers were obtained with molecular weights up to ca 10 000 and a polydispersity index of ca 2. The electron-transfer reactions of phenols and its derivatives are also important to the polymer industry for the stabilization of polymers, fats and oils. Pulse radiolysis of naphthols and hydroxybiphenyls in n-butyl chloride at room temperature forms two species-phenol-type radical cations and phenoxyl-type radicals. Two different electron-transfer channels are proposed. The naphthol and hydroxybiphenyl radical cations show increased stability compared with phenol radical cations, presumably due to extensive delocalization over the whole aromatic system. 

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