Diels-Alder reactions site selectivity

The Site Selectivity of Diels-Alder Reactions. Site selectivity is another kind of regioselectivity, in which a reagent reacts at one site (or more) of a polyfunctional molecule when several sites are, in principle, available. Thus butadiene reacts faster with the quinone 6.209 at C-2 and C-3 than at C-5 and C-6. The cyano groups will lower the coefficients at C-2 and C-3 more than those at C-5 and C-6. The dimer of hexatriene is 6.210 and not 6.211, which we can similarly explain by looking at the coefficients of the frontier orbitals, essentially narrowing the problem down to assessing the Zc2 term in Equation 3.4. 

The Site Selectivity of Diels-Alder Reactions. Site selectivity is another kind of regioselectivity, in which a reagent reacts at one site (or more) of a polyfunctional molecule when several sites are,... 

The discovery that Lewis acids can promote Diels-Alder reactions has become a powerful tool in synthetic organic chemistry. Yates and Eaton [4] first reported the remarkable acceleration of the reactions of anthracene with maleic anhydride, 1,4-benzoquinone and dimethyl fumarate catalyzed by aluminum chloride. The presence of the Lewis-acid catalyst allows the cycloadditions to be carried out under mild conditions, reactions with low reactive dienes and dienophiles are made possible, and the stereoselectivity, regioselectivity and site selectivity of the cycloaddition reaction can be modified [5]. Consequently, increasing attention has been given to these catalysts in order to develop new regio- and stereoselective synthetic routes based on the Diels-Alder reaction. 

The orbital mixing theory was developed by Inagaki and Fukui [1] to predict the direction of nonequivalent orbital extension of plane-asymmetric olefins and to understand the n facial selectivity. The orbital mixing rules were successfully apphed to understand diverse chemical phenomena [2] and to design n facial selective Diels-Alder reactions [28-34], The applications to the n facial selectivities of Diels-Alder reactions are reviewed by Ishida and Inagaki elesewhere in this volume. Ohwada [26, 27, 35, 36] proposed that the orbital phase relation between the reaction sites and the groups in their environment could control the n facial selectivities and review the orbital phase environments and the selectivities elsewhere in this volume. Here, we review applications of the orbital mixing rules to the n facial selectivities of reactions other than the Diels-Alder reactions. 

Ethoxy)-allylidenecyclopropane (136a) readily underwent Diels-Alder reaction with activated dienophiles under mild conditions (Table 14) [33]. Only one regioisomer was formed with unsymmetrically substituted dienophiles such as methyl maleic anhydride (137), and quinones 138-141 (entries 2 and 3-6). AH the cycloadducts 143-147 derive from an endo approach between the two reagents. Two site-isomers were obtained in 96 4 ratio with 3-isopropyl-6-methyl-p-quinone (141) (entry 6) and the high site-selectivity observed in this... 

The site selectivity in the Diels-Alder reactions of 19 and 20 with anthracene is especially noteworthy. The cycloaddition of 19 takes place at... 

Marchand and coworkers102 reported a difference in site selectivity between the thermodynamically and kinetically controlled Diels-Alder reactions of cyclopentadiene with 2,3-dicyano-p-benzoquinone (126) (equation 37). Under kinetic conditions, the more reactive double bond of 126 reacted with cyclopentadiene affording 127, whereas the less substituted double bond reacted under thermodynamic conditions affording 128. Both reactions proceeded with complete endo selectivity. These findings were in agreement with ab initio HF/3-21G calculations. 

The reasons for the ewrfo-selectivity of Diels-Alder reactions are only useful for the reactions of dienophiles bearing substituents with lone pairs without a Lewis basic site no secondary orbital interactions are possible. But even in reactions of pure hydrocarbons the ewrfo-selectivity is observed, requiring alternative explanations. For example, the ewrfo-preference of the reactions of cyclopropene with substituted butadienes have been rationalized on the basis of a special type of secondary orbital interactions70. Apart from secondary orbital interactions which are probably the most important reason for the selec-tivities of Diels-Alder reactions, recent literature also advocates other interpretations. 

The excellent yields and regioselectivities that are observed in many zeolite-catalyzed Diels-Alder reactions are probably the result of a combination of factors. The nature of the active site plays a prime role, e.g. extraframework Al3+ or Cu2+ or Cu+. The stability of the products towards the catalyst can be important as well. For instance, in the reaction of isoprene with methyl acrylate, a completely selective reaction is observed over zeolite H-Beta (33) ... 

Figure 6.19 shows an example of the application of this technique to select a catalytic site an RNA sequence that catalyzes Diels-Alder reactions. A library containing random sequences of RNA was first prepared using a uridine derivative with a pyridyl moiety instead of the usual uridine. Each oligo-RNA chain in the library was connected to a diene part via a flexible poly(ethylene glycol) (PEG) chain. 

The complexes are isolated, characterized and used as chiral Lewis acids. Dissociation of the labile ligand liberates a single coordination site at the metal center. These Lewis acids catalyze enantioselective Diels-Alder reactions. For instance, reaction of methacrolein with cyclopentadiene in the presence of the cationic iron complex (L = acrolein) occurs with exo selectivity and an enantiomeric excess of the same order of magnitude as those obtained with the successful boron and copper catalysts (eq 3). ... 

It has been reported that several transition metal complexes catalyze the hetero-Diels-Alder reaction between a variety of aldehydes, in particular benzaldehyde, and Danishefsky s diene (Sch. 52). With the [CpRu(CHIRAPHOS)] complex the ee is modest (25 %) (entry 1) [192]. The chiral complex VO(HFBC)2 performs better in this reaction (entry 2) [193]. In experiments directed towards the synthesis of anthra-cyclones, this complex was used in cycloadditions between anthraquinone aldehydes with silyloxy dienes. One example is shown in Sch. 53 [194]. Compared with the chiral aluminum catalyst developed earlier by Yamamoto and co-workers [195], the vanadium catalyst results in lower enantioselectivity but has advantages such as ease of preparation, high solubility, stability towards air and moisture, and selective binding to an aldehyde carbonyl oxygen in the presence of others Lewis-basic coordination sites on the substrate. 

Lanthanide Lewis acids catalyze many of the reactions catalyzed by other Lewis acids, for example, the Mukaiyama-aldol reaction [14], Diels-Alder reactions [15], epoxide opening by TMSCN and thiols [14,10], and the cyanosilylation of aldehydes and ketones [17]. For most of these reactions, however, lanthanide Lewis acids have no advantages over other Lewis acids. The enantioselective hetero Diels-Alder reactions reported by Danishefsky et al. exploited one of the characteristic properties of lanthanides—mild Lewis acidity. This mildness enables the use of substrates unstable to common Lewis acids, for example Danishefsky s diene. It was recently reported by Shull and Koreeda that Eu(fod)3 catalyzed the allylic 1,3-transposition of methoxyace-tates (Table 7) [18]. This rearrangement did not proceed with acetates or benzoates, and seemed selective to a-alkoxyacetates. This suggested that the methoxy group could act as an additional coordination site for the Eu catalyst, and that this stabilized the complex of the Eu catalyst and the ester. The reaction proceeded even when the substrate contained an alkynyl group (entry 7), or when proximal alkenyl carbons of the allylic acetate were fully substituted (entries 10, 11 and 13). In these cases, the Pd(II) catalyzed allylic 1,3-transposition of allylic acetates was not efficient. 

There is a special kind of site-selectivity which has been called periselectivity. When a conjugated system enters into a reaction, a cycloaddition for example, the whole of the conjugated array of electrons may be mobilized, or a large part of them, or only a small part of them. The Woodward-Hoffmann rules limit the total number of electrons (to 6, 10, 14 etc. in all-suprafacial reactions, for example), but they do not tell us which of 6 or 10 electrons would be preferred if both were feasible. Thus in the reaction of cyclopentadiene (355) and tropone (356), mentioned at the beginning of this book, there is a possibility of a Diels-Alder reaction, leading to 354, but, in fact, an equally allowed, ten-electron reaction is actually observed,121 namely the one leading to the adduct (357). The product is probably not thermodynamically much preferred to the... 

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