Site selectivity 6 + 4 cycloadditions

Site selectivity is that selectivity shown by a reagent towards one site (or more) of a polyfunctional molecule, when several sites are, in principle, available. The preference for electrophilic attack at the ortho and para positions of X-substituted benzenes is just one of many examples discussed in Chapter 3. In cycloadditions, site selectivity always involves a pair of sites thus, butadiene reacts faster with the quinone (308) at C-2 and C-3 than at C-5 and C-6,256 and Diels-Alder reactions of anthracene (309) generally take place257 across the... 

Site selectivity is the selectivity shown by a reagent toward one site (or more) of a polyfunctional molecule when several sites, in principle, are available. In cycloadditions, site selectivity always involves a pair of sites. For example, the Diels—Alder reaction of anthracene generally takes place across the 9,10 position than across the 1,4 or 3,9a. This may be explained by the fact that the highest coefficients in the HOMO of the anthracene are at the 9,10 position. Furthermore, addition at the 9,10 position creates two isolated benzene rings, which is a more stable system than that of a naphthalene system created by the addition at the 1,4 position. 

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. 

Besides short ELPS, longer ELPs have also been conjugated to synthetic polymers. In one approach, Cu(I)-catalyzed azide-alkyne cycloaddition click chemistry was applied. For this purpose, ELPs were functionalized with azides or alkynes via incorporation of azidohomoalanine and homopropargyl glycine, respectively, using residue-specific replacement of methionine in ELP via bacterial expression [133]. More recently, an alternative way to site-selectively introduce azides into ELPs was developed. Here, an aqueous diazotransfer reaction was performed directly onto ELP[V5L2G3-90] using imidazole-1-sulfonyl azide [134]. 

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

The intramolecular dipolar cycloaddition of a nitrone with an unactivated allene was also studied [76], Treatment of 5,6-heptadien-2-one with N-methylhydroxyl-amine in refluxing ethanol yielded allenyl nitrone 78, which cyclized with the terminal allenic C=C bond to give an unsaturated bicyclic isoxazolidine. On the other hand, the site selectivity decreased with an allenic ketone having a trimethylene tether. 

Monofluoroallene (24) underwent site-selective [4+ 2]-cycloadditions at the C2-C3 bond with some 1,3-dienes, although with little face selectivities [21,129]. 

The regiochemistry of nickel mediated cycloadditions of substituted norbomadienes has been investigated in detail. The regioselectivity, exo/endo selectivity and site selectivity seem to depend strongly on the substituents on both diene and dienophile. Tetracya-noethene, for example, reacted with 2-acetyloxymethyl substituted norbomadiene on the distal side331. 

Density functional and semiempirical AMI molecular orbital calculations have been used to investigate substituent effects on site selectivity in heterocumulene-hetero-diene4 + 2-cycloadditions between ketene imines and acroleins.The new and novel heterocumulenes a, /3-unsaturated thioaldehyde S -oxides (97) behave as both diene... 

Site selectivity in ketenimine cycloadditions has been studied using photoelectron helium (Hel) spectra.3723... 

From the foregoing survey of heterocyclic hydrazonoyl halides, it appears that the main emphasis has been restricted to both their preparation and use as intermediates for further synthesis. Large areas of their chemistry, particularly regarding their physical and biological properties, remain to be developed. A deeper understanding of some aspects of their 1,3-dipolar cycloaddition reactions, such as regiochemistry and site selectivity in terms of the frontier molecular orbital method, is also needed. 

Fabian examined the geometries of the possible cycloaddition products between ketenimine and acrolein as well as of the respective transition states by ab initio calculations at the MP2/6-31G level <1997JA4253>. Two of the 12 possible products of [4+2] and [2+2] cycloaddition are oxazetidines 3 and 4 (Scheme 1). With respect to the site selectivity of the heterodiene, the [2+2] products resulting from the addition of the ketenimine onto the dienic C=C... 

Photo-[4+2] reactions of the dienone steroid 105 illustrates interesting regio-, stereo-, and site selectivities (Sch. 24) [75-78]. Reaction with 1-acetoxy-1,3-diene 106 gives trans adduct 107 in good yield, epimeric at the acetate. The trans cycloaddition was attributed to a triplet pathway rather than a twisted enone intermediate [75]. Reaction with 2,3-dimethyl-1,3-butadiene 108 leads to four [4+2] adducts, with reaction at both alkenes groups of the dienone. Note that the products of reaction at the y,5-alkene are both cis. 

An interesting aspect of the type A heteropentalenes is the fact that each molecule is associated with two 1,3-dipolar fragments (45a<->45b) and, in principle, unsymmetrical systems can form two types of cycloadduct (46 or 47). In some cases the kinetically controlled product (46) is obtained at low temperature and the thermodynamically controlled product (47) is obtained at higher temperatures (see thieno[3,4-c]pyrroles, Chapter 3.18). For a given set of reaction conditions cycloaddition is usually site specific. For example, the non-classical thiophene derivatives of general structure (48) usually add across the thiocar-bonyl ylide fragment. This site selectivity is probably determined by the relative size of the HOMO coefficients at the alternative sites of addition. 

Nucleophilic carbenes, which might show a different site selectivity, rarely undergo cycloadditions, but methoxychlorocarbene, an ambiphilic carbene, adds to the exocyclic double bond of 6,6-dimethylfulvene 6.278, to give the cyclopropane 6.277, whereas dichlorocarbene adds to one of the ring double... 

In discussing pericyclic reactions so far, we have only been looking at the denominator of the third term of equation 2-7. However, the coefficients of the atomic orbitals also play their part. They particularly influence the regio-selectivity, the site-selectivity and the periselectivity of cycloaddition reactions. The former term refers to the orientation of a cycloaddition for example, methoxybutadiene (204) gives166 the ortho adduct (206) rather than the meta adduct (203) with acrolein (205). Site-selectivity and periselectivity,... 

Site selectivity in a number of other concerted cycloadditions which are not [4 + 2] cycloadditions is also explained by frontier orbital control. Thus diphenylketene (332) reacts with isoprene (333) mostly at the more substituted double bond, and with cis-butadiene-l-nitrile (334) at the terminal double bond.263 Dichlorocarbene reacts at the terminal double bond of cycloheptatriene (335),264 and the Simmons-Smith reaction (336 + 337)265 also takes place at the site with the higher coefficients in the HOMO. 

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... 

Daub and colleagues studied the [8 + 2] cycloaddition reactions of electron-rich 8-substituted heptafulvenes with a wide variety of acceptor substituted alkenes. 8-Methoxyheptafulvene (534) proved to give the best results, the more electron-rich heptafulvenes being less reactive toward [8 -b 2] cycloaddition reactions and more prone to oxidative dimerization . The reactions of 8-methoxyheptafulvene with acceptor substituted polyenophiles 535 can in principle produce up to 8 diastereomers. The reactions proved, however, highly regioselective, the exo and site selectivities being moderate to good, and afforded mixtures of 536, 537 and 538 (equation 155, Table 31). ... 

The Site Selectivity of 1,3-Dipolar Cycloadditions. The site selectivity of 1,3-dipolar cycloadditions is the same as for the Diels-Alder reactions in Section 6.5.2.6. To give just two examples, the unsaturated ester 6.356 reacts with diazomethane at the 4,5-double bond, to give the adduct 6.357,871 and diazoacetic ester adds to the terminal double bond of 1-phenylbutadiene 6.358, giving the pyrazoline 6.359, with the product actually isolated after the loss of nitrogen being the corresponding cyclopropane.872... 

Site selectivity in ketene cycloadditions is also explained by the frontier orbitals. Diphenylketene reacts with isoprene 6.397 mostly at the more substituted double bond to give the cyclobutanone 6.398 as the major product.890 In contrast, it reacts with cw-piperylene 6.399891 and with cw-butadiene-l-nitrile 6.400890 at the less substituted double bond. In all three cases the site of attack is the double bond having the largest coefficient in the HOMO. 

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