Ortho cycloaddition

The reaction is illustrated by the intramolecular cycloaddition of the nitrilimine (374) with the alkenic double bond separated from the dipole by three methylene units. The nitrilimine (374) was generated photochemically from the corresponding tetrazole (373) and the pyrrolidino[l,2-6]pyrazoline (375) was obtained in high yield 82JOC4256). Applications of a variety of these reactions will be found in Chapter 4.36. Other aspects of intramolecular 1,3-dipolar cycloadditions leading to complex, fused systems, especially when the 1,3-dipole and the dipolarophile are substituted into a benzene ring in the ortho positions, have been described (76AG(E)123). 

Several examples of [5C+1S] cycloaddition reactions have been described involving in all cases a 1,3,5-metalahexatriene carbene complex as the C5-syn-thon and a CO or an isocyanide as the Cl-synthon. Thus,Merlic et al. described the photochemically driven benzannulation of dienylcarbene complexes to produce ortho alkoxyphenol derivatives when the reaction is performed under an atmosphere of CO, or ortho alkoxyanilines when the reaction is thermally performed in the presence of an isonitrile [111] (Scheme 63). In related works, Barluenga et al. carried out analogous reactions under thermal conditions [36a, c, 47a]. Interestingly, the dienylcarbene complexes are obtained in a first step by a [2+2] or a [3S+2C] process (see Sects. 2.3 and 2.5.1). Further reaction of these complexes with CO or an isonitrile leads to highly functionalised aromatic compounds (Scheme 63). 

The ortho-para rule is explained by FMO theory on the basis of the orbital coefficients of the atoms forming the cr-bonds. The regiochemistry is determined by the overlap of the orbitals that have larger coefficients (larger lobes in Scheme 1.15). The greater the difference between the orbital coefficients of the two end atoms of diene and two atoms of dienophile, which form the two cr-bonds, the more regioselective the cycloaddition. 

Lewis-acid-catalyzed cycloadditions of dienophiles, such as a,/l-unsaturated carbonyl compounds, with open-chain carbon-dienes, are generally highly ortho-para regioselective because the oxygen complexation increases the difference of LUMO coefficients of the alkene moiety. 

Cycloaddition reactions of (E)-l-acetoxybutadiene (18a) and (E)-l-methoxy-butadiene (18b) with the acrylic and crotonic dienophiles 19 were studied under high pressure conditions [9] (Table 5.1). Whereas the reactions of 18a with acrylic dienophiles regioselectively and stereoselectively afforded only ortho-enJo-adducts 20 in fair to good yields, those with crotonic dienophiles did not work. Similar results were obtained in the reactions with diene 18b. The loss of reactivity of the crotonic dienophiles has been ascribed to the combination of steric and electronic effects due to the methyl group at the )S-carbon of the olefinic double bond. 

The symmetrical bis(ylidyl)phosphenium chlorides 103, obtained from the reaction of trimethylsilyl ylides 102 with PCI3 are the first phosphenium salts which do not need counterions of low basicity such as AICI4 to be isolated (Scheme 30) [119]. The explanation of their stability lies in the delocalisation of the phosphenium charge in the two phosphonium parts. The reactivity study of these species is reported and for example the phosphenium 103 (R=Ph) adds ortho quinones to the central phosphorus to give the corresponding dioxaphospholenium salts 104 via a [4-1-1] cycloaddition. 

A dipolarophile bearing an ionic group and an associated counterion provides enhanced selectivity as has been recently demonstrated by Raposo and Wilcox [14]. Cycloaddition of benzonitrile 4 and the uncharged amine 5 a (a chiral phenylmaleimide derivative) in THE or chloroform provides a mixture of cycloadducts 6-9a in 1 4 4 4 diastereomeric ratio (i.e., 8 5 in favor of the methyl face approach of the dipolarophile. The ortho-substituents of the... 

As expected, other enol ethers work well in these procedures. For example, Jones and Selenski find that implementation of method F, which occurs by addition of MeMgBr to benzaldehyde 5 in the presence of dihydropyran (DHP) at 78 °C affords a 66% yield of the corresponding tricyclic ketal 59 with better than 50 1 endo diastereoselectivity (Fig. 4.31).27 On the contrary, Lindsey reports use of method H with the benzyl alcohol 35 and diethylketene acetal. The cycloaddition reaction occurs almost instantaneously upon deprotonation of the benzyl alcohol 35 by f-butyl-magnesium bromide in the presence of the ketene acetal and yields the corresponding benzopyran ortho ester 60 in a 67% yield.29... 

The synthesized CPMV-alkyne 42 was subjected to the CuAAC reaction with 38. Due to the strong fluorescence of the cycloaddition product 43 as low as 0.5 nM, it could be detected without the interference of starting materials. TMV was initially subjected to an electrophilic substitution reaction at the ortho-position of the phenol ring of tyrosine-139 residues with diazonium salts to insert the alkyne functionality, giving derivative 44 [100]. The sequential CuAAC reaction was achieved with greatest efficiency yielding compound 45, and it was found that the TMV remained intact and stable throughout the reaction. 

Scheme 6.2S9 Diels-Alder cycloadditions of pyrazine ortho-quinodimethane with dienophiles.

That this difference in (4+2)-cycloaddition behavior most likely has steric origins—the methyl groups in 150 or the derived monoadduct preventing an ortho -addition of two equivalents of the dienophile—is supported by the observation that permethyl[6]radialene 95 is inert even towards the extremely reactive dienophile 4-phenyl-1,2,4-triazolinedione68. 

The stannaphosphenes R2Sn=PAr (R = (Me3Si)2CH or 2,4,6-triisopropylphenyl, Ar = 2,4,6-tri-f-butylphenyl) can be prepared by elimination of HF across the FSn-PH unit with /-butyllithium, but no crystal structures appear yet to have been reported. Protic reagents add across the Sn=P bond, and enones, 1,2-diones, and ortho-qmnones react by [2+4] cycloaddition.593-595... 

This formally [3+2+1] cycloaddition reaction proceeds with remarkable regioselectivity when unsymmetrical alkynes 1 are used. In this case, it is observed that the larger substituent (e.g. Ri in Figure 1) is incorporated ortho to the phenol function [4], with only few exceptions [5,6]. 

To rationalize the enantioselectivity of the TADDOL-catalyzed HDA reaction between Danishefsky s diene and benzaldehyde, eight possible diastereomeric transition states of different regio- and stereochemistry should in principle be considered for comprehensive analysis. The cycloaddition between the model diene and benzaldehyde can take place along two regio-isomeric meta (C1-06, C4-C5 bond formation) and ortho (C1-C5, C4-06 bond formation) reaction channels. For both of these pathways, an exo- and an endo-approach can be formulated (Scheme 11) [64]. 

Acyltriphenylphosphonium methylides (98) react with 86 in an 8 + 2 cycloaddition to afford intermediate 99. This then loses triphenylphos-phane oxide to yield 100. H-NMR was utilized to elucidate structure 100 Ortho protons in 100 were deshielded R = Ph was taken as support. 

Fusion of the imidazole ring to pyrrolo-benzothiadiazepine 340 can be achieved by straightforward TosMIC cycloaddition approach (Scheme 72, Section 4.2 (1994JHC1033)). An alternative sequence starts with the addition of nitromethane to the C-N double bond on the thiadiazepine ring, nitro group reduction and manganese oxide oxidation of the intermediate dihydroimidazole derived from amine 342 and tiiethyl ortho formate. 

Hydrogenated isoxazole derivatives were obtained by single electron transfer (SET) cyclization of /9,y-unsaturated oximes , by thermal [4- -2] cycloaddition of aldox-imes or ketoximes to conventional dienophiles or isomerization/cyclization of an ortho halogeno or nitro-substituted amidoximes. Preparation of 1,4-disubstituted 3-hydroximino-2-nitro-l-butenes and their oxidative cyclization to 4-nitroisoxazoles are reported " . Synthesis of fluorine-containing substituted isoxazolidines as well as isoxazoles by ultrasonic methods has been also described. 

Trimethyl-2-azidobiphenyl thermolyzed in n-hexadecane gave only 4% 2,4,9-trimethylcarbazole, that is, the product of nitrene insertion into the ortho C-methyl bond the main products were 2 -amino-2,4,6-trimethyl-biphenyl and 250 (R = Me). An intramolecular dipolar cycloaddition com-... 

Planar chiral arene Cr(CO)3 complexes have been shown to undergo highly diastereoselective cycloadditions and Kiindig has extended this protocol to the [3+2] cycloadditions of azomethine ylides (96). Enantiopure ortho- substituted p -benzaldehyde complex 337 underwent condensation with an ot-amino ester to afford imine 338 in the presence of EtaN. Subsequent treatment with methyl acrylate at ambient temperamre in the presence of LiBr and EtaN delivered cycloadduct 339, with excellent stereoinduction and high material yield. Photoinduced oxidative decomplexation in air furnished the final arylpyrrolidines (Scheme 3.114). 

Conformational constraints induced by various ortho-substitutents in 1-aUyloxy-2-azidomethylbenzenes (97) were used to accelerate intramolecular cycloadditions of the azide group to alkenes (21) (Scheme 9.21). For the unsubstituted azide 96, high temperature was required for the cycloaddition and the yield of the cycloadduct 100 was low. The monosubstituted azide 97 underwent cycloaddition in refluxing benzene in 10 h to give the cycloadduct 101 in good yield. Disubstituted azides 98 and 99 underwent 1,3-dipolar cycloaddition in 5-7 h to give the triazolines 102 and 103. 

Wilcox and co-workers (145) reported that the stereoselectivity of 1,3-dipolar cycloaddition reactions can be controlled in a predictable manner when ion pairs are located at a proper position near the reaction site (Scheme 11.40). He has employed an A-phenylmaleimide substrate having a chiral center in the substituent at ortho position of the phenyl group. Due to serious steiic hindrance, this phenyl group suffers hindered rotation around the aryl-nitrogen bond (rotation barrier 22 kcal/mol). Four diastereomeric cycloadducts are possible in the cycloaddition step with a nitrile oxide. When the cycloaddition reaction is carried out in... 

The present procedure of in situ generation and trapping of 2,3-dicyanobutadiene in the presence of olefins overcomes these problems and affords the [4 + 2]-cycloadducts in good yields, particularly in the case of olefins possessing a strained double bond.2 Substituted 1,2-dicyanocyclohexenes prepared by the in situ [4 + 2]-cycloadditions can be dehydrogenated to new aromatic ortho-dinitriles. For example, 2,3-dicyanofluorene is prepared in... 

The irradiation of benzenes with alkenes provides a fascinating array of photochemical reactions, not least because it converts the aromatic substrates into polycyclic, non-aromatic products. In principle, benzene can undergo reaction across the 1,2-(ortho). 1,3-(meta), or 1,4-(para) positions the 1,3-cycloaddition is structurally the most complex, but it is the predominant mode of reaction for many of the simplest benzene/alkene systems. The products are tricyclic compounds with a fusion of two five-membered rings and one three-membered ring, and an example is the reaction of benzene with vinyl acetate (3.411. For monosubstituted benzenes there can be a high... 

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