Intramolecular tether participation

Interestingly, the nucleophilic addition of water in the sequence of events giving rise to 41 represents a relevant model system for investigating the mechanism of the generation of DNA-protein cross-links under radical-mediated oxidative conditions [80, 81]. Thus, it was shown that lysine tethered to dGuo via the 5 -hydroxyl group is able to participate in an intramolecular cyclization reaction with the purine base at C-8, subsequent to one electron oxidation [81]. 

C-C bond formation mediated by silane.6,6a 6f With respect to the development of intramolecular variants, these seminal studies lay fallow until 1990, at which point the palladium- and nickel-catalyzed reductive cyclization of tethered 1,3-dienes mediated by silane was disclosed. As demonstrated by the hydrosilylation-cyclization of 1,3,8,10-tetraene 21a, the /rarcr-divinylcyclopentanes 21b and 21c are produced in excellent yield, but with modest stereoselectivity.46 Bu3SnH was shown to participate in an analogous cyclization.46 Isotopic labeling and crossover experiments provide evidence against a mechanism involving initial diene hydrosilylation. Rather, the collective data corroborate a mechanism involving oxidative coupling of the diene followed by silane activation (Scheme 15). 

When 1,3-dienes containing a tethered alcohol are subjected to Wacker-type reactions, the initial intramolecular oxypalladation event creates a 7r-allylpalladium species, which can then undergo an additional bond-forming process to effect an overall 1,4-difunctionalization of the diene with either cis- or // -stereochemistry (Scheme 18).399 An array of substrate types has been shown to participate in this reaction to generate both five- and six-membered fused or ro-oxacycles.435-437 Employing chiral benzoquinone ligands, progress toward the development of an asymmetric variant of this reaction has also been recorded, albeit with only modest levels of enantioselectivity (up to 55% ee).438... 

The presence or absence of the dioxolane protecting group in dienes dictates whether they participate in normal or inverse-electron-demand Diels-Alder reactions.257 The intramolecular inverse-electron-demand Diels-Alder cycloaddition of 1,2,4-triazines tethered with imidazoles produce tetrahydro-l,5-naphthyridines following the loss of N2 and CH3CN.258 The inverse-electron-demand Diels-Alder reaction of 4,6-dinitrobenzofuroxan (137) with ethyl vinyl ether yields two diastereoisomeric dihydrooxazine /V-oxide adducts (138) and (139) together with a bis(dihydrooxazine A -oxide) product (140) in die presence of excess ethyl vinyl ether (Scheme 52).259 The inverse-electron-demand Diels-Alder reaction of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine with 5-aminopyrazoles provides a one-step synthesis of pyrazolo[3,4-djpyrimidines.260 The intermolecular inverse-electron-demand Diels-Alder reactions of trialkyl l,2,4-triazine-4,5,6-tricarboxylates with protected 2-aminoimidazole produced li/-imidazo[4,5-c]pyridines and die rearranged 3//-pyrido[3,2-[Pg.460]

The silver(I)-mediated ring opening of halocyclopropanes has been used to construct complex frameworks through the inter- and intramolecular trapping of cationic intermediates with heteronucleophiles. An obvious extension of this work is the involvement of carbon-based nucleophiles to form new carbon-carbon bonds. In 1996, Kostikov and coworkers reported the participation of aromatic solvents in the capture of halocyclopropane-derived allyl cations even in the absence of silver(I).30 However, this early example of intermolecular attack by a carbon nucleophile is one of very few such reports. In the same year, Gassman et al. reported cationic cyclizations of gem-dibromocyclopropanes tethered to remote diene moieties (Scheme 4.16).31... 

The exploitation of intramolecular Diels-Alder reactions has included synthetic applications in the thienopyrimidine series as well. Thus, the 1,2,4-triazine with a tethered alkyne (276) participates in an intramolecular cyclization, with concomitant loss of RCN, to produce the thienopyrimidine (277) (Equation (97)) <87JOC4287>. A similar reaction occurs with oxygen analogues. 

Taylor and Raw recently designed a tethered imine-enamine cascade sequence that converts 1,2,4-triazenes into substituted pyridines. In the presence of molecular sieves, A-methylethylenediamine (147) underwent condensation with excess cyclic ketone 148 (n — 1-4) to give imine-enamine 150 (04CC508). The enamine portion of the molecule then participated in an inverse-demand Diels-Alder cycloaddition reaction with 149 to provide intermediate 151. Cycloreversion of 151 with loss of N2 then gave 152 in which the tertiary amino group underwent addition to the adjacent imine functionality to afford zwiterionic 153. Finally, an intramolecular Cope elimination produced 154 in 74-100% yield. Several other triazines were also shown to participate in this novel cascade (Scheme 27). 

In addition to alkenes and acetylenes, carbonyl-containing compounds also participate in [2+2] cycloaddition reactions with indoles. The first example of oxetane formation via the photoreaction of indoles with a carbonyl group (a type of Patemo-Biichi reaction) was reported by Machida and coworkers [34, 35] (Scheme 16), who carried out the intramolecular cyclization of iV-acetylindole with phthalimide tethered with appropriate linkers 67a-d. Interestingly, only the... 

Intramolecular [4+2] cycloaddition can also be initiated via incorporation of a dienophile into the nucleophilic participant in an oxidative dearomatization sequence (e.g., an ally lie alcohol) [45]. Additionally, dienophilic alcohol moieties can be tethered to phenol substrates... 

For unsymmetrical reactions, modest regioselectivity is observed, with the larger alkyne substituent (Scheme 7.10) and the larger alkene substituent (Scheme 7.12) ending up a- to the carbonyl group. The reaction is more efficient, and issues of regioselectivity are solved, when the reaction is carried out in an intramolecular fashion (Scheme 7.13). A chiral centre in the tether may also control the stereoselectivity of the reaction. Allenes can also provide the alkene component (Scheme 7.14) which of the two alkene moieties of the allene participates depends upon the precise structure. ... 

Also, the fluoroallenes 120 participate in intramolecular [2+2] cycloaddition reactions to tethered alkyne chains in the presence of Mo(CO)6 to give the cycloadducts 121 . 

In 2014, Rh(III)-catalyzed intramolecular annulation of alkyne-tethered acetanilides for the synthesis of fused tricyclic indoles 3 via C-H activation was developed by the groups of Liu, Jia, and Li [6a-c]. The reactions have a good substrate scope, utilize molecular oxygen as the cooxidant, and proceed with complete regioselectivity. It is interesting to note that only the sterically hindered ortho-C-H bond of the arene moiety participated in C-C bond formation (Eq. (5.3)). Similarly, the cyclization of anilides with allyl carbonates also proceeded to form 2-substituted indoles 4 (Eq. (5.4)) [6d]. 

Aside from the tethering of traditional alkenyl groups as dienophiles, it was also possible to cycloadd intramolecularly across the 2,3-indolyl double bond. Various substituted indoles of this type were synthesized (Scheme 13.70) and their participation in the IMDAF cycloaddition was evaluated. Incorporation of the amidocarbonyl group within the tether was absolutely crucial for the cycloaddition reaction to proceed in the desired manner at a reasonable temperature. For example, cycloaddition of substrate 311 without the presence of an amidocarbonyl linkage required temperatures... 

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