Norbomene 2 + 2 + 2 cycloaddition reactions

Secondary orbital interactions (SOI) (Fig. 2) [5] between the non-reacting centers have been proposed to determine selectivities. For example, cyclopentadiene undergoes a cycloaddition reaction with acrolein 1 at 25 °C to give a norbomene derivative (Fig. 2a) [6]. The endo adduct (74.4%) was preferred over the exo adduct (25.6%). This endo selectivity has been interpreted in terms of the in-phase relation between the HOMO of the diene at the 2-position and the LUMO at the carbonyl carbon in the case of the endo approach (Fig. 2c). An unfavorable SOI (Fig. 2d) has also been reported for the cycloaddition of cyclopentadiene and acetylenic aldehyde 2 and its derivatives (Fig. 2b) [7-9]. The exo-TS has been proposed to be favored over the endo- IS. 

It was found that 2-propenyloxymagnesium bromide reacts much more readily with nitrile oxides than other known dipolarophiles of electron-deficient, electron-rich, and strained types, including 3-buten-2-one, ethyl vinyl ether, and norbomene, respectively (147). Therefore, this BrMg-alkoxide is highly effective in various nitrile oxide cycloaddition reactions, including those of nitrile oxide/Lewis acid complexes. 

The 1,3-dipolar cycloaddition reactions of nitrile oxides to unsymmetrically substituted norbomenes (243) and to dicyclopentadiene and its derivatives (244) proceed with complete stereoselectivity. The approach of the dipole takes place exclusively from the exo-face of the bicycloheptane moiety, generally... 

Itoh and coworkers111 carried out tandem [2 + 2 + 2]/[4 + 2] cycloadditions catalyzed by a ruthenium catalyst. The reaction of diyne 147 with excess norbomene 148 in the presence of ruthenium catalyst 153, for example, afforded 149. Adduct 150 either dissociated from the catalyst or reacted with another equivalent of norbornene. In the latter case, a ruthenium catalyzed Diels-Alder reaction occurred, affording hexacyclic adduct 152 via 151 (equation 43). Compounds 150 and 152 were obtained in yields of 78% and 10%, respectively. Both cycloaddition reactions proceeded with complete stereoselectivity. When 1,6-heptadiyne was used instead of 147, only trace amounts of a cycloadduct were obtained. Replacing norbornene by norbornadiene, which was expected to result in polymer formation, did not afford any adduct at all. 

In addition to the role of substituents in determining regioselectivity, several other structural features affect the reactivity of dipolarophiles. Strain increases reactivity. Norbomene, for example, is consistently more reactive than cyclohexene in 1,3-dipolar cycloadditions. Conjugated functional groups also usually increase reactivity. This increased reactivity has most often been demonstrated with electron-attracting substituents, but for some 1,3-dipoles, enamines, enol ethers, and other alkenes with donor substituents are also quite reactive. Some reactivity data for a series of alkenes with a few 1,3-dipoles are given in Table 6.3. Scheme 6.5 gives some examples of 1,3-dipolar cycloaddition reactions. 

The meso-ionic l,3-dithiol-4-ones (134) participate - in 1,3-dipolar cycloaddition reactions giving adducts of the general type 136. They show a remarkable degree of reactivity toward simple alkenes including tetramethylethylene, cyclopentene, norbomene, and norbor-nadiene as well as toward the more reactive 1,3-dipolarophilic olefins dimethyl maleate, dimethyl fumarate, methyl cinnamate, diben-zoylethylene, A -phenylmaleimide, and acenaphthylene. Alkynes such as dimethyl acetylenedicarboxylate also add to meso-ionic 1,3-dithiol-4-ones (134), but the intermediate cycloadducts are not isolable they eliminate carbonyl sulfide and yield thiophenes (137) directly. - ... 

Zhang Z, Peng Z-W, Hao M-F, Gao J-G. Mechanochemical Diels-Alder cycloaddition reactions for straightforward synthesis of enrfo-norbomene derivatives. Synlett 2010 19 2895-8. 

Another example of chemical reaction which gives different products in ball mill than solution chemistry is phthalazine addition to fullerene [11], In the ball-milling conditions, intermolecular [4+2] cycloaddition of phthalazine 16 takes place, followed by spontaneous nitrogen elimination from 1 1 adduct 17. This adduct further in sohd state undergoes intermolecular cycloaddition and formation of the corresponding dimer 20 (Scheme 7.5). On the other hand, when reaction is carried out in solution, an intramolecular [4+4] addition takes place with formation of product 20, followed by retro- [2+2+2] addition and formation of product 21. This reaction sequence is characteristic for fullerene chemistry, which is not observed in analogous cycloaddition reactions of phthalazines with norbomenes [12]. 

To date, a few examples of iEDDA reactions on nucleic acids in vitro and in cells were reported. In 2010, Jaschke et al. [76] reported the first example of DNA modification by the inverse-electron-demand Diels-Alder reaction between nor-bomene dienophiles and tetrazine-derivatives. 3 - and 5 -terminal labeling, as well as internal modification of DNA with norbomenes and subsequent iEDDA reaction, was demonstrated [76]. Yields of 96 % are observed using a 1 1 stoichiometry of DNA and tetrazine derivative [76]. Lower reactant concentrations and considerably lower excess of labeling reagent (usually 1 3 stoichiometry) compared to CuAAC, as well as the absence of any toxic catalysts, shows the potential of this cycloaddition reaction for in cell and in vivo applications. 

Intermolecular cycloaddition reactions catalyzed by Cu(I) were studied by Salomon and Kochi, by Mackor and by others. The use of better soluble CuOTf instead of Cu-halides allowed reactions to be run more effectively and cleaner. Reactions studied are the 2 -t- 2 cycloaddition of norbomene giving the exo-trans-exo isomer exclusively (97 %), the analogous reaction with e d(9-dicyclopentadiene as substrate, the codimerization of norbomene with cyclooctene, the dimerization of cyclopentene, cyclohexene, cyclo-heptene and mixtures thereof. 

An effective way for introduction of a variety of heterocyclic fragments in the position 7 of the fluoroquinolone skeleton is the methodology of 1,3-dipolar cycloaddition reactions [164-167]. Indeed, the reaction of 7-azido derivative of 6-fluoroquinolone 39 with enamines of cyclic ketones and norbomene proceeds rather smoothly with the formation of the corresponding exo-l,2,3-triazolines 40 which undergo the cationic rearrangements into amidines 41 or aminonorbomane 42 [164, 165]. 7-Azido derivatives 39 are capable of reacting with heterocyclic amines to form new 7- fluoroquinolones (Scheme 20) [168]. 

Diels-Alder cycloadditions involving norbomene 57 [34], benzonorbomene (83), 7-isopropylidenenorbomadiene and 7-isopropylidenebenzonorbomadiene (84) as dienophiles are characterized as inverse-electron-demand Diels-Alder reactions [161,162], These compounds react with electron-deficient dienes, such as tropone. In the inverse-electron-demand Diels-Alder reaction, orbital interaction between the HOMO of the dienophile and the LUMO of the diene is important. Thus, orbital unsymmetrization of the olefin it orbital of norbomene (57) is assumed to be involved in these top selectivities in the Diels-Alder cycloaddition. 

A photosensitized dimerization of an isolated olefin, norbomene, has been reported by Scharf and Korte.<3) Irradiation in acetone or in the presence of acetophenone (Et = 74 kcal/mole) produced dimers (5) and (6) as major products. However, benzophenone (Et = 69 kcal/mole) failed to sensitize the reaction to (5) and (6), but in ether solution led to the quantitative formation of benzpinacol and in benzene to the oxetane (7) in 80% yield. Sensitizers of intermediate energy, such as xanthone (Et — 72 kcal/mole), demonstrated a competition between energy transfer to form triplet norbomene and cycloaddition to form the oxetane ... 

The reaction proceeds smoothly and gives 326 in 43% yield. The stereochemistry of the addition is exo with respect to the norbomene moiety and in line with the usual cycloaddition behavior of quadricyclane [358]. The norbomene double bond in 326 is easily accessible by electrophiles, and, for example, the anti-addition of benzenesulfenyl chloride proceeds quantitatively at room temperature (Scheme 4.66). 

Much less information is available about [2 + 2]-cycloadditions. These allow the formation of cyclobutane derivatives in the reaction between two alkenes, or that of cyclobutenes from alkenes and alkynes. The reaction can be achieved thermally via biradical intermediates,543 by photoreaction,544 and there are also examples for transition-metal-catalyzed transformations. An excellent example is a ruthenium-catalyzed reaction between norbomenes and alkynes to form cyclobutenes with exo structure ... 

As was mentioned, cycloaddition of unactivated hydrocarbons, namely, that of cyclopentadiene, has practical significance. 5-Vinyl-2-norbomene is produced by the cycloaddition of cyclopentadiene and 1,3-butadiene546,547 [Eq. (6.96)] under conditions where side reactions (polymerization, formation of tetrahydroindene) are minimal. The product is then isomerized to 5-ethylidene-2-norbomene, which is a widely used comonomer in the manufacture of an EPDM (ethylene-propylene-diene monomer) copolymer (see Section 13.2.6). The reaction of cyclopentadiene (or dicyclopentadiene, its precursor) with ethylene leads to norbomene548,549 [Eq. (6.97)] 550... 

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