Bifunctional cycloaddition reaction

Diazoazoles, because of charge polarization and potential bifunctional reactivity of the derived betaine, react with dipolarophiles to give cycloaddition products. Generally all the diazoazoles react with electron-rich, unsaturated derivatives. The cycloaddition reaction with isocyanates is readily observed in the case of the reactive 3-diazopyrazoles, but it is much slower with other diazoazoles. By contrast, reaction with ylides and diazoalkanes is only observed for 3-diazopyrazoles and 3-diazoindazoles. 

To enable linear templates to be used as general devices for building molecules, we have identified an ability of rigid bifunctional molecules to serve as linear templates in the organized environment of the solid state [6-12], The templates operate by assembling two complementary molecules by way of hydrogen bonds for a UV-induced [2 + 2] cycloaddition reaction [18]. By using the solid state as a medium for reaction, we have been able to circumvent the structure effects of... 

A more recent, and particularly successful, variant of the multifunctional coupling process to ladder polymers is the use of repetitive cycloaddition reactions that start from bifunctional monomers, for instance dienes and dienophiles (Diels-Alder-type cycloadditions) [2-4]. The fact, that both chains are generated simultaneously in a concerted process constitutes the important progress associated with such a route. 

Within this area, cinchona alkaloids have also catalyzed cycloaddition reactions with 2-pyrones. For example, treatment of 3-hydroxy-2-pyrone 74 and trany-3-benzoylacrytic ester 75 with 5mol% of cinchona alkaloid 76 affords cycloadduct exo-11 in 93 7 dr and 91% In this reaction, related mechanistic studies suggest that 76 (and derivatives) might function as a bifunctional catalyst by simultaneously raising the energy of the HOMO of the diene and... 

Cu(II) state mostly existed on the catalyst surface. However, after the reaction, the relative areal intensity ratio between Cu(l) and Cu(ll) states remaikably increases up to more than 1 1. Note that the Cu(ll) state after the chemical reaction might be formed by air oxidation during the sample preparation of the XPS measurement. Consequently, it is believed that the present cycloaddition reactions were proceeded by the Cu(l) species formed in situ during the reaction. The excess amount of phenylacetylene could behave as a reductant to convert Cu(l) from the activated Cu(ll) surface, via the formation of Cu(II)-acetylide. Apparently, such a well-defined hybrid system with bifunctional components provides a new way to design high-performance catalysts with high activity and reusability for gas- and solution-phase reactions. 

The catalytic asymmetric /-selective Diels-Alder annulation of a, -unsaturated /-butyrolactams with enones provided a synthesis of, y-functionalized bridged bi-or tri-cyclic dihydropyranopyrrolidin-2-ones in one step (up to 98% yield, >20 1 dr, and 99% ee) The inverse-electron-demand aza-Diels-Alder cycloaddition 0 of A-aryl-a,/0-unsaturated ketimines with enecarbamates in the presence of chiral bifunctional phosphoric acids produced 4,5,6-trisubstituted 1,4,5,6-tetrahydropyridines having three contiguous stereogenic centres in up to 84% yield, 95 5 dr, and 95% 5-Alkenylthiazoles react as in-out dienes with e-poor dienophiles in polar 44-2- 0 cycloaddition reactions. The cycloadditions are site selective. The mechanism is thought to lie between a concerted but highly asynchronous process and a stepwise process. 

By using the cinchona-alkaloid-thiourea-based bifunctional organocatalyst 55, Asano and Matsubara developed an organocatalytic formal [3 -t- 2] cycloaddition reaction, leading to optically active 1,3-dioxolanes 54 (Scheme 2.15). The reaction... 

A new bifunctional H-bond directing dienamine organocatalyst has been designed to catalyse the 2 -l- 2-cycloaddition reaction of a, -unsaturated aldehydes and nitroethenes to yield cyclobutanes with four contiguous centres. The 2-1-2-cycloaddition of 1,2-bis(trifluoromethyl)ethene-l,2-dicarbonitrile with vinyl ethers produced cyclobutanes... 

Cycl[3.2.2]azines may also be obtained by the cycloaddition of a bifunctional three-carbon unit to a 3//-pyrrolizine. Vinamidinium salts have been used for this purpose <1984CB1649>, although the reactions require the use of a strong base (sodium hydride) and extended reaction times. They appear to proceed via a stepwise mechanism, since intermediates (the conjugated enamines 354 and 355) have been isolated in certain cases (Scheme 94). 

Okamura and Nakatani [65] revealed that the cycloaddition of 3-hydroxy-2-py-rone 107 with electron deficient dienophiles such as simple a,p-unsaturated aldehydes form the endo adduct under base catalysis. The reaction proceeds under NEtj, but demonstrates superior selectivity with Cinchona alkaloids. More recently, Deng et al. [66], through use of modified Cinchona alkaloids, expanded the dienophile pool in the Diels-Alder reaction of 3-hydroxy-2-pyrone 107 with a,p-unsaturated ketones. The mechanistic insight reveals that the bifunctional Cinchona alkaloid catalyst, via multiple hydrogen bonding, raises the HOMO of the 2-pyrone while lowering the LUMO of the dienophile with simultaneous stereocontrol over the substrates (Scheme 22). 

Reactions at ring atoms consist mainly of electrophilic attack at nitrogen and cycloadditions. Examples of the reaction of 2-substituted 1,3,4-oxadiazoles with bifunctional compounds at both ring nitrogen and at the substituent, leading to cyclic systems, are included in Section 4.06.5.2 irrespective of where the initial point of attack took place. A few examples of nucleophilic attack at unsubstituted carbon are described, the more common nucleophilic attack at substituted carbon being included under reactions of the appropriate substituent (Sections 4.06.7.1-7.5). 

The latter number incorporates just the chemical step(s) of formation of triazole within cucurbituril. Since the product release step apparently is at least 100-fold slower than the actual cycloaddition, the net catalytic acceleration should be adjusted downward by that amount. An instructive alternative estimation of kinetic enhancement is to compare the extrapolated limiting rate for cycloaddition within the complex (i.e. cucurbituril saturated with both reactants, k — 1.9xl0 s ) with the uncatalyzed unimolecular transformation of an appropriate bifunctional reference substrate as in Eq. (3) (k, = 2.0x 10 s ). Such a comparison of first-order rate constants shows that the latter reaction is approximately a thousandfold slower than the cucurbituril-engendered transformation. This is attributable to necessity for freezing of internal rotational degrees of freedom that exist in the model system, which are taken care of when cucurbituril aligns the reactants, and concomitantly to an additional consideration which follows. 

A very large number of these systems with ring junction heteroatoms exists, and this number is constantly increasing. Only illustrative examples of the preparation of such systems can be given here. The synthetic methods for the formation of this type of heterocycle can be usefully classified as follows (i) various cyclocondensations between the corresponding heterocyclic derivatives and bifunctional units, (ii) intramolecular cyclizations of electrophilic, nucleophilic or (still rare) radical type, (iii) cycloadditions, (iv) intramolecular oxidative coupling, (v) intramolecular insertions, (vi) cyclization of open-chained predecessors, (vii) various reactions (quite often unusual) which are specific for each type of system. Examples given below illustrate all these cases. 

The tandem intermolecular 1,3-azaprotio cyclotransfer-intramolecular cycloaddition of divinyl sulfones 19 with oxime 193 resulted in the formation of bridged cycloadducts 194 and 195 (Scheme 42). In this reaction, the divinyl sulfone behaves either as a bifunctional dipole-generating component or as a bis-dipolarophile <1996TL4597, 1991T8297>. 

Bicyciic methy/enecyclopentanes. Trostand Chan2 have extended their synthesis of mcthylenecyclopentanes by cycloaddition of trimethylenemethanepalladium complexes to alkenes (9,454-455J3 to an intramolecular [3 + 2] cycloaddition to give bicyciic mcthylenecyclopentanes. The substrates (2) can be prepared by reaction of Ihc Grignard reagent prepared from 2-bromo-3-(trimethylsilyl)propene (1) with a suitable bifunctional aldehyde (equation I). 

Annulation to carbonyl functions has also been achieved with Trost s bifunctional reagents. Whereas the parent silyl acetate (97) yields only simple alkylation products with aldehydes under normal conditions, addition of only a few mole % of trimethyltin acetate to the reaction mixture results in facile formation of methylenetetrahydrofurans Furthermore, excellent diastereoselectivity is observed in the cycloaddition to a galactose-derived aldehyde (125) (equation 136). The tin acetate co-catalyst also promotes addition to relatively unreactive ketone carbonyls, such as in the case of benzofuran (126) and the acetylenic ketone (127) (equations 137, 138). It is remarkable that even the sterically hindered enone (128) reacts preferentially at the ketone function (equation 139). A tributyltin analog (129) of (97) has been used in the stepwise formation of a methylenetetrahydrofuran from aldehydes. Similarly, pyrrolidines can be prepared from the corresponding imines in two steps via a Lewis acid-catalyzed 1,2-addition of the tin reagent, which is then followed by a Pd-catalyzed cyclization (equation 140). Direct formation of pyrrolidine from the imine is possible if one uses a mesylate analog of (97) and a nickel(O) catalyst (equation 141). ... 

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