Activated dipolar

Under a variety of reaction conditions we found values for the ratio of tri-azole-to-cucurbituril of 2 or more. In one instance the value was as high as 6.8, although it is believed that in this specific case the higher reaction temperature led to a significant proportion of thermally activated dipolar cycloaddition. Triazole oligomers were identified by MS after they had been separated from the catalyst... 

The dielectric behavior of mineral filled PP composites is complicated by at least two factors one is the presence of phase heterogeneity, the other is the presence of adsorbed water. The former leads to the appearance of a new relaxation mode, interfacial relaxation and modifies the trap distribution. As to the latter, water is itself dielectrically active (dipolar relaxation) and its presence can modify the interfacial relaxation process, especially if the water layer adsorbed on the filler/matrix interface can dissolve some mobile ions. 

The regioselectivity benefits from the increased polarisation of the alkene moiety, reflected in the increased difference in the orbital coefficients on carbon 1 and 2. The increase in endo-exo selectivity is a result of an increased secondary orbital interaction that can be attributed to the increased orbital coefficient on the carbonyl carbon ". Also increased dipolar interactions, as a result of an increased polarisation, will contribute. Interestingly, Yamamoto has demonstrated that by usirg a very bulky catalyst the endo-pathway can be blocked and an excess of exo product can be obtained The increased di as tereo facial selectivity has been attributed to a more compact transition state for the catalysed reaction as a result of more efficient primary and secondary orbital interactions as well as conformational changes in the complexed dienophile" . Calculations show that, with the polarisation of the dienophile, the extent of asynchronicity in the activated complex increases . Some authors even report a zwitteriorric character of the activated complex of the Lewis-acid catalysed reaction " . Currently, Lewis-acid catalysis of Diels-Alder reactions is everyday practice in synthetic organic chemistry. 

Apart from the thoroughly studied aqueous Diels-Alder reaction, a limited number of other transformations have been reported to benefit considerably from the use of water. These include the aldol condensation , the benzoin condensation , the Baylis-Hillman reaction (tertiary-amine catalysed coupling of aldehydes with acrylic acid derivatives) and pericyclic reactions like the 1,3-dipolar cycloaddition and the Qaisen rearrangement (see below). These reactions have one thing in common a negative volume of activation. This observation has tempted many authors to propose hydrophobic effects as primary cause of ftie observed rate enhancements. 

The only example involving the 4-5 double bond in a 1-3 dipolar addition is given by the ozonolysis of the optically active 2-aminothiazOle (176) reported by Lardicci et al. (Scheme 112) (17). 

Polymerization via Nucleophilic Substitution Reaction. Halo- and nitro- groups attached to phthahmide groups are strongly activated toward nucleophilic substitution reactions. Thus polyetherimides ate synthesized by the nucleophilic substitution reaction of bishaloimides (59,60) and bisnitroimides (61,62) with anhydrous bisphenol salts in dipolar aptotic solvents. 

A" -Isoxazolines, which are readily accessible by 1,3-dipolar addition of nitrones and nitronic esters to activated alkynes, undergo facile rearrangement upon warming (<110 °C)... 

Azaquinolizinium tetrafluoroborate, 2-ethoxy-synthesis, 2, 573 1 -Azaquinolizin-2-one dipolar character, 2, 572 synthesis, 2, 575 UV spectra, 2, 572 1 - Azaquinolizin-4-one hypoglycemic activity, 2, 575 reactions, 2, 574 synthesis, 2, 575 UV spectra, 2, 572... 

Tetrazole synthesis (torn azides by dipolar cycloadd ition with activaled n ltnies or intramolecularly with nitriles in the presence of acids. 

The extent to which rearrangement occurs depends on the structure of the cation and foe nature of the reaction medium. Capture of carbocations by nucleophiles is a process with a very low activation energy, so that only very fast rearrangements can occur in the presence of nucleophiles. Neopentyl systems, for example, often react to give r-pentyl products. This is very likely to occur under solvolytic conditions but can be avoided by adjusting reaction conditions to favor direct substitution, for example, by use of an aptotic dipolar solvent to enhance the reactivity of the nucleophile. In contrast, in nonnucleophilic media, in which fhe carbocations have a longer lifetime, several successive rearrangement steps may occur. This accounts for the fact that the most stable possible ion is usually the one observed in superacid systems. 

Calculations at several levels of theory (AMI, 6-31G, and MP2/6-31G ) find lower activation energies for the transition state leading to the observed product. The transition-state calculations presumably reflect the same structural features as the frontier orbital approach. The greatest transition-state stabilization should arise from the most favorable orbital interactions. As discussed earlier for Diels-Alder reactions, the-HSAB theory can also be applied to interpretation of the regiochemistry of 1,3-dipolar cycloaddi-... 

Aryl bromides were also perfluoroethylated under these conditions [205] The key to improved yields was the azeotropic removal of water from the sodium perfluoroalkylcarboxylate [205] Partial success was achieved with sodium hepta-fluorobutyrate [204] Related work with halonaphthalene and anthracenes has been reported [206 207] The main limitation of this sodium perfluoroalkylcarboxylate methodology is the need for 2 to 4 equivalents of the salt to achieve reasonable yields A trifluoromethylcopper solution can be prepared by the reaction of bis(tri-fluoromethyl)mercury with copper powder in /V-methylpyrrolidone (NMP) at 140 °C [208] (equation 138) or by the reaction of N-trifluoromethyl-A-nitro-sotnfluoromethane sulfonamide with activated copper in dipolar aprotic solvents [209] This trifluoromethylcopper solution can be used to trifluoromethylate aro matic [209], benzylic [209], and heterocyclic halides [209]... 

Although cyclizations of fluonnated substrates to form five-membered rings were only rarely encountered in the literature prior to 1972, there has been an explosion of activity in this area recently, particularly with regard to 1,3-dipolar cycloadditions... 

The 1,3-dipolar cycloadditions offluonnatedallenes provide a rich and varied chemistry Allenes, such as 1,1-difluoroallene and fluoroallene, that have fluorine substitution on only one of their two cumulated double bonds are very reactive toward 1,3-dipoles Such activation derives from the electron attracting inductive and hyperconjugative effects of the allylic fluorine substituent(s) that give nse to a considerable lowering of the energy of the LUMO of the C(2)-C(3) n bond [27]... 

Fluorinated a., -unsaturated carbonyl compounds also are reactive dipo-larophiles Because ol the highly activating carbonyl substituent, these 1,3-dipolar cycloadditions are rapid and regiospecific Good examples are the additions of... 

Some 1,3-dipolar cycloadditions to hetero ft bond systems have been reported, including a couple of examples of additions of azides to the activated nitrile function of tnfluoroacetonitrile [30, 3I (equation 27)... 

Table 8-8 gives some nonelectrolyte transfer free energies, and Table 8-9 lists single ion transfer activity coefficients. Note especially the remarkable values for anions in dipolar aprotic solvents, indicating extensive desolvation in these solvents relative to methanol. This is consistent with the enhanced nucleophilic reactivity of anions in dipolar aprotic solvents. Parker and Blandamer have considered transfer activity coefficients for binary aqueous mixtures. 

It has been concluded from an estimate of Ki and K2 that the uncharged amino alcohol as well as the dipolar structure are present in small concentrations (24). The decomposition is strongly retarded as the pH is lowered and this phenomenon has been explained by assuming the zwitterions to be the active intermediates [Eq. (10)]. 

Active carbonyl compounds such as benzaldehyde attack the electron-rich double bond in DTDAFs to give a dipolar adduct, which immediately undergoes dissociation with formation of two molecules of 146 (64BSF2857 67LA155).Tlie existence of by-products such as benzoin led to the synthetic application of thiazolium salts in the acyloin condensation. For example, replacement of the classic cyanide ion by 3-benzyl-4-methyl-5(/3-hydroxyethyl) thiazolium salts allowed the benzoin-type condensation to take place in nonaqueous solvents (76AGE639) (Scheme 57). 

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

The normal electron-demand principle of activation of 1,3-dipolar cycloaddition reactions of nitrones has also been tested for the 1,3-dipolar cycloaddition reaction of alkenes with diazoalkanes [71]. The reaction of ethyl diazoacetate 33 with 19b in the presence of a TiCl2-TADDOLate catalyst 23a afforded the 1,3-dipolar cycloaddition product 34 in good yield and with 30-40% ee (Scheme 6.26). 

A mechanism for this reaction has been proposed [75], The first key intermediate in the reaction is the copper(I) acetylide 42. The additional ligand may be solvent or H2O. The acetylene moiety in 42 is activated for a 1,3-dipolar cycloaddition with the nitrone to give intermediate 43, with introduction of chirality in the product. A possible route to ris/traws-41 might be via intermediate 44. Finally, the cis isomer is isomerized into the thermally more stable trans-41. It should be mentioned that the mechanism outlined in Scheme 6.32 was originally proposed for a racemic version of the reaction to which water was added. 

For the activation of a substrate such as 19a via coordination of the two carbonyl oxygen atoms to the metal, one should expect that a hard Lewis acid would be more suitable, since the carbonyl oxygens are hard Lewis bases. Nevertheless, Fu-rukawa et al. succeeded in applying the relative soft metal palladium as catalyst for the 1,3-dipolar cycloaddition reaction between 1 and 19a (Scheme 6.36) [79, 80]. They applied the dicationic Pd-BINAP 54 as the catalyst, and whereas this type of catalytic reactions is often carried out at rt or at 0°C, the reactions catalyzed by 54 required heating at 40 °C in order to proceed. In most cases mixtures of endo-21 and exo-21 were obtained, however, high enantioselectivity of up to 93% were obtained for reactions of some derivatives of 1. 

The first report on metal-catalyzed asymmetric azomethine ylide cycloaddition reactions appeared some years before this topic was described for other 1,3-dipolar cycloaddition reactions [86]. However, since then the activity in this area has been very limited in spite of the fact that azomethine ylides are often stabilized by metal salts as shown in Scheme 6.40. 

Although the first metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction involved azomethine ylides, there has not been any significant activity in this area since then. The reactions that were described implied one of more equivalents of the chiral catalyst, and further development into a catalytic version has not been reported. 

Dipolar cydoadditions are one of the most useful synthetic methods to make stereochemically defined five-membered heterocydes. Although a variety of dia-stereoselective 1,3-dipolar cydoadditions have been well developed, enantioselec-tive versions are still limited [29]. Nitrones are important 1,3-dipoles that have been the target of catalyzed enantioselective reactions [66]. Three different approaches to catalyzed enantioselective reactions have been taken (1) activation of electron-defident alkenes by a chiral Lewis acid [23-26, 32-34, 67], (2) activation of nitrones in the reaction with ketene acetals [30, 31], and (3) coordination of both nitrones and allylic alcohols on a chiral catalyst [20]. Among these approaches, the dipole/HOMO-controlled reactions of electron-deficient alkenes are especially promising because a variety of combinations between chiral Lewis acids and electron-deficient alkenes have been well investigated in the study of catalyzed enantioselective Diels-Alder reactions. Enantioselectivities in catalyzed nitrone cydoadditions sometimes exceed 90% ee, but the efficiency of catalytic loading remains insufficient. 

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