Cycloaddition reactions identifying

The following transformations involve generation of anionic intermediates that then undergo cycloaddition reactions. Identify the anion intermediate and outline the mechanism for each transformation. 

Schemes 16-19 present the details of the enantioselective synthesis of key intermediate 9. The retrosynthetic analysis outlined in Scheme 5 identified aldoxime 32 as a potential synthetic intermediate the construction of this compound would mark the achievement of the first synthetic objective, for it would permit an evaluation of the crucial 1,3-dipolar cycloaddition reaction. As it turns out, an enantioselective synthesis of aldoxime 32 can be achieved in a straightforward manner by a route employing commercially available tetronic acid (36) and the MEM ether of allyl alcohol (74) as starting materials (see Scheme 16).

The type of cycloaddition reaction is identified by the topological notation which will be used in a formal sense to describe the number of atoms provided... 

Despite the lack of success in the attempts at intramolecular cycloaddition with substrates 83 and 91, a moderately promising outcome was observed for the nitroalkene substrate (98, Scheme 1.10c). Heating a dilute solution of oxido-pyridinium betaine 98 in toluene to 120 °C produced a 20 % conversion to a 4 1 mixture of two cycloadducts (110 and 112), in which the major cycloadduct was identified as 110. While initially very encouraging, it became apparent that the dipolar cycloaddition reaction proceeded to no greater than 20 % conversion, an outcome independent of choice of reaction solvent. Further investigation, however, revealed that the reaction had reached thermodynamic equilibrium at 20 % conversion, a fact verified by resubmission of the purified major cycloadduct 110 to the reaction conditions to reestablish the same equilibrium mixture at 20 % conversion. 

In addition, it has been discovered that there are naturally occurring enzymes that facilitate Diels-Alder type reactions within certain metabolic pathways and that enzymes are also instrumental in forming polyketides, isoprenoids, phenylpropanoids, and alkaloids (de Araujo et al., 2006). Agresti et al. (2005) identified ribozymes from RNA oligo libraries that catalyzed multiple-turnover Diels-Alder cycloaddition reactions. 

Both C-alkylation products and the corresponding O-alkyl nitronates were detected in the reaction mixture prepared by the reactions of above mentioned salt with primary alkyl halides (Scheme 3.9, Eq. 1). However, isoxazolidines (1) are the main identified products of the reactions with secondary or tertiary alkyl halides. The possible pathway of their formation is shown in Scheme 3.9. Here, the key event is generation of the corresponding olefins from alkyl halides. These olefins can be trapped with O-nitronates that are simultaneously formed in [3 + 2]-cycloaddition reactions. Presumably, these olefins are generated through deprotonation of stabilized cationic intermediates (see Scheme 3.9). 

Kato et al. (119) explored reactions of fulvenes with a variety of mesoionic heterocycles. Unfortunately, reactions of miinchnone 38 with several fulvenes afforded complex mixtures in each case, and no identifiable products were reported, although Friedrichsen and co-workers (120-122) previously reported the reaction between mtinchnones and fulvenes to give cycloadducts. Kato et al. (123) also studied the cycloaddition reactions of tropone with several mesoionic heterocycles. Despite heroic efforts, the reaction of tropone with miinchnone 38 was complex and could not be unraveled. However, as described later, the reaction of tropone with isomtlnchnones was successful. Wu et al. (124) effected the cycloaddition between a miinchnone and fullerene-60 (Ceo) to give the corresponding dihydropyrrole in excellent yield. 

The 7r-nature of the central bond in bicyclo[1.1.0]bulane is aptly demonstrated by its cycloaddition reaction with benzyne in 1,2-dichloroethane, from which two compounds 29 and 30 were isolated in moderate yield in a ratio of 6 1. The structures of the major and the minor compounds were identified as 3-phenylcyclobutene (29) and benzobicyclo[2.2.1]hex-2-ene (30), respectively.44 Deuterium labeling experiments showed that both products resulted from attack on bicy-clo[1.1.0]butane from the endo side.44... 

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 different explanation was identified in the quenching properties of these heterocycles. Thiophene and mono methyl derivatives are efficient quenchers of triplet benzophenone. The Stem-Volmer plot showed a linear relationship [104, 105]. On the contrary, 2,5-dimethylthiophene (a compound able to give the cycloaddition reaction) is not a good quencher of benzophene [106]. N-Benzoylpyrrole also does not act as a quencher of the triplet benzophenone [106]. On the contrary, pyrrole and selenophene are quenchers of the excited benzophenone [106]. In this case, the Stern-Volmer plot is not linear. This situation is commonly encountered when the quencher employed quenches two excited states. It seems reasonable that pyrrole acts as quencher of both triplet benzophenone and the exciplex between triplet benzophenone and pyrrole [106]. 

An entirely different description emerges for the two 1,3-dipolar cycloaddition reactions that we have studied [3,4]. For such systems, the bond breaking and bond formation involves instead the shifts of well-identifiable orbital pairs, rather than any spin recouplings. Such heterolytic mechanisms, that do not pass through an aromatic structure, now seem to be a likely outcome of studies on other gas-phase concerted 1,3-dipolar cycloaddition reactions. 

Numerous methods of preparing bicyclic systems from monocyclic precursors have been reported and four general strategies can be identified. These are (i) intermolecular cyclization reactions which do not involve 1,3-dipolar cycloaddition reactions (ii) intermolecular 1,3-dipolar cycloaddition reactions (iii) nonoxidative intramolecular cyclizations and (iv) oxidative intramolecular cyclization reactions. These four general methodologies are now considered. 

As has been mentioned earlier, it is often very difficult to distinguish between and identify the roles of exciplexes (and excimers) and biradicals in cycloaddition reactions. Caldwell and Creed (1978b) have studied the cycloaddition of dimethyl fumarate to phenanthrene and found that the quantum yield of the cyclobutane photoaddition product is increased in the presence of oxygen. It was suggested that oxygen enhances intersystem crossing in the triplet biradical formed between the two reactants. Nitroxide radicals have also been found to increase intersystem crossing (Sj -> Tj) in carbocyanines when nonpolar solvents are used (Kuzmin et al., 1978). When polar solvents are employed full electron transfer takes place. 

The alkene (dienophile) component has two electrons in a Tt-bond thus, the FMO theory identifies both HOMO and LUMO (Fig. 8.16). Likewise, the diene which has four electrons in conjugated TT-system can have its HOMO and LUMO (Fig, 8,16), The most common situation finds electron-withdrawing substituents (X) on the dienophilic double bond and electron-donating substituents (R) on the diene. The bonding interaction in a normal electron demand will therefore have electrons flowing from the HOMO of the diene ( F2) to the LUMO of the dienophile (tt ). Various possible ways for the [4+2]-cycloaddition reaction to occur are shown in Fig. 8.27. 

Of course, such an effective windfall upon retrosynthetic analysis does not happen very often. Nevertheless, it is generally recommended that the retro-synthetic analysis of polycyclic structures should be directed first to the search of pathways that lead to one stroke framework assemblage. These possibilities can usually be accomplished with the help of cycloaddition reactions. In the course of the initial analysis, special emphasis should be given to identify structural features of the strategic core which might lead to the use of cycloaddition transforms. Let us examine a few more examples that illustrate the fruitfulness of such a retrosynthetic beginning. 

An interesting example of this cycloaddition is its application to identifying 2- and 3-acetyl arsabenzenes, which are formed together with 3,6-dipyridylpyridazine 39 (81JOC88I). From a cycloaddition reaction of 2,7-... 

A potent inhibitor against human a(l,3)-fucosyltransferase VI was identified from a GDP-triazole library of 85 compounds, which was produced by the Cu(I)-catalyzed [2 + 3] cycloaddition reaction between azide and acetylene, followed by in situ screening without product isolation (O Scheme 13) [155]. Kinetic evaluation of the purified inhibitor (O Scheme 13) showed that it is a competitive inhibitor against GDP-fucose with Ki = 62 nM, which would make this compound the first nanomolar and most potent inhibitor of Fuc-Ts. 

The following are some key ways of identifying cycloaddition reactions ... 

Dipolar cycloaddition reactions lead to heterocyclic products, but our concern will be only with those in which a hetero-ring is already present in reactions involving benzyne. Heterocyclic (V-oxides (Section IX) and meso-ionic heterocycles (Section VI, B) provide most examples of this type, although there are some cases of apparent 1,3-cycloaddition of benzyne to heterocycles in which no formal 1,3-dipole is identifiable. 

In another group of (2 + 2)-cycloaddition reactions, the heterocyclic nucleus reacts via an electron-deficient carbon-carbon or carbon-nitrogen double bond with electron-rich aminoacetylenes (ynamines). For instance, thiete 1,1-dioxides, JV-benzylmaleimide, and 2,3-bis(methoxycarbonyl)-7-oxabicyclo( 2.2.1 lhepta-2,5-diene reacted with 1-diethylamino-l-propyne and with 1 -phenyl-2-( 1 -pyrrolidinyl)-acetylene to give the (2 + 2)-cycloadducts 48, 49, and 50, respec-tively.35,37,53 The latter product was thermally rather unstable, and its structure was identified on the basis of its conversion with 2,4,6-tri-methylbenzonitrile oxide into 51.53 (2 + 2)-Cycloaddition via a carbon-nitrogen double bond has been reported to take place in the reactions of 3,3-dimethyl-3//-indoles and 3,4-dihydroisoquinoline with ynamines, e.g., l-dimethylamino-2-phenylacetylene, in the presence of boron trifluoride.54 The (2 + 2)-cycloadducts 52 and 53 were not isolated, but... 

Reactions with dimethyl acetylenedicarboxylate have been found to occur with 1//-indoles and also with heteroaromatics substituted with an electron-donating amino substituent, in particular a 1-pyrrolidinyl group. The first (2 + 2)-cycloaddition reaction of an indole was described by Plieninger and Wild.26 They found that 2-ethoxy-1 //-indole (57, R = H) reacts with dimethyl acetylenedicarboxylate in refluxing dioxane to give a mixture of three products, identified as cis and trans... 

The Diels-Alder cycloaddition reaction of dihydropyran with acrolein was performed in the presence of various H-form zeolites such as H-Faujasites, H-p, H-Mordenites which differ both in their shape selective as well as their acidic properties. The activity of the different catalysts was determined and the reaction products were identified. High 3delds in cycloadduct were obtained over dealuminated HY (Si/Al=15) and Hp (Si/Al=25) compared to HM (Si/Al=10). These results were accounted for in terms of acidity, shape selectivity and microporosity vs mesoporosity properties. The activity and the regioselectivity were then discussed in terms of frontier orbital interactions on the basis of MNDO calculations for thermal and catalyzed reactions by complexing the diene and the dienophile with Bronsted and Lewis acidic sites. From these calculations, Bronsted acidic sites appeared to be more efficient than Lewis acidic sites to achieve Diels-Alder reactions. 

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