Dipolarophiles alkynes

A novel pyrolytic method of generating nitrile ylides in situ was reported by Burger [44] (equation 45) Such nitrile ylides react with various dipolarophiles alkynes [44] (equation 46), nitriles [45] (equation 47), dimethyl azodicarboxylate [45], aldehydes [45], and nitroso compounds [46]... 

The mechanism of the reaction has generally been discussed in terms of a thermally allowed concerted 1,3-dipoIar cycloaddition process, in which control is realized by interaction between the highest occupied molecular orbital (HOMO) of the dipole (diazoalkane) and the lowest unoccupied molecular orbital (LUMO) of the dipolarophile (alkyne).76 In some cases unequal bond formation has been indicated in the transition state, giving a degree of charge separation. Compelling evidence has also been presented for a two-step diradical mechanism for the cycloaddition77 but this issue has yet to be resolved. 

Anhydro-3-hydroxy-2-phenylthiazolo[2,3-6]thiazolylium hydroxide (407) underwent ready thermal reaction with alkynic and alkenic dipolarophiles in refluxing toluene. With the former dipolarophile sulfur was lost from the intermediate 1 1 cycloadduct (408) to give the substituted 5H-thiazolo[3,2- i]pyridin-5-ones (409). With the latter, the intermediate (410) lost H2S, also forming (409). 

The 1,3-dipolar molecules are isoelectronic with the allyl anion and have four electrons in a n system encompassing the 1,3-dipole. Some typical 1,3-dipolar species are shown in Scheme 11.4. It should be noted that all have one or more resonance structures showing the characteristic 1,3-dipole. The dipolarophiles are typically alkenes or alkynes, but all that is essential is a tc bond. The reactivity of dipolarophiles depends both on the substituents present on the n bond and on the nature of the 1,3-dipole involved in the reaction. Because of the wide range of structures that can serve either as a 1,3-dipole or as a dipolarophile, the 1,3-dipolar cycloaddition is a very useful reaction for the construction of five-membered heterocyclic rings. 

Numerous examples demonstrate that perfluoroalkylated alkynes are quite reactive dipolarophiles. Terminal alkynes, such as 3,3,3-trifIuoropropyne, exhibit... 

The types of cycloadditions discovered for enamines range through a regular sequence starting with divalent addition to form a cyclopropane ring, followed by 1,2 addition (i) of an alkene or an alkyne to form a cyclo-cyclobutane or a cyclobutene, then 1,3-dipolar addition with the enamine the dipolarophile 4), and finally a Diels-Alder type of reaction (5) with the enamine the dienophile. 

The 2n component 2, the so-called dipolarophile (analogously to the dieno-phile of the Diels-Alder reaction) can be an alkene or alkyne or a heteroatom derivative thereof. Generally those substrates will be reactive as dipolarophiles, that also are good dienophiles. 

The 1,3-dipolar eyeloaddition, also known as the Huisgen cycloaddition, is a elassie reaetion in organic chemistry consisting in the reaetion of a dipolar-ophile with a 1,3-dipolar compound that allows the produetion of various five-membered heteroeyeles. This reaction represents one of the most productive fields of modern synthetic organic chemistry. Most dipolarophiles are alkenes, alkynes, and molecules possessing related heteroatom functional... 

The other reactant in a dipolar cycloaddition, usually an alkene or alkyne, is referred to as the dipolarophile. Other multiply bonded functional groups such as imine, azo, and nitroso can also act as dipolarophiles. The 1,3-dipolar cycloadditions involve four it electrons from the 1,3-dipole and two from the dipolarophile. As in the D-A reaction, the reactants approach one another in parallel planes to permit interaction between the tt and tt orbitals. 

Nitrones, reactive 1,3-dipoles, react with alkenes and alkynes to form isoxazolidines and isoxazolines, respectively. With monosubstituted olefinic dipolarophiles, 5-substituted isoxazolidines are generally formed predominantly however, with olefins bearing strongly electron-withdrawing groups, 4-substituted derivatives may also be formed.631... 

In another variant of these intramolecular 1,3-dipolar cycloadditions, the alkyne-containing amino acid amide 183, when reacted with acetic anhydride, produces a zwitterionic thiazolo-oxazolium intermediate, which may then react intramolecularly with the dipolarophile and give the triheterocycle 184 < 1999J(P 1) 1219, 2002JOC4045> (Equation 18). The benzo-fused analogue 185 is obtained similarly (Equation 19). 

One obvious synthetic route to isoxazoles and dihydroisoxazoles is by [3+2] cycloadditions of nitrile oxides with alkynes and alkenes, respectively. In the example elaborated by Giacomelli and coworkers shown in Scheme 6.206, nitroalkanes were converted in situ to nitrile oxides with 1.25 equivalents of the reagent 4-(4,6-di-methoxy[l,3,5]triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) and 10 mol% of N,N-dimethylaminopyridine (DMAP) as catalyst [373], In the presence of an alkene or alkyne dipolarophile (5.0 equivalents), the generated nitrile oxide 1,3-dipoles undergo cycloaddition with the double or triple bond, respectively, thereby furnishing 4,5-dihydroisoxazoles or isoxazoles. For these reactions, open-vessel microwave conditions were chosen and full conversion with very high isolated yields of products was achieved within 3 min at 80 °C. The reactions could also be carried out utilizing a resin-bound alkyne [373]. For a related example, see [477]. 

A novel class of activators for chloride conductance in the cystic fibrosis transmembrane conductance regulator protein has been identified. These 3-(2-benzy-loxyphenyl)isoxazoles and 3-(2-benzyloxyphenyl)isoxazolines have been synthesized employing the 1,3-dipolar cycloaddition of nitrile oxides with various alkene and alkyne dipolarophiles (490). 

In the frequency of their use in 1,3-dipolar cycloadditions to nitrones, alkynes constitute the second group of dipolarophiles after alkenes. They are of particular interest due to the fact that isoxazolines, the products of initial cycloadditions,... 

Intermolecular Reactions Dimethyl acetylenedicarboxylate (DMAD) is frequently used as an alkyne dipolarophile (23, 24, 126b, 152, 241, 333). 

Other approaches including 1,3-dipolar cycloadditions of azomethine ylides or nitroxides to alkene or alkyne dipolarophiles have been applied to the synthesis of these ring systems. 

Alkyne dipolarophiles such as methyl propiolate or DMAD reacted with ylides derived from [l,2,3]triazolo[l,5-tf]-pyridines, but the mechanism proposed involved a Michael addition and subsequent nucleophilic attack rather than a concerted [4+2] cycloaddition <1996T10519> (see Section 11.13.8). 

Alkynes have been well explored as dipolarophiles in the [3 -t- 21-cycloaddition with almost all possible 1,3-dipoles (78), whereas the reaction of iminoboranes as dipolarophiles has focused on covalent azides as 1,3-dipoles. Most well-characterized iminoboranes were reacted with phenyl azide, according to Eq. (52) (11-14,17, 20). 

The reactions of 1,2,3-triazolium 1-imide (277) with a range of alkene and alkyne dipolarophiles give rise to a variety of new ring systems (Scheme 54). Compounds (276) and (278) are obtained from (277) by reaction with acrylonitrile and DMAD, respectively. These reactions are tandem 1,3-dipolar (endo) cycloadditions and sigmatropic rearrangements which are regio- and stereospecific <90JCS(Pl)2537>. Kinetic and mechanistic studies show that these reactions are dipole-HOMO controlled. The second-order rate constants are insensitive to solvent polarity, the reaction indicates... 

Cycloaddition of p-methoxyphenyl azide to alkynic dipolarophiles at room temperature gives triazoles (697) and (698) (Equation (54)). A regiospecific addition is only observed in the case of Z = CH(OMe)2 <89H(29)967>. Phenyl azide and substituted benzyl azides undergo 1,3-dipolar cycloadditions with DM AD, phenylacetylene, and ethyl propiolate to afford 1-phenyl- and 1-benzyl-... 

The meso-ionic 1,3-oxazol-S-ones show an incredible array of cycloaddition reactions. Reference has already been made to the cycloaddition reactions of the derivative 50, which are interpreted as involving cycloaddition to the valence tautomer 51. In addition, an extremely comprehensive study of the 1,3-dipolar cycloaddition reactions of meso-ionic l,3-oxazol-5-ones (66) has been undertaken by Huisgen and his co-workers. The 1,3-dipolarophiles that have been examined include alkenes, alkynes, aldehydes, a-keto esters, a-diketones, thiobenzophenone, thiono esters, carbon oxysulfide, carbon disulfide, nitriles, nitro-, nitroso-, and azo-compounds, and cyclopropane and cyclobutene derivatives. In these reactions the l,3-oxazol-5-ones (66)... 

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