Vinyl substitutions intramolecular

If a bromomethyl- or vinyl-substituted cyclopropane carbon atom bears a hydroxy group, the homoallyiic rearrangement leads preferentially to cyclobutanone derivatives (J. Sa-laun, 1974). Addition of amines to cydopropanone (N. J. Turro, 1966) yields S-lactams after successive treatment with tert-butyl hypochlorite and silver(I) salts (H.H. Wasserman, 1975). For intramolecular cyclopropane formation see section 1.16. 

Whereas the cycloaddition of arylazirines with simple alkenes produces A -pyrrolines, a rearranged isomer can be formed when the alkene and the azirine moieties are suitably arranged in the same molecule. This type of intramolecular photocycloaddition was first detected using 2-vinyl-substituted azirines (75JA4682). Irradiation of azirine (54) in benzene afforded a 2,3-disubstituted pyrrole (55), while thermolysis gave a 2,5-disubstituted pyrrole (56). Photolysis of azirine (57) proceeded similarly and gave 1,2-diphenylimidazole (58) as the exclusive photoproduct. This stands in marked contrast to the thermal reaction of (57) which afforded 1,3-diphenylpyrazole (59) as the only product. 

Fig. 6 Microwave promoted intramolecular cyclization of o-vinyl substituted isocyanates 16 leading to 2-quinolones...

The Heck reaction, a palladium-catalyzed vinylic substitution, is conducted with olefins and organohalides or pseudohalides are frequently used as reactants [15, 16], One of the strengths of the method is that it enables the direct monofunctionalization of a vinylic carbon, which is difficult to achieve by other means. Numerous elegant transformations based on Heck chemistry have been developed in natural and non-natural product synthesis. Intermolecular reactions with cyclic and acyclic al-kenes, and intramolecular cyclization procedures, have led to the assembly of a variety of complex and sterically congested molecules. 

Both inter- and intramolecular Heck reactions of indoles have been pursued and these will be considered in turn. Appropriately, Heck and co-workers were the first to use Pd-catalyzed vinyl substitution reactions with haloindoles [239]. Thus, l-acetyl-3-bromoindole (217) gave a 50% yield of 3-indolylacrylate 218. A similar reaction with 5-bromoindole yielded ( )-methyl 3-(5-indolyl)acrylate (53% yield), but 3-bromoindole gave no identifiable product. 

Activation of one the double bonds of the allene by coordination to an electrophilic metal center such as Hg(II), Ag(I), Pd(II), Rh(I), Cu(I) or Au(III). Then an intramolecular nucleophile can attack and the product is formed by protodemetallation of the intermediate (Scheme 15.1). Depending on electronic and steric factors, either the proximal or the distal Jt-bond of the allene 1 is activated in that way (2 and/or 3). For each of these two possibilities now an exo or endo attack of the nucleophile is conceivable, leading to intermediates 4—7. An equilibrium between both 5 and 6 and 9 is possible. Finally, from 4 the vinyl-substituted 8 is formed. From 5, 6 or 9 the exocyclic alkene 10 and/or the endocyclic alkene 11 can be observed. Compound 7 would deliver the endocyclic alkene 12. 

Particularly interesting is the reaction of enynes with catalytic amounts of carbene complexes (Figure 3.50). If the chain-length between olefin and alkyne enables the formation of a five-membered or larger ring, then RCM can lead to the formation of vinyl-substituted cycloalkenes [866] or heterocycles. Examples of such reactions are given in Tables 3.18-3.20. It should, though, be taken into account that this reaction can also proceed by non-carbene-mediated pathways. Also Fischer-type carbene complexes and other complexes [867] can catalyze enyne cyclizations [267]. Trost [868] proposed that palladium-catalyzed enyne cyclizations proceed via metallacyclopentenes, which upon reductive elimination yield an intermediate cyclobutene. Also a Lewis acid-catalyzed, intramolecular [2 + 2] cycloaddition of, e.g., acceptor-substituted alkynes to an alkene to yield a cyclobutene can be considered as a possible mechanism of enyne cyclization. 

Alkyl halides with (3-hydrogens generally undergo only elimination reactions under the conditions of the vinyl substitution (100 C in the presence of an amine or other base). Exceptions are known only in cases where intramolecular reactions are favorable. Even alkyl halides without (3-hydrogens appear not to participate in the intermolecular alkene substitution since no examples have been reported, with the exception of reactions with benzyl chloride and perfluoroalkyl iodides. 

Intramolecular vinyl substitutions are commonly used to form cyclic products. In a typical reaction, p-in-doleacetic acid has been prepared in up to 43% yield from an o-bromoaniline derivative, as shown in equation (23).74... 

The same reactions, carried out with potassium carbonate as base in place of a secondary amine, yield exocyclic dienes in good yield, although double-bond isomerization sometimes occurs (equation 38).93 Inclusion of tetra-zi-butylammonium chloride in the reaction mixture stops the double-bond isomerization. Thus, the reaction in equation (38) with the chloride yields only the bis(exomethylene) product in 45% yield in a slow reaction. Some N- and O-heterocyclic products, also, have been prepared by the intramolecular vinyl substitution reaction.94 A 16-membered ring lactone was made by the ring closure of a vinylic iodide group with a vinyl ketone group. The yield, based upon the reactant, was 55% but a stoichiometric amount of bis(acetonitrile)palladium dichloride was employed. The catalyst was prereduced with formic acid so that the reaction proceeded at 25 C (equation 39).95... 

In 2008 Yang and coworkers have reported an efficient synthesis of substituted a-alkilidene-fi-lactams via aNaOH- promoted intramolecular aza-Michael addition of a-carbamoyl, a-(l-chlorovinyl) ketene-S,S-acetals and subsequent nucleophilic vinylic substitution reaction in alcoholic media (Scheme 90), [198]. 

In the case of the formation of a cycloaliphatic polymer with bicyclic units in the main chain, such as the polymer with poly[methylene-l,3-(2,5-methanocy-clohexane)] structural units obtained in the cyclopolymerisation of 3-vinyl-1,5-hexadiene, the intramolecular insertion, analogous to that presented in scheme (89), is followed by another intramolecular insertion involving a vinyl substituting group ... 

Vinyl-substituted 2-oxazolidinones 208 were synthesised by a catalytic <02JOC974> and also asymmetric intramolecular aminopalladation of readily available derivatives of (Z)-2-buten-l,4-diol 207 <02JA12>. 

The catalytic cycle proposed for ethylene to acetaldehyde is shown in Fig. 8.2. The tetrachloro palladium anion 8.1 is used as the precatalyst. Conversion of 8.1 to 8.3 involves substitution of two chloride ligands by ethylene and water. Nucleophilic attack on coordinated ethylene leads to the formation of 8.4. The latter then undergoes substitution of another Cl- ligand. Conversion of 8.5 to 8.6 involves /3-hydride abstraction and coordination by vinyl alcohol. Intramolecular hydride attack to the coordinated vinyl group leads to the formation of 8.7. The latter eliminates acetaldehyde, proton, and CF and in the process is reduced to a palladium complex of zero oxidation state. 

Whereas the cycloaddition of arylazirines with simple alkenes produces d -pyrrolines, a rearranged isomer (i.e., 29) can be formed when the alkene and the 2H-azirine moieties are suitably arranged in the same molecule. This type of intramolecular photocycloaddition was first detected using 2-vinyl-substituted 2H-azirines (75JA4682). 

The second general ttansformation is the intramolecular version with multiple vinyl substitution steps (equations 23 and 24). There is high potential for synthesis of complex rings in a very efficient manner. ... 

An excellent example of vinylic substitution in the formation of a five-membered ring by an intramolecular Heck reaction is found in Comins and co-workers remarkably short synthesis of camptothecin (30) [six steps to ( )-camptothecin [7] and ten steps to (S)-camptothecin [8]. In the enantioselective synthesis, intermediate 29, which is obtained from /V-alkylation of the corresponding pyridone with a bromomethyl-bromoquinoline inteimediate, undergoes Heck closure to provide (5)-camptothecin (30) in 59% yield (Scheme 6-5). From a strategic standpoint, use of the Heck cyclization achieves excellent convergency as the central C-ring is formed late in the synthesis after combining two... 

An asymmetric total synthesis of bacillariolide III is achieved in fifteen linear steps with a good overall yield.253 The key feature of this synthetic route involves a highly stereoselective construction of a vinyl-substituted bicyclic lactone by an intramolecular Pd(0)-catalyzed tt-allylie alkylation with an a-sulfonyl carbanion (Eq. 146). 

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