Alkene intramolecular arylations

Intramolecular Arylation of Aromatic and Alkene sp2-Hybridized Carbon Atoms 261... 

Intramolecular arylation of alkenes. The intramolecular palladium-catalyzed condensation of aryl halides with an alkene group (Heck arylation5) can actually proceed more readily than the original bimolecular version. These intramolecular cyclizations typically proceed in acetonitrile at room temperature, particularly when catalyzed by Ag2C03, which also inhibits isomerization of the double bond of the product. They can be used to obtain spiro, bridged, and fused systems. Even tetrasubstituted alkenes can participate, with formation of quaternary centers.6... 

In this section we include the intramolecular arylation of the Pschorr type, the inter-molecular arylation (Gomberg-Bachmann reaction), the arylation of alkenes and alkynes (Meerwein reaction) and related processes. 

Scheme 1 Intramolecular aryl radical addition to alkenes...

A radical cation is involved in the direct synthesis of chromans by an intramolecular oxidative cyclisation of 3-arylpropanols 32 brought about by a hypervalent iodine(III) reagent <04TL2293> and iodonium species catalyse the intramolecular arylation of alkenes which yields iodo-substituted chromans 33 <04JA3416>. 3-Allenylchroman-4-ols result from a one-pot reaction between salicylaldehydes and 1,4-dibromobut-2-yne in which the intramolecular cyclisation of the intermediate ether is mediated by In metal <04SL45>... 

In contrast to facile reactions of aryl halides with alkenes and alkynes, reactions of aromatic compounds with aryl halides have received less attention. Only intramolecular arylation of benzene derivatives, except phenols, is known [1]. On the other hand, electron-rich heterocycles such as ffirans, thiophenes, pyrroles, oxa-zoles, imidazoles, and thiazoles undergo facile inter- and intramolecular arylation with aryl halides. These are called heteroaryl Heck reactions [2]. 

In this section, only examples of Mizoroki-Heck reactions where a proper addition of the cr -aryl- or a -alkeny Ipalladium(II) complex to a double bond of an alkene or alkyne occurs are considered. As a consequence, an often-met deviation from the classic Mizoroki-Heck mechanism, the so-called cyclopalladation, will not be treated in further detail [12, 18]. However, as it is of some importance, especially in heterocycle formation and mainly because it will be encountered later during polycyclization cases, it shall be mentioned briefly below. Palladacycles are assumed to be intermediates in intramolecular Mizoroki-Heck reactions when j3-elimination of the formed intermediate cannot occur. These are frequently postulated as intermediates during intramolecular aryl-aryl Mizoroki-Heck reactions under dehydrohalogenation (Scheme 6.1). The reactivity of these palladacycles is strongly correlated to their size. Six-membered and larger palladacycles quickly undergo reductive elimination, whereas the five-membered species can, for example, lead to Mizoroki-Heck-type domino or cascade processes [18,19]. 

Scheme 8.47 Intramolecular aryl-aryl as well as intra—intermolecular aryl—aryl and aryl-alkene coupling cascades [357, 358],...

Scheme 8.49 Inter-intramolecular alkenyl-alkene and aryl-alkene coupling cascades involving C-H activation [1 1 5, 357d,e], A Pd(OAc)j, KjCOj, riBu NBr, DMF, 80°C, 24h. B Like A, but, 100°C for 7 and 21 days, respectively [115],...

Barluenga, J., Trincado, M., Rubio, E., Gonzdlez, J. M. (2004). Intramolecular arylation reactions of alkenes a flexible approach to chromans and tetrahydroquinoline derivatives. Journal of the American Chemical Society, 126, 3416-3417. 

Oxoesters are oxidized with Mn(OAc)3 to the corresponding radicals that can add intermolecularly or intramolecularly (eq Ib)" to generate alkyl radicals. In the presence of Cu(OAc)2 the latter are rapidly quenched and oxidized to give alkenes. Radical arylation with alkyl iodides can be induced with dibenzoyl peroxide the yield of the reaction can be improved using a catalytic amount of Cu(0Ac)2-H20, which minimizes hydrogen abstraction by the intermediate radical but introduces a competitive electron-transfer oxidation of the intermediate radical. The oxidative addition of disulfides to alkenes (Trost hydroxysulfenylation ) can be promoted by catalytic amounts ofCu(OAc)2. ... 

Using a similar concept, Wolfe and Rossi developed a novel palladium-catalyzed stereoselective synthesis of tetrahydrofurans from y-hydroxy alkenes and aryl bromides [27] (Scheme 6.17). After a series of deuterium labeling experiments, the authors suggested that the predominant mechanistic pathway for tetrahydrofiiran formation probably involves a rare syn insertion of an alkene into the Pd-O bond of an intermediate palladium aryl alkoxide [28]. Later, the same group reported similar intramolecular [29] and intermolecular [30] cyclizations to synthesize a series of tetrahydrofurans. 

In the reaction of Q,/3-unsaturated ketones and esters, sometimes simple Michael-type addition (insertion and hydrogenolysis, or hydroarylation, and hydroalkenylation) of alkenes is observed[53,54]. For example, a simple addition product 56 to methyl vinyl ketone was obtained by the reaction of the heteroaromatic iodide 55[S5]. The corresponding bromide affords the usual insertion-elimination product. Saturated ketones are obtained cleanly by hydroarylation of o,/3l-unsaturated ketones with aryl halides in the presence of sodium formate, which hydrogenolyses the R—Pd—I intermediate to R— Pd—H[56]. Intramolecular hydroarylation is a useful reaction. The diiodide 57 reacts smoothly with sodium formate to give a model compound for the afla-toxin 58. (see Section 1.1.6)[57]. Use of triethylammonium formate and BU4NCI gives better results. 

An efficient carboannulation proceeds by the reaction of vinylcyclopropane (135) or vinylcyclobutane with aryl halides. The multi-step reaction is explained by insertion of alkene, ring opening, diene formation, formation of the TT-allylpalladium 136 by the readdition of H—Pd—I, and its intramolecular reaction with the nucleophile to give the cyclized product 137[I08]. 

The cycloaddition of alkynes and alkenes to nitrile oxides has been used in the synthesis of functionalised azepine systems <96JHC259>, <96T5739>. The concomitantly formed isoxazole (dihydroisoxazole) ring is cleaved by reduction in the usual way. Other routes to 1-benzazepines include intramolecular amidoalkylation <96SC2241> and intramolecular palladium-catalysed aryl amination and aryl amidation <96T7525>. Spiro-substituted 2-benzazepines have been prepared by phenolic oxidation (Scheme 5) <96JOC5857> and the same method has been applied to the synthesis of dibenzazepines <96CC1481>. 

Similar intramolecular hydroarylations of alkynes and alkenes, which obviate the need for a halide or triflate group on the aryl ring, are now well established. Sames group screened over 60 potential catalysts and over 200 reaction conditions, and found that Ru(m) complexes and a silver salt were optimal. This process appears to tolerate steric hindrance and halogen substrates on the arene (Equations (175)—(177)). The reaction is thought to involve alkene-Ru coordination and an electrophilic pathway rather than a formal C-H activation of the arene followed by alkene hydrometallation, and advocates the necessary cautious approach to labeling this reaction as a C-H functionalization... 

Intramolecular Heck reactions.6 Heck intramolecular coupling of alkenyl or aryl iodides substituted by 3-cycloalkenyl group is an attractive route to fused, spiro, and bridged polycyclic products. Coupling is achieved with a Pd-phosphine catalyst such as Pd[P(QH5),]4 in combination with a base, N(C2H5)3 or NaOAc. The coupling tends to produce a mixture of two isomeric alkenes, in which the newly formed bond is allylic or homoallylic to the ring juncture. 

The reaction is carried out with aryl triflates and other details such as solvent and base used are also important. Intramolecular additions of aryl halides or triflates to alkenes in a side-chain leading to cyclic compounds have been reported by Overman [24], Rather complicated ring structures can be made stereospecifically. While initially BINAP seemed the best ligand for this conversion, the number of useful ligands is increasing [25],... 

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