Cyclization of aryl halides

Scheme 68 2-Oxindol derivatives by nickel-catalyzed cyclization of aryl halides.

The cyclization of aryl halides provides a useful route to benzo-fused carbo- and heterocycles as illustrated in equations 122 and 123762-767. In some cases isomerization of the intermediate radical may cause product mixtures and hence decreased synthetic utility762. 

The recently reported cyclization of aryl halides via intramolecular addition of an organometallic complex to double bonds has been extended to the formation of seven-membered rings e.g., the benzazepine (30) from o-chloroaniline via treatment of (29) with MeMgBr and [NiCl2(PPh3)2]. ... 

Under mild conditions (1-4 bar CO, 25-60 °C), high yields of the desired produets were produced. Benzyl, allyl, aryl, and vinyl halides containing primary, secondary, or tertiary aleohol groups were readily converted to a variety of lactones, including phthalides and butenolides (Scheme 2.160a). Sinee then, 2-bromo benzyl aleohol has been tested as a substrate in various systems, such as carbonylation with a flow microreactor,[ C]-labelled compounds, and microwave-promoted with Mo(CO)g as a carbon monoxide source (Scheme 2.160b). Cobalt carbonyl as a cheaper catalyst was also applied in the intramolecular cyclization of aryl halides (Scheme 2.160c). ... 

Available information on the mechanism of cyclocondensation is rather contradictory. According to one hypothesis, both the condensation of aryl halides with copper acetylides and the cyclization occur in the same copper complex (63JOC2163 63JOC3313). An alternative two-stage reaction route has also been considered condensation followed by cyclization (66JOC4071 69JA6464). However, there is no clear evidence for this assumption in the literature and information on the reaction of acetylenyl-substituted acids in conditions of acetylide synthesis is absent. 

Examples of the intermolecular C-P bond formation by means of radical phosphonation and phosphination have been achieved by reaction of aryl halides with trialkyl phosphites and chlorodiphenylphosphine, respectively, in the presence of (TMSlsSiH under standard radical conditions. The phosphonation reaction (Reaction 71) worked well either under UV irradiation at room temperature or in refluxing toluene. The radical phosphina-tion (Reaction 72) required pyridine in boiling benzene for 20 h. Phosphinated products were handled as phosphine sulfides. Scheme 15 shows the reaction mechanism for the phosphination procedure that involves in situ formation of tetraphenylbiphosphine. This approach has also been extended to the phosphination of alkyl halides and sequential radical cyclization/phosphination reaction. ... 

Buchwald has developed a route to indolines by the Pd-catalyzed intramolecular amination of aryl halides <96T7525> and applied this method to the synthesis of natural products. Thus, cyclization of tetrahydroquinoline 70 provided 71 which was elaborated to a key intermediate in syntheses of damirones A and B and makuluvamine <96JA1028>. 

Among early reported Pd-catalyzed reactions, the Mori-Ban indole synthesis has proven to be very useful for pyrrole annulation. In 1977, based on their success of nickel-catalyzed indole synthesis from 2-chloro-fV-allylaniline, the group led by Mori and Ban disclosed Pd-catalyzed intramolecular reactions of aryl halides with pendant olefins [122]. Compound 102, easily prepared from 2-bromo-lV-acetylaniline and methyl bromocrotonate, was adopted as the cyclization precursor. Treatment of 102 with Pd(OAc)2 (2 mol%), Ph3P (4 mol%) and NaHCQ3... 

Boger and co-workers were the first to report the intramolecular amination of aryl halides in their synthesis of lavendamycin [436-438], Thus, biaryl 366 is smoothly cyclized under the action of 1.5 equivalents of Pd(PhjP)4 to P-carboline 367, which comprises the CDE rings of lavendamycin. 

Arylbenzoxazoles were prepared by Pd-catalyzed three-component condensation of aryl halides with o-aminophenols and carbon monoxide followed by dehydrative cyclization [24], A variant of such methodology using o-fluorophenylamines in place of o-aminophenols was used to synthesize arylbenzoxazoles [25]. 

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... 

Germanes are also used for the reduction of various organic halides at ambient temperature under Et3B/C>2 initiation. For example, tri-2-furylgermane mediated radical cyclizations of aryl iodides proceed in good yields (Scheme 6, Eq. 6a) and are also possible with NaBH4 in the presence of a catalytic amount of triphenylgermane (Eq. 6b) [ 16]. 

Annulation of aryl halides with ortho side chains bearing a pendant electi ophilic moiety via treatment with an organolithium reagent, involving halogen-metal exchange and subsequent nucleophilic cyclization to form 4- to 7-membered rings. 

Electrochemically Induced Radical Cyclization Reactions of Aryl Halides... 

Phenyl o-radicals generated by reduction of aryl halides can also interact with an intramolecular alkene bond. Ihe method has been developed for the formation of dihydroindoles by reductive cyclization of N-allyl-2-chloroacetanilides. The results indicate the importance of a time interval between electron addition to give a radical-anion and the fragmentation of this species to give the active a-radical, The time interval allows the radical-anion to diffuse away from the electrode surface so that when the a-radical is foimed, it has time to cyclize before it can be reduced at the surface. 

Electrochemical reduction of aryl halides in the presence of olefins (94), (equation 54) leads to the formation of arylated products (95). Electroreduction of several aralkyl halides at potentials ranging from -1.24 V to -1.54 V (see) gives products which involve dimerization, cyclization, and reduction to the arylalkanes. Carbanions and/or free radicals were again postulated as intermediates79. Aryl radicals generated from the electrochemical reduction of aryl halides have been added to carbon-carbon double bonds80,81. Electrochemical reduction of aryl halides in the presence of olefins leads to the formation of arylated products78. Preparative scale electrolyses were carried out in solvents such as acetonitrile, DMF and DMSO at constant potential or in liquid ammonia at constant current. The reaction is proposed to involve an S l mechanism. 

R. S. Davidson, J. W. Goodwin and G. Kemp, Advances in Physical Organic Chemistry, voi. 20, Academic Press (1984), p. 191. The photochemistry of aryl halides and related compounds is reviewed, including substitution and cyclization reactions. 

A practical ligand-free palladium-catalyzed intramolecular reductive Heck cyclization was developed by Liu et al. <07TL2307>. The authors found that water was an essential component of the reaction mixture. Using a series of aryl halide intermediates this cyclization resulted in the desired 1,2,3,4-tetrahydroisoquinolines in high yields. Cook and co-workers found that InCU was an efficient catalyst for an intramolecular Friedel-Crafts cyclization of Ar-(4-bromobut-2-enyl)-A-(bcnzyl)-4-methylbcnzcncsulfonamidc to form the desired 3-substituted tetrahydroisoquinolines <07OL1311>. 

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