Cycloadditions palladium bromide

Another recent development in the field of palladium-catalyzed reactions with alkynes is a novel multicomponent approach devised by the Lee group. Starting from a-bromovinyl arenes and propargyl bromides, the assembly ofeight-membered car-bocycles can be realized via a cross-coupling/[4+4] cycloaddition reaction. The authors also presented the combination of a cross-coupling and homo [4+2], hetero [4+2], hetero [4+4] or [4+4+1] annulation leading to various cyclic products [147]. 

Aryl and vinyl nitriles have been prepared very efficiently from the corresponding bromides by palladium-catalyzed reactions under microwaves. This energy source has been employed for the conversion of these nitriles into aryl and vinyl tetrazoles by cycloaddition reactions with sodium azide (Scheme 9.66). The direct transformation of aryl halides to the aryl tetrazoles in a one pot procedure could be accomplished both in solution and on a solid support [115], The reactions were complete in a few minutes, a reaction time considerably shorter than those previously reported for the thermal reactions. The cydoadditions were performed with sodium azide and ammonium chloride in DMF and, although no explosion occurred in the development of this work, the authors point out the necessity of taking adequate precautions against this eventuality. 

An improvement of the palladium-catalyzed cyanation of aryl bromides, in which zinc cyanide was used as the cyanide source, was reported in the middle of the nineties [49], Typically, the conversion from halide to nitrile takes at least 5 h by this route and the subsequent cycloaddition to the tetrazole is known to require even longer reaction times. 

A single-mode microwave procedure has been reported for the palladium-catalyzed preparation of both aryl and vinyl nitriles from the corresponding bromides. The reaction times were short and full conversions were achieved in just a few minutes (Eq. 11.33) [50], The cycloadditions to yield the tetrazoles needed slightly longer reaction times, from 10 to 25 min, but only 20 W of power was required as a temperature of 220 °C was reached after 10 min heating. The yields in this step ranged from 36% to 96%. This method for transforming halides into tetrazoles has been used for the synthesis of a novel HIV-protease inhibitor [50],... 

In 2006, the palladium-catalyzed carbonylative [2+2] cycloaddition of allyl bromide with heteroaryliden anilines was reported to afford 2-azetidinones... 

Ring expansion of the enantiopure 1,2-oxazines 32a and 32b involving dibromocarbene cycloaddition, followed by methanolysis of the intermediates 33a and 33b, provided a convenient route to the 1,2-oxazepines 34a and 34b in moderate yields (Scheme 2). The vinylic bromide was then used as a site for the introduction of other functionality via palladium-catalyzed C-C bond-forming reactions <2005SL2376>. 

Another interesting type of 1,3-dipolar cycloaddition with azides involves condensation with nitriles as dipolarophiles to form tetrazoles. These products are of particular interest to the medicinal chemist, because they probably constitute the most commonly used bioisostere of the carboxyl group. Reaction times of many hours are typically required for the palladium-catalyzed cyanation of aryl bromides under the action of conventional heating. The subsequent conversion of nitriles to tetrazoles requires even longer reaction times of up to 10 days to achieve completion. Under microwave irradiation conditions, however, the nitriles are rapidly and smoothly converted to tetrazoles in high yields. An example of a one-pot reaction is shown in Scheme 11.54 [110], in which the second step, i.e. the cycloaddition, was achieved successfully under the action of careful microwave irradiation. The flash heating method is also suitable for conversion of 212 and 214 to tetrazoles 213 and 215, respectively, on a solid support, as shown in Scheme 11.54. 

Perfluoropropene and perfluorobutene-2 react with benzyl azide at 150 °C to give the [3+2] cycloadducts in 85% and 65% yields, respectively. Trimethylvinylsilane also undergoes the [3+2] cycloaddition reaction with 4-nitrophenyl- and 4-cyanophenyl azide to give the triazolines in high yields. Also, ]V-alkylmaleimides react with trimethylsilyl azide to give the corresponding [3+2] cycloadduct . The reaction of maleimide A -proponic acid and a heterocyclic azide is accelerated by molecular recognition . The palladium-catalyzed reaction of alkenyl bromides with sodium azide in dioxane at 90 °C or DMSO at 110 °C affords the 4-substituted 1,2,3-triazoles 55. ... 

In addition to intermolecular reactions, intramolecular variants have been developed. In 1992, Negishi et al. reported the Pd(PPh3)4/AcOH-catalyzed intramolecular [2 -I- 2 -I- 2] cycloaddition of triyne 12 (Scheme 6.4) [9]. In this reaction, cascade-type cycloaddition via generation of Pd—H species from palladium and acetic acid proceeded to afford fused benzene 13 in good yield. The reaction of endiyne 14 bearing an alkenyl bromide moiety in the presence of EtsN also afforded the same product, 13, presumably through a similar mechanism (Scheme 6.4). 

Not only aryl iodides but also aryl bromide could be employed without decreasing the product yield. A plausible mechanism of this cycloaddition is as follows. (2-Biphenyl)palladium species, generated through insertion of an aryne into an aryl-palladium, undergoes C—H bond activation followed by reductive elimination to give the substituted triphenylenes. Three-component [2 -f 2 -f 2] cycloaddition product 61 could also be obtained in the presence of additional alkynes 60 (Scheme 6.19) [22]. 

Craft and Gung developed a paUadium-catalyzed transannular [4+3] cycloaddition route in which all of the rings of cortistatins are prepared in one step from a single macrocyclic precursor (Scheme 19.50) [114]. Exposure of macrocyclic allene 233 to a catalytic amount of palladium (II) acetate in the presence of excess lithium bromide resulted in the formation of 238 as a single isomer in 37% yield. This is the first report of a transannular [4+3] cycloaddition. The proposed mechanism is shown in Scheme 19.50. The formation of allene-palladium complex 234 affords a a-allylpalladium intermediate, which rapidly isomerizes to the 7i-allylpalladium intermediate 235. This can then undergo intramolecular cycloaddilion via an endo (compact) transition strucmre 236 to give bromonium ion 237. The loss of a proton results in the formation of the observed product 238. Cycloadduct 238 was readily converted into the tetracyclic core skeleton of cortistatins 239 by selective reduction of the olefin formed by cycloaddition with furan, followed by reductive debromination. 

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