Palladium -mediated oxidative couplings

Scheme 1. Palladium-mediated oxidative coupling reactions of olefins and water.

In a palladium-mediated oxidative coupling reaction, alkenes such as methyl acrylate, acrylonitrile, or styrenes cyclize with 6- [(diinethylainino)methylene]amino -l,3-dimethyluracil to give the corresponding 6-substituted pyrido[2,3-[Pg.128]

A molybdenum-mediated oxidative coupling of aniline 1 with cyclohexene 2a provides carbazole 3. Alternatively, the same overall transformation of aniline 1 to carbazole 3 is achieved by iron-mediated oxidative coupling with cyclo-hexa-1,3-diene 2b or by palladium-catalyzed oxidative coupling with arenes 2c. The use of appropriately substituted anilines and unsaturated six-membered hydrocarbons opens up the way to highly convergent organometallic syntheses of carbazole alkaloids. 

An even more direct approach to carbazole-3,4-quinone alkaloids is provided by the palladium(II)-mediated oxidative coupling of ort/zo-quinones with ary-lamines, which gives access to this class of natural products in a three-step route [137]. 

In addition to the aforementioned total syntheses. Shannon et al. observed the formation of an N-C3-linked dimer during the transformation of a 3-bromocarbazole to a 3-cyanocarbazole by reaction with copper(I) cyanide in DMF under reflux (668). Harrity et al. reported the synthesis of non-natural (+ )-N,N -dimethylbismurrayafoline A via a chromium-mediated benzannulation, followed by a palladium-catalyzed oxidative coupling reaction (669). 

The palladium(II)-mediated oxidative coupling of olefins with oxygen-nucleophiles (ROH water, alcohols, carboxylic acids) is a stoichiometric reaction with respect to Pd(II), resulting in an oxygenated product and Pd(0). To convert Pd(0) back to Pd(II) and start a new reaction cycle, a reoxidation reaction (which can itself be stoichiometric or catalytic) using a terminal oxidant is required. In this way, the overall process becomes catalytic with respect to the expensive Pd salt. 

Palladium(II)-mediated oxidative coupling reactions involving the indole nucleus have been studied extensively in the literature. Fujiwara et al. [8b] reported that the reaction of A-acetylindole (8) with methyl acrylate (4b) gives (ii)-methyl 3-(l-acetyl-l//-indol-2-yl)acrylate (9, 4%) and ( )-methyl 3-(l-acetyl-l//-indol-3-yl)acrylate (10, 20%), along with A-acetyl-2,3-bis(methoxycarbonyl)carbazole (12,9%) which was believed to be generated by an electrocyclization and subsequent dehydrogenation of a 2,3-dialkenylated indole intermediate (11, Scheme 9.1). 

Disubstituted isocoumarins arise from the copper(II)-catalyzed addition of o-halobenzoic acids to active internal alkynes (13JOC1660), rhodium(III)-mediated oxidative coupling ofbenzoic acids with disubsti-tuted alkynes (13T4454), palladium(II)-catalyzed tandem annulation reaction of o-alkynylbenzoates with methyl vinyl ketone (13T8626), and nickel(II)-promoted t-butyl isocyanide insertion in 2-(o-bromophenyl)-1-ethanones followed by hydrolysis (Scheme 69) (13SC3262). 

Another compound 9 with three heterocyclic rings linearly fused (5 5 5) with two heteroatoms has been prepared from 1,1 -carbonyl diindole 297 <2001T5199>. Palladium-mediated coupling of the 2- and 2 -positions of 297 afforded the 1,1 -carbonyl-2,2 -biindolyl 9. 1,1 -Carbonyl diindole 297 was in turn obtained in 41% yield from 1,1 -carbonyldiimidazole 296 by reaction with indole in DMSO at 125 °C. The palladium-catalyzed coupling step afforded the desired product 9 in low yield and required a stoichiometric amount of palladium acetate. Therefore, it was felt prohibitively expensive. Addition of various co-oxidants (Ac20, Mn02, and Cu(OAc)2, etc) to make the reaction catalytic in palladium did not result in any improvement of the yield of 18 (Scheme 53). 

C-C bond formation mediated by silane.6,6a 6f With respect to the development of intramolecular variants, these seminal studies lay fallow until 1990, at which point the palladium- and nickel-catalyzed reductive cyclization of tethered 1,3-dienes mediated by silane was disclosed. As demonstrated by the hydrosilylation-cyclization of 1,3,8,10-tetraene 21a, the /rarcr-divinylcyclopentanes 21b and 21c are produced in excellent yield, but with modest stereoselectivity.46 Bu3SnH was shown to participate in an analogous cyclization.46 Isotopic labeling and crossover experiments provide evidence against a mechanism involving initial diene hydrosilylation. Rather, the collective data corroborate a mechanism involving oxidative coupling of the diene followed by silane activation (Scheme 15). 

The formation of carbon-carbon bonds by palladium-promoted reactions has been widely used in organic synthesis [114-116]. A major advantage is that most of these coupling reactions can be performed with catalytic amounts of palladium. Palladium(II)-catalyzed reactions, e.g., the Wacker process, are distinguished from palladium(O)-catalyzed reactions, e.g., the Heck reaction, since they require oxidative regeneration of the catalytically active palladium(II) species in a separate step [117]. Several groups have applied palladium-mediated and -catalyzed coupling reactions to the construction of the carbazole framework. 

The palladium(II)-mediated oxidative cyclization of Ar,AT-diarylamines is useful for convergent total syntheses of a range of structurally different carbazole alkaloids. Goldberg coupling of 2,3-dimethoxyacetanilide 80 and 2-bromo-5-methylanisole 81 and subsequent alkaline hydrolysis affords the diarylamine 82... 

The Goldberg coupling between 5-acetylamino-2,2-dimethylchromene 84 and 5-bromo-2-methylanisole 85 followed by hydrolysis leads to the diarylamine 86, which on palladium(II)-mediated oxidative cyclization affords pyrayafoline A 87 [ 17] (Scheme 30). Starting from 7-acetylamino-2,2-dimethylchromene, the method has been applied to the synthesis of 0-methylpyrayafoline B [54]. 

Retrosynthetic analysis of carbazoquinocin C (274) and (+ )-carquinostatin A ( + )-278 based on our highly convergent palladium(II)-mediated intramolecular oxidative coupling of arylamino-l,2-benzoquinones provides aniline (839) and 4-heptyl-3-methyl-l,2-benzoquinone (946) as precursors for 274, and 4-prenylaniline (945) and 4-(2-hydroxypropyl)-3-methyl-l,2-benzoquinone (947) as precursors for ( + )-278 (646) (Scheme 5.126). 

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