Palladium-catalyzed cyclization-coupling

The palladium-catalyzed cyclizative coupling reaction of a-allenols 41 with alkenyl halides was also explored. The transformation of allenols 41 into spirocyclic disubstituted dihydrofuran (3-lactams 43 was readily achieved in high yields, by treatment with allyl bromide or 2,3-dibromopropene in the presence of palladium (II) chloride (5 mol%) (Scheme 14) [60]. 

On the basis of this palladium-mediated Michael addition cyclization process, a novel two-step synthetic entry into functionalized furan derivatives 67 has also been devised (Scheme 28). Substitution of benzylidene (or alkyli-dene) malonates for their ethoxymethylene analog (65) as activating olefins gave rise to the formation of the corresponding 2-ethoxy-4-arylidene tetrahy-drofurans 66. An in situ addition of potassium ferf-buloxidc induced a decar-boxylative elimination reaction which was followed by an isomerization of the exocyclic double bond. The entire process successively involved a conjugate addition, a palladium-catalyzed cyclization-coupling reaction, a base-induced eliminative decarboxylation, and finally, a double bond isomerization [73]. 

Aurrecoechea and co-workers used a palladium(Il) catalyst to perform a palladium-catalyzed cyclization-coupling reaction to prepare... 

The palladium-catalyzed reductive coupling reactions were used in the synthesis of several natural products, including laurene [75], ceratopicanol [80], and dihydrostreptazolin 141 [81]. The cyclization leading to dihydrostrepta-zolin shown in Eq. 26 highlights the diastereoselectivity and functional group compatibility seen with this catalytic system. 

Knochel demonstrated the effectiveness of soluble potassium or cesium alkoxides such as KO Bu or CsO Bu as well as KH in iV-methylpyrrolidinone (NMP) for promoting the 5-endo-dig cyclizations of 2-alkynylanilines to 2-substituted indoles in solution or the solid-phase <00AG(E)2488>. Alternatively, Cacchi coupled a palladium-catalyzed cyclization of o-alkynyltrifluoroacetanilides with the addition of benzyl bromide or ethyl iodoacetate to afford 2-substituted-3-benzyl or 3-indolylcarboxylate esters, respectively <00SL394>. Yamamoto reported a new palladium catalyzed indole synthesis in which 2-(l-alkynyl)-Ar-alkylideneanilines 117 give 2-substituted-3-(l-alkenyl)indoles 118 directly from the imine by the in situ coupling of an aldehyde with the alkynylaniline <00JA5662>. 

Palladium-catalyzed cyclization reactions with aryl halides have been used to synthesize pyrazole derivatives. V-Aryl-lV-(c>-bromobenzyl)hydrazines 26 participated in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2W-indazoles 27 . Palladium-catalyzed cascade intermolecular queuing-cyclocondensation reaction of o-iodophenol (28) with dimethylallene and aryl hydrazines provided pyrazolyl chromanones 29 <00TL7129>. A novel one-pot synthesis of 3,5-disubstituted-2-pyrazolines 32 has been achieved with an unexpected coupling-isomerization sequence of haloarene 30, propargyl alcohol 31, and methylhydrazine <00ACIE1253>. 

A distannation product of 2-butyne-l,4-diol oxidatively cyclizes to provide 3,4-bis(stannyl)furan, which then undergoes palladium-catalyzed cross-coupling with an aryl iodide to give 3,4-diarylfuran (Scheme 31).152,153... 

A few synthetic applications of palladium catalysis appeared this year. The palladium-catalyzed cyclization of amino allenes 58 occurs with coupling of aryl iodides or vinyl triflates at the 3-position <990L717, 99SL324>. The cyclization can also proceed by the exo-trig pathway, but under suitable reaction conditions the piperidine 59 is prepared selectively. The intramolecular cyclization of amines onto N-allylbenzotriazoles similarly affords piperidines <99JOC6066>. 

The [2,3- ]> [2,3- ]. and [i,Z-b] isomers of 2,3-disubstituted furopyridines can be obtained from alkynes and o-iodoacetoxypyridines by a palladium-catalyzed cross-coupling reaction followed by an electrophilic iodocyclization reaction or a palladium-catalyzed cyclization in the presence of CO, as illustrated in Scheme 32 for [2,3-3] and [3,2-3] derivatives. When the pyridine ring contains strongly electron-withdrawing substituents such as carboethoxy, the reaction proceeded smoothly with benzyloxyalkynylpyridines <20020L2409>. 

By contrast, for iodide 18 having the triple bond activated by a phenyl group, conversion to the cyclic organozinc species 25 occurred effectively and the latter could be efficiently functionalized, provided that traces of moisture were excluded by pre-treatment of zinc powder with Mel. The substituted benzylidene cyclopentanes 26 and 27 were respectively obtained after iodinolysis and palladium-catalyzed cross-coupling reaction with benzoyl chloride (equation 10). However, it could not be assessed whether the formation of organozinc 25 was attributable to an anionic or a radical cyclization pathway (or both) as, had iodide 26 been produced by a radical iodine atom-transfer, it would have been converted to 25 by reaction with metallic zinc due to the presence of the activating phenyl group21. 

The industrial synthesis of vinyl acetate [14] via palladium-catalyzed oxidative coupling of acetic acid and ethene using direct 02 reoxidation has already been mentioned (Scheme 3, d). Some NaOAc is required in the reaction medium, and catalysis by Pd clusters, as alternative to Pd(II) salts, was proposed to proceed with altered reaction characteristics [14]. Similarly, the alkenyl ester 37 (Table 5) containing an isolated vinyl group yields the expected enol acetate 38 [55] whereas allylphenol 39 cyclizes to benzofuran 40 with double bond isomerization [56]. 

Cationic palladium-catalyzed addition of arylboronic acids to nitriles for the formation of benzo[h]furans was reported <06OL5987>, an example of which is illustrated in the following scheme. The palladium-catalyzed cross coupling of alkynes with appropriately substituted aryl iodides for the synthesis of substituted dibenzofurans in moderate to excellent yields was also achieved <06JOC5341>. The benzo[fc]furan core of heliannuls G and H were constructed by a palladium-catalyzed Ji-allyl cyclization reaction <06TL7353>. The palladium-catalyzed oxidative activation of arylcyclopropanes was applied to the synthesis of 2-substituted benzo[Z>]furans <06OL5829>. 

This carbonylative coupling procedure is applicable to macrocyclization. The core structure of phomactins C and D has been successfully assembled by palladium-catalyzed cyclization of a stannyl triflate under an atmosphere of carbon monoxide (Scheme 12.102) [204]. 

The stereochemical outcome was in agreement with a mechanism for the palladium-catalyzed cyclization/carboalkoxylation of a substituted alkene (Scheme 47) that involves outer-sphere attack of the indole on the palladium-olefin complex I which, coupled with loss of HCI, would form the alkylpalladium intermediate II. 1,1-Migratory insertion of CO into the Pd-C bond of II with retention of stereochemistry would form the acyl-palladium complex III, which could undergo methanolysis to release c/.v-product and form a palladium(0) complex. Oxidation with Cu(II) would then regenerate the active Pd(II) catalyst. 

Conditions first described by Fagnou were used to affect the C-H to C-H bond cyclization, which proceeded in 47% yield. Mechanistically the direct coupling reaction is thought to proceed via intramolecular nucleophilic attack of the pyrrole moiety onto the Pd(II) centre. It was postulated that the electron rich DavePhos ligand facilitates both oxidative addition and forms a more reactive cationic Pd(II) species by dissociation of the halide. Following a deprotonation step, reductive elimination of Pd(0) then resulted in formation of the biaryl bond, completing the core framework. Application of this direct palladium-catalyzed biaryl coupling facilitates a very efficient and concise synthesis of rhazinilam as a racemate. 

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