Palladium-catalyzed intramolecular

In this chapter we describe a novel, safe and efficient large-scale synthetic approach to tricycle thienobenzazepines. The key steps in the synthesis include a chemoselective hydrogenation of an aryl-nitro functionality in the presence of a 3-bromo thiophene and a subsequent palladium-catalyzed intramolecular aminocarbonylation telescoped sequentially after simple catalyst and solvent exchange. 

Isoxazole derivatives have also been synthesized in variable yield by the palladium-catalyzed intramolecular oxidative cyclization of a,/i-unsaturated oximes (Scheme 110).174 Reactions of this type are reminiscent of procedures... 

The mechanism of palladium-catalyzed intramolecular cyclization of o-bromo(aminoalkyl)benzenes has been discussed earlier (see Scheme 50 in Section IV,A,4). This approach is illustrated by the preparation of 1,2,3,4-tetrahydroisoquinolin-l-ones in Scheme 146,86 and examples of applications in benzazepinone synthesis are given later (see Scheme 173 in Section VI,B). 

A synthesis of 2-acyl and 2-alkoxycarbonyl-indoles was carried out by Tamariz and coworkers via an intramolecular Friedel-Crafts heteroannulation of enaminone precursors <06SL749>. A lac type palladium-catalyzed intramolecular indolization of alkyne-tethered 2-chloroanilines has been reported by Lu and co-workers <06OL3573>. 

The reaction was applied to an acyclic system for the synthesis of furanoid terpenes (Scheme ll)51. The palladium-catalyzed intramolecular reaction of 47 afforded 48 which was transformed to the target molecule. The latter product was obtained as a 1 1 mixture of marmelo oxide A and B, which is the isomeric mixture found in nature. 

Watanabe reports a new method for the direct conversion of o-choroacetaldehyde N,N-disubstituted hydrazones into 1-aminoindole derivatives 93 by palladium-catalyzed intramolecular ring closure of 92 in the presence of P Bu3 or the bisferrocenyl ligand 94 <00AG(E)2501>. When X = Cl, this cyclizative process can be coupled with other Pd-catalyzed processes with nucleophilic reagents (e.g., amines, azoles, aryl boronic acids) so as to furnish indole derivatives with substituents on the carbocyclic ring. 

A novel approach towards the construction of the morphine skeleton is demonstrated by the total synthesis of ( )-desoxycodeine-D. One of the key steps for this synthesis is the palladium-catalyzed intramolecular Heck reaction. Therefore, this synthetic strategy for the construction of the polycyclic ring systems has provided an efficient access to the complete pentacyclic skeleton of morphine <00TL915>. 

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>. 

Several examples of transition metal catalysis for the synthesis of piperidines appeared this year. Palladium catalyzed intramolecular urethane cyclization onto an unactivated allylic alcohol was described as the key step in the stereoselective synthesis of the azasugar 1-deoxymannojirimycin . A new synthetic entry into the 2-azabicyclo[3.3.1]nonane framework was accomplished through a palladium mediated intramolecular coupling of amine tethered vinyl halides and ketone enolates in moderate yields . A palladium catalyzed decarboxylative carbonylation of 5-vinyl... 

Another approach is based on the palladium-catalyzed intramolecular carbocyclization of the allylic acetate moiety with the alkene moiety (Scheme 96). After the formation of a 7t-allylpalladium complex, with the first double bond the intramolecular carbometallation of the second double bond occurs to form a new C-C bond. The fate of the resulting alkylpalladium complex 393 depends on the possiblity of /3-elimination. If /3-elimination is possible, it generates a metallated hydride and furnishes the cycloadduct 394. This cyclization could be viewed as a pallada-ene reaction, in which palladium replaces the hydrogen atom of the allylic moiety.231... 

Distannation of allenynes initially takes place at the allene moiety (Scheme 34).159,161 Upon heating, the produced allylstannane moiety further undergoes palladium-catalyzed intramolecular allylstannation of the alkyne moiety, affording the corresponding cyclized product. 

Palladium-catalyzed intramolecular cross-coupling reaction of bis-aryl halides using ditin reagents. 

Salcedo A, Neuville L, Zhu JP (2008) Palladium-catalyzed intramolecular C-arylation of benzylic carbon synthesis of 3-benzoxazolylisoindolinones by a sequence of Ugi-4CR/ postfunctionalization. J Org Chem 73 3600-3603... 

Bonnaterre F, Bois-Choussy M, Zhu JP (2008) Synthesis of dihydrophenanthridines by a sequence of Ugi-4CR and palladium-catalyzed intramolecular C-H functionalization. Beilstein J Org Chem 4(10)... 

Benzopiperazinones 200 were prepared by Erb et al. via the Ugi four-component reaction followed by palladium-catalyzed intramolecular Al-arylation [61]. XPhos was used as a supporting ligand to afford the 3,4-dihydroquinoxalin-3-ones 200 (Scheme 36). Microwave irradiation was found to be determinant on the reaction efficiency. 

A one-step method has been developed for elaboration of fused indole 87 via a palladium-catalyzed intramolecular indolization of 2-chloroaniline 86 bearing tethered acetylene (Equation (11) (2006OL3573)). 

The next two examples illustrate intramolecular oxepine C-C bond formation of the furan precursors. Palladium catalyzed intramolecular arylation of 153... 

The annelation of benzo rings on pyridazines was covered in CHEC-II(1996) <1996CHEC-II(6)1>. Maes and Matyus reported new examples in their synthesis of the dibenzo[// ]phthalazin-l(27r)-one and dibenzo[//]cinnolin-3(27/)-one skeleton. Palladium-catalyzed intramolecular arylation of 2-benzyl-5-(2-bromophenyl)-4-phenylpyridazin-3(2//)-one yielded 2-benzyldibenzo[/,4]phthalazin-l(2//)-one. The synthesis of this new tetracyclic pyridazinone from 2-benzyl-5-(2-aminophenyl) -phenylpyridazin-3(2//)-one via a Pschorr-type reaction was also investigated. Similarly, the con-stmction of 2-methyldibenzo[/, ]cinnolin-3(2//)-one from 2-methyl-5-(2-bromophenyl)-6-phenylpyridazin-3(27T)-one and 2-methyl-5-(2-aminophenyl)-6-phenyl-pyridazin-3(2//)-one was performed <2003T5919>. 

Phenazine 175 was prepared by palladium-catalyzed intramolecular reaction (Equation 28) <2000TL355>. The ting-closure step was accomplished according to the procedure of Buchwald. 

General procedures for the synthesis of 10f/-[l]benzothieno[3,2- ]indoles 359a-c <2003T3737> and 2,4-dimethylpyrrolo[3,2-, ]indole 360 <1997J(P1)2843> using palladium-catalyzed intramolecular cyclization of the appropriate o-bromodiarylamines and palladium-catalyzed arylation of a cyano group, respectively, were described. 

The palladium catalyzed intramolecular coupling of aryl halides and classical carbanions, sometimes considered a variant of the Buchwald-Hartwig coupling, might also be used for the formation of heterocyclic systems. 7V-(2 -bromophenyl)-propionamides were converted in the presence of the appropriate palladium catalyst and lithium hexamethyldisilazide to oxindoles (3.2.). Under the applied conditions a series of electron deficient and electron rich aniline derivatives, including 2-chloroanilines were transformed successfully.2... 

The formation of chromane derivatives has also been realised in the palladium catalyzed intramolecular nucleophilic substitution of allyl carbonates (Tsuji-Trost reaction). In most cases the reaction is accompanied by the formation of a new centre of chirality. Using Trost s chiral ligand the ring closure was carried out in an enantioselective manner. The asymmetric allylation of the phenol derivative shown in 4.20. was achieved both in good yield and with excellent selectivity.23... 

The palladium catalyzed intramolecular nucleophilic substitution of allyl alcohol derivatives (Tsuji-Trost reaction) has successfully been extended to the closure of a seven membered ring. The coupling of the allyl alcohol unit and the enamide was the key step in the preparation of the natural product claviciptic acid (5.14.),14... 

Hydroamination of Alkynes The discovery of palladium-catalyzed intramolecular addition of amines to acetylene coupled with the spectacular contribution of Hutchings opened the door for the synthesis of several nitrogen heterocycles. The first study in this field was performed by Utimoto et al., who researched gold catalyzed intramolecular 6-exo-dig hydroamination. Tautomerization of the initial enamines allowed them to obtain imines, which were thermodynamically more stable [111] (Scheme 8.20). 

A palladium-catalyzed intramolecular hydroamidation (using 106 as the catalyst) with the alkyne 105 has been shown to proceed regioselectively to provide access to the 3-benzazepinone 107 either KOH or NaOEt can be used, as the base. Other alkynes can also be used in this reaction (Equation 12) <2006TL3811>. 

Zucco, M. Le Bideau, F. Malacria, M. Palladium-catalyzed intramolecular cyclization of vinyloxirane. Regioselective formation of cyclobutanol derivatives. Tetrahedron Lett. 

Palladium-catalyzed intramolecular bis-silylation of allyldisilanyl ether produced /ram-siloxctane, which undergoes a fast dimerization <2005CEJ2954>. 

Scheme 24 Palladium-catalyzed intramolecular amidination generating substituted ben...

Jt-allyl complex can be generated after cyclization, as suggested by Takacs in a Fe(0)-catalyzed cyclization of polyenes. It also can be preformed if an active functional group is present in the allylic position. The palladium-catalyzed intramolecular cycloisomerization reaction of allylic acetates is an efficient method for constructing five- or six-membered rings [56, 57]. An asymmetric approach to this transformation has been studied and so far only poor enantioselectivity has been achieved (0-20% ee) [58]. Very recently, Zhang et al. also reported a Rh-catalyzed cycloisomerization involving a Jt-allylrhodium intermediate formed from an allylic halide [59]. 

The palladium-catalyzed intramolecular annulation of alkynes and /i r7-butylimines of o-iodobenzaldehydes and 3-halo-2-alkenals to produce isoquinoline and quinolines has been reported <2001JOG8042>. 

Methylene chromans can be prepared by a palladium-catalyzed intramolecular cyclization of 2-iodophenyl alkynyl ethers 455. Simple modifications to the reaction conditions lead to either (E)- or (Z)-4-methylene chromans (Scheme 103) <2001TL2657>. 2-Iodophenyl alkynyl acetals are also viable substrates for this reaction <2005JOG489>. Addition of tris(2,6-diphenylbenzyl)tin hydride (TDTH) to a triethylborane-mediated intramolecular cyclization of 2-iodophenyl alkynyl ethers ensures complete (A)-selectivity is observed in the resulting 4-methylene chroman <2001AGE411>. 

The palladium-catalyzed intramolecular coupling between an aryl iodide and an allyl moiety 460 proceeds under thermal heating or microwave irradiation, with improved yields of the l-vinyl-benzo[/]chroman obtained with the latter (Equation 189) <2005JA72>. 

A palladium-catalyzed intramolecular 1,4-dialkoxylation of (2-(cyclohexa-l,5-dienyl)phenyl)methanol provides a stereocontrolled route to isochromans 542 (Equation 224) <1998TL1223>. A tandem nucleophilic allylation-alkoxyal-lylation reaction of an ortio-alkynylbenzaldchydc 543, allyl chloride and allyltributylstannane in the presence of allylpalladium chloride furnishes the isochroman 544 via a (i-mdo-diycycl ization process (Equation 225) <2002TL7631 >. 

A palladium-catalyzed intramolecular benzannulation of bis-enynes 1135 proceeds chemoselectively to afford dihydroisocoumarins 1136 (Equation 441) <2002JOC2653>. A reaction sequence involving ruthenium-catalyzed yne-ene cross-metathesis of a polystyrene supported undecynoic acid ester followed by a Diels-Alder cycloaddition reaction with DMAD provides the basis for a combinatorial approach to dihydroisocoumarins featuring a variety of side chains at C-6 and C-8 <1999SL1879>. 

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