Palladium intramolecular arylations

The cycloaddition of alkynes and alkenes to nitrile oxides has been used in the synthesis of functionalised azepine systems <96JHC259>, <96T5739>. The concomitantly formed isoxazole (dihydroisoxazole) ring is cleaved by reduction in the usual way. Other routes to 1-benzazepines include intramolecular amidoalkylation <96SC2241> and intramolecular palladium-catalysed aryl amination and aryl amidation <96T7525>. Spiro-substituted 2-benzazepines have been prepared by phenolic oxidation (Scheme 5) <96JOC5857> and the same method has been applied to the synthesis of dibenzazepines <96CC1481>. 

Several different alkyl to aryl palladium migration processes have been also recently discovered using our standard palladium migration conditions (Scheme 28).24 Thus, both intramolecular Heck and intramolecular arylation... 

Intramolecular cyclization using palladium-catalyzed arylation of nitro compounds has been reported recently (Eq. 5.71).114... 

Intramolecular arylation of G-H bonds gives cyclic aromatic compounds. In this intramolecular arylation, the carbon-palladium cr-bond is first formed by the oxidative addition of Pd(0) species and then the resulting electrophilic Pd(n) species undergoes the intramolecular G-H bond activation leading to the formation of the palladacycle, which finally affords the cyclic aromatic compounds via reductive elimination.87 For example, the fluoroanthene derivative is formed by the palladium-catalyzed reaction of the binaphthyl triflate, as shown in Scheme 8.88 This type of intramolecular arylation is applied to the construction of five- and six-membered carbocyclic and heterocyclic systems.89 89 89 ... 

The intramolecular arylation of sp3 C-H bonds is observed in the reaction of l-/ r/-butyl-2-iodobenzene under palladium catalysis (Equation (71)) 94 94a 94b The oxidative addition of Arl to Pd(0) gives an ArPdl species, which undergoes the electrophilic substitution at the tert-butyl group to afford the palladacycle. To this palladacycle, another molecule of Arl oxidatively adds, giving the Pd(iv) complex. 

Hartwig has reported an intramolecular/intermolecular process affording the 3-aryloxindoles 105 (Scheme 32).115 The intermolecular arylation of acetanilide derivative 104 is slower than the intramolecular arylation to form the oxindole. Thus, the overall transformation starts with cyclization followed by intermolecular arylation of indole. In order to slow down the intermolecular process and speed up the intramolecular reaction, chloroarene and bromine-substituted acetanilide precursors are used according to their respective reactivity with palladium(O) in the oxidative addition process. 

Palladium-catalyzed arylation of olefins and the analogous alkenylation (Heck reaction) are the useful synthetic methods for carbon-carbon bond formation.60 Although these reactions have been known for over 20 years, it was only in 1989 that the asymmetric Heck reaction was pioneered in independent work by Sato et al.60d and Carpenter et al.61 These scientists demonstrated that intramolecular cyclization of an alkenyl iodide or triflate yielded chiral cyclic compounds with approximately 45% ee. The first example of the intermolecular asymmetric Heck reaction was reported by Ozawa et al.60c Under appropriate conditions, the major product was obtained in over 96% ee for a variety of aryl triflates.62... 

Rawal s group developed an intramolecular aryl Heck cyclization method to synthesize benzofurans, indoles, and benzopyrans [83], The rate of cyclization was significantly accelerated in the presence of bases, presumably because the phenolate anion formed under the reaction conditions was much more reactive as a soft nucleophile than phenol. In the presence of a catalytic amount of Herrmann s dimeric palladacyclic catalyst (101) [84], and 3 equivalents of CS2CO3 in DMA, vinyl iodide 100 was transformed into ortho and para benzofuran 102 and 103. In the mechanism proposed by Rawal, oxidative addition of phenolate 104 to Pd(0) is followed by nucleophilic attack of the ambident phenolate anion on o-palladium intermediate 105 to afford aryl-vinyl palladium species 106 after rearomatization of the presumed cyclohexadienone intermediate. Reductive elimination of palladium followed by isomerization of the exocyclic double bond furnishes 102. 

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... 

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>. 

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 C-H transformation of imines via palladacycles has recently provided a novel synthesis of fluoren-9-ones [4], This high yielding synthesis is achieved by migration of palladium from an aryl position to an imidoyl position via C-H activation of the imine moiety, followed by intramolecular arylation (Scheme 2). 

Iodo-l-(3-methylbut-3-enyloxy)-4-phenoxybenzene 461 undergoes palladium(n)-mediated ring closure via a 1,4-shift of palladium from alkyl to aryl followed by intramolecular arylation to afford the fused chroman 462 (Equation 190) <2004JA7460>. Similarly, l-iodo-2-(3-methylbut-3-enyloxy)benzene can undergo a palladium(n)-mediated cyclocarboformylation to afford the chroman 463 (Equation 191) <2001T1347>. 

B. Gomez-Lor, A. M. Echavarren, Synthesis of a Triaza Analogue of Crushed Fullerene by Intramolecular Palladium-catalyzed Arylation, Org. Lett. 2004, 6, 2993-2996. 

The palladium-catalyzed arylation and alkenylation of olefins, which were first discovered in the 1970 s by Heck (7,2) and Mizoroki (3) and have been often called the "Heck reaction", are versatile synthetic means for making a carbon-carbon bond. These reactions have been extensively used for organic synthesis during the past two decades (4-7). However, no reports on the "asymmetric Heck reaction" have been appeared until very recently. Shibasaki reported an asymmetric intramolecular cyclization of alkenyl iodides to give c/j-decalin derivatives of 80-91% ee (8-10). Overman reported an intramolecular cyclization of alkenyl triflate, giving a chiral quaternary carbon center of 45% ee (77). We report herein the first example of intermolecular asymmetric Heck-type arylation of cyclic olefins catalyzed by (7 )-BINAP-coordinated palladium complexes (Scheme 1) (12,13). 

Zhao and Larock have introduced a convenient method for the preparation of substituted dibenzofurans as well as carbazoles and indoles by palladium-catalyzed cross-coupling of alkynes and appropriately substituted aryl iodides. These reactions proceed by carbopalladation of the alkyne, heteroatom-directed migration of palladium from a vinyl to the adjacent aryl position, and ring closure via intramolecular arylation (Scheme 87) <2006JOC5340>. 

Several different methods of synthesis of benzimidazoles have been reported. Intramolecular aryl guanidinylation of aryl bromides 103 with copper- and palladium-catalyzed methods led to... 

Larock and co-workers [47] have studied the palladium-catalyzed arylation of 1,3-dienes followed by intramolecular attack by an oxygen nucleophile. o-Iodophenols and o-iodobenzyl alcohol were used as substrates. However these reactions, which are annulation reactions, lead to a 1,2-addition to the conjugated dienes and will not be further treated here. Amides, also, were used as nucleophiles in these reactions. 

An extension of the palladium(0) catalyzed direct arylation reactions was reported by Lautens et al. in 2005. Based on the Catellani reaction [32], a direct intramolecular arylation of indole (C2) followed ort/m-alkylation, via a norbor-nene-mediated tandem aromatic alkylation/Heck reaction (Scheme 17) [33]. An analogous process was later developed for thiophenes and furans, allowing formation of a range of interesting hetero-aryl polycyclic products (Scheme 17) [34]. 

The first detailed study of alkyl to aryl palladium migrations, reported in 2004, involved homobenzylic to phenyl migration (Table 5) [58], The process was demonstrated using aryl iodides tethered to an olefin. An additional hap, either intramolecular arylation or intermolecular Heck olefination, was used to hap the migrated palladium. The reaction gives high yields of the desired polycyclic products. 

Garcia-Cuadrado D, Braga AAC, Maseras F, Echavarren AM (2006) Proton abstraction mechanism for the palladium-catalyzed intramolecular arylation. J Am Chem Soc 128 1066-1067... 

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