Intramolecular cyclizations palladium-catalyzed arylation

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

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... 

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 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). 

Secondary amides and carbamates are very good substrates for the palladium-catalyzed arylation. Buchwald reports the intramolecular cyclization of amides and... 

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. 

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>. 

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... 

Fagnou et al. reported the synthesis of mukonine (11) starting from methyl vanillate (644). This synthesis uses both a palladium(0)-catalyzed intermolecular direct arylation and an intramolecular cyclization reaction. Triflation of methyl vanillate (644) afforded the aryl triflate 645. Using a Buchwald-Flartwig amination protocol, the latter was subjected to direct arylation with 2-chloroaniline (646) to furnish the corresponding diarylamine 647. Finally, intramolecular cyclization of 647 afforded mukonine (11). To date, this is the best synthesis (three steps, 75% overall yield) available for mukonine based on commercially available methyl vanillate (644) (582) (Scheme 5.45). 

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>. 

Palladium-catalyzed oxidative cyclization of aryl homoallyl ethers affords 4-methyl-2//-chromenes in moderate yield. The reaction is proposed to proceed via activation of the alkene by coordination to Pd(ll) followed by intramolecular nucleophilic attack by the arene. Subsequent [1-hydride elimination and isomerization then affords 4-methyl-27/-chromenes (Scheme 13). Electron-rich aryl homoallyl ethers give the best yield and good regio-selectivity is observed for the reaction of unsymmetrical arenes <2005OL3355>. 

Vinyl-l//-isochromenes can be prepared in moderate yield by a palladium-catalyzed coupling of ( )-(3-(2-bromo-phenyl)allyloxy)tenM)i i r l)si Iyl derivatives 157 with ketones. The reaction proceeds via initial ketone arylation to furnish the intermediate 158 followed by intramolecular cyclization of the ketone enolate onto the tethered allylic system (Scheme 50) <2000CG1675>. 

The palladium-catalyzed hydroboration of allyl phenyl ether 456 is followed by cyclization of the corresponding triflate to afford the chroman core of the tocopheryls 457 (Equation 186) <1998JA9074>. The intramolecular hydroarylation of l-(but-3-enyloxy)-3,5-dimethylbenzene to afford 4,5,7-trimethylchroman can be accomplished using a RuCh/AgOTf catalytic system (Equation 187) <20040L581>. 2,2-Dimethylchromans 458 are formed by a Mo(CO)6 catalyzed intramolecular cyclization of aryl prenyl ethers 459 (Equation 188) <1998S256>. 

Stoichiometric palladium-mediated cyclization was used in natural product synthesis by Boger a number of years ago, as was noted in the introduction. More recently, an intramolecular palladium-catalyzed amination of a heteroaromatic halide has been used as a step in the synthesis of an a-carboline natural product analog [146]. As discussed above, the diphenylhydrazone arylation can also be used for nitrogen heterocycle synthesis [140]. 

Intramolecular palladium-catalyzed cyclization reactions are commonly used to synthesize indazole derivatives . For example, A-Aryl-A-(<9-bromobenzyl)hydrazines 203 participate in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2//-indazoles 204 (Scheme 121) <20000L519>. 

A practical ligand-free palladium-catalyzed intramolecular reductive Heck cyclization was developed by Liu et al. <07TL2307>. The authors found that water was an essential component of the reaction mixture. Using a series of aryl halide intermediates this cyclization resulted in the desired 1,2,3,4-tetrahydroisoquinolines in high yields. Cook and co-workers found that InCU was an efficient catalyst for an intramolecular Friedel-Crafts cyclization of Ar-(4-bromobut-2-enyl)-A-(bcnzyl)-4-methylbcnzcncsulfonamidc to form the desired 3-substituted tetrahydroisoquinolines <07OL1311>. 

A number of additional cyclizations involving alkynes have been reported. For instance, it has been shown that indoles may also be accessed from 2-bromo- or 2-chloroanilines, as illustrated by the regioselective preparation of the carbinol 373 in the presence of the ferrocene 374 (Equation 104) <20040L4129>, whereas a one-pot sequence featuring titanium catalyzed hydroamination of 2-chloroanilines with acetylenes, followed by intramolecular Heck cyclization in the presence of an imidazol-2-ylidene palladium complex, has also been reported <2004CC2824>. A set of aryl-2-indolyl carbinols have been prepared in high enantiomeric purity by palladium-catalyzed annulation of... 

This suggests that in the case that both intramolecular C- and 0-arylations are of geometrically equal possibility, the former preferentially takes place. The reaction of o-bromobenzaldehydes with dibenzylketones gives l,3-diaryl-2-naphthols that may be useful materials as bulky 0-ligands (Eq. 24) [62]. This cyclization involves palladium-catalyzed a-arylation and base-promoted dehy-drative condensation. Treatment of o-iodoanilines with ketones produces indole derivatives (Eq. 25) [63]. In this case, dehydrative condensation between the amino group and the carbonyl group occurs initially and the subsequent car-bopalladation (mechanism A) leads to the products. 

Fused pyrazole compounds have been prepared from A -alkyl-substituted pyrazoles. For example, a palladium-catalyzed/norbornene-mediated sequential coupling reaction involving an aromatic sp C-H functionalization as the key step has been described, in which an alkyl-aryl bond and an aryl-heteroaryl bond are formed in one pot. A variety of highly substituted six-membered annulated pyrazoles 433 were synthesized in a one-step process in moderate yields from iV-bromoalkyl pyrazoles 431 and aryl iodides 432 (Equation 87) <20060L2043>. An intramolecular cyclization version has also been reported. Exposure of 2equiv of -butyllithium to l//-pyrazole-l-alkanoic acids 434 afforded the cyclic ketones 435 via a Parham-type cyclization process (Equation 88) <1997SL1013>. 

Intramolecular palladium-catalyzed cyclization reactions have also been used to synthesize pyrazole derivatives. iV-Aryl-iV-(o-bromobenzyl)hydrazines 494 participated in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2//-indazoles 495 (Equation 101) <20000L519>. Palladium-catalyzed intramolecular C-N bond formation of iV-acetamino-2-(2-bromo)arylindolines 496, followed by hydrolysis and air oxidation in the presence of aluminium oxide, allowed the preparation of indolo[l,2-3]indazoles 498 via intermediate 497 (Scheme 58) <2002TL3577>. 3-Substituted pyrazoles have been prepared from the intramolecular cyclization of A -tosyl-iV-(l-aryl/ vinyl-1-propyn-3-yl)hydrazine and then exposme of the reaction mixture of the cyclization to potassium /i //-butoxide <1997SL959>. iV-Aryl-iV -(o-bromobenzyl)hydrazines 499 or [A -aryl-A -(t>-bromobenzyl)hydrazinato-A ]-triphenyl-phosphonium bromides 501 participated in a palladium-catalyzed intramolecular amination reaction to give 1-phenyl-l//-indazoles 500 (Scheme 59) <2001TL2937>. 

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