Intramolecular cyclizations, palladium bromide

Most of the work on the C-N bond-forming crosscoupling reactions has concentrated on the formation of aromatic C-N bonds. Recent studies show that the application of cross-coupling reactions to alkenyl halides or triflates furnished enamines (Scheme 19) (for palladium-catalyzed reaction, see 28,28a-28d, and for copper-catalyzed reaction, see 28e-28g). Brookhart et al. studied the palladium-catalyzed amination of 2-triflatotropone 109 for the synthesis of 2-anilinotropone 110.28 It was found that the reaction of 109 proceeded effectively in the presence of racemic BINAP and a base. As a simple method for the synthesis of enamines, the palladium-catalyzed reactions of alkenyl bromide 111 with secondary amine were achieved under similar conditions.2841 The water-sensitive enamine 112 was isolated as pure compound after dilution with hexane and filtration through Celite. The intramolecular cyclization of /3-lactam 113, having a vinyl bromide moiety, was investigated by Mori s... 

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>. 

Condensation of 1 with 3,4-dimethoxybenzyl cyanide afforded the epimeric cyano alcohols 2, which on alkaline hydrolysis gave the epimeric y -lactones 3 in 64% yield. Treatment of 3 with crotyl bromide afforded the a,a-disubstituted lactone 4. Acid-catalyzed debenzy-lation of 4 afforded the alcohol 5, which on sequential saponification, periodate cleavage and reduction gave the lactone 7 via 6. Palladium-catalyzed oxidation of 7 afforded 8, which underwent intramolecular cyclization to produce 9 in 66% yield. Treatment of 9 with methylamine gave 10 (41%) and 11 (7%) however, the former can be cyclized into the latter in 85% yield. Reduction of 11 furnished 12 in 77% yield. 

A stoichiometric, intramolecular variant of the Buchwald-Hartwig amination was reported by D, L. Boger and J, S. Panek as early as 1984 in the synthesis of lavendamycin.7 They showed that 1.2 equiv of Pd(PPh3)4 could effect the intramolecular cyclization of an amino bromide 1 to the desired heterocycle 2. The absence of an external base to sequester the generated HBr rendered this reaction super-stoichiometric in palladium. 

An analogous reaction sequence can be used to generate benzimidazoles and aminobenzimidazoles, involving the palladium-catalyzed intramolecular cyclization of aryl bromide-substituted amidines and guanidines, respectively (e.g.. Scheme 6.37) [48]. With aryl bromides, simple Pd(PPh3)4 or Pd2dba3/PPh3 catalysts are sufficient to mediate cyclization. This same approach is equally applicable to indazoles and polycyclic benzimidazoles [49]. 

Free-radical cyclization reactions nicely complement the Pd(0)-catalyzed intramolecular Heck reaction, which also provides cyclic products from unsaturated halides. Free radicals can be generated easily at saturated carbons from saturated alkyl bromides, and the products are reduced relative to the reactants. In contrast, intramolecular Heck reactions work best for vinyl and aryl bromides (in fact they do not work for alkyl halides), and the products are at the same oxidation level as the reactants. Moreover, free radicals attack the double bond at the internal position, whereas palladium insertion causes cyclization to occur at the external carbon. 

The formation of compound 175 could be rationalized in terms of an unprecedented domino allene amidation/intramolecular Heck-type reaction. Compound 176 must be the nonisolable intermediate. A likely mechanism for 176 should involve a (ji-allyl)palladium intermediate. The allene-palladium complex 177 is formed initially and suffers a nucleophilic attack by the bromide to produce a cr-allylpalladium intermediate, which rapidly equilibrates to the corresponding (ji-allyl)palladium intermediate 178. Then, an intramolecular amidation reaction on the (ji-allyl)palladium complex must account for intermediate 176 formation. Compound 176 evolves to tricycle 175 via a Heck-type-coupling reaction. The alkenylpalladium intermediate 179, generated in the 7-exo-dig cyclization of bro-moenyne 176, was trapped by the bromide anion to yield the fused tricycle 175 (Scheme 62). Thus, the same catalytic system is able to promote two different, but sequential catalytic cycles. 

Palladium-catalyzed cyclization reactions with aryl bromides have been used to synthesize pyrazole derivatives. lV-Aryl-Ar -(o-bromobenzyl)hydrazines 20 or [A-Aryl-N -(o-bromobenzyl)hydrazinato-N ]-triphenylphosphonium bromides 21 participated in palladium-catalyzed intramolecular amination reactions to give l-aryl-l//-indazoles 22 <01TL2937>. Thermal extrusion of sulfur dioxide or carbon dioxide from their respective heterocyclic precursors 23 or 24 generated 1,2-diaza-l, 3-butadicnes 25, which underwent palladium(0)-catalyzed carbonylation to yield 2,3-pyrazol-l(5//)-ones 26 <01OL3651> or [4 + 2) Diels-Alder reactions with Af-phenyldiazamaleimide to afford cycloadducts 27 <01OL3647>. 

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