Arylation-cyclization, cascade

Optically active trifluoromethyl-substituted tetrahydroimidazo[l, 5-c] quinazoline derivatives 44 were synthesized by Zhao and coworkers via a diastereo- and enantioselective Mannich-type cyclization cascade reaction of a-aryl isocyanoacetates and trifluoromethyl-substituted cyclic ketimines, using a multihydrogen-bonding donor squaramide/AgOAc cooperative catalytic system in THF at 0°C (Scheme 30) (140L4566). The products were obtained in 76—99% yield with a diastereomeric ratio of greater than 15 1 and 58-98% enantiomeric excess. 

Scheme 3.44b).Another efficient palladium-catalyzed intramolecular carbopalladation-cyclization cascade toward tetra- and pentacyclic N-fused heterocycles was developed in 2010. This transformation proceeds via the palladium-catalyzed coupling of aryl halides with internal propargylic esters or ethers followed by a 5-endo-dig cyclization leading to polycyclic pyrrolo-heterocycles in moderate to excellent yields (Scheme 3.44c). 

The Heck cyclization proceeds via methylene indolenines (83) (isolable in the presence of Ag salts) and migration of their exocyclic double bond to the internal enamine position under the reaction conditions. A variety of 3-methylindoles (84) is accessible directly from 2-bromoiodobenzenes by a Pd-catalyzed aryl amination (Hartwig-Buchwald reaction)/Heck cyclization cascade [172]. 

MacMillan and co-workers developed a novel catalytic asymmetric cascade arylation-cyclization reaction of indole-based nucleophiles with diaryliodonium salts using Cu(I)-bisoxazoline catalysis under mild conditions (Scheme 39)... 

Scheme 39 Asymmetric cascade arylation-cyclization reaction...

One final example that underscores the power of intramolecular domino reactions to achieve the stereoselective synthesis of complex nitrogen heterocycles comes from the work of Barluenga and Gonzalez, who studied the preparation of tetrahydro-quinolines by intramolecular arylation of olefins induced by the in-house developed IPy2BF4 iodonium reagent. When applied to amine 102, this method afforded the tetracyclic compound 103 by the creation of three rings and five stereocenters in an elegant, fully diastereoselective cationic cyclization cascade (Scheme 3.32) [79]. 

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>. 

Zhang236 has also reported a Pd(0)-catalyzed cyclization-arylation cascade of 1,6-enynes that proceeds via the formation of a 7r-allylpalladium intermediate and the subsequent Suzuki coupling, yielding adducts with stereo-defined exocyclic double bonds (Scheme 60). 

Thermolysis of benzoenyneallene (113) in cyclohexadiene at 75 °C produced the cycloaromatized adduct (116) in 22% yield. A biradical is believed to form through a cascade sequence involving an initial Myers cyclization. Trapping of the aryl radical centre in (114) with the tetrarylallenic moiety intramolecularly affords (115), having two triaryl radical centres. Hydrogen abstraction from cyclohexa-1,4-diene by (115)... 

The interaction of cyanogen bromide vapors with solid o-hydroxyaniline (236u) or the solid benzhydrazides 324 at room temperature provides the 2-aminobenzoxazole (433) or the 2-amino-5-aryl-aminooxadiazole salts 434 [92] (Scheme 68). These 3-cascades imply formation of the cyanamide, its cyclization, and tautomerization. 

Radical cyclization is an effective approach to the synthesis of isoquinolines (Scheme 8). In some cases these offer an alternative to the palladium-catalyzed reactions with aryl halide intermediates <99EJOC1925, 99TL1125>. For example, the radical cyclization of the iodide 37 onto the vinylsulfide moiety was followed by a cascade cyclization to form the benzo[n]quinolizidine system <99TL1149>. In some cases the radical cyclization can take place without the need for a halo intermediate. The reactive intermediate of 38 was formed on the nitrogen as an amidyl radical, which underwent tandem cyclizations to the lycorane system <99TL2125, 99SL441>. 

With (i ,i )-BINAP as the ligand, Keay and Lau have been able to achieve the cascade cyclizations of the dienyl-substituted aryl triflates 134 toward the total synthesis of the natural product (+)-halenaquinone with ee s of up to 96% (Scheme 35). For these substrates, they observed an interesting influence of the remote substituent in 134. ... 

Nitroquinoline 209 enters into a direct cyclocondensation with aromatic hydra-zones in NaOH/DMF giving pyrazolo[3,4-/]quinolines 210 and (or) triazino[6,5-/ quinolines 211 in low to moderate yield (Scheme 62) (OOOL413). Their ratio mainly depends on the structure of the starting hydrazone. For example, electron-donating substituents in its aryl moiety assist triazine ring closure. Evidently, pyrazoles 210 are products of two consecutive SNH and SN ipso reactions, whereas conversion of 209 into 211 looks rather complicated and better corresponds with cascade hetero-cyclizations considered in Section III.D.l. 

The role of pyridine as a u-donor more than as a base was examplified by the use of ortho-chloro- or bromo-benzyllead triacetate reagents, which required addition of a strong base to reach good to high yields of tricyclic derivatives resulting from the cascade arylation and base-catalyzed cyclization (Equation (17)). 4 The influence of the... 

A radical cascade reaction has been accompHshed by StaHnski and coworkers which converts dipeptide derivatives to nitrogen-containing heterocycles (Scheme 6) [9]. In this work, N-bromobenzyl-hf-propargyl-substituted dipeptides such as 10 were subjected to Stork s catalytic procedure with tributyltin hydride [10]. An aryl radical is formed followed by a 1,5-hydrogen shift, generating the a-centered carbon radical 11. 5-Fxo-dig radical cyclization... 

Co(I) species and radical 688. Cyclization of 688 would lead to the formation of radical 689 that then combines with the Co(I) species to afford the organometallic species 690. Reductive elimination produced 687 and regenerated the Co(0) species. Whereas a variety of aryl and heteroaryl Grignard reagents readily participated in this cascade, o-substituted aryl Grignards appeared to be too sterically encumbered to efficiently react. 

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