Alkynes, cyclization with 2-haloaniline

The von Richter cinnoline process was further extended to solid-phase synthesis. The route began from benzylaminomethyl polystyrene and the required diverse o-haloaryl resins represented by 21 were prepared from substituted o-haloanilines. A Pd-mediated cross-coupling reaction with 21 and the alkynes provided the alkynylaryl derivatives represented by alkyne 22. The von Richter cyclization reaction with hydrobromic or hydrochloric acid in acetone/HaO and cleavage from the resin occurred in the same step to furnish the cinnoline derivatives 23 in 47-95% yield and 60-90% purity (no yield reported for each entry). 

A few additional Pd-catalyzed schemes have been employed for Ilac type cyclization chemistry. Palladium-phenanthroline complexes were used by the Ragaini group to prepare indoles via the intermolecular cyclization of nitroarenes and alkynes in the presence of carbon monoxide <06JOC3748>. Jia and Zhu employed Pd-catalysis for the annulation of o-haloanilines with aldehydes <06JOC7826>. A one-pot Ugi/Heck reaction was employed in the preparation of polysubstituted indoles from a four-component reaction system of acrylic aldehydes, bromoanilines, acids, and isocyanides <06TL4683>. 

The related cyclization of 2-ethynylanilines 67 also represents one of the usefiil methods for the synthesis of 2-substituted indoles since the precursors are easily prepared from 2-haloanilines 66 by Pd-catalyzed cross-coupling with terminal alkynes. Althou cyclizations of such alkynes are normally effected using Cu(I) or Pd(II) species, Sakamoto showed that in the absence of such metals, base catalysis (e.g., NaOEt) alone can accomplish the same goal. This author now reports that tetrabutylammonium fluoride (TBAF) is capable of inducing cyclization to the indoles 68 without affecting functionalities such as bromo, cyano, ethoxycarbonyl, and ethynyl <99JCS(P1)529>. 

Pyridopyrimidines and pyrimidines fused with five- or six-membered heterocycles can be prepared via the ring closure of intermediate ethynylpyrimidines, which are themselves obtained by the Pd-catalyzed cross-coupling of halopyrimidines with alkynic compounds (Scheme 34). ° ""° o-Alkynylanilines such as (51), which are made by Pd-catalyzed coupling reactions of alkynes with o-haloaniline precursors, are easily cyclized to the indoles in the presence of base (Scheme 35). " " Similar meth( s can be employed in the synthesis of isocoumarins," thienopyridines," furopy-ridines" and the marine alkaloid asptamine." ... 

Yamanaka and co-workers studied Pd-catalyzed couplings of o-haloaniline derivatives with terminal alkynes, but cyclization to give indoles occurred upon treatment with mild base or Cul, often in one pot [213c, 216]. These workers also described the Pd-induced coupling of 1- and 2-substituted 2- and 3-iodomdoles with terminal alkynes to give the corresponding... 

A formal [3 + 2] cydoaddition route leading to the preparation of di- and tri-substituted indoles 264 from ortho-haloanilines 261 and copper(I) acetylides 262 was introduced by Castro (Scheme 9.92) [75, 76, 111], simultaneously with the mentioned earlier coupling-cyclization reaction en route to benzofurans 57 (Scheme 9.21). It is believed that this stoichiometric in copper cascade reaction proceeded with the generation of an intermediary ortho-alkynylaniline 263 [77]. Attempts to turn this reaction into a more practical catalytic process, using basic conditions to generate Cu(I)-acetylide from a terminal alkyne in the presence of Cul, provided poor yields of the respective indoles 264. 

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