Sonogashira alkynylation-cyclization

Activated charcoal is used as a heterogeneous support to prepare different supported metal catalysts because of its robustness and inertness. Recently Felpin et al. [72] developed a bimetallic Pd-Cu heterogeneous catalyst supported on active charcoal and used it to synthesize benzofurans by the same protocol of Sonogashira alkynylation-cyclization sequence (Scheme 53). 

Pinto etal. [52] have reported a consecutive three-component synthesis of oxin-doles that proceeds in the sense of a Sonogashira alkynylation-carbopalladation-CH activation-cyclization sequence, furnishing 3-(diarylmethylene)oxindoles 31 in moderate to good yields (Scheme 12.20). 

Vollhardt et al. recently reported the synthesis of hexaethynylated PAM 11 using a combined Sonogashira/Stephens-Castro approach [20]. The requisite compound for cyclization, molecule 12, was prepared in stepwise fashion from 1,2,3,4-tetrabromobenzene. Regioselective alkynylation at positions 1 and 4 afforded dibromophenyldiacetylene (13), which was then monoalkynylated at... 

Sonogashira coupling of o-iodothioanisole (73) with phenylacetylene affords o-(l-alkynyl)thioanisole 74, which cyclizes to give 2-substituted 3-iodobenzothio-phene 75 by the treatment with iodine. Furthermore, Suzuki coupling of 75 affords the 2,3-disubstituted benzothiophene 76 [45]. The iminoalkyne 78 is prepared by Sonogashira coupling of the alkenyl iodide 77, and the substituted pyridine 79 is obtained by the Cul-catalyzed cyclization [46]. 

A well-established preparative method of alkynyl ketones 110 is the Sonogashira-type carbonylation of aryl halides in the presence of terminal alkynes. (Trimethylsi-lyOpyridylethyne (111), deprotected in situ, reacted with 3-iodotoluene and CO to give the alkynyl m-tolyl ketone 112 using DPPF as a hgand. Pd-catalyzed reductive cyclization of 112 using HCO2H afforded the 1,8-naphthyridine 113 [48]. 

With the development of Buchwald-Hartwig amination reactions, the amine component of these indoles can also be introduced into these precursors via palladium catalysis [8]. As shown by Ackermann, this can be coupled with aryl halide alkynylation and cyclization to provide a one-pot, three-component synthesis of substituted indoles (Scheme 6.6) [9]. In this case, simple ortho-dihaloarene derivatives S were employed as starting materials, with Sonogashira coupling occurring at the more activated aryl-iodide bond, followed by selective coupling of various alkyl or arylamines. Alternatively, Zhao has recently demonstrated that amination can be performed on both bromoalkyne 6, followed by the aryl-bromide bond, to provide a route to 2-amidoindoles (Scheme 6.7) [10]. 

Reddy and collaborators reported a new one-pot, three-component procedure toward the synthesis of novel 4-phenyl-2-[3-(alkynyl/alkenyl/aryl) phenyl] pyrimidine libraries starting with the Michael addition of enaminone 64 with 3-bromobenzimidamide hydrochloride (65) (Scheme 28) (13S75). This was followed by a cyclization, an isomerization, a dehydration, and a subsequent Sonogashira reaction with terminal alkynes or a Suzuki reaction with arylboronic acids or a Heck coupling reaction with alkenes. 

The metal-catalysed cyclization of o-alkynyl anilines to indoles and o-alkynylphenols to benzofurans has been studied (Scheme 6.19). It is a useful method because the starting materials are readily available by Sonogashira reactions (Section 2.8). Cyclization followed by protonolysis of the t -intermediate 6.51 gives the heterocycle. As protonolysis regenerates a palladium(II) species, no added oxidant is required. In some cases, protonolysis is slow, and the reaction must be carried out in acidic conditions. ... 

A plausible mechanism was proposed in Scheme 7.10. Firstly, 2- alkynyl-benzaldehydes 20 could be easily obtained via a Sonogashira reaction of 2-bromobenzaldehyde with alkyne. After condensation with sulfonohydrazide, N -(2-alk50iylbenzylidene)hydrazide I would be afforded. Subsequently, the 6-endo-cyclization would occur to generate the isoquinolinium-2-yl amide II in the presence of suitable Lewis acid. In this step, the formation of a p-complex via coordination of the alkynyl moiety of 20 to the Lewis acid would be involved, thus activating the triple bond for further cyclization. Meanwhile, die in situ formed enolate (derived from ketone or aldehyde in the presence of base) would attack the isoquinolinium-2-yl amide II to produce intermediate III. Subsequent intramolecular condensation and aromatization would give rise to the desired product 22. 

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