Tandem Sonogashira Research Articles

Synthesis of some new 1,4-benzoxazine-pyrazoles in water as EGFR targeting anticancer agents

• A general and efficient synthesis • Eco-friendly water as solvent • Compounds 4c and 4n were shown comparable activity over four human cancer cell with the standard etoposide. • Compounds 4c and 4n displayed promising inhibitory activity on tyrosine kinase EGFR when compared with the standard Erlotinib. A general and efficient synthesis of some new 3,5-disubtituted 1,4-benzoxazine-pyrazole hybrids ( 4a-4n ) in eco-friendly water via a tandem Sonogashira coupling and cyclocondensation sequence from aromatic acid chlorides, 3-(3- oxo -2 H -benzo[ b ][1,4]oxazin-4(3 H )-yl)propanenitrile, and hydrazine hydrate was reported herein. Among them, the compounds 4c and 4n showed comparable activity against four human cancer cell lines like MCF-7 (breast), A549 (lung), HeLa (cervical), and PC3 (prostate) with the standard etoposide. In addition, the compounds 4b , 4e, 4i , and 4j exhibited promising activity against all the cell lines when compared with the etoposide. Moreover, the compounds 4c and 4n displayed promising inhibitory activity over tyrosine kinase EGFR when compared with the standard erlotinib.The results of in silico pharmacokinetic and docking studies of two most potent analogues 4c and 4n were also supported the consistent in vitro anticancer activity results.

Copper-catalyzed 1,1-alkynylalkylation of alkynes: access toward conjugated enynes

A copper-catalyzed 1,1-alkynylalkylation of alkynes with α-haloacetamides for the construction of conjugated enynes has been developed.

Synthesis of 8-carbo substituted 2-(trifluoromethyl)-4H-furo[2,3-h]chromen-4-ones and their thienoangelicin derivatives

Tandem Sonogashira cross-coupling and heteroannulation of 7-hydroxy-8-iodo-2-(trifluoromethyl)chromen-4-one with terminal acetylenes afforded the 8-carbo–substituted 2-(trifluoromethyl)-4H-furo[2,3-h]chromen-4-ones 2a–i. The latter were reacted with methyl mercaptoacetate in the presence of triethylamine to afford the corresponding 7,8-dihydro-5H-furo[2,3-h]thieno[2,3-c]chromen-5-one derivatives 3a–i. The structures of the prepared compounds were characterized using a combination of NMR (1H-, 13C &19F-), IR and mass spectroscopic techniques, and confirmed by single X-ray crystal structures of 8-(3-fluorophenyl)-2-(trifluoromethyl)-4H-furo[2,3-h]chromen-4-one (2b) and 2-phenyl-7-(trifluoromethyl)-7,8-dihydro-5H-furo[2,3-h]thieno[2,3-c]chromen-5-one (3a). The highlight of this investigation is the conversion of 2-(trifluoromethyl)–substituted 4H-furo[2,3-h]chromen-4-ones into trifluoromethyl–substituted thienoangelicin analogues.

One‐Pot Synthesis of Benzofurans via Cu–Catalyzed Tandem Sonogashira Coupling‐Cyclization Reactions

AbstractAn efficient one‐pot strategy for the synthesis of 2‐arylbenzofuran derivatives has been achieved using a Cu‐catalyzed tandem Sonogashira coupling‐cyclization methodology. This protocol is found to be cost effective and has wide substrate scope compared to the conventional Pd‐catalyzed methods. Additionally, this protocol was successfully applied for the synthesis of the natural product Corsifuran C.

Synthesis of Polysubstituted 3-Chalcogenated Indoles through Copper(I) Iodide-Catalyzed Three-Component Domino Reactions

Polysubstituted 3-chalcogenated indoles were synthesized by a three-component, one-pot, domino reaction of a N-(2-bromophenyl)trifluoroacetamide, a 1-alkyne, a disulfides or diselenides, CuI, and proline in DMF. In this process, tandem Sonogashira coupling, N-cyclization, and sulfenyl/selenyl electrophilic substitution occurred sequentially and smoothly to form the anticipated products in good to excellent yields (20 examples; 65–96%). Notably, no palladium catalyst was used in this catalytic system, supporting its cost effectiveness and potential industrial application.

Diastereodivergent Reductive Cross Coupling of Alkynes through Tandem Catalysis: Z- and E-Selective Hydroarylation of Terminal Alkynes.

A diastereodivergent hydroarylation of terminal alkynes is accomplished using tandem catalysis. The hydroarylation allows highly selective synthesis of both E and Z diastereoisomers of aryl alkenes, from the same set of starting materials, using the same combination of palladium and copper catalysts. The selectivity is controlled by simple changes in the stoichiometry of the alcohol additive. The hydroarylation has excellent substrate scope and can be accomplished in the presence of various classes of compounds, including esters, nitriles, alkyl halides, epoxides, carbamates, acetals, ethers, silyl ethers, and thioethers. The Z-selective hydroarylation is accomplished using a new approach based on tandem Sonogashira coupling and catalytic semireduction. The E-selective hydroarylation involves an additional catalytic isomerization of the Z-alkene. Our explorations of the reaction mechanism explain the role of individual reaction components and how the subtle changes in the reaction conditions influence the rates of specific steps of the hydroarylation. Our studies also show that, although the Z- and E-selective hydroarylation reactions are mechanistically closely related, the roles of the palladium and copper catalysts in the two reactions are different.

Palladium/copper-catalyzed tandem Sonogashira coupling/lactonization of methyl 2-(2′,2′-dibromovinyl)benzoate with terminal alkynes: Facile access to 3-alkynyl isocoumarins

An efficient palladium/copper-catalyzed tandem Sonogashira reaction/lactonization of methyl 2-(2′,2′-dibromovinyl)benzoate with terminal alkynes has been developed. This facile and direct approach furnishes a variety of 3-alkynyl isocoumarins in moderate to good yields under mild reaction conditions. Furthermore, this method enables concise total synthesis of natural products 3′-hydroxycorfin and gymnopalynes A.

Novel tricyclic diamines 2. Synthesis of 1,7-diazaisoadamantane, 1,5-diazaisoadamantane and 1,6-diazahomobrendane

Three novel tricyclic diamines (1,7-diazaisoadamantane, 1,5-diazaisoadamantane and 1,6-diazahomobrendane) were prepared. A flexible synthetic strategy was employed which used flat, aromatic azaindoles as the starting materials. The requisite azaindoles were prepared by a tandem Sonogashira coupling/intramolecular cyclization reaction. Ring saturation, appropriate functionalization and intramolecular alkylation provided the three novel tricyclic diamines cores.

Synthesis of Furo[2,3-c]pyridazines via Tandem Transition-Metal Catalysis.

A general and efficient catalytic approach to synthesis of the furo[2,3-c]pyridazine ring system is reported. Building on the easily accessible 2-bromo-3-aminopyridizinone skeleton, a tandem Sonogashira coupling-cycloisomerization provides ready access to functionalized furopyridazines. A wide functional group tolerance was observed in the tandem reaction, which proceeds in high yield in 1-3 h. The structure of the heterocyclic ring system was confirmed through single-crystal X-ray crystallography.

Synthesis and biological evaluation of novel non-racemic indole-containing allocolchicinoids

Two novel indole-containing allocolchicinoids were prepared from naturally occurring colchicine exploiting the Curtius rearrangement and tandem Sonogashira coupling/Pd-catalyzed cyclization as the key transformations. Their cytotoxic properties, apoptosis-inducing activity, tubulin assembly inhibition and short-time cytotoxic effects were investigated. Compound 7 demonstrated the most pronounced anti-cancer activity: IC50 < 1 nM, cell cycle arrest in the G2/M phase, 25% apoptosis induction, as well as lower destructive short-time effects on HT-29 cell line in comparison with colchicine. Docking studies for prepared indole-derived allocolchicine analogues were carried out.

Synthesis of 4‐Formyl‐2‐arylbenzofuran Derivatives by PdCl(C3H5)dppb‐Catalyzed Tandem Sonogashira Coupling‐Cyclization under Microwave Irradiation ‐ Application to the Synthesis of Viniferifuran Analogues

AbstractHerein we present the use of low catalyst loading of PdCl(C3H5)dppb (1 mol%) to directly prepare 4‐CHO‐2‐arylbenzofurans by copper‐free tandem Sonogashira coupling‐cyclization under microwave irradiation. The method was utilized to prepare highly substituted analogues of viniferifuran, a biologically active resveratrol dimer. Key transformations included the application of PdCl(C3H5)dppb (5 mol%) catalyzed direct arylation of C‐3 sterically congested C‐2 and C‐4 substituted benzofuran substrates. Finally, we demonstrated that BCl3/TBAI is superior to BBr3 for final demethylation.

Synthesis of substituted benzofurans and indoles by Zn-catalyzed tandem Sonogashira-cyclization strategy

Transition metal catalyzed cross-coupling reactions are one of the predominant strategies for the construction of heterocyclic structures which possess wide applications in the synthesis of natural products, pharmaceuticals, polymers, etc. Due to the vast importance of substituted benzofurans and indoles, numerous synthetic methodologies have been introduced for their synthesis. Among these methods, transition metal catalyzed cyclization reactions possess a unique position. In this manuscript, we disclose the first and efficient zinc-catalyzed protocol for the cyclization reactions of alkynes with 2-iodophenol and 2-iodoaniline leading to benzofurans and indoles respectively via a tandem Sonogashira coupling-cyclization process. Among the different metal catalysts, zinc has enormous potential due to its great availability, non-toxicity, eco-friendly and inexpensive nature.Zn(II) with N,N′-dimethylethylenediamine represents a suitable and efficient catalytic system for the desired tandem CC coupling-cyclization reactions, and a broad spectrum of functional groups are tolerated during the catalysis. A variety of substituted benzofurans and indoles have been successfully prepared in moderate to good yields under this new protocol.

A one-pot, multi-component reaction cascade for the rapid synthesis of diversely functionalized heteroaryl methyl substrates

A novel one-pot, “green” protocol to rapidly access pharmaceutically relevant heteroaryl methyl substrates is described. This process allows for a tandem SN2/Suzuki-Miyaura reaction or Sonogashira reaction across a breadth of chemical diversity with yields ranging between 31 and 87% for the tandem Suzuki-Miyaura process and 50–66% for the tandem Sonogashira process. This procedure tolerates S, N, and O heteroatom linkers and is amenable for both rapid and robust lead development screening. In addition, T-type and N-type calcium channel blocker (15) was synthesized in 43% yield using this methodology which stands as an improvement in both yield and reaction time of the previously reported synthesis. The one-pot protocol also allows for the inclusion of greater chemical diversity within the scaffold of 15.

Facile Synthesis of [1,2,3]Triazolo[5,1‐a]isoquinolines through a Copper‐Catalyzed Tandem Sonogashira Coupling/Cyclization Reaction

A highly efficient synthesis of [1,2,3]triazolo[5,1‐a]isoquinoline derivatives was developed that proceeds through copper‐catalyzed tandem Sonogashira coupling/regioselective 6‐endo cyclization. This NH‐triazole‐directed annulation approach showed good functional‐group tolerance and gave the corresponding N‐fused heterocycles in good to excellent yields.

ChemInform Abstract: Construction of Substituted Benzenes via Pd‐Catalyzed Cross‐Coupling/Cyclization Reaction of Vinyl Halides and Terminal Alkynes.

AbstractThe one‐pot tandem Sonogashira coupling/cyclization/aromatization reaction of β‐halo vinyl sulfones or ketones with terminal aryl or alkyl alkynes provides polysubstituted, functionalized benzenes endowed with a versatile sulfonyl or acyl group in high yields.

Construction of Substituted Benzenes via Pd-Catalyzed Cross-Coupling/Cyclization Reaction of Vinyl Halides and Terminal Alkynes.

A tandem Sonogashira coupling/cyclization/aromatization sequence of β-halo vinyl sulfones/ketones with terminal alkynes has been developed for the construction of benzene rings. Polysubstituted functionalized benzenes containing a sulfonyl or an acyl group could be obtained in up to 95% yield.

Enantioselective tandem reaction over a site-isolated bifunctional catalyst.

Construction of a site-isolated heterogeneous catalyst to realize the compatibility of bimetallic complexes for a feasible tandem reaction is a significant challenge in heterogeneous asymmetric catalysis. Herein, taking advantage of yolk-shell-structured mesoporous silica, we assemble an active site-isolated bifunctional catalyst through assembly of organopalladium-functionality into silicate channels as an outer shell and chiral organoruthenium-functionality onto silicate yolk as an inner core, realizing the one-pot enantioselective tandem reaction from Pd-catalyzed Sonogashira coupling to Ru-catalyzed asymmetric transfer hydrogenation. As presented in this study, this tandem Sonogashira coupling-asymmetric transfer hydrogenation of haloacetophenones and arylacetylenes affords various chiral conjugated alkynols with high yields and up to 99% enantioselectivity. Moreover, a catalyst can also be recovered easily and recycled repeatedly, making it an interesting feature in a practical organic transformation.

A new general synthesis of annulated 1,2,3-triazoles using tandem Sonogashira-CuAAC reaction

A number of novel, fused 1,2,3-triazoles have been synthesized efficiently by the palladium(0)-copper(I)-catalyzed intramolecular heteroannulation of 2-/1-azidomethyl-1-/2-bromodihydro-naphthalenes, -arene and -cycloalkenes with terminal alkynes involving tandem Sonogashira coupling-CuAAC reaction.

ChemInform Abstract: Stereoselective Synthesis of C‐Fused Pyranoindoles, Pyranobenzofurans and Pyranobenzothiophene Scaffolds Using Oxa‐Pictet—Spengler Type Reaction of Vinylogous Carbonates.

C-fused pyranoheterocycles can be readily assembled using an intramolecular oxa-Pictet–Spengler type reaction of vinylogous carbonates in a highly stereoselective manner. Required indole and benzofuran rings tethered to vinylogous carbonates are prepared by a tandem Sonogashira coupling–nucleopalladation reaction. The entire process can also be carried out in a ‘one-pot’ manner starting from homopropargyl alcohol. The C-fused pyranoindoles could be converted to spirooxindoles as well as to ring expanded products under oxidative conditions.

Stereoselective synthesis of C-fused pyranoindoles, pyranobenzofurans and pyranobenzothiophene scaffolds using oxa-Pictet-Spengler type reaction of vinylogous carbonates.

C-fused pyranoheterocycles can be readily assembled using an intramolecular oxa-Pictet-Spengler type reaction of vinylogous carbonates in a highly stereoselective manner. Required indole and benzofuran rings tethered to vinylogous carbonates are prepared by a tandem Sonogashira coupling-nucleopalladation reaction. The entire process can also be carried out in a 'one-pot' manner starting from homopropargyl alcohol. The C-fused pyranoindoles could be converted to spirooxindoles as well as to ring expanded products under oxidative conditions.