Copper-free Sonogashira Coupling Research Articles

Palladium-Catalyzed Copper-Free Sonogashira Coupling of 2-Bromoarylcarbonyls: Synthesis of Isobenzofurans via One-Pot Reductive Cyclization

Palladium-catalyzed copper-free Sonogashira coupling of 2-bromocarbonyls is presented. This method afforded the 2-alkynylaryl carbonyls, useful synthons for the accomplishment of many carbocyclic and heterocyclic motifs. Significantly, the strategy was extended to the one-pot synthesis of isobenzofurans via reduction followed by intramolecular 5-exo-dig cyclization.

Copper-Free Sonogashira Coupling with Palladium Nanoparticles

Key words heterogeneous catalysis - palladium - nanoparticles - Sonogashira coupling - haloarenes - alkynes

Synthesis and properties of octa-distyryl-BODIPY substituted zinc(II) phthalocyanines

A novel type octa-distyryl-BODIPY substituted zinc(II) phthalocyanines 9 and 10 were prepared by the copper-free Sonogashira coupling and “Click” reactions, respectively. The terminal ethynyl functionalized BODIPY (4,4’-difluoro-8-(4-propynyloxy)-phenyl-1,7-dimethyl-3,5-bis(4-4″-diethylaminophenyl)ethenyl)-4-bora-3a,4a-diaza-s-indacene, 8) compound was reacted with octakis (iodo) zinc(II) phthalocyanine (2) for the synthesis of BODIPY substituted zinc(II) phthalocyanine 9. On the other hand, the same BODIPY compound (8) was used to the synthesis of BODIPY substituted zinc(II) phthalocyanine 10 by the reaction of this BODIPY with octakis-(2-azidoethoxy) zinc(II) phthalocyanine (7). While eight distyryl-BODIPY groups were linked to the phthalocyanine core through ethynyl bonds for phthalocyanine 9, these BODIPY groups were connected to the phthalocyanine core via triazole ring for phthalocyanine 10. All newly synthesized compounds were characterized by elemental analysis and general spectroscopic methods such as 1H NMR, mass, FT-IR, UV–Vis and fluorescence. Moreover, the photophysical and photochemical properties of these conjugates were investigated for determination of their photosensitizer and fluorescence abilities for photodynamic therapy.

Oxine based unsymmetrical (O−, N, S/Se) pincer ligands and their palladium(ii) complexes: synthesis, structural aspects and applications as a catalyst in amine and copper-free Sonogashira coupling

Newly synthesized and characterized (single crystal structure) complexes, [Pd(O−, N, S/Se)Cl], efficiently catalyse Sonogashira coupling of ArX at 0.5–1 mol%.

ONO pincer type binuclear Pd(II) complex: Synthesis, crystal structure and catalytic utilization of the resulting organopalladium complex in catalytic copper-free Sonogashira coupling reaction

New binuclear palladium (II) complex featuring ONO pincer type hydrazone ligand was synthesized and characterized by spectroscopic and single-crystal XRD analysis. This complex showed excellent catalytic activity towards the copper-free Sonogashira cross coupling reaction. The main advantages over previous methodologies include low catalyst loading, less problematic reaction media (H2O–DMSO) and reusability in homogenous systems for optimal performance.

Novel phthalocyanine–BODIPY conjugates and their photophysical and photochemical properties

Novel zinc(II) phthalocyanines bearing boron dipyrromethene (BODIPY) (8) and its mono-styryl (9) and di-styryl (10) derivatives containing p-(N,N-diethylamino)benzaldehyde moieties were designed and synthesized for the first time. These phthalocyanines (8–10) were prepared by the copper-free Sonogashira coupling reaction of terminal ethynyl functionalized BODIPYs [4,4′-difluoro-8-(4-propynyloxy)-phenyl-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene (2), 4,4′-difluoro-8-(4-propynyloxy)-phenyl-3,5,7-trimethyl-1-((4-diethylaminophenyl)ethenyl)-4-bora-3a,4a-diaza-s-indacene (5), or 4,4′-difluoro-8-(4-propynyloxy)-phenyl-3,5-dimethyl-1,7-bis((4-4″-diethylaminophenyl)ethenyl)-4-bora-3a,4a-diaza-s-indacene (6)] with tetrakis(iodo) zinc(II) phthalocyanine (7). All newly synthesized compounds were fully characterized by elemental analysis and general spectroscopic methods such as 1H NMR, FT-IR, mass, UV–Vis, and fluorescence. The photophysical (fluorescence quantum yields and lifetimes), photochemical (singlet oxygen generation capability and photodegradation behaviors) properties of these phthalocyanines were also investigated for determination of their photodynamic therapy (PDT). The results obtained indicated that these conjugates could be promising photosensitizers for PDT applications.

2-Aryl-8-aza-3-deazaadenosine analogues of 5′-O-[N-(salicyl)sulfamoyl]adenosine: Nucleoside antibiotics that block siderophore biosynthesis in Mycobacterium tuberculosis

A series of 5′-O-[N-(salicyl)sulfamoyl]-2-aryl-8-aza-3-deazaadenosines were designed to block mycobactin biosynthesis in Mycobacterium tuberculosis (Mtb) through inhibition of the essential adenylating enzyme MbtA. The synthesis of the 2-aryl-8-aza-3-deazaadenosine nucleosides featured sequential copper-free palladium-catalyzed Sonogashira coupling of a precursor 4-cyano-5-iodo-1,2,3-triazolonucleoside with terminal alkynes and a Minakawa–Matsuda annulation reaction. These modified nucleosides were shown to inhibit MbtA with apparent Ki values ranging from 6.1 to 25nM and to inhibit Mtb growth under iron-deficient conditions with minimum inhibitory concentrations ranging from 12.5 to >50μM.

Mechanistic Insights and Implications of Dearomative Rearrangement in Copper-Free Sonogashira Cross-Coupling Catalyzed by Pd-Cy*Phine

The reaction mechanism for the in situ prepared Pd-Cy*Phine catalyst used in copper-free Sonogashira coupling was investigated using density functional theory. In addition, the significance of the meta-terarylphosphine ligand architecture of Cy*Phine was probed, as it had been previously shown experimentally to augment catalytic activity relative to its biarylphosphine analogue, XPhos. The calculated reaction barriers and free energies for the steps in the catalytic cycle suggest that the suppression of a dearomative rearrangement pathway is likely to be an important feature for the improved catalytic performance observed for the Pd-Cy*Phine system.

Ligand and copper free Sonogashira coupling to achieve 2-alkynyl d-glucal derivatives: regioselective electrophile promoted nucleophilic 5-endo-dig cyclization

A general approach for the synthesis of 2-alkynyl-d-glucal derivatives has been achieved through a ligand and copper-free Sonogashira coupling of 2-iodo-3,4,6-tri-O-acetyl-d-glucal and terminal alkynes using palladium acetate in DMF at room temperature with very good to excellent yields. The scope of this reaction is shown by regioselective electrophile promoted nucleophilic (EPN) 5-endo-dig cyclization of these alkynyl-d-glucal derivatives using gold(III) chloride in 1,4-dioxane at reflux.

Synthesis, structural characterization and in vitro anti-cancer activity of functionalized N-heterocyclic carbene platinum and palladium complexes

A series of platinum(II) and palladium(II) complexes bearing N-heterocyclic carbene ligands functionalized by specific functionalities such as alcohol, nitrile or ester were synthesized. The novel complexes were fully characterized and X-ray diffraction was used for the structure determination of eight derivatives. The reactivity of the functional groups has been studied; for example, Pt and Pd NHC complexes containing tBu ester functions were easily hydrolyzed giving water-soluble NHC complexes. The palladium complex 21 containing dangling COOH group was evaluated in copper-free Sonogashira coupling reaction. In addition, platinum NHC complexes are attractive metal-based systems for the development of anticancer drugs. Preliminary results of the biological effects on various human cancer and non-cancer cells are also reported.

Application of palladium complexes bearing acyclic amino(hydrazido)carbene ligands as catalysts for copper-free Sonogashira cross-coupling

Metal-mediated coupling of one isocyanide in cis-[PdCl2(CNR1)2] (R1=C6H11 (Cy) 1, tBu 2, 2,6-Me2C6H3 (Xyl) 3, 2-Cl-6-MeC6H34) and various carbohydrazides R2CONHNH2 [R2=Ph 5, 4-ClC6H46, 3-NO2C6H47, 4-NO2C6H48, 4-CH3C6H49, 3,4-(MeO)2C6H310, naphth-1-yl 11, fur-2-yl 12, 4-NO2C6H4CH213, Cy 14, 1-(4-fluorophenyl)-5-oxopyrrolidine-3-yl 15, (pyrrolidin-1-yl)C(O) 16, 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propane-1-yl 17, EtNHC(O) 18] or sulfohydrazides R3SO2NHNH2 [R3=Ph 19, 4-MeC6H420] led to a series of (hydrazido)(amino)carbene complexes cis-[PdCl2{C(NHNHX)N(H)R1}(CNR1)]; X=COR2, SO2R3(21–48, isolated yields 60–96%). All prepared species were characterized by elemental analyses (C, H, N), HR ESI+-MS, IR, 1H and 13C{1H} NMR spectroscopy, and by a single-crystal X-ray diffraction for 38. Complexes 21–48 demonstrated excellent activity as catalysts in copper-free Sonogashira coupling of aryl iodides and a variety of aromatic terminal alkynes. Catalytic system runs in environmentally benign EtOH ensuring product yields of up to 75–96% and TONs of up to 104. Mechanism of the copper-free Sonogashira catalytic cycle involving 21–48 as catalysts was proposed upon identification of key intermediates using HRESI-mass.

An efficient one-pot synthesis of 2-bromo-6-aryl[5H]pyrrolo[2,3-b]pyrazines

We report a two step one-pot method for the synthesis of 2-bromo-6-aryl[5H]pyrrolo[2,3-b]pyrazines. The process makes use of a cleaner copper-free Sonogashira coupling and an improved base-mediated 5-exo-dig cyclisation to afford the products in good yields. This method expands the scope to structures that are poorly represented in the literature and incorporates a halide for further synthetic elaboration.

Effective palladium(II)-bis(oxazoline) catalysts: synthesis, crystal structure, and catalytic coupling reactions

New bis(oxazoline) ligands and their palladium complexes were synthesized and characterized. X-ray crystal structures of the two new complexes showed distorted square planar geometry with the palladium ion bonded to nitrogens of two bidentate heterocycles in addition to two bromides and two acetate ions for Pd-BOX-1 and Pd-BOX-2, respectively. The complexes adopt a chair structure with a rigid curvature inducing an inherent chirality. The complexes were effective catalysts for Suzuki–Miyaura, Mizoroki–Heck, and copper-free Sonogashira coupling reactions in aqueous dimethylformamide and under aerobic conditions. The reaction conditions were optimized for best solvent, base, and temperature. The substrate scope of the new catalytic system was evaluated for coupling reactions of a variety of aryl halides with aryl boronic acids, alkenes, and alkynes.

3,6-Di(pyridin-2-yl)-1,2,4,5-tetrazine capped Pd(0) nanoparticles: a catalyst for copper-free Sonogashira coupling of aryl halides in aqueous medium

3,6-Di(pyridin-2-yl)-1,2,4,5-tetrazine (pytz) capped Pd(0) nanoparticles (TzPdNPs) act as a catalyst in Sonogashira coupling under copper- and ligand-free conditions in aqueous medium.

Green synthesis of Pd/Fe3O4 nanoparticles using Euphorbia condylocarpa M. bieb root extract and their catalytic applications as magnetically recoverable and stable recyclable catalysts for the phosphine-free Sonogashira and Suzuki coupling reactions

This work reports on the green synthesis of Pd/Fe3O4 nanoparticles using Euphorbia condylocarpa M. bieb root extract as reducing agents and stabilizers and their catalytic applications in ligand- and copper-free Sonogashira and Suzuki coupling reactions. This method has such advantages as high yields, simple methodology and easy work up. In addition, the catalyst can be recovered by using a magnet and reused several times without significant loss of its catalytic activity. The catalyst was characterized using UV–vis, powder XRD, SEM and EDS techniques.

Palladium-ADC complexes as efficient catalysts in copper-free and room temperature Sonogashira coupling

The metal-mediated coupling between cis-[PdCl2(CNR1)2] [R1=cyclohexyl (Cy) 1, t-Bu 2, 2,6-Me2C6H3 (Xyl) 3, 2-Cl-6-MeC6H3 4] and hydrazones H2NNCR2R3 [R2, R3=Ph 5; R2, R3=C6H4(OMe-4) 6; R2/R3=9-fluorenyl 7; R2=H, R3=C6H4(OH-2) 8] provided carbene complexes cis-[PdCl2{C(N(H)NCR2R3)N(H)R1}(CNR1)] (9–24) in good (80–85%) yields. Complexes 9–24 showed high activity [yields up to 99%, and turnover numbers (TONs) up to 3.7×104] in the Sonogashira coupling of various aryl iodides with a range of substituted aromatic alkynes without the need of copper co-catalyst. The catalytic procedure runs at 80°C for 1h in EtOH using K2CO3 as a base. No formation of homocoupling or acetylene decomposition products was observed. Designed copper-free Sonogashira system can also run at room temperature giving target products with yields up to 87% and TONs up to 87.

Green synthesis of water-dispersable palladium nanoparticles and their catalytic application in the ligand- and copper-free Sonogashira coupling reaction under aerobic conditions

Pd nanoparticles were prepared from PdCl2 by green method and were characterized with UV–vis, XRD and TEM methods. Catalytic studies indicated that Pd nanoparticles exhibited high activity for ligand-, amine- and copper-free Sonogashira coupling between aryl iodides and terminal alkynes under mild and aerobic conditions. This method has the advantages of high yields, simple methodology and easy work up. More importantly, the catalyst exhibits high catalytic activity, superior cycling stability and excellent substrate applicability.

Picolinic diamide pincers for transition metal complexation and their electrochemical properties

A series of novel molecular pincers was successfully synthesised by a copper-free Sonogashira coupling methodology. Complexation of the pincers with Cu(II), Ni(II) and Co(II) was performed in the presence of triethylamine. The formation of the desirable pincer ligands and complexes was confirmed by nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy and mass spectrometry. Electrochemical properties of the complexes of the target pincer dimers investigated by means of cyclic voltammetry suggested that the pincer dimers should be able to serve as an electron donor for phenyl-C61-butyric acid methyl ester and as an electron acceptor for poly(3-hexylthiophene) in bulk heterojunction solar cells.

Synthesis of chlorophyll derivatives possessing a mono/bi/terpyridinyl group at the C3-ethynyl terminal and optical properties of the π-conjugates

Chlorophyll-a derivatives possessing a pyridyl, 2,2′-bipyridinyl, or 2,2′:6′,2″-terpyridinyl group in the C3-substituent were synthesized by copper-free Sonogashira coupling of methyl 3-ethynyl-pyropheophorbide-a with the corresponding bromo/iodopyridine, bromobipyridine, or trifluoromethylsulfonyloxy-terpyridine, respectively. Their visible absorption spectra in dichloromethane showed that the maxima of all the coupling products gave similar peak positions and were shifted to a longer wavelength than those of the starting 3-ethynyl-chlorin. The red shifts are ascribable to the intramolecular π-conjugation between the chlorin ring and (oligo)pyridinyl moiety through the CC linker. The products in a diluted solution gave an intense fluorescence emission band at the red-side region of redmost absorption band. Their fluorescence quantum yields were about 25% and comparable to that of the starting unsubstituted 3-ethynyl-chlorin.

Practical synthesis of aryl-2-methyl-3-butyn-2-ols from aryl bromides via conventional and decarboxylative copper-free Sonogashira coupling reactions

Two efficient protocols for the palladium-catalyzed synthesis of aryl-2-methyl-3-butyn-2-ols from aryl bromides in the absence of copper were developed. A simple catalytic system consisting of Pd(OAc)2 and P(p-tol)3 using DBU as the base and THF as the solvent was found to be highly effective for the coupling reaction of 2-methyl-3-butyn-2-ol (4) with a wide range of aryl bromides in good to excellent yields. Analogously, the synthesis of aryl-2-methyl-3-butyn-2-ols was performed also through the decarboxylative coupling reaction of 4-hydroxy-4-methyl-2-pentynoic acid with aryl bromides, using a catalyst containing Pd(OAc)2 in combination with SPhos or XPhos in the presence of tetra-n-butylammonium fluoride (TBAF) as the base and THF as the solvent. Therefore, new efficient approaches to the synthesis of terminal acetylenes from widely available aryl bromides rather than expensive iodides and using 4 or propiolic acid rather than TMS-acetylene as inexpensive alkyne sources are described.