Novel cyclometallated Pd(II) and Pt(II) complexes with indole derivatives and their use as catalysts in Heck reaction

Several palladacycle and platinacycle complexes have been prepared from easily available or naturally occurring indole derivatives, such as gramine and related compounds. Dimeric complexes were obtained with Pd(OAc)₂, while Pt(DMSO)₂Cl₂ mainly afforded monomeric structures. A notable feature of these reactions was the formation of new M-C bonds between Pd or Pt and C-2 and C-3 of the indole ring. With ligands like 2-(2′-pyridyl)-1H-indoles, N-N metallacycles were generated instead: in fact new C-M bonds with the C-3 position could only form if N-substituted indoles were used. The reactivity of Pd dimeric complexes with PPh₃, sym-collidine and DMAP was explored to obtain monomeric complexes. Three such compounds were prepared, one of which was characterized by X-ray diffraction. Metathetical reactions were carried out to effect a ligand exchange replacing OAc with halide ions, with the aim to synthesize μ-Cl and μ-Br bridged structures. Turning to the synthesis of hetaryl complexes, functionalization of the C-2 position on the indole ring was achieved. These complexes were prepared by substitution reactions starting from gramine and/or its alkylammonium salts.     

The optimization for cyclization reaction of 2-(2-carbomethoxyethynyl)aniline derivatives and formal synthesis of pyrroloquinoline quinone and its analogue utilizing a sequential coupling-cyclization reaction

The reaction conditions for the Pd-catalyzed cyclization reaction of 2-(2-carbomethoxyethynyl)aniline derivatives were investigated. The amounts of Pd(PPh₃)₄, methyl propiolate, and ZnBr₂ could be significantly reduced compared with those reported in our preliminary publication by careful tuning of the solvent and the reaction temperature. In addition to the above results, formal syntheses of pyrroloquinoline quinone (PQQ) and its analogue from 2-amino-5-nitrophenol using a Pd-complex-catalyzed sequential coupling-cyclization reaction between methyl propiolate and 2-iodoaniline derivatives are described.     

AlCl3 induced C-N bond formation followed by Pd/C-Cu mediated coupling-cyclization strategy: synthesis of pyrrolo[2,3-b]quinoxalines as anticancer agents

AlCl₃ facilitated C-N bond forming reaction between 2,3-dichloroquinoxaline and anilines affording a convenient method for the preparation of N-aryl substituted 3-chloroquinoxalin-2-amines. A related N-benzyl derivative, however, was prepared via a conventional method. These N-alkyl/aryl substituted 3-chloroquinoxalin-2-amines on coupling with terminal alkynes in toluene under Pd/C-Cu catalysis afforded a range of 1,2-disubstituted pyrrolo[2,3-b]quinoxalines within 3-5 h in good to excellent yields. Some of the compounds synthesized showed promising anti-proliferative properties when tested in vitro against two cancer cell lines. Docking studies indicated that these molecules interact well with human Akt in silico.     

Pd(0)-catalyzed intramolecular Heck reaction: a versatile route for the synthesis of dibenzoazocinone derivatives

Two efficacious synthetic methodologies for the construction of medium-sized nitrogen heterocycles dibenzoazocinones have been developed. The phosphine-assisted protocol afforded better yields of the dibenzoazocinones (73-82%).     

1,1'-(3-methyl-4-phenylthieno[2,3-b]thiophene-2,5-diyl)diethanone as a building block in heterocyclic synthesis. Novel synthesis of some pyrazole and pyrimidine derivatives

A series of new bis(heterocycles) featuring thieno[2,3-b]thiophene rings was synthesized in a combinatorial manner. Intramolecular cyclization of enaminone derivatives with appropriate N-nucleophiles afforded the target compounds. All compounds were characterized by 1H-, 13C-NMR, GCMS, IR, and UV-Vis spectrometry. These compounds represent a new class of sulfur- and nitrogen-containing heterocycles that should also be of interest as new materials.     

Suzuki reaction catalysed by a PCsp3P pincer Pd(II) complex: Evidence for a mechanism involving molecular species

{Cis-1,3-bis[(di-tert-butylphosphino)methyl]cyclohexyl}palladium(II)trifluoroacetate (1) acts as a precatalyst for the Suzuki reaction of aryl halides with phenylboronic acid in the absence or presence of mercury to give the product in modest to reasonably good yields. The reaction was monitored by ³¹P- and ¹H NMR spectroscopy in a stepwise fashion, concluding that complex 1 reacts with activated boronic acids in the first reaction step to yield the corresponding phenyl complex 2. Complex 2 thereafter generates the Suzuki cross-coupling product upon addition of aryl halide. This shows that (PCP)Pd complexes, in addition to the previously demonstrated Pd(0)/Pd(II) mechanism, can mediate cross-coupling reactions using molecular species in a non-zero oxidation state.     

Ag(I) and Pd(II) complexes of a 1,3-dibenzhydryl substituted benzannulated N-heterocyclic carbene: Unexpected rearrangement, structures and catalytic studies

Reaction of the sterically bulky 1,3-dibenzhydrylbenzimidazolium bromide (Bh₂-bimyH⁺Br⁻) (A) with Pd(OAc)₂ in DMSO yielded a mono(carbene) Pd(II) complex 1 with a N-bound benzimidazole derivative, which resulted from an unusual NHC rearrangement reaction. Reaction of A with Ag₂O, on the other hand, cleanly gave the Ag(I) carbene complex [AgBr(Bh₂-bimy)] (2), which has been used as a carbene-transfer agent to prepare the acetonitrile complex trans-[PdBr₂(CH₃CN)(Bh₂-bimy)] (3). Dissociation of acetonitrile from complex 3 and subsequent dimerization afforded the dinuclear Pd(II) complex [PdBr₂(Bh₂-bimy)]₂ (4) in quantitative yield. All complexes were fully characterized by multinuclear NMR spectroscopies, ESI mass spectrometry and X-ray diffraction analysis. Furthermore, the catalytic activity of complex 4 in aqueous Suzuki-Miyaura cross-coupling reactions was studied and compared with that of its previously reported less bulky analogue [PdBr₂(ⁱPr₂-bimy)]₂.     

Synthesis of indolo[2,3-a]quinolizine and hexahydro-1H-indolizino[8,7-b]indole derivatives by cascade condensation, cyclization, and Pictet-Spengler reaction: an application to the synthesis of (±)-harmicine

Synthesis of indole alkaloid related compounds using Schiff base formation, intramolecular cyclization (or N-alkylation), and Pictet-Spengler reaction as a cascade one pot condensation has been reported. The cascade chemistry has been applied to the synthesis of (±)-harmicine as a key step.     

Reaction of 2-trifluoroacetyl-1,8-Bis(dimethylamino)naphthalene with strong organic bases: Deprotonation of 1-NMe2 group resulting in the formation of Benzo[g]indole derivatives versus nucleophilic addition to CO group

A novel approach to pyrrole ring closure in 2-trifluoroacetyl- and 2-ethoxycarbonyl-1,8-bis(dimethylamino)naphthalenes via treatment with 2-lithium-1,8-bis(dimethylamino)naphthalene producing the corresponding benzo[g]indole derivatives, was examined with different alkyl- and aryllithium compounds as well as with LDA. It was found that the highest yields of benzo[g]indoles (up to 70%) are obtained with aryllithium reagents when they contain NMe₂ group in ortho-position to the carbanionic centre. In all other cases the formation of acyclic alcohol arising from ordinary intermolecular addition of the carbanion to the CO group strongly prevails. The dramatic facilitation of deprotonation of the N-Me group in substrate followed by pyrrolic cyclization in the case of 2-lithium-N,N-dimethylanilines was explained through a specific structure of the reaction transition state.     

One-pot,solvent-free Pd(II)-catalyzed direct β-C-H arylation of carboxamides involving anhydrides as substrates via in situ installation of directing group

A one-pot, multicomponent-type, solvent-free Pd(II)-catalyzed direct β-C-H activation/arylation of carboxamides involving anhydrides as substrates via in situ installation of directing group (DG) is reported. Typically, the DG-assisted β-C-H activation/arylation of carboxamides is a two-step process comprising the installation of DG and Pd(II)-catalyzed CH arylation. We attempted a multicomponent-type reaction comprising an anhydride, a DG (e.g. 8-aminoquinoline), an aryl iodide in the presence of the Pd(II) catalyst and an appropriate additive. Different anhydrides, DGs, aryl iodides, catalysts and additives were screened to reveal the scope of this multicomponent-type CH arylation reaction process and various β-C-H arylated carboxamides were obtained in satisfactory to good yields.     

Facile synthesis of N-(benzyl, methyl)-lysine as a building block for site-specifically lysine monomethylated peptides

Facile, mild and efficient one-pot preparation of N^α-Fmoc-N^ε-(benzyl, methyl)-lysine, a building block for monomethylated peptide synthesis, was described. This building block was proved to be efficient for the synthesis of site-specifically monomethylated peptide. Benzyl group, which was incorporated by reductive benzylation and removed via catalytic hydrogenolysis, served as an excellent protecting group.     

Electrochemical oxidation of catechol in the presence of indole: a facile and one-pot method for the synthesis of trisindolyl-o-benzoquinone

The electrochemical oxidation of catechol has been studied in the presence of indole as the nucleophile in water/acetonitrile (50:50) using cyclic voltammetry and controlled-potential coulometry methods. The results revealed that the quinone derived from the oxidation of catechol participates in Michael addition reactions with indole, and via a novel ECECECE mechanism, converts it to the trisindolyl-o-quinone in a good yield via electrochemical oxidation under controlled-potential conditions without any toxic reagents at the carbon electrode in a two-compartment cell.     

Photochemical synthesis of a palladium dichloromethyl complex, {(hexyl)HC(N-methyl-imidazol-2-yl)2}Pd(CHCl2)Cl.: X-ray molecular structures of {(hexyl)HC(N-methylimidazolyl-2-yl)2}Pd(X)Cl, X=Cl, and CHCl2

The reaction of (hexyl)HC(mim)₂ (1, mim=N-methyl-imidazol-2-yl) with (cod)PdMeCl in C₆H₆ yields {(hexyl)HC(mim)₂}Pd(Me)Cl (3). The photochemical reaction of 3 with CH₂Cl₂ at 23 °C in ambient room light yields {(hexyl)HC(mim)₂}Pd(CHCl₂)Cl (4). It is proposed that this reaction proceeds by homolytic scission of the PdMe bond of 3.     

Elaboration of the ether cleaving ability and selectivity of the classical Pearlman's catalyst [Pd(OH)2/C]: concise synthesis of a precursor for a myo-inositol pyrophosphate

The cleavage of propargyl, allyl, benzyl, and PMB ethers by Pd(OH)₂/C can be tuned in that order, by varying the reaction conditions. Other moieties such as C-C double bonds, esters, trityl ether, p-bromo and p-nitrobenzyl ethers are stable to these reaction conditions. Cleavage of allyl ethers can be made catalytic by using 1:1 mixture of Pd(OH)₂/C and Pd/C. The synthetic potential of the selective ether cleaving ability of Pd(OH)₂/C, essentially under neutral conditions, has been demonstrated by an efficient synthesis of a precursor for the preparation of an inositol pyrophosphate derivative.     

Substrate scope in the direct imine acylation of ortho-substituted benzoic acid derivatives: the total synthesis (±)-cavidine

The direct imine acylation (DIA) and subsequent cyclisation of a range of imines with ortho-substituted benzoic acid derivatives is described. Variation in the coupling reagents, imine and benzoic acid were all examined. The DIA procedure was also applied in the total synthesis of (±)-cavidine.     

Development of a LC-MS/MS method for the analysis of volatile primary and secondary amines as NIT (naphthylisothiocyanate) derivatives

High-performance liquid chromatography with mass spectrometric detection was used for the structure elucidation of eighteen primary and secondary amines and ammonia derivatised with naphthylisothiocyanate (NIT). A fragmentation scheme was established using reference compounds and the scheme was applied to real air samples from a tyre repair shop and from the air above a bacterial culture. The sampling was performed using a solid sorbent, XAD-2, impregnated with NIT, and the derivatives were extracted with acetonitrile and analysed with LC-MS/MS. A three-step process was developed for screening and identifying of volatile amines. The first step, selected reaction monitoring; SRM was applied in order to screen the samples for NIT derivatives. In the second step, a precursor ion scan gave the [M+H]⁺ ion, and in the third step a product ion scan gave the fragments needed for identification. The detection limits varied between 0.12 and 0.25 ng L^–1 when screening for unknown derivatised amines. It was possible to separate and identify all the amines with the structural information obtained and the method proved to be general, sensitive and well suited for sampling and analysis of complex environmental samples.     

Total synthesis of (−)-2-epi-lentiginosine by use of chiral 5-hydroxy-1,5-dihydropyrrol-2-one as a building block

We have developed a practical synthesis of the chiral lactam as a new chiral building block for alkaloid synthesis. Lipase-catalyzed kinetic resolution of hydroxylactam 8, followed by isolation-racemization of the chiral acetoxylactam 9 provided the optically pure hydroxylactam 8 in 96.0% yield with >99% ee after five cycles of kinetic resolution-racemization process. Chemical transformation of (S)-hydroxylactam 8 furnished chiral (−)-2-epi-lentiginosine (1) in 20% yield in 10 steps with no loss of enantiomeric excess.     

Pd-catalyzed regioselective hydroarylation of α-(2-aminoaryl)-α,β-ynones with organoboron derivatives as a tool for the synthesis of quinolines: experimental evidence and quantum-chemical calculations

The Pd-catalyzed hydroarylation of β-(2-aminoaryl)-α,β-ynones with organoboron derivatives, leading to 2,4-diarylquinolines in good to excellent yields through sequential cycloamination, has been investigated. The reaction is catalyzed by both Pd(II) and Pd(0) precatalysts, and can be carried out even under neutral conditions. The regiochemical outcome is inverted with respect to the Pd-catalyzed hydroarylation of β-(2-aminoaryl)-α,β-ynones with aryl iodides. This aspect has been rationalized using quantum-chemical calculations, which show significant differences between the energy barriers of the regioisomeric transition states for the migratory insertion (hydropalladation) step, and are consistent with the charge density of the π complex that undergoes such insertion.     

Synthesis and characterizations of N,N,N′,N′-tetrakis (diphenylphosphino)ethylendiamine derivatives: Use of palladium(II) complex as pre-catalyst in Suzuki coupling and Heck reactions

Oxidation of N,N,N′,N′-tetrakis(diphenylphosphino)ethylendiamine (1) with elemental sulfur and selenium gives the corresponding sulfide and selenide, respectively, [(Ph₂P(E))₂NCH₂CH₂N(P(E)Ph₂)₂] (E: S 1a, Se 1b). Complexes of 1 [(M₂Cl₄){(Ph₂P)₂NCH₂CH₂N(PPh₂)₂}] (M: Ni(II) 1c, Pd(II) 1d, Pt(II) 1e) were prepared by the reaction of 1 with NiCl₂ or [MCl₂(COD)] (M = Pd, Pt). The new compounds were characterized by NMR, IR spectroscopy and elemental analysis. The catalytic activity of Pd(II) complex 1d was tested in the Suzuki coupling reaction and Heck reaction. The palladium complex 1d catalyses the Heck reaction between styrene and aryl bromides as well as Suzuki coupling reaction between phenylboronic acid and arylbromides affording stilbenes and biphenyls in high yield, respectively.     

NMR approach for the identification of dinuclear and mononuclear complexes: The first detection of [Pd(SPh)2(PPh3)2] and [Pd2(SPh)4(PPh3)2] - The intermediate complexes in the catalytic carbon-sulfur bond formation reaction

In the present study we have analyzed the nature of palladium complexes in the catalytic system for selective carbon-sulfur bond formation via the addition of S-S and S-H bonds to alkynes. For the first time the mononuclear and dinuclear palladium complexes were clearly detected by DOSY NMR under the catalytic conditions. It was demonstrated that the concentration of these palladium complexes strongly depends on the amount of phosphine ligand available under reaction conditions.