Asymmetric cyano-ethoxycarbonylation of aldehydes catalyzed by self-assembled titanium catalyst

A new self-assembled catalyst based on titanium complex has been developed for the effective enantioselective cyano-ethoxycarbonylation of aldehydes. The self-assembled catalyst was readily prepared from (R)-3,3′-bis((methyl((S)-1-phenylethyl)amino)methyl)-1,1′-binaphthyl-2,2′-diol (1h), N-((1S,2R)-2-hydroxy-1,2-diphenylethyl)acetamide (2b), and tetraisopropyl titanate (Ti(OiPr)₄). A variety of aromatic aldehydes, aliphatic aldehydes, and α,β-unsaturated aldehydes were found to be suitable substrates in the presence of the self-assembled titanium catalyst (5 mol % 1h, 5 mol % 2b, and 5 mol % Ti(OiPr)₄). The desired cyanohydrin ethyl carbonates were afforded with high isolated yields (up to 95%) and moderate to good enantioselectivities (up to 92% ee) under mild conditions (at −15 °C). A possible catalytic cycle based on the experimental observation was proposed.     

Asymmetric allylation of aldehydes with allyltrichlorosilane using aza-paracyclophane-oxazoline-N-oxide catalysts

Novel aza-paracyclophane-oxazoline catalysts 4, 5 were produced from Vögtle’s R_p-2-cyano-aza-paraclycophane and amino alcohols reacted with zinc chloride followed by m-chloroperbenzoic acid. 4′-Benzyl and tert-butyl-S and R-oxazoline variants were produced and explored as catalysts for asymmetric allylation of aldehydes using trichloroallylsilane. With R_p,S-4a (R = tert-butyl) (1.5 mol %) aromatic aldehydes reacted with high yields and selectivities, as with benzaldehyde (95%, 93% ee). R_p,S-4b (R = benzyl) was superior with dihydrocinnamaldehyde (77%, 85% ee).     

Kinetics and mechanistic studies of the interaction of thiosulfate with cis-diaqua-bis[1-alkyl-2-(arylazo)imidazole]ruthenium(II) complexes

The nucleophilic substitution reaction of S₂O₃²⁻ with [Ru(HaaiR′)₂(OH₂)₂](ClO₄)₂ (1) [HaaiR′ = 1-alkyl-2-(phenylazo)imidazole] and [Ru(ClaaiR′)₂(OH₂)₂](ClO₄)₂ (2) [ClaaiR′ = 1-alkyl-2-(chlorophenylazo)imidazole] [where R′ = Me(a), Et(b) or Bz(c)] in acetonitrile–water (50% v/v) medium to yield Na₂[Ru(HaaiR′)₂(S₂O₃)₂] (3a, 3b or 3c) and Na₂[Ru(ClaaiR′)₂(S₂O₃)₂] (4a, 4b or 4c) has been studied. The products were characterized by microanalytical data and spectroscopic techniques (UV–Vis, NMR and mass spectroscopy). The reaction proceeds in two consecutive steps (A → B → C); each step follows first order kinetics with respect to each complex and S₂O₃²⁻, and the first step second order rate constant (k′₂) is greater than the second step one (k″₂). An increase in the π-acidity of the ligand increases the rate. Thermodynamic parameters, the standard enthalpy of activation (Δ^‡H⁰) and the standard entropy of activation (Δ^‡S⁰), have been calculated for both steps using the Eyring equation from variable temperature kinetic studies. The low Δ^‡H⁰ and large negative Δ^‡S⁰ values indicate an associative mode of activation for both aqua ligand substitution processes.     

A highly stereoselective preparation of CF3-substituted 1-aryl-1,2-diphenylethenes: application to the synthesis of panomifene

β-CF₃-α,β-diphenylvinyl sulfide 3a was prepared stereoselectively in 77% yield from the reaction of 2 with phenyllithium at room temperature for 5 h. Oxidation of 3a with MCPBA afforded the corresponding vinyl sulfone 4a, in which (E)-4a can be crystallized in a mixture of CH₂Cl₂ and hexane. The addition-elimination reaction of (E)-4a with phenyllithium having substituents on the benzene ring provided 5a-j in 51-82% yields stereospecifically. Similarly, the treatment of (E)-4a with p-chloroethoxyphenyllithium in the presence of 12-crown-4 (20 mol %) at −10 °C, followed by slowly warming to room temperature, resulted in the formation of the corresponding panomifene precursor 6 in 82% yield.     

Synthesis and characterization of polybinaphthalene incorporating chiral (R) or (S)-1,1′-binaphthalene and oxadiazole units by Heck reaction

Chiral conjugated polymers P-1 and P-2 were synthesized by the polymerization of (R)-3,3′-diiodo-2,2′-bisbutoxy-1,1′-binaphthalene ((R)-M-1) and (S)-3,3′-diiodo-2,2′-bisbutoxy-1,1′-binaphthalene ((S)-M-1) with 2,5-bis(4-vinylphenyl)-1,3,4-oxadiazole (M-2) under Pd-catalyzed Heck coupling reaction, respectively. Both monomers and polymers were analysed by NMR, MS, FT-IR, UV, DSC-TG, fluorescent spectroscopy, GPC and CD spectra. The chiral conjugated polymers exhibit strong Cotton effect in their circular dichroism (CD) spectra indicating a high rigidity of polymer backbone. CD spectra of polymers P-1 and P-2 are almost identical and have opposite signs for their position. These polymers have strong blue fluorescence.     

New chiral ferrocenyl amidophosphine ligand for remarkable improvement of enantioselectivities in copper-catalyzed addition of diethylzinc to N-sulfonylimines

(S)-N-Ferrocenoyl-2-[(diphenylphosphino)methyl]-pyrrolidine 3 was conveniently prepared from commercially available l-proline and ferrocenecarboxylic acid. In the presence of a catalytic amount of chiral ligand 3 (4 mol %) and Cu(OTf)₂ (3 mol %), the asymmetric addition of diethylzinc to N-sulfonylimines was achieved in 57-99% yield with up to 88% ee.     

A facile synthesis of 3 or 3,3′-substituted binaphthols and their applications in the asymmetric addition of diethylzinc to aldehydes

By using a direct ortho-lithiation, the ligands (S)-3-methoxymethyl-1,1′-bi-2-naphthol [(S)-1], (S)-3,3′-bis(methoxymethyl)-1,1′-bi-2-naphthol [(S)-2], (S)-3-(quinolin-2-yl)-1,1′-bi-2-naphthol [(S)-3] and (S)-3,3′-bis(quinolin-2-yl)-1,1′-bi-2-naphthol [(S)-4] have been synthesized. (S)-1 and (S)-3 show moderate catalytic properties for the asymmetric diethylzinc addition to aromatic aldehydes.     

Asymmetric addition of phenylacetylene to aldehydes catalyzed by soluble optically active polybinaphthols ligand

A chiral polymer ligand was synthesized by the polymerization of (S)-5,5′-dibromo-6,6′-dibutyl-2,2′-binaphthol (S-M-1) with (S)-2,2′-bishexyloxy-1,1′-binaphthyl-6,6′-boronic acid (S-M-2) via Pd-catalyzed Suzuki reaction. The application of the chiral polymer ligand to the asymmetric addition of phenylethynyl zinc to various aldehydes has been studied. The results show that the soluble chiral polybinaphthols ligand in combination with Et₂Zn and Ti(OⁱPr)₄ can exhibit excellent enantioselectivity for phenylacetylene addition to both aromatic and aliphatic aldehydes. The catalytically active center of the repeating unit S-1 used as a catalyst produced the opposite configuration of the propargylic alcohols to that of S-1, on the contrary, the chiral polymer gave the same configuration as the optically active binaphthol moiety of the polybinaphthols ligand. Moreover, the chiral polymer ligand can be easily recovered and reused without loss of catalytic activity as well as enantioselectivity.     

Synthesis of sulfur containing analogues of the soluble guanylate cyclase inhibitor 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one NS2028

Sulfur analogues of the soluble guanylate cyclase (sGC) inhibitor NS2028 1a are synthesized. Treating 8-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one oxime (6) with 1,1′-thiocarbonyldiimidazole (1.1 equiv) gave the carbamothioate 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazine-1-thione (3a) in 83% yield. Alternatively reacting NS2028 1a with P₂S₅ (0.5 equiv) affords the carbamothioate 3a in 80% yield. Similar treatment of 8-aryl substituted NS2028 analogues 1b-d with P₂S₅ gave the carbamothioates 3b-d in 64-91% yields. Although quite stable, the carbamothioates 3a-d could be thermally isomerized in the presence of Cu (10 mol %) to afford the thiocarbamates 4a-d in high yields. Interestingly, in the case of carbamothioate 3a Pd and In metals also facilitated the isomerization. Furthermore, treatment of the thiocarbamates 4a-d with P₂S₅ (0.5 equiv) affords the carbamodithioates 5a-d in 72-89% yields. All new compounds are fully characterized including single crystal X-ray data for carbamothioate 3a and thiocarbamate 4a. Finally, a mechanism is proposed for the carbamothioate to thiocarbamate isomerization.     

Asymmetric addition of diethylzinc to aromatic aldehydes by chiral ferrocene-based catalysts

A series of chiral C₁- and C₂-symmetric ferrocenyl Schiff bases (1a-c), ferrocenyl aminoalcohols (2a), ferrocenylphosphinamides (2b-c), 1,1′-ferrocenyl-diol (3), and 1,1′-ferrocenyl-disulfonamide (4) were prepared and employed as base catalysts or as ligand for titanium(IV) complexes in the asymmetric addition of diethylzinc to aromatic aldehydes. High enantioselectivity up to almost 100% ee was achieved for the alkylation of benzaldehyde and p-methoxybenzaldehyde with 1 or 3. In contrast, however, the β-aminoalcohol (2a) and phosphinamides (2b and c) that are ubiquitous classes of base catalysts for this reaction proved inefficient in our hands, regardless of the types of substrates or reaction conditions. Comparative studies show that there exist various reaction parameters governing not only chemical yields but also optical yields. These include steric and electronic environment of the substrate, the solvent, the reaction temperature, and the nature of the ferrocene moieties.     

Convenient preparation of chiral phase-transfer catalysts with conformationally fixed biphenyl core for catalytic asymmetric synthesis of α-alkyl- and α,α-dialkyl-α-amino acids: application to the short asymmetric synthesis of BIRT-377

Chiral phase-transfer catalysts (S)-1a, (S)-1b, and (S)-2 with conformationally fixed biphenyl cores were conveniently prepared from the known, easily available (S)-6,6′-dimethylbiphenyl-2,2′-diol 3 and (S)-4,5,6,4′,5′,6′-hexamethoxybiphenyl-2,2′-dicarboxylic acid 14, respectively, in five steps. The catalysts, (S)-1a and (S)-1b are readily applicable to asymmetric alkylation of N-(diphenylmethylene)glycine tert-butyl ester with excellent enantioselectivity. In particular, catalyst (S)-1b was found to exhibit the unique temperature effect on the enantioselectivity, and asymmetric alkylation of glycine derivatives at room temperature gave higher enantiomeric excess than that at 0 °C. In addition, the catalyst (S)-2 exhibited the high catalytic performance (0.01-1 mol %) in the asymmetric alkylation of N-(diphenylmethylene)glycine tert-butyl ester and N-(p-chlorophenylmethylene)alanine tert-butyl ester compared to the existing chiral phase-transfer catalysts, thereby allowing to realize a general and useful procedure for highly practical enantioselective synthesis of structurally diverse natural and unnatural α-alkyl-α-amino acids as well as α,α-dialkyl-α-amino acids. This approach is successfully applied to the short asymmetric synthesis of cell adhesion BIRT-377.     

Carbonylation studies of Pd-methyl complexes modified with 1,4-Cs-symmetrical diphosphine ligands

Neutral palladium methyl chloride 2a-d [PdCH₃(PˆP′)Cl] and cationic palladium methyl acetonitrile mono-triflate 3a-d [PdCH₃(PˆP′)(CH₃CN)](CF₃SO₃) complexes were synthesized and fully characterized (PˆP′ = 1a-d). All the neutral and cationic complexes containing a C_s-symmetric diphosphine exist in solution as a mixture of geometric isomers. The carbonylation at atmospheric pressure of the neutral and cationic complexes revealed that migratory insertion of carbon monoxide is not stereospecific in these systems. The neutral and cationic acyl complexes were formed in situ as mixtures of stereoisomers, which were characterized by means of NMR spectroscopy.The crystal structures of [Pd(1a)Cl]₂(OTf)₂ and 2d are described.     

Synthesis and characterisation of six Fe(II or III), Co(II) or Zr(IV) complexes containing the ligand [CH(SiMe2R)P(Ph)2NSiMe3] (R = Me, NEt2) and of [Co{N(SiMe3)C(Ph)C(H)P(Ph)2NSiMe3}2]

The C,N-(trimethylsilyliminodiphenylphosphoranyl)silylmethylmetal complexes [Fe(L)₂] (3), [Co(L)₂] (4), [ZrCl₃(L)]·0.83CH₂Cl₂ (5), [Fe(L)₃] (6), [Fe(L′)₂] (7) and [Co(L′)₂] (8) have been prepared from the lithium compound Li[CH(SiMe₂R)P(Ph)₂NSiMe₃] [1a, (R = Me) {≡ Li(L)}; 1b, (R = NEt₂) {≡ Li(L′)}] and the appropriate metal chloride (or for 7, FeCl₃). From Li[N(SiMe₃)C(Ph)C(H)P(Ph)₂NSiMe₃] [≡ Li(L″)] (2), prepared in situ from Li(L) (1a) and PhCN, and CoCl₂ there was obtained bis(3-trimethylsilylimino- diphenylphosphoranyl-2-phenyl-N-trimethylsilyl-1-azaallyl-N,N′)cobalt(II) (9). These crystalline complexes 3-9 were characterised by their mass spectra, microanalyses, high spin magnetic moments (not 5) and for 5 multinuclear NMR solution spectra. The X-ray structure of 3 showed it to be a pseudotetrahedral bis(chelate), the iron atom at the spiro junction.     

Microwave-assisted synthesis of novel bis(2-thioxothiazolidin-4-one) derivatives as potential GSK-3 inhibitors

(5Z,5′Z)-3,3′-(1,4-Phenylenebis(methylene)-bis-(5-arylidene-2-thioxothiazolidin-4-one) derivatives (5a-r) have been synthesized by the condensation reaction of 3,3′-(1,4- or 1,3-phenylenebis(methylene))bis(2-thioxothiazolidin-4-ones) (3a,b) with suitably substituted aldehydes (4a-f) or 2-(1H-indol-3-yl)2-oxoacetaldehydes (8a-c) under microwave conditions. The bis(2-thioxothiazolidin-4-ones) were prepared from the corresponding primary alkyl amines (1a,b) and di-(carboxymethyl)-trithiocarbonyl (2). The 2-(1H-indol-3-yl)-2-oxoacetaldehydes (8a-c) were synthesized from the corresponding acid chlorides (7a-c) using HSnBu₃.     

Efficient ball-mill procedure in the ‘green’ asymmetric aldol reaction organocatalyzed by (S)-proline-containing dipeptides in the presence of water

The organocatalytic activity of (S)-proline-based dipeptides 1a-c has been evaluated in the asymmetric aldol reaction between representative ketones with various aromatic aldehydes under solvent-free conditions in a ball mill. In particular, the methyl ester of (S)-proline-(S)-tryptophan, (S,S)-1c, proved to be an efficient organocatalyst, and the aldol reaction proceeded with good chemical yields and excellent diastereo- and enantioselectivity (up to 98:2 anti/syn dr and up to 98% ee), in the presence of water, and 5 mol % of benzoic acid as additive.     

Synthesis and properties of novel 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-triones: methodology for synthesizing cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates

Novel condensation reaction of tropone with N-substituted and N,N′-disubstitued barbituric acids in Ac₂O afforded 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (8a-f) in moderate to good yields. The ¹³C NMR spectral study of 8a-f revealed that the contribution of zwitterionic resonance structures is less important as compared with that of 8,8-dicyanoheptafulvene. The rotational barriers (ΔG^‡) around the exocyclic double bond of mono-substituted derivatives 8a-c were obtained to be 14.51-15.03 kcal mol⁻¹ by the variable temperature ¹H NMR measurements. The electrochemical properties of 8a-f were also studied by CV measurement. Upon treatment with DDQ, 8a-c underwent oxidative cyclization to give two products, 7 and 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates (11a-c·BF₄⁻ and 12a-c·BF₄⁻) in various ratios, while that of disubstituted derivatives 8d-f afforded 7,9-disubstituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborate (11d-f·BF₄⁻) in good yields. Similarly, preparation of known 5-(1′-oxocycloheptatrien-2′-yl)-pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (14a-d) and novel derivatives 14e,f was carried out. Treatment of 14a-c with aq. HBF₄/Ac₂O afforded two kinds of novel products 11a-c·BF₄⁻ and 12a,c·BF₄⁻ in various ratios, respectively, while that of 14d-f afforded 11d-f. The product ratios of 11a-c·BF₄⁻ and 12a-c·BF₄⁻ observed in two kinds of cyclization reactions were rationalized on the basis of MO calculations of model compounds 20a and 21a. The spectroscopic and electrochemical properties of 11a-f·BF₄⁻ and 12a-c·BF₄⁻ were studied, and structural characterization of 11c·BF₄⁻ based on the X-ray crystal analysis and MO calculation was also performed.     

Synthesis and characterization of coordination polymers of a carboxylato cyclophane with metal [Zn(II) and Cd(II)]-2,2′-bipyridines

N,N′,N′′,N′′′-Tetrakis(3-carboxy-propionyl)-1,6,20,25-tetraaza-[6.1.6.1] paracyclophane, H₄cp has been complexed with metal (Zn(II) and Cd(II)) 2,2′-bipyridyls. The resulting complexes of the composition [{Zn(2,2′-bpy)}₂(cp)]_n·4H₂O 1 and [{Cd(2,2′-bpy)}₂(cp)]_n·5H₂O 2 (2,2′-bpy = 2,2′-bipyridine) have been characterized using spectroscopic (IR, solid state UV–Vis), elemental analysis and single-crystal X-ray diffraction measurements. In these complexes the cyclophane coordinates in different modes, and in complex 2, Cd(II) is hepta-coordinated. However, under harsh reaction conditions (using excess nitric acid and a longer reaction time) debranching of the cyclophane is observed in the reaction of Zn(2,2′-bpy)(NO₃)₂ with H₄cp, and a complex of the composition [Zn(2,2′-bpy)(Suc)]_n3 (suc = succinate) is isolated. Using non-covalent interactions, complexes 1 and 2 provide 3D supramolecular structures, whereas an infinite 1D chain structure is observed for complex 3. The thermal and photoluminescence properties of the complexes have also been studied.     

Monomeric and dimeric ruthenium thiooxalate complexes: Structures of CpRu(PPh3)2SCOCO2Me and CpRu(dppe)SCOCO2Et

The hydrosulfido complexes CpRu(L)(L′)SH react with one equivalent of O-alkyl oxalyl chlorides (ROCOCOCl) to form the corresponding O-alkylthiooxalate complexes CpRu(L)(L′)SCOCO₂R (L = L′ = PPh₃ (1), (2); L = PPh₃, L′ = CO (3); R = Me (a), Et (b)). The reactions of the hydrosulfido complexes with half equivalent of oxalyl chloride produce the bimetallic complexes [CpRu(L)(L′)SCO]₂ (L = L′ = PPh₃ (4), (5); L = PPh₃, L′ = CO (6)). The crystal structures of CpRu(PPh₃)₂SCOCO₂Me (1a) and CpRu(dppe)SCOCO₂Et (2b) are reported.     

A practical and efficient procedure for reduction of carboxylic acids and their derivatives: use of KBH4-MgCl2

The use of KBH₄-MgCl₂ to reduce carboxylic acids and their derivatives to the corresponding alcohols or the respective reduced products is described. Methyl (S)-3,4-O-isopropylidene-3,4-dihydroxy butanoate 2 used as a reference substrate was reduced with KBH₄ and MgCl₂ in 1:1 mol ratio to (S)-1,2-O-isopropylidene-1,2,4-butanetriol 1.     

Chiral organotin complexes stabilized by C,N-chelating oxazolinyl-o-carboranes

A series of chiral organotin halides containing 2-(4-R)-oxazolinyl-o-carboranes (R = i-propyl 1, t-butyl 2; Cab^Oxa) was prepared from o-carborane with a chiral oxazoline auxiliary. X-ray structural analysis of the representative chiral organotin halide, [2-(4-i-propyl)-oxazolinyl-o-carboranyl]SnMe₂Br (4), revealed the formation of a stable penta-coordinated tin center due to a N → Sn interaction. Similar O → Sn assisted intramolecular penta-coordinated tin complexes (9 and 10) were prepared from methoxy-o-carborane ligands, MeOCH(Z)-o-carborane (Z = H 7, Ph 8; Cab^OMe), respectively, and a rigid o-carboranyl backbone provided the basic skeleton for the facile formation of organotin complexes.