Micelle-derived polymer supports for enantioselective catalysts

The BINOL moieties are successfully immobilized on the surface of a micelle-derived polymer. Ti-BINOLate complexes prepared from the polymer with Ti(O-i-Pr)₄ exhibited high catalytic activity for the asymmetric alkylation of benzaldehyde with Et₂Zn to afford the adduct in up to 96% yield with 84% ee.     

Commercially available neat organozincs as highly reactive reagents for catalytic enantioselective addition to ketones and aldehydes under solvent free conditions

Neat Et₂Zn, Ph₂Zn, and highly concentrated Me₂Zn are highly reactive organozinc reagents, which are commercially available in bulk quantities. We here report a catalytic enantioselective Et₂Zn, Ph₂Zn, and Me₂Zn addition to ketones and aldehydes under solvent free or highly concentrated conditions without Ti(Oi-Pr)₄ as a conventional activator of organozinc reagents. The desired optically active tertiary and secondary alcohols were obtained in good yield with high enantioselectivity when compared to the conventional solvent-use conditions. From the viewpoint of ecological and environmental reasons in green chemistry, this catalysis would be practical for not only academic but also industrial use.     

Synthesis and structure of titanium alkoxide complexes with bulky ligands derived from natural products: Asymmetric epoxidation of cinnamyl alcohol

A family of titanium(IV) alkoxide compounds [{Ti(OPrⁱ)₃(OR)}₂], [{Ti(OPrⁱ)₂(OR)₂}₂], and Ti(OR)₄ (1-12) have been prepared using two different routes: by metathesis reaction of TiCl(OPrⁱ)₃ and TiCl₂(OPrⁱ)₂ with ROH in the presence of Et₃N and alternatively by alcohol exchange of Ti(OPrⁱ)₄ and the corresponding higher boiling alcohol (ROH=adamantanol, 1,2:3,4-di-O-isopropylidene-α-d-galactopyranose, 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose, 1R,2S,5R-(−)-menthol). These tetra alkoxide titanium(IV) compounds have been characterized by spectroscopic techniques. In addition, some of these chiral Lewis acid titanium compounds, derived from diacetone galactose and diacetone glucose, have been studied in the asymmetric epoxidation of cinnamyl alcohol in order to evaluate their catalytic activity and stereoselectivity.     

Enantioselective diethylzinc addition to aromatic and aliphatic aldehydes using (3R,5R)-dihydroxypiperidine derivatives catalyst

A series of chiral (3R,5R)-dihydroxypiperidine derivatives 3a-f were conveniently prepared from trans-4-hydroxy-l-proline and applied to the catalytic enantioselective addition of diethylzinc to benzaldehyde and heptanal. Among them, 3d was found to show the best asymmetric induction in promoting the addition of Et₂Zn to various aldehydes, providing (R)-secondary alcohols in up to 98% ee.     

Reversal of enantioselectivity by adding Ti(OiPr)4: novel sulfamide-amine alcohol ligands for the catalytic asymmetric addition of diethylzinc to aldehydes

Novel sulfamide-amine alcohol ligands (6) derived from (−)-ephedrine (4a) and (+)-pseudoephedrine (4b) with multiple stereogenic centers were applied to the catalytic asymmetric addition of diethylzinc to aldehydes, providing (S)-products in high yields and good enantioselectivities. These sulfamide-amine alcohols together with Ti(OⁱPr)₄ were shown to obtain the (R)-products in significant enantiomeric excesses (e.e.) and high yields. In addition, sulfamide-amine alcohols were superior to the original chiral sources 4a and 4b, which afforded no enantioselectivity in the Ti(OⁱPr)₄-mediated reaction.     

Synthesis and characterization of cationic and zwitterionic allyl zirconium complexes derived from trimethylenemethane (TMM) cyclopentadienylzirconium acetamidinates

Protonation of the trimethylenemethane derivatives, Cp*Zr(σ²,π-C₄H₆)[N(R¹)C(Me)N(R²)] (1a: R¹=R²=i-Pr and 1b: R¹=Et, R²=t-Bu) (Cp*=η⁵-C₅Me₅), by [PhNMe₂H][B(C₆F₅)₄] in chlorobenzene at −10 °C provides the cationic methallyl complexes, Cp*Zr(η³-C₄H₇)[N(R¹)C(Me)N(R²)] (2a: R¹=R²=i-Pr and 2b: R¹=Et, R²=t-Bu), which are thermally robust in solution at elevated temperatures as determined by ¹H NMR spectroscopy. Addition of B(C₆F₅)₃ to 1a and 1b provides the zwitterionic allyl complexes, Cp*Zr{η³-CH₂C[CH₂B(C₆F₅)₃]CH₂}[N(R¹)C(Me)N(R²)] (3a: R¹=R²=i-Pr and 3b: R¹=Et, R²=t-Bu). The crystal structures of 2b and 3a have been determined. Neither the cationic complexes 2 or the zwitterionic complexes 3 are active initiators for the Ziegler-Natta polymerization of ethylene and α-olefins.     

Rapid Ti(Oi-Pr)4 facilitated synthesis of α,α,α-trisubstituted primary amines by the addition of Grignard reagents to nitriles under microwave heating conditions

A series of carbinamines (α,α,α-trisubstituted amines) have been prepared in a simple and efficient one-pot procedure by the addition of Grignard reagents to a series of aliphatic, aromatic and heteroaromatic nitriles. The resulting magnesium imines are subsequently converted to the desired amine after treatment with Ti(Oi-Pr)₄ and additional microwave heating. Key to this procedure is the use of microwave heating for both steps of the reaction protocol, which significantly improves both reaction yields and reduces reaction times. In general, the Grignard addition reaction is complete within 5-10 min at 100 °C followed by conversion with Ti(Oi-Pr)₄ and additional microwave heating to give the target amines in good yields.     

Asymmetric C–C bond forming reactions with chiral crown catalysts derived from d-glucose and d-galactose

New chiral monoaza-15-crown-5 derivatives anellated to methyl-4,6-O-benzylidene-α-d-glucopyranoside 2a, 2e, 2g–i and to methyl-4,6-O-benzylidene-α-d-galactopyranoside 3a, 3e, 3i have been synthesized. These crown ethers showed significant asymmetric induction as phase transfer catalysts in the Michael addition of 2-nitropropane to chalcone (87% ee), in the Darzens condensation of phenacyl chloride with benzaldehyde (71% ee) and in the self-condensation of phenacyl chloride (64% ee) to give 14. The absolute configurations of (−)-(2R,3S)-epoxy-3-(4-chlorophenyl)-1-phenyl-1-propanone 12 and (−)-4-chloro-(2R,3S)-epoxy-1,3-diphenyl-1-butanone 14 have also been determined by X-ray diffraction.     

Syntheses of (R)-(+)-cibenzoline and analogues via catalytic enantioselective cyclopropanation using (S)-phenylalanine-derived disulfonamide

Cyclopropanation of 3,3-diaryl-2-propen-1-ols 1 with Et₂Zn and CH₂I₂ proceeded in the presence of a catalytic amount of (S)-2-(methanesulfonyl)amino-1-(p-toluenesulfonyl)amino-3-phenylpropane 2 to afford the corresponding cyclopropylmethanols with 20–76% ee. (+)-2,2-Diphenylcyclopropylmethanol 3a (76% ee) was oxidized with IBX in DMSO, followed by NaClO₂, H₂O₂, and NaH₂PO₄ in MeCN–H₂O to give the corresponding acid 5a, which was converted with ethylenediamine, in the presence of PyBOP and Et₃N in CH₂Cl₂, to the amide 6a in quantitative overall yield from 3a. Amide 6a was cyclized at 160 °C under reduced pressure (2 mmHg) to afford (R)-(+)-cibenzoline in 55% yield.     

Enantioselective arylation of aldehydes catalyzed by a soluble optically active polybinaphthols ligand

A soluble chiral polymer ligand was synthesized by the polymerization of (R)-6,6′-dibutyl-3,3′-diformyl-2,2′-binaphthol (R-M-1) with 2,5-diaminopyridine (M-2) via a nucleophilic addition-elimination reaction. While arylboronic acids were used as the source of the transferable aryl group, the chiral polybinaphthols ligand in combination with Et₂Zn without Ti(OⁱPr)₄ exhibited higher enantioselectivity in asymmetric addition to aromatic aldehydes than alphatic aldehydes. When aromatic aldehydes with electron-withdrawing groups were chosen as substrates, the resulting diarylmethanols were produced in higher ee values than those with electron-donating groups as substrates. 2-Naphthaldehyde used as a substrate afforded product in 95% ee, which could be ascribed to the steric effect influence on this asymmetric arylation reaction. Moreover, the chiral polymer was easily recovered and reused, but exhibited a decrease of enantioselectivity in the third recycle.     

Synthesis of new bis-BINOL-2,2′-ethers and bis-H8BINOL-2,2′-ethers evaluation of their Titanium complexes in the asymmetric ethylation of benzaldehyde

The preparation by means of different synthetic paths of a series of bis-BINOL and bis-H₈BINOL ligands is described. The ligands consist of two BINOL or H₈BINOL fragments, joined by diverse linkages through the oxygen at the 2′-position of the arylic fragments. These ligands were applied to the Ti(OⁱPr)₄ catalyzed asymmetric alkylation of benzaldehyde with Et₂Zn. The performance of these catalysts is very sensitive to the nature of the ether linkage. The ligand with a propylene link shows better enantioselectivity (ca. 70%) than those with two or four carbon atoms joining the BINOL fragments. Furthermore, using the propylene link, but replacing (R)-BINOL by (R)-H₈BINOL, a significant improvement in the stereoselectivity of the catalysts was achieved (ca. 80% ee in (R)-1-phenylpropan-1-ol). A cooperative effect was observed between the chirality at the BINOL fragment and that of a (S,S)-4,5-bis(methylene)-2,2-dimethyl-1,3-dioxolane link, derived from tartaric acid. When this chiral link combines with two (S)-BINOL fragments, the alkylation of benzaldehyde in toluene produces 70% ee of (S)-1-phenylpropan-1-ol, while the (R)-BINOL derivative ligand with the same link, in identical conditions, yields only 40% ee of the (R)-alcohol.     

Synthesis of N-substituted 2-arylpyrroles by the reaction of (η-imine)titanium complexes with 3,3-diethoxypropyne

(η²-Imine)Ti(O-i-Pr)₂ complexes generated from arylaldehyde imines and a divalent titanium reagent, Ti(O-i-Pr)₄/2i-PrMgCl, reacted with 3,3-diethoxypropyne to afford 2-arylpyrroles.     

Synthesis and structural studies of some titanium and zirconium complexes with chiral bis(amide), amidinate or bis(amidinate) ligands

Reaction of bis(amide) sodium Na₂[(1R,2R)-(−)-1,2-(NSiMe₃)₂-C₆H₁₀] (Na₂[L¹]) with Ti(OiPr)₂Cl₂ in different conditions gave mixed-ligand complexes [Ti(OiPr)Cl][L¹] (1) or [Ti(OiPr)₂Cl]₂[L¹] (2); 2 is a dinuclear titanium example in which Ti atoms are bridged by nitrogen and oxygen atoms simultaneously forming a distorted rhombic core. Reaction of the amine-amidinate ligand (1R,2R)-(−)-1-Li[NC(Ph)N(SiMe₃)]-2-(NHSiMe₃)-C₆H₁₀(Li[L²]) or rarely linked bis(amidinate) ligand Li₂[(1R,2R)-(−)-1,2-{NC(Ph)N(SiMe₃)}₂-C₆H₁₀](Li₂[L³]) with ZrCl₄ yielded the unbridged and bridged bis(amidinate) complexes ZrCl₂[L²]₂ (3) and [ZrCl₂(THF)][L³] (4), respectively; Moreover, the reaction of (1R,2R)-(−)-1-Li[NC(Ph)N(SiMe₃)]-2-Li(NSiMe₃)C₆H₁₀(Li₂[L²]) with Ti(OiPr)₂Cl₂ gave a new type of tridentate amido-amidinate product [Ti(OiPr)₂][L²] (6), which is a distinct model compared to [Ti(OiPr)₂Cl][L²] (5) yielded from Li[L²]. All the products have been characterized by X-ray crystallography and the structural studies are presented detailedly comparing with relevant compounds.     

Short-step syntheses and complexation properties of Z,Z-tribenzodidehydro- and all-Z-tribenzo[12]annulenes

Syntheses of all-Z-tribenzo[12]annulenes (1a-c) and Z,Z-tribenzodidehydro[12]annulenes (2a-c) by the reduction of the corresponding tribenzohexadehydro[12]annulenes 3a-c were carried out using a low valent titanium complex generated from Ti(O-i-Pr)₄ and i-PrMgCl. The unique structure of the first reduction products 2a-c as well as 1a-c was fully characterized. Complexation of these annulenes with silver(I) ions produces the corresponding silver complexes. Among them, the silver complexes of 2a-c exhibit interesting monomer-dimer equilibrium.     

3,3′-Functionalized octahydro-BINOL: a facile synthesis and its high enantioselectivity in the alkyne addition to aldehydes

A facile synthesis of an enantiomerically pure 3,3′-bismorpholinylmethyl H₈-BINOL ligand has been developed. This compound in combination with Et₂Zn and Ti(OⁱPr)₄ is found to catalyze the highly enantioselective reaction of phenylacetylene with aromatic aldehydes. The enantioselectivity of this catalytic process for the reactions of ortho-substituted benzaldehydes is significantly higher than that based on H₈-BINOL.     

Stereoselective synthesis of (2S,3S,7S)-3,7-dimethylpentadecan-2-ol and its propionate,the sex pheromones of pine sawflies

The stereoselective synthesis of (2S,3S,7S)-3,7-dimethylpentadecan-2-ol (diprionol) and its propionate, the sex pheromones of pine sawflies (Neodiprion sp. and other), in high enantiomeric purity was achieved from (1R,3S)-2,2-dichloro-3-methylcyclopropanecarboxylic acid. The carbon skeleton of diprionol was formed via copper-catalyzed cross-coupling reactions and diastereoselective methylation of the intermediate chiral α-methylbranched aldehyde with MeTi(Oi-Pr)₃ in the presence of [(R,R)-TADDOL]Ti(Oi-Pr)₂. The latter transformation leads to a syn-adduct with high stereoselectivity, which depends on the presence and configuration of the α-stereogenic center in the aldehyde. The diastereomeric purity of (2S,3S,7S)-diprionol can be substantially increased via crystallization of its 3,5-dinitrobenzoate.     

Calix[n]arene/Ti(IV) complexes as active catalysts in aldol reaction of Chan's diene

The aldol condensation of Chan's diene with benzaldehyde is catalyzed by only 8% mol of the calix[n]arene/Ti(O-i-Pr)₄ complexes. Studies have revealed that the size of calixarene molecule and the number of hydroxyl groups affected the efficiency of the reaction. The reaction conditions (solvent and temperature) have been examined.     

Convenient preparation of optically active cibenzoline and analogues from 3,3-diaryl-2-propen-1-ols

(R)-(+)-Cibenzoline (95% ee) was synthesized in two steps from (+)-2,2-diphenylcyclopropylmethanol 3a (98% ee), which was oxidized with IBX in DMSO, followed by treatment with ethylenediamine in the presence of I₂ and K₂CO₃ in tBuOH. Compound (R)-(+)-3a (98% ee) was prepared by cyclopropanation of 3,3-diphenyl-2-propen-1-ol 1 with Et₂Zn and CH₂I₂ in the presence of a catalytic amount of (S)-2-(methanesulfonyl)amino-1-(p-toluenesulfonyl)amino-3-phenylpropane 2, followed by esterification with 3,5-dinitorobenzoyl chloride, recrystallization, and hydrolysis.     

Palladium-catalyzed asymmetric allylic substitution using novel phosphino-ester (PHEST) ligands with 1,1′-binaphthyl skeleton

The asymmetric allylic alkylation of rac-1,3-diphenyl-2-propenyl acetate 1 with dimethyl malonate 2a proceeded smoothly in the presence of lithium acetate, BSA (N,O-bis(trimethylsilyl)acetamide), [Pd(η³-C₃H₅)Cl]₂, and the chiral ligand (R)-i-Pr₂N-PHEST (R)-5a to give the allylic alkylation product (R)-3a in 89% yield with 99% ee. Furthermore, the asymmetric allylic amination of 1 with potassium phthalimide 2c has been carried out using the same ligand to give the allylic amination product (S)-3c in 10% yield with 66% ee.     

Palladium-catalyzed coupling reactions of (ArCH2)Ti(O-i-Pr)3 with aromatic or heteroaromatic bromides

Three benzyltitanium compounds of (ArCH₂)Ti(O-i-Pr)₃ (Ar = Ph (1a), 4-MeOC₆H₄ (1b), 4-FC₆H₄ (1c)) were prepared and used as benzyl nucleophiles for coupling reactions with aromatic or heteroaromatic bromides. The simple catalytic system of 1 mol % Pd(OAc)₂ and 2 mol % PCy₃ worked efficiently for a wide variety of aromatic bromides, producing diarylmethanes in good to excellent yields of up to 96%. Coupling reactions of hindered aromatic bromides or aromatic bromides containing electron-withdrawing substituents were slower over longer reaction times of 3–6 h. Reactions of heteroaromatic bromides of bromopyridines, bromofurans, or bromothiophenes with benzyl reagents of 1a or 1b required either longer reaction times of 12–24 h or a higher reaction temperature of 80 °C, producing pyridyl-, furyl-, and thienyl-arylmethanes in moderate yields.