Enantioselective addition of organolithium reagents to imines mediated by C2-symmetric bis(aziridine) ligands

The C₂-symmetric bis(aziridine) ligands 1–5 have been screened in the enantioselective addition of organolithium reagents to imines. Ligand 1 (used in stoichiometric amounts) was found to be superior in terms of chemical yield and enantioselectivity, the best result being 90% yield and 89% e.e. in the addition of vinyllithium to imine 6a. Use of ligand 1 in substoichiometric amounts gave poorer yield and lower enantioselectivity. The enantioselectivity of the reaction was investigated as a function of substrate, reagent, stoichiometry and temperature, but no firm mechanistic conclusions could be drawn. Preliminary results with deuterium-labelled methyllithium indicate complexation/exchange processes involving ligand, reagent and substrate.     

Competing reaction pathways from α-halo-α-protioalkyl aryl sulfoxides initiated by organometallic reagents

The reactions of syn-1-haloethyl p-chlorophenyl sulfoxides (halogen = Cl, Br) with main-group organometallic reagents (n-BuMgCl, MeLi, n-BuLi, s-BuLi, and t-BuLi) in THF and PhMe solvents were examined. Product distributions were analyzed to determine the extent of competing sulfoxide ligand exchange, halogen-metal exchange, and deprotonation reaction pathways. A combination of t-BuLi in PhMe was optimal for initiation of sulfoxide ligand exchange from syn-1-chloroethyl p-chlorophenyl sulfoxide.     

Catalytic asymmetric deprotonation of a phosphine borane: comparison of two-ligand and one-ligand catalysis

The catalytic asymmetric deprotonation of tert-butyldimethylphosphine borane using s-BuLi or n-BuLi and sub-stoichiometric amounts of (?)-sparteine under one-ligand and two-ligand manifolds has been investigated. Using s-BuLi, slightly higher enantioselectivity was obtained using two-ligand catalysis (use of sub-stoichiometric (?)-sparteine in the presence of a stoichiometric amount of a second achiral ligand) compared to one-ligand catalysis (use of sub-stoichiometric (?)-sparteine only). With n-BuLi, two-ligand catalysis using LiDMAE (DMAE = dimethylaminoethanol) as the stoichiometric ligand was the only method for obtaining good yield and enantioselectivity. In this case, one-ligand catalysis failed as the (?)-sparteine was not turned over.     

Structure-fluorescence relationship of push-pull 2-phenylbenzothiazole derivatives designed based on the firefly light-emitter

6-Dimethylamino-2-phenylbenzothiazole (1a) mimicking the firefly oxyluciferin structure and the derivatives with an electron-withdrawing substituent on the phenyl group were prepared, and their fluorescence properties were investigated in various solvents. 1a showed solvatochromic fluorescence with good fluorescence quantum yields (Φ_f >0.8). The introduction of an electron-withdrawing group led to a red-shift of the emission maximum. In particular, the derivatives with the 2,2-dicyanoethenyl and (1,3-dihydro-1,3-dioxo-2H-inden-2-ylidene)methyl groups showed near-infrared fluorescence in chloroform. In addition, the derivative with the phenylimine moiety showed efficient solid-state fluorescence, resulted from a molecular arrangement inhibiting intermolecular interactions for quenching the fluorescence state in crystals.     

Synthesis of stable 1-ethoxy-2,3-diferrocenylcyclopropenylium tetrafluoroborate and its reactions with lithium reagents

1-Ethoxy-2,3-diferrocenylcyclopropenylium tetrafluoroborate selectively reacts with MeLi, n-BuLi, sec-BuLi with formation of the 3,3-dialkyl-1,2-diferrocenylcyclopropenes, while with tert-BuLi both 2-tert-butyl-1,3-diferrocenylcyclopropene and 1,3-di-tert-butyl-2,3-diferrocenylcyclopropene are obtained. The structures of 3,3-dimethyl-, 3,3-dibutyl-1,2-diferrocenyl and 2-tert-butyl-1,3-diferrocenylcyclopropenes were confirmed by X-ray crystallographic analysis.     

Reaction of 3-phenylisoxazole with alkyllithiums

Alkyllithiums react with 3-phenylisoxazole giving C₅-H abstraction followed either mainly by ring fragmentation to benzonitrile and ethynolate ion (in the case of t-BuLi) or (less hindered alkyllithiums: n-BuLi, EtLi, MeLi) also by formation of alkylated enaminones. Appreciable amounts of 2-alkyl-4,6-diphenylpyrimidines have also been isolated for certain alkyllithiums (EtLi and MeLi). This is at variance with the reported behaviour with hindered lithium amides (LTMP) for which only C₅-H abstraction followed by ring fragmentation was described. The mechanistic significance of the observed results is discussed.     

Stereochemistry of addition of carbanion reagents to `diacetone fructose aldehyde'. Configurational assignment of a 1-deoxyheptulose derivative by X-ray crystallography and NMR studies directed to the assignment of isomeric adducts

The addition of carbanionic reagents to `diacetone fructose aldehyde' (6) was investigated with a focus on the stereocontrol. The Grignard reagents, MeMgBr, EtMgBr, i-PrMgBr, and MeMgI, gave a high bias (≥90%) for one diastereomer, assigned as the R-isomer, in ether at −78 to 0°C. The reaction of PhMgBr showed diminished diastereoselectivity under these conditions, with a significant dependence of the isomer ratio on temperature and solvent. PhCH<sub>2</sub>MgBr only afforded the adduct of `allylic rearrangement', namely 13, with poor diastereocontrol (ca. 60:40). MeLi, t-BuLi, PhLi, and LiCH₂CO₂-t-Bu provided adducts of 6 enriched in the R-isomer in the range of 80–89%, whereas 2-lithio-2-ethyl-1,3-dithiane gave a 94:6 ratio of R:S adducts (15a:15b). The R absolute stereochemistry at the carbinol C1 center of 4a was established through X-ray analysis of sulfamate derivative 2a. Carbon-13 NMR chemical shift criteria (the chemical shifts for C1 and C3) were identified to facilitate the stereochemical assignment of C1 adducts of 6.     

The enantioselective diethylzinc addition to imines catalyzed by chiral Cu(II)–oxazoline complexes

A series of copper complexes of chiral bisoxazolines has been applied in the catalytic diethylzinc addition to N-sulfonyl imines. It has been found that the tridentate ligands 3–5 provided higher enantioselectivity than bidentate ones. Addition of 4 Å molecular sieves to the reaction system benefits the enantioselectivity. The optimal procedure for diethylzinc addition to different imines resulted in moderate yields and enantioselectivities of up to 82% ee.     

Reactions of 3-Hydroxy-2-phenyl-1H-benzo[e]isoindol-1-one: A Route to 3-Hydroxy-/3-anilinobenzo[e]indan-1-ones and Benzo[f]phthalazin-1(2H)-ones

New hydroxy- and anilinoindanone derivatives 3 and 4 were synthesized starting from 3-hydroxybenzo[e]isoindolinone 1 via the addition of alkyllithium (s-BuLi, n-BuLi, MeLi or i-PrLi) to the carbonyl group, followed by lactam ring opening and, finally, an intramolecular cyclization leading to target compounds. The same starting material was used for the preparation of the new benzo[f]phthalazinone derivatives 12–16 through multi-step reactions. The target derivative 16 was obtained from the corresponding bromolactam 15 by the Buchwald–Hartwig amination. Structures of the obtained compounds were confirmed by the NMR spectra.     

Synthesis and characterization of titanium and zirconium complexes with silicone-bridged phenoxycyclopentadienyl ligands

Dimethylsilyl(2,3,4,5-tetramethylcyclopentadienyl)(3-tert-butyl-5-methyl-2-phenoxy)titanium dichloride (1a), a useful catalyst precursor for olefin copolymerization, was synthesized at high yield starting from allyl-protected phenolic ligand 3a,which was first treated with 2 equiv. of n-BuLi to selectively give the dilithium salt of 3a along with 1-heptene, a coupling product of a protected allyl ether moiety and butyl anion. Addition of TiCl₄ to the resulting dilithium salt of 3a in toluene afforded 1a in 50% isolated yield. This methodology could be applied to the preparation of related titanium and zirconoium complexes 1b-1d, 8 with silicone-bridged Cp-phenoxy ligands, whereas the reaction starting from methyl-protected precursor 2a did not produce the zirconium complex 8. Copolymerization of ethylene and 1-hexene with the newly prepared complexes was also investigated.     

Synthesis and characterization of chalcogen (S and Se) derivatives of 4-chloro- and 4-methoxy-N,N-diisopropylpyridine-2-carboxamide: X-ray structure of 4-methoxy-3-(sulfanylmethyl)- and 4-chloro-3-(selenenylbenzyl)-N,N-diisopropylpyridine-2-carboxamide

Synthesis of chalcogen (S and Se) derivatives of 4-chloro- and 4-methoxy-N,N-diisopropylpyridine-2-carboxamide (1a and 1b respectively) has been reported. 1a and 1b were lithiated with 2 equiv. of n-BuLi or LDA at ?78 °C. Addition of elemental sulfur or selenium to the carbanion led to the formation of corresponding thiolate or selenolate anions respectively. The selenolate anions were aerial oxidized to afford the corresponding diselenides. The thiolate/selenolate anions were quenched with a variety of electrophiles to give unsymmetrical thio/selenoalkanes in moderate to good yields. Reductive cleavage of Se–Se bond has also been studied. The synthesized compounds were characterized by elemental analysis, NMR (¹H, ¹³C and ⁷⁷Se), FT-IR and mass spectral techniques. Crystal structures of two compounds, 6b and 7a, were determined by single crystal X-ray crystallography. Their crystal structure exhibits 1,4-type S?OCH₃ and Se?Cl intramolecular secondary interactions respectively. The relative thermal stability of 3a, 3b and 4a has also been established by thermogravimetric analysis.     

A new pseudo C2-symmetric tertiary diamine for the enantioselective addition of MeLi to aromatic imines

A new tertiary pseudo C₂-symmetric 1,2-diamine derived from (1S,2S)-(+)-pseudoephedrine was synthesized and tested in the enantioselective addition of MeLi to aromatic imines. A comparative study with the analogous C₂-symmetric ligand successfully used previously in the same reaction showed comparable selectivity and better reactivity for this novel diamine.     

Synthesis of new 3-substituted-2H-1,2-naphthothiazin-4(3H)-one 1,1-dioxides via directed ortho-metalation reaction

The reaction of compounds 6a–i, readily available from α-amino acids, with an excess of lithium diisopropylamide, leads to new 3-substituted-2H-1,2-naphthothiazin-4(3H)-one 1,1-dioxides 7a–i, with yields ranging between 21 and 70%. The key steps are: the naphthylsulfonyl ortho-deprotonation based on the directed ortho-metalation reaction followed by a regiospecific intramolecular cyclisation reaction. Lithiation–deuteration experiments carried out on the naphthylsulfonamides 8 and 9 using n-BuLi and LDA demonstrated the regioselectivity of the deprotonation of the H-3 over the H-1 one of the naphthalene ring.     

The use of bifunctional catalyst systems in the asymmetric addition of alkynylzinc to aldehydes

The bifunctional ligand 2a showed a more enhanced reactivity than that of the corresponding amino alcohol ligand in the asymmetric addition of alkynylzinc to benzaldehyde. The bifunctional ligand 2a can catalyze the addition of phenylacetylene to various types of aldehydes including aromatic aldehydes, aliphatic aldehydes, and α,β-unsaturated aldehydes with high enantioselectivity (81–98% ee). The conditions of this catalytic process are both mild and simple.     

The synthesis of chiral amino diol tridentate ligands and their enantioselective induction during the addition of diethylzinc to aldehydes

A series of C₂-symmetric chiral amino diol tridentate ligands 3a–g were prepared from achiral bulky organolithiums, achiral bulky primary amines, and optically active epichlorohydrin (ECH). The prepared C₂-symmetric chiral amino diol tridentate ligands were capable of inducing enantioselectivity in the model reaction of aromatic and aliphatic aldehydes with diethylzinc with an ee of up to 96%. The enantioselectivity can be modulated by adjusting the steric hindrance of the achiral reagents employed in the synthesis of the chiral ligand. The configuration of the addition product depended on the configuration of the amino diol ligands, which can be simply controlled as desired by using the ECH with the desired configuration during the preparation of the ligand.     

Lipase-catalyzed asymmetric acylation of boron cluster-containing secondary alcohols

The lipase-catalyzed asymmetric acetylation of secondary alcohols containing a carborane (boron cluster) moiety was investigated. Most lipases examined showed poor catalytic activity toward carborane-containing secondary alcohol 1a, but lipase TL efficiently catalyzed the acetylation of 1a with high enantioselectivity, to afford (R)-3a. This selectivity is similar to that of the general lipase-catalyzed acylation of secondary alcohols. Utilizing lipase TL, we succeeded in the resolution of carborane-containing alcohol 5, synthesized as a progesterone receptor ligand candidate, and evaluated the activities of the two enantiomers.     

Total synthesis of (+)-eupomatilone 2 via asymmetric [2,3]-Wittig rearrangement of highly oxygenated biphenylmethyl ethers

We have achieved the total synthesis of (±)- and (+)-eupomatilone 2 isolated from the Australian shrub Eupomatia bennettii. The key reaction was an asymmetric [2,3]-Wittig rearrangement employing a bis(oxazoline) chiral ligand. Although the highly oxygenated biphenylmethyl ether exhibited considerably lowered enantioselectivity as compared with the non-substituted biphenylmethyl ether, the selectivity was improved to 89% ee by using n-BuLi and ether as the base and the co-solvent, respectively.     

Enantioselective addition of phenylacetylene to aldehydes catalyzed by 1,3-aminophenol ligand

The 1,3-aminophenol ligand (R)-1 was found to be a good catalyst for the zinc phenylacetylene addition to aldehydes. The high activity and enantioselectivity could be improved upon by basic additives. The enantioselectivity follows a linear free energy relationship with higher enantioselectivity obtained for the more reactive aryl aldehydes.     

Screening of ligands in the asymmetric metallocenethiolatocopper(I)-catalyzed allylic substitution with Grignard reagents

Screening of metallocenethiolate ligands for copper(I)-catalyzed substitution of allylic acetates with Grignard reagents has been carried out. The previously used ligand, lithium (R,S_p)-2-(1-dimethylaminoethyl)ferrocenylthiolate (4a), possessing both central and planar chirality, was the starting point for the screening. It was found that the diastereomeric ligand lithium (R,R_p)-2-(1-dimethylaminoethyl)ferrocenylthiolate (4b) exhibiting reversed planar chirality gave increased enantioselectivity in the allylic substitution, at least when cinnamyl acetate was used as a substrate. The ruthenocene-based ligand lithium (R,S_p)-2-(1-dimethylaminoethyl)ruthenocenylthiolate (4c) gave an enhanced reaction rate, but lower chiral induction. The use of disulfide bis[(R,S_p)-2-(1-dimethylaminoethyl)ferrocenyl]disulfide (7a) as a ligand precursor worked well but resulted in lower enantioselectivity.