Diastereoselective addition of diethyl difluoromethylphosphonate to enantiopure sulfinimines: synthesis of α,α-difluoro-β-aminophosphonates, phosphonic acids, and phosphonamidic acids

Addition of diethyl lithiodifluoromethylphosphonate to enantiomerically pure aromatic, heteroaromatic, and aliphatic aldehyde-derived sulfinimines afforded N-sulfinyl α,α-difluoro-β-aminophosphonates with generally good enantioselectivity and in high yield. The reaction with acetophenone-derived sulfinimine resulted in the formation of the addition product with high diastereoselectivity and in only moderate yield. A two-step deprotection involving treatment of diastereomerically pure N-sulfinyl α,α-difluoro-β-aminophosphonates with trifluoroacetic acid in EtOH followed by refluxing with 10 N HCl provided enantiopure α,α-difluoro-β-aminophosphonates and α,α-difluoro-β-aminophosphonic acids. The N-Cbz derivative of (R)-2-amino-1,1-difluoro-2-phenylethylphosphonate was a convenient starting point for the preparation of corresponding difluorophosphonate monoester, difluorophosphonic acid, and difluorophosphonamidic acid. At 21 °C difluorophosphonamidic acid was stable in aqueous solution at pH above 5.     

Diastereoselective addition of dimethyl phosphite to 3,3′,4,4′-tetramethyl-1,1′-diphosphaferrocene-2-carboxaldehyde

Addition of dimethyl phosphite to racemic 3,3′,4,4′-tetramethyl-1,1′-diphosphaferrocene-2-carboxaldehyde gives almost exclusively one diastereomer of the corresponding α-hydroxyphosphonate (d.r. ?96:4). Its absolute configuration (S, R_p)-(R, S_p) was established by X-ray diffraction.     

Solid-phase synthetic method for (±)-α-amino acids via phase-transfer catalytic alkylation

A solid supported glycineimine t-butyl ester was designed and successfully applied to the synthesis of (±)-α-amino acids. The phase-transfer catalytic alkylation, followed by acidic hydrolysis and benzoylation gave N-benzoyl-α-amino acid tert-butyl esters in high yields (up to 92%).     

α-Oxohydrazones as imine component in the synthesis of 4-functionalized azetidinones by the Staudinger reaction

1-(Methyl-p-tolyl-amino)-3-phenoxy-2-azetidinones 4-COX and 4-R substituted (COX: X=Me, Et, Ph, NMe₂, NEt₂, OBu^t; R=Me, Et, Ph) were smoothly prepared from the corresponding α-(methyl-p-tolyl)hydrazonylated ketones, amides and esters via [2+2] cycloaddition with phenoxyketene. The reaction was generally high-yielding and diastereoselective, leading to β-lactams with a cis relationship between the PhO and the COX moieties, except for R=Ph, where an opposite stereoselectivity was instead observed. The azetidinones represent interesting intermediates which couple protection at N(1) and functionalization at position 4 of the ring. Deprotection of N(1) can be easily attained by oxidative N-N cleavage with magnesium monoperoxyphthalate.     

An unprecedented highly efficient solvent-free oxidation of alkynes to α,β-acetylenic ketones with tert-butyl hydroperoxide catalyzed by water-soluble copper complex

The catalytic system composed of CuCl₂ and 2,2′-biquinoline-4,4′-dicarboxylic acid dipotassium salt (BQC) was found to be highly efficient for the selective α-oxidation of internal alkynes to the corresponding α,β-acetylenic ketones, with aqueous tert-butyl hydroperoxide under mild conditions. For the first time, full conversions of alkynes were reached with excellent selectivities, and propargylic tert-butylperoxy ethers were observed and suggested as the reaction intermediates. In the case of terminal alkynes, the oxidations are sluggish and low yields ranging from 32% to 40% were obtained.     

First iodocyclization of β-allenic phosphonates: a novel synthesis of α-difluoromethylenephostones

Six-membered α-difluoromethylenephostones were prepared in moderate to good yields with high regioselectivities under mild conditions from the iodocyclization reaction of diethyl β-allenic α,α-difluorophosphonates using I₂ or ICl as the electrophile.     

A novel method for asymmetric synthesis of both enantiomers of α-substituted carboxylic acid derivatives from optically active 1-chlorovinyl p-tolyl sulfoxides and lithium ester enolates with 1,4-chiral induction from the sulfur chiral center

Treatment of optically active 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from symmetrical ketones and (R)-(−)-chloromethyl p-tolyl sulfoxide in three steps, with lithium enolate of carboxylic acid tert-butyl esters gave optically active adducts having a substituent at the α-position with high 1,4-chiral induction from the sulfur chiral center in high yields. The adducts were converted to optically active esters and carboxylic acids having a chiral center at the α-position. When this addition reaction was carried out with the ester enolate generated from excess carboxylic acid tert-butyl ester with LDA in the presence of HMPA, the diastereomer of the adduct was obtained. By using the two reaction conditions for the generation of the ester enolates, a new method for asymmetric synthesis of both enantiomers of carboxylic acid derivatives having a substituent at the α-position from the one chiral source, (R)-(−)-chloromethyl p-tolyl sulfoxide, was realized.     

LiBF4-Catalyzed three-component coupling of an aldehyde, acetic anhydride and allyltrimethylsilane/TMSCN

Lithium tetrafluoroborate is found to be an efficient catalyst for allylation and cyanation of aldehydes with allyltrimethylsilane and trimethylsilyl cyanide in the presence of acetic anhydride at room temperature to produce homoallylic acetates and α-cyano acetates in excellent yields. A solution of 10 mol % of LiBF₄ in acetonitrile provides a convenient reaction medium to carry out allylation and cyanation reactions under very mild and neutral conditions.     

Acylation of α-(N-carbamoyl)alkylcuprates and alkyl- or aryl(halo)cuprates

α-(N-Carbamoyl)alkylcuprates [R₂CuLi·LiX or RCuXLi (X=CN, Cl)] when prepared from THF soluble CuX·2LiCl (X=Cl, CN) undergo a reliable and generally high yield reaction with aroyl, alkanoyl, and alkenoyl chlorides to provide a rapid and efficient synthesis of α-carbamoyl ketones. Cuprates prepared from acyclic, cyclic, and a functionalized carbamate can be utilized. Although yields are a function of cuprate reagent and substrate structure, nearly quantitative yields can be obtained with reagents generated from 2RLi+CuCN·2LiCl. The use of reagents generated from CuCl·2LiCl are more efficient in the α-(N-carbamoyl)alkyl ligand, although yields are slightly lower. Acylation of alkyl(chloro)cuprates generated from one equivalent of CuCl·2LiCl and organolithium or Grignard reagents provides an efficient and high yield procedure for ketone synthesis.     

Determination of trace levels of mercury in water samples based on room temperature phosphorescence energy transfer

A novel method has been developed for the sensitive determination of mercury in aqueous media by room temperature phosphorescence (RTP). The measurement principle is based on the energy transfer (ET) from a phosphor molecule (acting as a donor) to a Hg-sensitive dye (acceptor). To our acknowledgment this is the first RTP method for mercury measurement developed so far. α-Bromonaphthalene (BrN) was selected as the phosphorescent donor molecule (BrN can produce significant RTP emission in aqueous media in a β-cyclodextrin rigid microenvironment without deoxygenation).The absorption spectrum of the complex formed between mercury and the dithizone dye possesses a desirable spectral overlap with the RTP emission spectrum of the donor (BrN), giving rise to a nonradiative ET from the phosphor molecules to the mercury complex. An increase in the concentration of Hg(II) causes an increase on the concentration of the dithizone complex (acceptor) with the subsequent increase of the absorbance and, therefore, resulting in a decrease of the RTP emission. Both, RTP intensities and triplet lifetimes of the BrN decreased with increases on the Hg(II) concentration.Possible interferences present in natural waters, including different cations and anions, which could affect the analytical response, were evaluated and the analytical performance characteristics investigated. The use of phosphorescence measurements (low background noise signals) resulted in an improvement on the sensitivity of the Hg(II) detection higher than five times as compared to the molecular absorption spectrophotometric method for Hg(II) detection based on dithizone as Hg-indicator. A detection limit (D.L.) of 14 ng ml⁻¹ of Hg(II) was obtained by RTP with a precision of ±4.8% for five replicates of 300 ng ml⁻¹ of Hg(II). The usefulness of the method was successfully evaluated by the determination of Hg(II) in spiked natural water samples.