Use of allylzinc halide as a source of halide: Differential addition of nucleophiles to Ts-aziridines and aldehydes under similar reaction conditions

We have observed that the allylic zinc halide under identical reaction conditions acts in different modes for different electrophiles. For Ts-aziridines the halide part of the allylic halide has been introduced as a nucleophile and for the carbonyl compounds the simple allylation reaction occurs. To the best of our knowledge this is the first report where the allylic zinc halide is the source of halide acting as nucleophile. The main advantages of the present procedure are easy to handle, no need of inert atmosphere, mild reaction conditions, and applicability to a wide variety of substrates for aziridines and carbonyl compounds.     

Identification of conjugation positions of urinary glucuronidated vitamin D3 metabolites by LC/ESI–MS/MS after conversion to MS/MS‐fragmentable derivatives

A liquid chromatography/electrospray ionization–tandem mass spectrometry‐based method was developed for the identification of the conjugation positions of the monoglucuronides of 25‐hydroxyvitamin D₃ [25(OH)D₃] and 24,25‐dihydroxyvitamin D₃ [24,25(OH)₂D₃] in human urine. The method employed derivatization with 4‐(4‐dimethylaminophenyl)‐1,2,4‐triazoline‐3,5‐dione to convert the glucuronides into fragmentable derivatives, which provided useful product ions for identifying the conjugation positions during the MS/MS. The derivatization also enhanced the assay sensitivity and specificity for urine sample analysis. The positional isomeric monoglucuronides, 25(OH)D₃‐3‐ and ‐25‐glucuronides, or 24,25(OH)₂D₃‐3‐, ‐24‐ and ‐25‐glucuronides, were completely separated from each other under the optimized LC conditions. Using this method, the conjugation positions were successfully determined to be the C3 and C24 positions for the glucuronidated 25(OH)D₃ and 24,25(OH)₂D₃, respectively. The 3‐glucuronide was not present for 24,25(OH)₂D₃, unlike 25(OH)D₃, thus we found that selective glucuronidation occurs at the C24‐hydroxy group for 24,25(OH)₂D₃.     

Reaction of allylic and benzylic alcohols and esters with PPh3/I2: one-pot synthesis of β,γ-unsaturated compounds

The treatment of tertiary and secondary allylic alcohols containing a terminal double bond, and their acetyl derivatives, with triphenylphosphine and iodine under mild conditions leads regiospecifically and in high stereoselectivity to the corresponding primary allylic iodides, which can react ‘in situ’ with diverse nucleophiles. Primary allylic alcohols and benzyl alcohols and acetates are also transformed into the corresponding iodides under these conditions.     

A third generation chiral phosphorus-containing dendrimer as ligand in Pd-catalyzed asymmetric allylic alkylation

The synthesis of a third generation phosphorus-containing dendrimer possessing 24 chiral iminophosphine end groups derived from (2S)-2-amino-1-(diphenylphosphinyl)-3-methylbutane is described. In situ complexation of this dendrimer by [Pd(η³-C₃H₅)Cl]₂ affords a catalyst, which is used in asymmetric allylic alkylations of rac-(E)-diphenyl-2-propenyl acetate and pivalate. The percentage of conversion, the yield of isolated 2-(1,3-diphenylallyl)-malonic acid dimethyl ester, and its enantiomeric excess have been measured in each case, and were found to be good to very good (ee from 90% to 95%). Furthermore, the dendritic catalyst can be recovered and reused at least two times, with almost the same efficiency.     

Diastereoselective addition of organolithiums to 1,3-oxazolidines complexed with aluminum tris(2,6-diphenylphenoxide) (ATPH)

1,3-Oxazolidines were easily obtained by condensation of N-substituted (R)-phenylglycinol with aldehydes. Addition of organolithium reagents to 1,3-oxazolidines by complexation with the bulky Lewis acid aluminum tris(2,6-diphenylphenoxide) (ATPH) readily produced the corresponding chiral amines with good yield and high diastereoselectivity. The configuration of the new stereogenic center was shown to be opposite to that of adducts obtained for the same 1,3-oxazolidines using Grignard reagents. The best diastereoselectivity was achieved using N-isopropyl-1,3-oxazolidines. The mechanism of addition was deduced by determining the stereochemistry of the iminium-aluminum complex by NOE experiments.     

First example of the C-alkylation of indoles with Baylis-Hillman acetates

Baylis-Hillman acetates undergo S_N2′ allylic substitution with indoles in the presence of 20 mol % of indium tribromide under mild conditions to afford a new class of substituted indoles in high yields with (E)-stereoselectivity. The stereochemistry of the products was assigned by various NMR experiments.     

Bismuth-catalyzed allylic oxidation using t-butyl hydroperoxide

Bismuth(III) salts are efficient catalysts for the selective allylic oxidation using tert-butyl hydroperoxide. BiCl₃ is especially effective and can be easily recovered and reused as BiOCl. Using BiCl₃/K-10 as catalyst, an increase in the reaction rate was observed.     

Chiral Phosphinophenyloxazolines Bearing Alkoxymethyl Substituents: Synthesis and Application in the Palladium Catalyzed Allylic Substitution Reactions

The chiral phosphine‐oxazoline ligands 3 and 4 bearing 4‐alkoxymethyl substituents on the oxazoline ring with (R)‐configuration were prepared from L‐serine methyl ester in 66% and 33% yields, respectively. Along this synthetic pathway, the β‐hydroxylamides derived from L‐serine methyl ester and 2‐halobenzoyl chlorides were expediently converted to the corresponding oxazolines by using diethylaminosulfur trifluoride as the activation agent. Potassium diphenylphosphide was the reagent of choice for replacing the bromine atom on the phenyl ring, giving the desired oxazoline‐phosphine ligands 3 and 4 . Together with [Pd(η³‐allyl)Cl]₂, ligands 3 and 4 induced an enantioselective allylic substitution reaction of 1,3‐diphenyl‐2‐pro‐penyl acetate by dimethyl malonate. Although ligands 3 and 4 exhibit the (R)‐configuration, differing from the (S)‐configuration of Pfaltz‐Helmchen‐Williams phosphine‐oxazoline ligands, all these ligands led to the same enantiotopic preference in the allylic substitution reaction. To facilitate the recovery and reuse of the phosphine‐oxazoline ligand, immobilization on Merrifield resin was attempted, albeit in low loading.     

On the formation of Pd(II) complexes of Trost modular ligand involving N-H activation or P,O coordination in Pd-catalyzed allylic alkylations

Specific chiral ligands have been designed by Trost et al. to perform enantioselective Pd-catalyzed allylic alkylations. It is shown that the Pd(0) complex formed by addition of the Trost ligand (4) to Pd⁰(dba)₂ is not stable in most solvents (acetone, DMF, CH₂Cl₂). Indeed, Pd⁰(dba)(4) leads to the formation of a stable Pd^II complex 5 (X-ray structure), likely by activation of the two N-H bonds of the ligand by the Pd⁰ centre. The formation of the Pd^II complex competes with the reaction of Pd⁰(4) with (E)-PhCHCH-CH(OAc)-Ph, excluding any investigation of the kinetics of the latter reaction. The ionization steps from intermediate (η²-PhCHCH-CH(OAc)-Ph)Pd⁰(4) were found to be very slow. The cationic P,P complex [(η³-Ph-CH-CH-CH-Ph)Pd(4)]⁺, expected to be generated by addition of 2 equiv. of 4 to the precursor [(η³-Ph-CH-CH-CH-Ph)Pd(μ-Cl)]₂, in the presence of a chloride scavenger, leads to a complex mixture whereas addition of 1 equiv. of 4 affords a stable bis-cationic Pd^II complex {[(η³-Ph-CH-CH-CH-Ph)Pd]₂(4)]}²⁺, (X-ray structure) via a P,O complexation of each allyl-Pd moieties. This dissymmetric P,O coordination will favour the enantioselectivity of Pd-catalyzed allylic alkylation of (E)-PhCHCH-CH(OAc)-Ph by the control of the regioselectivity of the nucleophilic attack onto the allylic ligand which is responsible of the enantioselectivity of the overall catalytic reaction.     

Palladium(II)-allyl complexes containing chiral N-donor ferrocenyl ligands

A study of the reactivity of enantiopure ferrocenylimine (S_C)-[FcCHN-CH(Me)(Ph)] {Fc =  (η⁵-C₅H₅)Fe{(η⁵-C₅H₄)-} (1a) with palladium(II)-allyl complexes [Pd(η³-1R¹,3R²-C₃H₃)(μ-Cl)]₂ {R¹ = H and R² = H (2), Ph (3) or R¹ = R² = Ph (4)} is reported. Treatment of 1a with 2 or 3 {in a molar ratio Pd(II):1a = 1} in CH₂Cl₂ at 298 K produced [Pd(η³-3R²-C₃H₄){FcCHN-CH(Me)(Ph)}Cl] {R² = H (5a) or Ph (6a)}. When the reaction was carried out under identical experimental conditions using complex 4 as starting material no evidence for the formation of [Pd(η³-1,3-Ph₂-C₃H₃){FcCHN-CH(Me)(Ph)}Cl] (7a) was found. Additional studies on the reactivity of (S_C)-[FcCHN-CH(R³)(CH₂OH)] {R³ = Me (1b) or CHMe₂ (1c)} with complex 4 showed the importance of the bulk of the substituents on the palladium(II) allyl-complex (2-4) or on the ferrocenylimines (1) in this type of reaction. The crystal structure of 5a showed that: (a) the ferrocenylimine adopts an anti-(E) conformation and behaves as an N-donor ligand, (b) the chloride is in acis-arrangement to the nitrogen and (c) the allyl group binds to the palladium(II) in a η³-fashion. Solution NMR studies of 5a and 6a and [Pd(η³-1,3-Ph₂-C₃H₃){FcCHN-CH(Me)(CH₂OH)}Cl] (7b) revealed the coexistence of several isomers in solution. The stoichiometric reaction between 6a and sodium diethyl 2-methylmalonate reveals that the formation of the achiral linear trans-(E) isomer of Ph-CHCH-CH₂Nu (8) was preferred over the branched derivative (9). A comparative study of the potential utility of ligand 1a, complex 5a and the amine (S_C)-H₂N-CH(Me)(Ph) (11) as catalysts in the allylic alkylation of (E)-3-phenyl-2-propenyl (cinnamyl) acetate with the nucleophile diethyl 2-methylmalonate (Nu⁻) is reported.