γ-Selective allylic substitution reaction with Grignard reagents catalyzed by copper N-heterocyclic carbene complexes and its application to enantioselective synthesis

The reaction of allylic compounds with alkyl Grignard reagents in the presence of a catalytic amount of copper N-heterocyclic carbene (NHC) complexes proceeded predominantly in an S_N2′ reaction pathway to give γ-substituted product in excellent yield. The method was applied to asymmetric reaction by using optically active NHC ligands.     

Origins of enantioselectivity during allylic substitution reactions catalyzed by metallacyclic iridium complexes

In depth mechanistic studies of iridium catalyzed regioselective and enantioselective allylic substitution reactions are presented. A series of cyclometalated allyliridium complexes that are kinetically and chemically competent to be intermediates in the allylic substitution reactions was prepared and characterized by 1D and 2D NMR spectroscopies and single-crystal X-ray difraction. The rates of epimerization of the less thermodynamically stable diastereomeric allyliridium complexes to the thermodynamically more stable allyliridium stereoisomers were measured. The rates of nucleophilic attack by aniline and by N-methylaniline on the isolated allyliridium complexes were also measured. Attack on the thermodynamically less stable allyliridium complex was found to be orders of magnitude faster than attack on the thermodynamically more stable complex, yet the major enantiomer of the catalytic reaction is formed from the more stable diastereomer. Comparison of the rates of nucleophilic attack to the rates of epimerization of the diastereomeric allyliridium complexes containing a weakly coordinating counterion showed that nucleophilic attack on the less stable allyliridium species is much faster than conversion of the less stable isomer to the more stable isomer. These observations imply that Curtin-Hammett conditions are not met during iridium catalyzed allylic substitution reactions by η(3)-η(1)-η(3) interconversion. Rather, these data imply that when these conditions exist for this reaction, they are created by reversible oxidative addition, and the high selectivity of this oxidative addition step to form the more stable diastereomeric allyl complex leads to the high enantioselectivity. The stereochemical outcome of the individual steps of allylic substitution was assessed by reactions of deuterium-labeled substrates. The allylic substitution was shown to occur by oxidative addition with inversion of configuration, followed by an outer sphere nucleophilic attack that leads to a second inversion of configuration. This result contrasts the changes in configuration that occur during reactions of molybdenum complexes studied with these substrates previously. In short, these studies show that the factors that control the enantioselectivity of iridium-catalyzed allylic substitution are distinct from those that control enantioselectivity during allylic substitution catalyzed by palladium or molybdenum complexes and lead to the unique combination of high regioselectivity, enantioselectivity, and scope of reactive nucleophile.     

Copper catalyzed enantioselective allylic substitution by MeMgX

Methyl Grignard undergoes highly regio (>90/10) and enantioselective (ee 91-96%) copper catalyzed allylic substitution on cinnamyl-type chlorides. CuBr (3%) and 3.3% of a chiral phosphoramidite ligand are sufficient for a complete reaction. The synthesis of a precursor of (+)-Naproxen is described. The reaction can be extended to alkyl substituted allylic chlorides (ee 72%).     

o-DPPB-directed copper-mediated and -catalyzed allylic substitution with Grignard reagents

The ortho-diphenylphosphanylbenzoyl (o-DPPB) group was explored as a directing leaving group in copper-mediated and copper-catalyzed allylic substitution with Grignard reagents. Complete control of chemo-, regio- and stereoselectivity with complete syn-1,3-chirality transfer was observed as a result of the directed nature of the reaction. No excess of organometallic reagent is required and the directing group can be recovered quantitatively. Coordination studies in the solid state and in solution have shown that two substrates are bound via the phosphine function of the directing group at copper. Dynamic NMR experiments in solution are in agreement with a ligand-exchange process at copper, a prerequisite for the development of a substoichiometric process.     

Copper-catalyzed asymmetric allylic substitution with aryl and ethyl Grignard reagents

Phenyl- and ethyl-magnesium bromides undergo regioselective asymmetric allylic substitution with high enantioselectivity under the catalysis of chiral amidophosphane-copper(I) complexes.     

Olefinic substitution reaction catalyzed by sulfur-containing polymeric palladium complexes

Silica-supported sulfur-containing polymeric palladium complexes were synthesized by the coordination of sulfur-containing polymeric ligands with palladium acetate or palladium chloride. The activated alkenes were reacted selectively with iodobenzene in the presence of tertiary amines and polymeric palladium complexes containing sulfur to give phenyl-substituted derivatives. High yields can be obtained under appropriate conditions with a low catalyst concentration. The sulfur-containing polymeric palladium complexes showed higher activities and better selectivities and stabilities than the corresponding phosphine-containing systems.     

Lewis acid catalyzed substitution of allylic nitro compounds with cyanotrimethylsilane

The nitro group in allylic nitro compounds is replaced by cyano group on treatment with cyanotrimethylsilane in the presence of Lewis acid.     

Dealkylation reactions catalyzed by Grignard reagents

Some reactions of 2,3-dihydrobenzofuran derivatives with Grignard reagents were re-examined in order to account for discrepancies between the yields of starting materials and reaction products. Phenol was found to be present in addition to the products previously described. On the basis of the results it is assumed that phenol results from dealkylation of o-alkylphenol, catalyzed by the magnesium halide moiety of the Grignard reagent.     

First enantioselective allylic etherification with phenols catalyzed by chiral ruthenium bisoxazoline complexes

Regio- and enantioselective substitution of cinnamyl chloride by phenols has been achieved with up to 82% enantiomeric excess, using a ruthenium catalyst prepared from [Cp*(CH(3)CN)(3)Ru][PF(6)] and a chiral bisoxazoline ligand.     

Development of biisoquinoline-based chiral diaminocarbene ligands: enantioselective SN2' allylic alkylation catalyzed by copper-carbene complexes

Chiral biisoquinoline-based diaminocarbene ligands (BIQ) were designed to create a chiral environment extended toward the metal center, which was confirmed by an X-ray structure. The concise ligand synthesis is highlighted by a modified Bischler-Napieralski cyclization of bisamides prepared from readily available chiral phenethylamines, and allows easy variation of the stereodifferentiating groups. The cyclohexyl-BIQ-copper complex is an efficient catalyst for enantioselective SN2' allylic alkylation with Grignard reagents showing SN2' regioselectivity higher than 5:1 and enantioselectivity in the range of 68-77% ee.     

Synthesis of chiral oxime ethers based on regio- and enantioselective allylic substitution catalyzed by iridium-pybox complex

The oxygen atom of oximes acts as a reactive nucleophile in the iridium-catalyzed allylic substitution of unsymmetrical substrates to give the branched oxime ethers. Among several chiral ligands evaluated, the iridium complex of pybox ligand having phenyl group catalyzed the allylic substitution of phosphates with high activity to form the branched oxime ethers with good enantioselectivities.     

Allyation of carbonucleophiles with allylic carbonates under neutral conditions catalyzed by rhodium complexes

Rhodium-phosphine complexes catalyze the allylation of carbonucleophiles with allylic carbonates under neutral conditions. In addition, we found unusual regioselectivity in the rhodium catalyzed allylation.     

Asymmetric allylic substitution catalyzed by C1-symmetrical complexes of molybdenum: structural requirements of the ligand and the stereochemical course of the reaction

Application of new chiral ligands (R)-(-)-12 a and (S)-(+)-12 c (VALDY), derived from amino acids, to the title reaction, involving cinnamyl (linear) and isocinnamyl (branched) type substrates (4 and 5 --> 6), led to excellent regio- and enantioselectivities (>30:1, < or =98 % ee), showing that ligands with a single chiral center are capable of high asymmetric induction. The structural requirements of the ligand and the mechanism are discussed. The application of single enantiomers of deuterium-labeled substrates (both linear 38 c and branched 37 c) and analysis of the products (41-43) by (2)H{(1)H} NMR spectroscopy in a chiral liquid crystal matrix allowed the stereochemical pathways of the reaction to be distinguished. With ligand (S)-(+)-12 c, the matched enantiomer of branched substrate was found to be (S)-5, which was converted into (R)-6 with very high regio- and stereoselectivity via a process that involves net retention of stereochemistry. The mismatched enantiomer of the branched substrate was found to be (R)-5, which was also converted into (R)-6, that is, with apparent net inversion, but at a lower rate and with lower overall enantioselectivity. This latter feature, which may be termed a "memory effect", reduced the global enantioselectivity in the reaction of the racemic substrate (+/-)-5. The stereochemical pathway of the mismatched manifold has been shown also to be one of net retention, the apparent inversion occurring through equilibration via an Mo-allyl intermediate prior to nucleophilic attack. Incomplete equilibration leads to the memory effect and thus to lower enantioselectivity. Analysis of the mismatched manifold over the course of the reaction revealed that the memory effect is progressively attenuated with the nascent global selectivity increasing substantially as the reaction proceeds. The origin of this effect is suggested to be the depletion of CO sources in the reaction mixture, which attenuates turnover rate and thus facilitates greater equilibrium. The linear substrate was also converted into the branched product with net syn stereochemistry, as shown by isotopic labeling. An analogous process operates in the generation of small quantities of linear product from branched substrate.     

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.     

Cross coupling of magnesium diacetylenides with functional allylic and halide-containtng-compounds catalyzed by transition metal complexes

Conclusions An efficient method has been developed for the synthesis of 1,4-enynes, conjugated acetylenes and aryl acetylenes by the cross coupling of magnesium diacetylenides with allyl ethers and esters, alkyl halides, allyl halides, aryl halides, allyl sulfides, and allylsulfones, using Ni and Pd complexes as the catalyst.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 2, pp. 429–433, February, 1936.     

Cross-coupling of alkenyl,aryl or allylic selenides and grignard reagents catalyzed by nickel-phosphine complexes

Alkenyl, aryl or allylic selenides smoothly couple with Grignard reagents in the presence of Ni(II)-phosphine complexes as catalysts to afford the corresponding unsaturated compounds in good yields. The reactivity order of coupling reaction with BuMgBr catalyzed by NiCl₂ [Ph₂PCH₂CH₂CH₂PPh₂] was found to be PhSeMe « PhCl > PhSMe by the competitive reactions.     

New 1,10-phenanthroline ligands for asymmetric catalysis: enantioselective palladium catalyzed allylic substitution

A number of new chiral C₁-symmetric 1,10-phenathrolines have been prepared and assessed in the enantioselective palladium catalyzed allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethylmalonate. Enantioselectivities up to 84% were obtained.     

Sequential catalytic isomerization and allylic substitution. Conversion of racemic branched allylic carbonates to enantioenriched allylic substitution products

A catalytic protocol for the conversion of readily accessible racemic, branched aromatic allylic esters to branched allylic amines, ethers, and alkyls has been developed. Palladium-catalyzed isomerization of branched allylic esters to terminal allylic esters, followed by sequential iridium-catalyzed allylic substitution, gave the branched allylic products in good yield with high regioisomeric and enantiomeric selectivity. Both electron-rich and electron-poor branched allylic esters gave products in >90% ee. High enantiomeric excesses were also observed for the products from the reactions of 2-thienyl acetates and dienyl carbonates.