Pd-catalyzed Substitution Research Articles

Synthesis of Enantiomerically Pure 1,2,3-Trisubstituted Cyclopropane Nucleosides Using Pd-Catalyzed Substitution via Directing Group-Mediated C(sp3)-H Activation as a Key Step.

A series of enantiomerically pure 1,2,3-trisubstituted cyclopropane nucleosides Ia-Id and IIa-IId of medicinal chemical interest was designed and synthesized. In the synthesis, a Pd-catalyzed substitution reaction via a directing group-mediated C(sp3)-H activation was effectively used to construct the 1,2,3-trisubstituted cyclopropane structure as a key step.

Pd-Catalyzed Substitution of the OH Group of Nonderivatized Allylic Alcohols by Phenols

Nonactivated phenols have been employed as nucleophiles in the allylation of nonderivatized allylic alcohols to generate allylated phenolic ethers with water as the only byproduct. A Pd[BiPhePhos] catalyst was found to be reactive to give the O-allylated phenols in good to excellent yields in the presence of molecular sieves. The reactions are chemoselective in which the kinetically favored O-allylated products are formed exclusively over the thermodynamically favored C-allylated products.

An Efficient Approach to Alkenyl Nitriles from Allyl Esters

A novel and efficient approach to alkenyl nitriles from allylesters has been developed. A tandem Pd-catalyzed substitution andthe subsequent oxidative rearrangement are involved in this transformation.The method provides an important supplement for the synthesis ofalkenyl nitriles from allyl esters.

ChemInform Abstract: Substrate-Leaving Group Control of the Enantioselectivity in the Palladium-Catalyzed Asymmetric Allylic Substitution of 4-Alkyl-1- vinylcyclohexyl Derivatives.

The strong influence of the nature of the leaving group in allylic derivatives in their enantioselective Pd-catalyzed substitution by nucleophile is reported. Analysis of the stereochemical course of the Pd-catalyzed substitution of achiral trans-4-tert-butyl-1-vinylcyclohexyl derivatives with nucleophiles indicates the enantioselective step to be oxidative addition of the allylic substrate onto the chiral Pd complex. The asymmetric induction may be understood as the reuslt of the selection by the chiral Pd catalyst between two reactive enantiomeric conformations of the allylic substrate and, hence, was shown to be strongly dependent upon reaction conditions and especially upon the nature of the substrate leaving group

ChemInform Abstract: Sequential Nitromethane Conjugate Addition/Elimination-Pd-Catalyzed Allylation of β-Trifloxy Acrylates. Application to Carbapenem Synthesis.

Sequential reactions of nitromethane via conjugate addition−elimination to β-trifloxy acrylates followed by Pd-catalyzed substitution of the resulting allyl nitro compounds with nucleophiles afforded homologation products at the β-position. 2-Naphthosultammethyl carbapenem, an anti-MRS carbapenem intermediate, was prepared in one pot from the corresponding 2-trifloxy compound. The scope and limitation of the one-pot method were investigated using several cyclic unsaturated esters and nucleophiles.

A novel synthesis of tocopheryl amines and amides

We report the synthesis of tocopheryl amines and amides from commercially available tocopherols. This synthesis improves the yield and diastereomeric purity of these biologically important compounds. The tocopheryl amines were prepared from the corresponding α- and δ-tocopherols using two distinct synthetic routes. The introduction of the C(6)-amino group can be achieved by aryl nitration/reduction or by Pd-catalyzed substitution of an aryl triflate, depending on the structure of the starting material. We also prepared the succinamide and maleamide derivatives of each amine. Tocopheryl amides are more potent pro-apoptotic anti-cancer agents than the corresponding α-tocopheryl esters. These compounds act selectively within the mitochondria of cancer cells.

A superior P-H phosphonite: asymmetric allylic substitutions with fenchol-based palladium catalysts.

The fenchol-based P-H phosphonite BIFOP-H exeeds with 65% ee other monodentate ligands in the Pd-catalyzed substitution of 1-phenyl-2-propenyl acetate with dimethylmalonate.

Divergence en Route to Nonclassical Annonaceous Acetogenins. Synthesis of Pyranicin and Pyragonicin

Syntheses of the nonclassical annonaceous acetogenins, pyranicin, and pyragonicin from common late-stage intermediates are presented. The construction of key elements relies on asymmetric HWE reactions, including the desymmetrization of a meso-dialdehyde and a parallel kinetic resolution of a racemic aldehyde. A stereoconvergent Pd-catalyzed substitution serves to install the C4 stereocenter in protected form with different orthogonal protective groups. A divergent strategy to form 1,4- and 1,6-diols, employing stereoselective Zn-mediated alkynylations, is used for completion of the core structures. Notably, the stereoselective coupling reaction toward pyragonicin proceeds with highly functionalized fragments. The methodology is further expanded by a divergent synthesis of all stereoisomers of the 2,3,6-trisubstituted tetrahydropyran subunit.

Pd‐Catalyzed Substitution Reactions with Organoindium Reagents in situ Generated from Indium and Allyl or Propargyl Halides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of 4′‐Methyl and 4′‐Cyano Carbocyclic 2′,3′‐Didehydro Nucleoside Analogues via 1,4‐Addition to Substituted Cyclopentenones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Pd-Catalyzed Substitution Reactions with Organoindium Reagents in situ Generated from Indium and Allyl or Propargyl Halides

Allylindium and propargylindium reagents in situ generated from the reactions of indium with allyl halides and propargyl halides could participate as nucleophiles in Pd-catalyzed substitution reactions of allyl carbonates to produce 1,5-dienes and 1,5-enynes in good yields. <TEX>$\beta$</TEX>-Hydride elimination products were produced in case of carbonates having <TEX>$\beta$</TEX>-hydrogens. Because organoindium reagents obtained from allyl or propargyl halides and indium have previously not been used to Pd-catalyzed allylic and propargylic substitution reactions, these results should provide more opportunities for the development of new C-C bond forming reactions.

Synthesis of 4‘-Methyl and 4‘-Cyano Carbocyclic 2‘,3‘-Didehydro Nucleoside Analogues via 1,4-Addition to Substituted Cyclopentenones

Carbocyclic 4'-methyl and 4'-cyano nucleoside analogues were synthesized using the Michael reaction to introduce the 4'-substituent and Pd-catalyzed allylic substitution to introduce the nucleoside base. Use of both the desired beta- and undesired alpha-1'-carbonate diastereomers in the Pd-catalyzed substitution was demonstrated in principle by epimerization of the alpha-diastereomer and kinetic diastereodifferentiation of a 1:1 alpha/beta mixture of 1'-carbonates.

Synthesis of Alkylated Aminofluorenes by Palladium‐Catalyzed Substitution at Halofluorenes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of alkylated aminofluorenes by palladium-catalyzed substitution at halofluorenes.

New N-substituted 2-amino-9,9-dialkylfluorenes optionally bearing electron-withdrawing substituents such as nitro or cyano in position 7 can be synthesized starting from 2-halo-9,9-dialkylfluorenes by Pd-catalyzed substitution with amines. Chiral amino groups can be introduced by this method too. 2-N,N-Dimethylamino-7-nitro-9H-fluorene was obtained in a convenient way by reductive amination. The N-substituted 2-amino-7-nitro-9H-fluorenes are promising candidates for fluorescence probes for femtosecond solvation dynamics.

Sequential Nitromethane Conjugate Addition/Elimination−Pd-Catalyzed Allylation of β-Trifloxy Acrylates. Application to Carbapenem Synthesis

Sequential reactions of nitromethane via conjugate addition−elimination to β-trifloxy acrylates followed by Pd-catalyzed substitution of the resulting allyl nitro compounds with nucleophiles afforded homologation products at the β-position. 2-Naphthosultammethyl carbapenem, an anti-MRS carbapenem intermediate, was prepared in one pot from the corresponding 2-trifloxy compound. The scope and limitation of the one-pot method were investigated using several cyclic unsaturated esters and nucleophiles.

A Bimetallic Palladium Catalyst for Asymmetric Allylic Substitution Reactions

With 1,1‘-diacetylruthenocene (9) as starting material, the preparation of 1,1‘-bis[1-(1-{(R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyl})-1H-pyrazol-3-yl]ruthenocene ((R,R)-(S,S)-12) is attained in three steps. 12 coordinates to two independent Pd(II)−π-allyl units to form the dicationic complex 15, isolated as a bis(hexafluorophosphate) salt. This has been characterized by X-ray and 2D NMR methods in solution, along with the analogous derivative 14, which contains 1-{(R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyl}-3-ruthenocenyl-1H-pyrazole ((R)-(S)-8b). The three Pd(II)−allyl fragments in these two complexes show very similar conformational features. In the Pd-catalyzed substitution reaction of ethyl (1,3-diphenylallyl)carbonate (1) with benzylamine, the bimetallic catalyst containing ligand 12 and the mononuclear catalyst formed by 8b afford the same high enantioselectivity (99.3%).

A remarkable anion effect on the enantioselectivity of the Pd-catalyzed allylic amination using ferrocenyl ligands

The effect of several anions on the enantioselectivity of the Pd-catalyzed substitution reaction of 1,3-diphenylprop-2-enylethyl carbonate 1 with benzylamine, utilizing chiral ferrocenyl ligands such as 1-[( R)-1-[( S)-2-(diphenylphosphino)-ferrocenyl]ethyl]-3-(1-adamantyl)-1 H-pyrazole 3a, was investigated. Small hard anions such as F − and BH 4 −, added in co-catalytic amounts to the catalyst, were found to enhance the ee to >99.5%. On the other hand, non-coordinating anions, e.g. PF 6 −, had a detrimental effect on the enantioselectivity (<10% ee). The beneficial effect of fluoride is discussed in terms of its establishing Curtin-Hammett conditions, by virtue of its coordination to Pd.

Substrate leaving group control of the enantioselectivity in the palladium-catalyzed asymmetric allylic substitution of 4-alkyl-1-vinylcyclohexyl derivatives

The strong influence of the nature of the leaving group in allylic derivatives in their enantioselective Pd-catalyzed substitution by nucleophile is reported. Analysis of the stereochemical course of the Pd-catalyzed substitution of achiral trans-4-tert-butyl-1-vinylcyclohexyl derivatives with nucleophiles indicates the enantioselective step to be oxidative addition of the allylic substrate onto the chiral Pd complex. The asymmetric induction may be understood as the reuslt of the selection by the chiral Pd catalyst between two reactive enantiomeric conformations of the allylic substrate and, hence, was shown to be strongly dependent upon reaction conditions and especially upon the nature of the substrate leaving group