Organozinc Additions Research Articles

Enantioselective Organozinc Addition to Aldehydes Using Planar Chiral [2.2]Paracyclophane-Imidazoline N,O-ligands.

We present an improved and convenient synthesis of [2.2]paracyclophane-imidazoline N,O-ligands with central and planar chirality in seven steps starting from [2.2]paracyclophane. The utility of these ligands in organozinc additions to aldehydes is described. The asymmetric ethylation of aldehydes proceeded with enantioselectivities of up to 97% ee, while the asymmetric arylation of aldehydes gave up to 95% ee (R) and 82% ee (S) using (S,S,SP)-UCD-Imphanol and (S,S,RP)-UCD-Imphanol, respectively.

Difluorocarbene Enables Modular Synthesis of Difluoroalkylated Bicyclopentanes

A straightforward method for the synthesis of difluoroalkylated bicyclopentanes (BCPs) from [1.1.1]propellane (TCP) through a stepwise procedure has been developed. This process involves nucleophilic addition of organozinc or ArMgBr rea‐gents to TCP, followed by reaction with difluorocarbene to generate BCP substituted difluoroalkylzinc species, which subsequently couple with electrophiles, including allyl/propargyl bromides, (hetero)aryl disulfides, and proton, to provide a wide range of difluoroalkylated BCPs that otherwise are difficult to access through conventional methods. The transformations of the resulting products demonstrate the synthetic utility of this modular synthesis.

Preparation and Asymmetric Induction Evaluation of the First Ephedrine-Based Ligands Immobilized on Magnetic Nanoparticles.

Herein, the synthesis and catalytic activity of two ephedrine-based catalysts and two ephedrine-based magnetic nanoparticle-supported catalysts are reported. All catalysts developed were tested in the addition of diethylzinc to aromatic aldehydes and in the Henry reaction. The homogeneous catalysts showed moderate catalytic activity in the organozinc addition and good activity in the Henry reaction, whereas in the case of the nanocatalyst, it was not effective in the addition of diethylzinc to aldehydes and gave reasonable results in the Henry reaction. Moreover, the nanocatalyst remained unchanged over the course of up to three catalytic cycles. To the best of our knowledge, the proposed system is the first recyclable ephedrine-based magnetic nanocatalyst employed in an enantioselective reaction.

Alkylation of Electron‐Deficient Olefins through Conjugate Addition of Organozinc Reagents: An Update

AbstractThis review focuses on the applications of organozinc reagents in conjugate addition reactions. Organozinc compounds are a class of organometallic reagent used in various reactions such as addition, substitution, and coupling reactions. The conjugate addition or 1, 4‐addition is one of the most useful bond forming strategies used in organic synthesis since broad range of nucleophiles can be employed in the reaction. Addition of organozinc to electron‐deficient olefins attracts synthetic chemists as it preferably undergoes conjugate addition over 1,2‐addition unlike other organometallic reagents, such as Grignard reagent or organolithium. Many natural products were also synthesized by applying the conjugate addition reaction of organozinc. Moreover, organozinc reagents have superior functional group compatibility and can be easily prepared relative to other organometallic compounds. Consequently, conjugate additions of organozinc reagents were highly studied and having a review on it is very important at present. Though a few reviews are available, they either do not focus directly on the organozinc reagents or not on the conjugate addition. We hope that this review article will be of great use to organic researchers.

Observation of hyperpositive non‐linear effect in catalytic asymmetric organozinc additions to aldehydes

Asymmetric amplification is a phenomenon that is believed to play a key role in the emergence of homochirality in life. In asymmetric catalysis, theoretical and experimental models have been investigated to provide an understanding of how chiral amplification is possible, in particular based on non-linear effects. Interestingly, it has been proposed a quarter century ago that chiral catalysts, when not enantiopure might even be more enantioselective than their enantiopure counterparts. We show here that such hyperpositive non-linear effect in asymmetric catalysis is indeed possible. An in-depth study into the underlying mechanism was carried out, and the scheme we derive differs from the previous proposed models.

Unified Synthesis of 1,2-Oxy-aminoarenes via a Bio-inspired Phenol-Amine Coupling

Summary 1,2-Aminophenols and their related nitrogen-containing heterocycles are ubiquitous in medicine, agriculture, and materials science. Here, we describe a bio-inspired and unified approach for their synthesis through a direct, catalytic aerobic coupling of phenols and amines. Key to the formation of the aromatic C–N bond is a facile condensation between the amine and an ortho -quinone, which triggers redox isomerization to an ortho -iminophenol before a series of downstream events. We discuss the factors that govern regioselectivity during aerobic ortho -oxygenation of the phenol and condensation of the amine, and we demonstrate synthetic utility by preparing a structurally diverse family of immunosuppressive heterocycles and the indole alkaloid cephalandole A. Our conditions involve a wide range of simple, un-activated substrates, occur at room temperature with an earth-abundant copper-catalyst and a commercially available diamine ligand, and produce water as the only stoichiometric by-product.

The Cu-catalyzed asymmetric conjugate addition with chiral diphosphite ligands derived from D-(-)-tartaric acid

ABSTRACTA series of diphosphite ligands, which were derived from D-(-)-tartaric acid, have been synthesized and successfully applied in the Cu-catalyzed asymmetric conjugate addition of organozincs to enones. There was a synergic effect between the stereogenic centers of the D-(-)-tartaric acid skeleton and the axially H8-binaphthyl moieties of ligand 2c. And ligand 2c shows a comparative catalytic performance to ligand 1-N-benzylpyrrolidine-3,4-bis[(S)-1,1′-H8-binaphthyl-2,2′-diyl]phosphite-L-tartaric acid1d derived from L-(+)-tartaric acid. Therefore, for cyclic enones, both enantiomers of the addition products can be obtained in high enantioselectivity (ees up to 96%) by simply selecting ligands 1d or 2c derived from D-(-)-tartaric acid or L-(+)-tartaric acid. Moreover, the sense of enantiodiscrimination of the products was mainly determined by the configuration of the binaphthyl phosphite moieties.

Synthesis of novel cyclohexanediol-derived chiral phosphite ligands and their application in the Cu-catalyzed conjugate addition of organozinc to cyclic enones

Abstract A series of novel chiral diphosphite ligands have been synthesized from (1 R ,2 R )- trans -1,2-cyclohexanediol, (1 S ,2 S )- trans -1,2-cyclohexanediol, racemic trans -1,2-cyclohexanediol and chlorophosphoric acid diary ester, and were successfully employed in the Cu-catalyzed asymmetric 1,4-conjugate addition of diethylzinc to cyclohexenone with up to 99% ee . It was found that ligand 1,2-bis[( R )-1,1′-binaphthyl-2,2′-diyl]phosphitecyclohexanediol 6a derived from racemic diol skeleton can show similar catalytic performance compared with ligand (1 R ,2 R )-bis[( R )-1,1′-binaphthyl-2,2′-diyl]phosphitecyclohexanediol 6a′ derived from enantiopure starting material. A significant dependence of stereoselectivity on the type of enone and the ring size of the cyclic enone was observed. Moreover, the configuration of the products was mainly determined by the configuration of the binaphthyl moieties of diphosphite ligands in the 1,4-addition of cyclic enones.

ChemInform Abstract: Asymmetric Functional Organozinc Additions to Aldehydes Catalyzed by 1,1′‐Bi‐2‐naphthols (BINOLs)

AbstractReview: 66 refs.

Asymmetric functional organozinc additions to aldehydes catalyzed by 1,1'-bi-2-naphthols (BINOLs).

ConspectusChiral alcohols are ubiquitous in organic structures. One efficient method to generate chiral alcohols is the catalytic asymmetric addition of a carbon nucleophile to a carbonyl compound since this process produces a C–C bond and a chiral center simultaneously. In comparison with the carbon nucleophiles such as an organolithium or a Grignard reagent, an organozinc reagent possesses the advantages of functional group tolerance and more mild reaction conditions. Catalytic asymmetric reactions of aldehydes with arylzincs, vinylzincs, and alkynylzincs to generate functional chiral alcohols are discussed in this Account.Our laboratory has developed a series of 1,1′-bi-2-naphthol (BINOL)-based chiral catalysts for the asymmetric organozinc addition to aldehydes. It is found that the 3,3′-dianisyl-substituted BINOLs are not only highly enantioselective for the alkylzinc addition to aldehydes, but also highly enantioselective for the diphenylzinc addition to aldehydes. A one-step synthesis has been achieved to incorporate Lewis basic amine groups into the 3,3′-positions of the partially hydrogenated H8BINOL. These H8BINOL–amine compounds have become more generally enantioselective and efficient catalysts for the diphenylzinc addition to aldehydes to produce various types of chiral benzylic alcohols. The application of the H8BINOL–amine catalysts is expanded by using in situ generated diarylzinc reagents from the reaction of aryl iodides with ZnEt2, which still gives high enantioselectivity and good catalytic activity. Such a H8BINOL–amine compound is further found to catalyze the highly enantioselective addition of vinylzincs, in situ generated from the treatment of vinyl iodides with ZnEt2, to aldehydes to give the synthetically very useful chiral allylic alcohols.We have discovered that the unfunctionalized BINOL in combination with ZnEt2 and Ti(OiPr)4 can catalyze the terminal alkyne addition to aldehydes to produce chiral propargylic alcohols of high synthetic utility. The reaction was conducted by first heating an alkyne with ZnEt2 in refluxing toluene to generate an alkynylzinc reagent, which can then add to a broad range of aldehydes at room temperature in the presence of BINOL and Ti(OiPr)4 with high enantioselectivity. It was then found that the addition of a catalytic amount of dicyclohexylamine (Cy2NH) allows the entire process to be conducted at room temperature without the need to generate the alkynylzincs at elevated temperature. This BINOL–ZnEt2–Ti(OiPr)4–Cy2NH catalyst system can be used to catalyze the reaction of structurally diverse alkynes with a broad range of aldehydes at room temperature with high enantioselectivity and good catalytic activity.The work described in this Account demonstrates that BINOL and its derivatives can be used to develop highly enantioselective catalysts for the asymmetric organozinc addition to aldehydes. These processes have allowed the efficient synthesis of many functional chiral alcohols that are useful in organic synthesis.

Design of novel chiral N,N,O-tridentate phenanthroline ligands and their application to enantioselective addition of organozinc reagents to aldehydes.

The novel N,N,O-tridentate phenanthroline ligand (BinThro) bearing an axially chiral binaphthyl backbone prepared from BINOL was found to be an effective chiral catalyst for enantioselective addition of diethylzinc to aromatic aldehydes with high enantioselectivity (up to 95% ee).

Chiral phosphite ligands derived from l-(+)-tartaric acid: synthesis and application in the Cu-catalyzed 1,4-conjugate addition of organozincs to cyclic enones

A new series of chiral phosphite ligands derived from readily available l-(+)-tartaric acid and binaphthol derivatives were designed and prepared in convenient synthetic routes. These ligands were successfully employed in the Cu-catalyzed asymmetric conjugate addition of organozincs to cyclic enones. The ligands bearing (R)- and (S)-binaphthol and/or 3,3′-bis(trimethylsilyl)-2,2′-dihydroxy-1,1′-binaphthol afforded both enantiomers of the product in high yields and good enantioselectivities (up to 95% ee). The chiral organocopper reagent did exhibit high enantioselectivities for cyclic enones bearing different ring sizes. The stereochemically matched combination of l-(+)-tartaric acid backbone and (R)-binaphthyl in ligand 1-N-benzylpyrrolidine-3,4-bis[(R)-1,1′-binaphthyl-2,2′-diyl]phosphite-l-tartaric acid was essential to afford 95% (R) ee for 3-ethylcyclopentanone, 95% ee (S) for 3-ethyl-cyclohexanone, and 63% ee (R) for 3-ethylcycloheptanone in ether as solvent, using (CuOTf)2·C6H6 as a catalytic precursor. Moreover, the sense of the enantio discrimination of the products was mainly determined by the configuration of the binaphthyl phosphite moieties.

New C-Glycosylated α-Amino Acid Synthesis by Addition Reaction of an Amino Acid Organozinc Reagent on Carbohydrate-Derived Aldehydes

Two unreported C-glycosylated amino acid structures could be prepared by addition of an amino acid organozinc on carbohydrates bearing an aldehyde function. For this purpose, a new iodinated amino acid bearing a four-carbon side chain was conveniently prepared in two steps. Conversion into the corresponding organozinc reagent was optimal in acetonitrile using zinc/copper activated with 1,2-dibromoethane and trimethylsilyl chloride. A protocol was developed for the addition of this organozinc compound to simple aldehydes in acetonitrile using BF3 · OEt2 as a Lewis acid. When applied to riboside and glucoside aldehyde derivatives, this protocol led to new C-glycosylated amino acids in acceptable yields.

Ephedrine-based diselenide: a promiscuous catalyst suitable to mimic the enzyme glutathione peroxidase (GPx) and to promote enantioselective C–C coupling reactions

The ephedrine-based diselenide appears as a new promiscuous catalyst, able to generate optically active alcohols by addition of organozinc to aldehydes (up to 97% ee), and shows powerful GPx like activity, reducing H(2)O(2) to water in only 16.33 min (eleven times faster than PhSeSePh).

ChemInform Abstract: Synthesis of Novel Diphosphite Ligands Derived from D‐Mannitol and Their Application in Cu‐Catalyzed Enantioselective Conjugate Addition of Organozinc to Enones.

AbstractUnder optimized conditions, high enantioselectivities for cyclic enones but only low enantioselectivities for acyclic enones are obtained.

Synthesis of novel diphosphite ligands derived from d-mannitol and their application in Cu-catalyzed enantioselective conjugate addition of organozinc to enones

A series of novel chiral diphosphite ligands have been synthesized from d-mannitol derivatives and chlorophosphoric acid diary ester, and were successfully employed in the copper catalyzed enantioselective conjugate addition of organozinc reagents diethylzinc and dimethylzinc to cyclic and acyclic enones. The stereochemically matched combination of d-mannitol and (R)-H8-binaphthyl in ligand 1,2:5,6-di-O-isopropylidene-3,4-bis[(R)-1,1′-H8-binaphthyl-2,2′-diyl] phosphite-d-mannitol was essential to afford 93% ee for 3-ethylcyclohexanone, 92% ee for 3-ethylcyclopentanone, and 90% ee for 3-ethylcycloheptanone in toluene, using Cu(OTf)2 as a catalytic precursor. The results clearly indicated that the chiral organocopper reagent exhibited high enantioselectivies for cyclic enones bearing different ring sizes. As for the backbone of this type of ligand, it has been demonstrated that 1,2:5,6-di-O-isopropylidene-d-mannitol was more efficient than 1,2:5,6-di-O-cyclohexylidene-d-mannitol. The sense of the enantiodiscrimination was mainly determined by the configuration of the diaryl phosphite moieties in the 1,4-addition of cyclic enones.

ChemInform Abstract: Enantioselective Addition of Organozinc to Aldehydes and Ketones Catalyzed by Immobilized Chiral Ligands

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Application of Enantiopure 1‐(Aminoalkyl)naphthols and 2‐(Aminoalkyl)phenols in the Enantioselective Addition of Organozinc to α,β‐Unsaturated Carbonyl Compounds.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Enantioselective synthesis of quaternary stereogenic centers through catalytic asymmetric addition of dimethylzinc to α-ketoesters with chiral cis-cyclopropane-based amide alcohol as ligand

A new amino alcohol with a chiral cyclopropane backbone has been developed and used in the catalytic asymmetric diethylzinc addition to various types of α-ketoesters. This cyclopropane-based chiral amino alcohol shows moderate enantioselectivity in the addition of organozinc to α-ketoesters. For dimethylzinc addition to α-ketoesters, up to 81% ee are obtained, respectively.

Application of Enantiopure 1-(Aminoalkyl)naphthols and 2-(Aminoalkyl)phenols in the Enantioselective Addition of Organozinc to α,β-Unsaturated Carbonyl Compounds

Several enantiopure 1-(aminoalkyl)naphthols and a 2-(aminoalkyl)phenol were tested as ligands in the Nickel-catalyzed enantioselective addition of organozinc to chalcones.