Alkynylzinc Reagents Research Articles

Synthesis of 1,4-enynes via nickel-catalyzed cross-coupling of allylic alcohols with alkynylzinc reagents.

Synthesis of 1,4-enynes was performed via nickel-catalyzed cross-coupling of allylic alcohols with alkynylzinc reagents. The reaction features high regio- and E/Z-selectivity when aryl-substituted allylic alcohols were employed. The method also exhibits a wide scope of substrates and good compatibility of functional groups.

Direct Propargylation of ortho-Quinone Methides with Alkynyl Zinc Reagents: An Application to the One-Pot Synthesis of 2,3-Disubstituted Benzofurans

A transition-metal-free propargylation of ortho-quinone methides (o-QMs) with alkynyl zinc reagents was achieved. A conjugate alkynylation of an o-QM and subsequent cyclization sequence in the presence of KOt-Bu for the synthesis of 2,3-disubstituted benzofurans in one pot was developed. This efficient strategy exhibits good functional-group compatibility and gives moderate to good yields. The present reaction might serve as an attractive method for the synthesis of polysubstituted benzofurans.

In Situ Generation of Alkynylzinc and Its Subsequent Negishi Reaction in a Flow Reactor

A highly efficient and convenient Negishi cross‐coupling reaction has been developed for the synthesis of unsymmetrical alkynes and enynes in a continuous‐flow process. The reaction proceeds through an in situ generated alkynylzinc reagent by the reaction of lithium acetylide with zinc halide at room temperature followed by a cross‐coupling reaction with aryl or vinyl iodides. The notable features of this work compared to the conventional benchtop method are mild reaction conditions, good to excellent yields, broad functional‐group compatibility, short residence time (73 sec) and especially desilylation of TMS group with the residence time of only 10.5 sec.

Activation of Alkynylzinc Reagents by a Hemiaminal‐Driven Catalytic Microenvironment

1,2‐Aziridinyl propargylic amines have been obtained through a zinc‐catalyzed multicomponent reaction. This process relies on the dimeric amino aldehyde assembly orchestrating the intramolecular 1,2‐alkyne addition to an iminium ion. The resulting products can be readily elaborated through regioselective aziridine ring opening. A catalytic cycle and stereochemical rationale for the highly anti‐selective alkyne addition is proposed.

Application of Ru(II)-Catalyzed Enyne Cyclization in the Synthesis of Brefeldin A.

The approach to brefeldin A described herein hinges on Ru(II)-catalyzed cycloisomerization of an enyne obtained by the reaction of an alkynylzinc reagent with an α-chloro sulfide. Other key steps include Mislow-Evans rearrangement, cross-metathesis, and macrocyclization using a Roush-Masamune protocol.

Single electron transfer-induced coupling of alkynylzinc reagents with aryl and alkenyl iodides.

Alkynylzinc reagents were found to undergo coupling with aryl and alkenyl iodides to give arylalkynes and alkenylalkynes without the aid of transition metals. The coupling reaction proceeds through a single electron transfer mechanism, where a substoichiometric amount of a phosphine works as an indispensable activator.

Ligand‐Free Copper‐Catalyzed Negishi Coupling of Alkyl‐, Aryl‐, and Alkynylzinc Reagents with Heteroaryl Iodides

AbstractReported herein is an unprecedented ligand‐free copper‐catalyzed cross‐coupling of alkyl‐, aryl‐, and alkynylzinc reagents with heteroaryl iodides. The reaction proceeds at room temperature for the coupling of primary, secondary, and tertiary alkylzinc reagents with heteroaryl iodides without rearrangement. An elevated temperature (100 °C) is required for aryl–heteroaryl and alkynyl–heteroaryl couplings.

Ligand‐Free Copper‐Catalyzed Negishi Coupling of Alkyl‐, Aryl‐, and Alkynylzinc Reagents with Heteroaryl Iodides

Reported herein is an unprecedented ligand-free copper-catalyzed cross-coupling of alkyl-, aryl-, and alkynylzinc reagents with heteroaryl iodides. The reaction proceeds at room temperature for the coupling of primary, secondary, and tertiary alkylzinc reagents with heteroaryl iodides without rearrangement. An elevated temperature (100 °C) is required for aryl-heteroaryl and alkynyl-heteroaryl couplings.

ChemInform Abstract: The Total Syntheses of Basiliolide C, epi‐Basiliolide C, and Protecting‐Group‐Free Total Syntheses of Transtaganolides C and D.

The total syntheses of basiliolide C and previously unreported epi-basiliolide C are achieved by an Ireland–Claisen/Diels–Alder cascade. The development of a palladium catalyzed cross-coupling of methoxy alkynyl zinc reagents allows for the protecting-group-free syntheses of transtaganolides C and D. Syntheses of transtaganolides C and D are accomplished in a single operation to generate three rings, two all-carbon quaternary centers, and four tertiary stereocenters from a monocyclic, achiral precursor.

Total synthesis of each enantiomer of falcarinol and panaxjapyne A via asymmetric catalytic alkynylation of an aldehyde

A concise and highly enantioselective (>99% ee) synthesis of falcarinol and panaxjapyne A and their enantiomers has been accomplished. The key steps involve the asymmetric addition of alkynylzinc reagent to acrolein and propionaldehyde catalyzed by a BINOL–Ti(OiPr)4 complex and a classic Cadiot–Chodkiewicz cross-coupling reaction. The chiral polyacetylenic alcohols synthesized herein have potential utility in the development of antitumor drugs and antidiabetic agents.

ChemInform Abstract: Zinc Mediated Activation of Terminal Alkynes: Stereoselective Synthesis of Alkynyl Glycosides.

AbstractA series of glycosyl donors such as glycals (I) and anomeric acetals (IV) are tested towards an alkynyl zinc reagent obtained from alkynes (II), zinc dust, and ethyl bromoacetate.

The total syntheses of basiliolide C, epi-basiliolide C, and protecting-group-free total syntheses of transtaganolides C and D.

The total syntheses of basiliolide C and previously unreported epi-basiliolide C are achieved by an Ireland-Claisen/Diels-Alder cascade. The development of a palladium catalyzed cross-coupling of methoxy alkynyl zinc reagents allows for the protecting-group-free syntheses of transtaganolides C and D. Syntheses of transtaganolides C and D are accomplished in a single operation to generate three rings, two all-carbon quaternary centers, and four tertiary stereocenters from a monocyclic, achiral precursor.

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.

Zinc mediated activation of terminal alkynes: stereoselective synthesis of alkynyl glycosides.

Zinc mediated alkynylation reaction was studied for the preparation of C-glycosides from unactivated alkynes. Different glycosyl donors such as glycals and anomeric acetates were tested towards an alkynyl zinc reagent obtained from alkynes using zinc dust and ethyl bromoacetate as an additive. The method provides simple, mild and stereoselective access to alkynyl glycosides both from aromatic and aliphatic acetylenes.

Inside Cover: Construction of Optically Active Quaternary Propargyl Amines by Highly Enantioselective Zinc/BINOL-Catalyzed Alkynylation of Ketoimines (Chem. Eur. J. 36/2013)

Chinese mythology was used to describe the challenges involved in the catalytic enantioselective alkynylation of ketoimines. The arrow shows the alkynylzinc reagent generated from alkyne and Me2Zn; BINOL, an accelerator for the reaction, is the bow. The substrates ketoimines are the suns. The three suns shot down in the sea are the three types of products, chiral quaternary propargyl amines. For more details, see the Full Paper by X. Zhang et al. on page 11992 ff.

Asymmetric Alkyne Addition to Aldehydes Catalyzed by BINOL and Its Derivatives

This Account describes our research over the past decade in theasymmetric alkyne addition to aldehydes to generate optically activepropargylic alcohols. Our methods employ a dialkylzinc reagent toreact with a terminal alkyne to form an alkynylzinc nucleophile,and can be grouped into the BINOL-catalyzed reactions and the functionalizedBINOL catalyzed reactions. We first describe the development ofthe BINOL-ZnEt 2 -Ti(O I-Pr) 4 catalystsystem, and its modification through the use of Lewis base additivesto form the alkynylzinc at room temperature. The substrate scopecompatible with these methods and the enantioselectivities achievedare discussed. We then describe the functionalized BINOL and H 8 BINOL catalystsystems, which can be further divided into classes based on themanner in which the BINOL framework has been modified. Generally,these functionalized BINOL and H 8 BINOL derivatives containinternal Lewis basic sites which can both promote the formationof the nucleophilic alkynylzinc reagents at reduced temperatureand modify the catalytic properties of the chiral biaryl unit. In afew cases, these catalysts also show good efficiency even without theuse of the Ti(IV) reagent. The catalytic methods in this Account havedemonstrated that a wide range of alkyne and aldehyde substratescan be subjected to the asymmetric addition reactions to generatestructurally diverse chiral propargylic alcohols with high enantioselectivity.Some of these methods have exhibited high practicality in synthesis. 1 Introduction 2 BINOL-Based Catalytic Systems 2.1 Catalysis by BINOL-ZnEt 2 -Ti(O I-Pr) 4 2.2 Catalysis by BINOL-ZnEt 2 -Ti(O I-Pr) 4 -HMPA 2.3 Catalysis by BINOL-ZnEt 2 -Ti(O I-Pr) 4 -NMI 2.4 Catalysis by BINOL-ZnEt 2 -Ti(O I-Pr) 4 -Cy 2 NH 3 Functionalized BINOL-Based Catalytic Systems 3.1 Catalysis by 3,3′-Dianisyl-BINOLs and -H 8 BINOLs 3.2 Catalysis by 3,3′-Bis(diphenylmethoxy)methyl Substituted BINOLs 3.3 Catalysis by Acyclic and Macrocyclic Binaphthyl Salens 3.4 Catalysis by 3,3′-Bismorpholinomethyl H 8 BINOL 3.5 Catalysis by C 1 -SymmetricBINOL-Terpyridine 4 Summary

Facile access to sterically hindered aryl ketones via carbonylative cross-coupling: application to the total synthesis of luteolin

A general and mild protocol for achieving the carbonylative cross-coupling of sterically hindered, ortho-disubstituted aryl ketones is reported. The commercially available PEPPSI-IPr catalyst is shown to efficiently promote the carbonylative cross-coupling of hindered ortho-disubstituted aryl iodides to give diaryl ketones; traditional phosphine catalysts are less effective. Carbonylative Suzuki-Miyaura cross-couplings provide a diverse array of biaryl ketones in good to excellent yields. The same catalyst is also shown to catalyze a carbonylative Negishi cross-coupling reaction, utilizing a variety of alkynyl-zinc reagents to give the corresponding alkynyl aryl ketones. Application of this new methodology to the synthesis of the natural product luteolin is reported.

ChemInform Abstract: Recent Progress in a Chiral Multinucleating System Utilizing Tartaric Acid Esters

AbstractReview: 125 refs.

Asymmetric Alkynylation of Nitroalkenes

The authors report on the rhodium-catalyzed alkynylation of nitroalkenes. Previously, alkynylzinc reagents were reported to undergo conjugate addition to nitroalkenes in the presence of a stoichiometric amount of a chiral amino alcohol (M. Yamashita, K. Yamada, K. Tomioka Org. Lett. 2005, 7, 2369). Thus, this report represents a significant improvement in terms of atom economy and provides an efficient route to chiral homo­propargyl amines.

Formal Total Synthesis of Fostriecin by 1,4‐Asymmetric Induction with an Alkyne–Cobalt Complex

The synthesis of a protected dephosphofostriecin, and thereby a formal synthesis of fostriecin, has been accomplished. The synthetic challenges were the construction of four stereogenic centers and the conformationally labile cis-cis-trans-triene moiety. Previous total syntheses have employed at least two asymmetric reactions that required the use of an external chiral auxiliary. Although remote stereoinduction in a 1,4-relationship is considered difficult, we have developed a notable 1,4-asymmetric induction that utilizes an alkyne-cobalt complex for the control of C5 stereochemistry by the C8 stereogenic center. The stereochemistry at C11 was established by 1,3-asymmetric induction with a higher-order alkynyl-zinc reagent. Thus, only one asymmetric reaction requiring an external chiral auxiliary was employed in this route. The labile cis-cis-trans-triene unit was constructed at a late stage of the synthesis by diastereoselective coupling of a dienyne and an aldehyde unit, followed by reduction.