Homoallylic Alcohols Research Articles

Regio- and Stereoselective Synthesis of Multi-Alkylated Allylic Boronates through Three-Component Coupling Reactions between Allenes, Alkyl Halides, and a Diboron Reagent.

Multisubstituted allylic boronates are attractive and valuable precursors for the rapid and stereoselective construction of densely substituted carbon skeletons. Herein, we report the first synthetic approach for differentially 2,3,3-trialkyl-substituted allylic boronates that contain a stereodefined tetrasubstituted alkene structure. Copper(I)-catalyzed regio- and stereoselective three-component coupling reactions between gem-dialkylallenes, alkyl halides, and a diboron reagent afforded sterically congested allylic boronates. The allylboration of aldehydes diastereoselectively furnished the corresponding homoallylic alcohols that bear a quaternary carbon. A computational study revealed that the selectivity-determining mechanism was correlated to the coordination of a boryl copper(I) species to the allene substrate as well as the borylcupration step.

Cobalt-Catalyzed Diastereo- and Enantioselective Reductive Allyl Additions to Aldehydes with Allylic Alcohol Derivatives via Allyl Radical Intermediates.

Catalytic generation of ambiphilic π-allyl-metal complexes and their utility in enantioselective transformations constitutes a powerful approach for introduction of allyl groups to a molecule. Herein an unprecedented cobalt-catalyzed highly site-, diastereo-, and enantioselective protocol for stereoselective formation of nucleophilic allyl-Co(II) complexes followed by addition to aldehydes is presented. The reaction features diastereo- and enantioconvergent conversion of easily accessible allylic alcohol derivatives to diversified enantioenriched homoallylic alcohols with a remarkably broad scope of allyl groups that can be introduced. Mechanistic studies indicated that allyl radical intermediates were involved in this process. These new discoveries establish a new strategy for development of enantioselective transformations through capture of radicals by chiral Co complexes, pushing forward the frontier of Co complexes for enantioselective catalysis.

Copper-Catalyzed Highly Enantioselective 1,4-Protoboration of Terminal 1,3-Dienes

Copper-Catalyzed Highly Enantioselective 1,4-Protoboration of Terminal 1,3-Dienes

Copper-Catalyzed Ring-Opening/Borylation of Cyclopropenes

Copper-Catalyzed Ring-Opening/Borylation of Cyclopropenes

NbCl5-Mg Reagent System in Regio- and Stereoselective Synthesis of (2Z)-Alkenylamines and (3Z)-Alkenylols from Substituted 2-Alkynylamines and 3-Alkynylols.

The reduction of N,N-disubstituted 2-alkynylamines and substituted 3-alkynylols using the NbCl5–Mg reagent system affords the corresponding dideuterated (2Z)-alkenylamine and (3Z)-alkenylol derivatives in high yields in a regio- and stereoselective manner through the deuterolysis (or hydrolysis). The reaction of substituted propargylamines and homopropargylic alcohols with the in situ generated low-valent niobium complex (based on the reaction of NbCl5 with magnesium metal) is an efficient tool for the synthesis of allylamines and homoallylic alcohols bearing a 1,2-disubstituted double bond. It was found that the well-known approach for the reduction of alkynes based on the use of the TaCl5-Mg reagent system does not work for 2-alkynylamines and 3-alkynylols. Thus, this article reveals a difference in the behavior of two reagent systems—NbCl5-Mg and TaCl5-Mg, in relation to oxygen- and nitrogen-containing alkynes. A regio- and stereoselective method was developed for the synthesis of nitrogen-containing E-β-chlorovinyl sulfides based on the reaction of 2-alkynylamines with three equivalents of methanesulfonyl chloride in the presence of stoichiometric amounts of niobium(V) chloride and magnesium metal in toluene.

Brown Allylation: Application to the Synthesis of Natural Products

AbstractAsymmetric allylation represents an important reaction applied in the natural product synthesis. The stereoselective introduction of an allyl group allows to obtain versatile chiral building blocks, which may further undergo various transformations due to the presence of the carbon–carbon double bond. In this review, we address the Brown allylation, which involves the conversion of aldehydes into homoallylic alcohols using B‐allyldiisopinocampheylborane as a chiral reagent. We provide a comprehensive overview of the reaction and highlight its application in the synthesis of natural products, while assessing its performance in comparison to other approaches. The total of 17 syntheses have been described, including the synthesis of biologically active macrolides disciformycin B, biselyngbyolide B, peloruside A, and gliomasolide A, bis‐piperidine alkaloid (−)‐anaferine and dysoxylactam A.

Palladium‐Catalyzed Diastereoselective Synthesis of (Z)‐Conjugated Enynyl Homoallylic Alcohols

AbstractThe diastereoselective synthesis of anti‐homoallylic alcohols bearing conjugated (Z)‐enynes through a palladium‐catalyzed three‐component reaction is described. This reaction features a broad substrate scope, good functional group compatibility, and high levels of (Z)‐alkene stereocontrol. In this reaction, Pd(0) functions as a catalyst in two fundamental steps of the tandem sequence: 1) the generation of a borylated π‐allylpalladium species from bifunctional conjunctive reagents, inducing umpolung allylation of aldehydes, and 2) C(sp2)−C(sp) cross‐coupling. Further transformations of the obtained products highlight their synthetic utility.magnified image

A Computational Mechanistic Study of Cp*Co(III)-Catalyzed Three-Component C-H Bond Addition to Terpenes and Formaldehydes: Insights into the Origins of Regioselectivity.

Transition metal-catalyzed three-component reactions of arenes, dienes, and carbonyls enable the convergent synthesis of homoallylic alcohols. Controlling regioselectivity is a central challenge for the difunctionalization of substituted 1,3-dienes in which multiple unbiased C═C bonds exist. Here, the mechanisms of Cp*Co(III)-catalyzed three-component C-H bond addition to terpenes and formaldehydes were investigated by density functional theory calculations. The reaction proceeds via sequential C(sp2)-H activation, migratory insertion, β-hydride elimination, hydride reinsertion, and C-C bond formation to yield the final product. The migratory insertion is the rate- and regioselectivity-determining step of the overall reaction. We employed an energy decomposition approach to quantitatively dissect the contributions of different types of interactions to regioselectivity. For the 2-alkyl substituted 1,3-dienes, the orbital interactions in the 3,4-insertion are intrinsically more favorable as compared to that in the 4,3-insertion, while the stronger steric effects between metallacycle and 1,3-diene override the intrinsic electronic preference. However, the steric effects failed to rationalize the unfavorable 1,2-insertion that is analogous to 4,3-insertion and even bears smaller steric effects. The donor-acceptor interaction analysis indicates that orbital interactions between σCo-C and πC═C decreased significantly in the 1,2-insertion transition state, which leads to higher activation energy barriers. These insights into the dominant effects controlling regioselectivity will enable rational design of new catalysts for selective functionalization of dienes.

ZnBr2Mediated C−N Bond Formation using Cinnamyl Alcohol and 2‐Amino Pyridines

AbstractA simple method for C−N bond formation is disclosed by using cinnamyl alcohols and 2‐amino pyridine derivatives in the presence of stoichiometric amount of zinc bromide. This reaction works with a wide range of substrates, and is compatible with primary, secondary, and homoallylic alcohols. To the best of our knowledge, this is the first report for C−N bond formation using cinnamyl alcohol and 2‐amino pyridines using zinc bromide as a Lewis acid.

Ni-Catalyzed Reductive Allylation of α-Chloroboronates to Access Homoallylic Boronates.

The transition-metal-catalyzed allylation reaction is an efficient strategy for the construction of new carbon-carbon bonds alongside allyl or homoallylic functionalization. Herein we describe a Ni-catalyzed reductive allylation of α-chloroboronates to efficiently render the corresponding homoallylic boronates, which could be readily converted into valuable homoallylic alcohols or amines or 1,4-diboronates. This reaction features a broad substrate scope with good functional group compatibility that is complementary to the existing methods for the preparation of homoallylic boronates.

(Invited) Catalytic Allylation of Aldehydes Using Feedstock Alkenes

The efficient production of fine chemicals from simple and readily available bulk materials such as simple alkenes is an important research area in synthetic organic chemistry. Lower alkenes are produced by one of the most common chemical processes (i.e. hydrocarbon cracking) on over 500 million metric tons scale. Development of catalytic methods which enable the direct use of these abundant organic molecules as carbon sources is highly demanded for practical and selective chemical reactions. However, despite several previous examples, the use of feedstock alkenes in synthetically useful transformations remains a challenging task.Catalytic aldehyde allylation plays an important role in synthetic organic chemistry. Traditionally, nucleophilic allylmetal species as stoichiometric starting materials have contributed to the development of this catalytic process. Despite usefulness of this approach, however, there is room for improvement in the overall efficiency, redox/atom/step economy, and environmental sustainability. The catalytic generation of nucleophilic allylmetal species in situ from simple and feedstock alkenes via allylic sp3 C-H bond activation would be a straightforward approach. We envisioned that radical sp3 C-H bond activation followed by oxidative interception of the resulting carbon-centered radical by a metal complex is a promising strategy for the catalytic generation of organometallic species from inert substrates. We supposed the ternary hybrid catalysis comprising a photoredox catalyst, a hydrogen-atom-transfer (HAT) catalyst, and a metal catalyst would realize catalytic allylation of aldehydes with simple alkenes.We planned to use a combination of an acridinium photoredox catalyst (Mes-Acr+) and a thiophosphoric imide (TPI) HAT catalyst to activate an allylic C-H bond of the alkenes through the HAT process. Under visible light irradiation, single-electron oxidation of TPI by a photo-excited acridinium catalyst (*Mes-Acr+) generates a sulfur-centered radical (RS•). The RS• radical abstracts the allylic C-H bond of alkenes, affording allyl radicals. Based on the mechanism of Nozaki-Hiyama allylation, we expected that a chromium(II) complex catalyst oxidatively intercepted allyl radicals, giving allylchromium(III) species. This species reacts with aldehydes via a Zimmerman-Traxler transition state to produce chromium alkoxides in an anti-selective fashion. Protonolysis by the proton generated in the HAT catalysis should afford the target homoallylic alcohols and chromium(III) species. Single-electron reduction by the photoredox catalyst (Mes-Acr•) would close the catalytic cycle with regenerating a chromium(II) complex catalyst and the oxidized form of the photoredox catalyst (Mes-Acr+).Based on this mechanism, we studied the substrate scope with a combination of 5 mol% CrCl2, 10 mol% TPI catalyst (HAT) and 5 mol% acridinium photoredox catalyst (PC). First, the scope of alkenes was investigated. In all cases, the branched constitutional isomer was produced exclusively (>20/1). The reactions of C4 feedstocks, 1-butene and 2-butenes which are annually produced on a 105 metric ton scale, with benzaldehyde afforded the product in 94% and 100% yield, respectively, with high diastereoselectivity (14-16/1). This crotylation reaction using butenes as a starting material will significantly streamline polyketide synthesis. 3-Methyl-1-butene selectively afforded the product containing a quaternary carbon. Branched C6 alkenes were also competent substrates. Other alkenes, including cyclic, halide-containing, and ether-containing, all afforded the product in high yield. The aldehyde scope was then investigated by fixing the alkene substrate to 2-butene. A series of aromatic aldehydes bearing halogens, electron-withdrawing groups, and a boronate ester afforded the corresponding products with high diastereoselectivity. A methyl substituent at the ortho-, meta-, and para positions of the aromatic ring did not affect the results. The reactions of aliphatic aldehydes, including those containing potentially sensitive functional groups (e.g. amine, alkyl halide, sulfide and benzyl oxy moiety), also proceeded efficiently. Next, we investigated the application to highly functionalized substrates. Propranolol derivative bearing free hydroxy group were competent substrate. A dipeptide and a nucleic acid derivative containing coordinating polar functional groups such as amides and an adenine heterocycle did not affect the reaction progress. Therefore, the allylation of aldehydes mediated by the ternary hybrid catalysis realized high functional group compatibility and chemoselectivity using easily available feedstock alkenes.In conclusion, we developed a ternary hybrid catalysis, enabling catalytic allylation of aldehydes using simple alkenes, under visible light irradiation at room temperature. This hybrid catalysis is applicable to various types of unactivated alkenes including feedstock lower alkenes. Due to the high chemoselectivity and mild conditions, the reaction was applicable to highly functionalized bioactive molecules. The asymmetric variant enabled facile access to enantiomerically and diastereomerically enriched homoallylic alcohols by introducing a chiral ligand to the chromium catalyst. Further studies to expand the scope are ongoing. Figure 1

Asymmetric Synthesis of Homoallylic Alcohols Featuring Vicinal Tetrasubstituted Carbon Centers via Dual Pd/Photoredox Catalysis.

Dual palladium/photoredox-catalysis provides an effective method for the decarboxylative asymmetric synthesis of vicinal α,β-tri/tetra- or α,β-tetrasubstituted homoallylic alcohols using Hantzsch-type esters as radical precursors. This mild methodology capitalizes on vinyl cyclic carbonates as accessible reagents providing the target molecules in appreciable to good yields, high branch selectivity, and enantiomeric ratios of up to 94:6, making it a rare example of using prochiral electrophiles for the creation of vicinal congested carbon centers.

Reconstruction of Carbon Bond Frameworks via Oxapalladacycles Promoted by the Synergistic Effect of Palladium Catalyst and Triethylborane

AbstractPd-catalyzed β-carbon elimination of 3-hydroxy-4-pent­enoic acid derivatives promoted by triethylborane proceeds to form conjugated dienes via a decarboxylation process. The formed conjugated dienes undergo the Prins reaction with aldehydes in situ to afford conjugated homoallylic alcohols. These sequential transformations enable the conversion of diastereomeric mixtures of 3-hydroxy-4-pentenoic acids, which are readily prepared from the simple crossed aldol reaction of esters and α,β-unsaturated aldehydes, into 3,5-hexadienyl alcohols with high regio- and stereoselectivities in a single manipulation.

Palladium/norbornene-catalyzed distal alkenyl C-H arylation and alkylation of cis-olefins.

In this full article, a detailed study of a distal alkenyl C-H arylation and alkylation through the palladium/norbornene (NBE) cooperative catalysis is described. Both aminopyridine- and oxime ether-type directing groups have been found effective for this transformation, allowing functionalization of diverse allyl amines and homoallyl alcohols. In addition, the C5,C6-substititued NBEs show optimal reactivity and selectivity. Various cis-olefins can be transformed to the corresponding arylated or alkylated trisubstituted alkenes with excellent regio- and stereoselectivity. Preliminary mechanistic studies support the Catellani pathway instead of the Heck pathway.

Making and breaking of Zn–C bonds in the cases of allyl and propargyl organozincs

This review aims to sum up recent developments in the synthesis of homoallylic and homopropargylic alcohols or amines by using methods based on catalytic or stoichiometric use of metallic zinc for allylation and propargylations of carbonyls or imines. These methods encompass various transformations which are now commonly expressed as Barbier-Grignard type reactions including several chemical or electrochemical processes.

Catalytic Enantioselective Allylation of Acetylenic Aldehydes by Chiral Phosphoric Acid/Transition Metal Cooperative Catalysis: Formal Synthesis of Fostriecin.

An enantioselective allylation of silyl-substituted acetylenic aldehydes by chiral phosphoric acid (CPA)/transition metal cooperative catalysis was developed. Enantioenriched homoallylic propargyl alcohols were obtained in good yields with excellent enantioselectivities (>99% ee) under mild conditions. Moreover, the shortest formal synthesis of fostriecin was achieved by the present enantioselective allylation protocol as the key step. The known intermediate of fostriecin reported by McDonald and co-worker was synthesized in only nine steps in 39% total yield.

Cobalt-catalyzed diastereo- and enantioselective allyl addition to aldehydes and α-ketoesters through allylic C–H functionalization

Development of catalytic generation of allyl–metal complexes through allylic C–H cleavage of alkenes without prefunctionalization followed by site- and stereoselective carbon–carbon bond formation is of great importance in organic synthesis, providing a straightforward and step-economical approach to introduce a versatile allyl group into organic molecules. Although significant advances have been achieved in enantioselective transformations of electrophilic allyl–metal complexes and allyl radicals, enantioselective reactions of nucleophilic allyl–metal intermediates furnished through allylic C–H cleavage remain undeveloped. Herein, we identify a multi-tasking chiral catalyst derived from a commercially available phosphine ligand and cobalt salt that precisely controls the chemoselective formation of the allyl–cobalt complex and the site- and stereoselective addition to carbonyls, delivering a broad scope of homoallylic alcohols with high yield and stereoselectivity. This work may establish a platform for the development of enantioselective transformations of nucleophilic organometallic complexes generated from catalytic C–H functionalization.

Electrodeposition of tin onto a silver textile electrode for Barbier-type electro-organic synthesis of homoallylic alcohols

The development of electrodes (for sensors, energy technologies, and electrosynthesis) from abundant resources is necessary as a contribution to sustainability. Cellulose, the most abundant polymer, offers robust substrates for metalization towards the electrode development for electrosynthesis of organic chemicals. Electroless and electrodeposition methods are used to convert non-conductive cellulose-based textiles into electrically conductive textiles. The effect of current density on the electrodeposition of Sn onto a silver-coated textile is shown here to lead to Ag-Sn alloy and Sn deposits. The prepared Sn-Ag-VF textile electrode was investigated for electrifying the organic synthesis of homoallylic alcohol using benzaldehyde and allyl bromide as a model reaction. The homoallylic alcohol is synthesized in an undivided cell in the millimolar scale via constant current electrolysis method with 86 % conversion efficiency and up to a maximum of 72 % current efficiency.

Regio- and Trans-Selective Ni-Catalyzed Coupling of Butadiene, Carbonyls, and Arylboronic Acids to Homoallylic Alcohols under Base-Free Conditions.

We herein report a Ni-catalyzed three-component coupling of 1,3-butadiene, carbonyl compounds, and arylboronic acids as a general synthetic approach to 1,4-disubstituted homoallylic alcohols, an important class of compounds, which have previously not been straightforward to access. The reaction occurs efficiently using a Ni(cod)2 catalyst without any external base and ligand at ambient temperature and allows a highly regioselective and trans-selective 1,4-dicarbofunctionalization of feedstock butadiene in a single operation. This simple and practical protocol could apply to a comprehensive scope of substrates. The neutral conditions show extraordinary tolerance for even highly base-sensitive functional groups.

A Stereodivergent Strategy for Total Syntheses of Antirhine Alkaloids.

Total syntheses of the antirhine alkaloids are described. The cyanide-catalyzed imino-Stetter reaction of the aldimine derived from ethyl 2-aminocinnamate and 4-bromopyridine-2-carboxaldehyde provided a 2-pyridinyl substituted indole-3-acetate, which was further converted into the corresponding indoloquinolizidinium intermediate through C-ring formation. Subsequent trans-selective installation of the homoallylic alcohol side-chain at C-15 in the resulting indoloquinolizidinium allowed the total syntheses of antirhine and its known epimer.