Allylic Substrates Research Articles

Rh(I)/Sulfoxide-Imine-Olefin Complex Catalyzed Enantioselective Allylic Alkylation of 2-Fluoromalonate: Synthesis of Chiral α-Fluorolactone Bearing Vicinal Stereogenic Centers.

Highly enantioselective Rh-catalyzed allylic substitution of the racemic branched allylic substrates with 2-fluoromalonate was realized enabled by a novel chiral sulfoxide-imine-olefin ligand under mild reaction conditions. The utilization of CuSO4 is beneficial for improving the enantioselectivity. Notably, the chiral fluoro-containing allyl products can be employed in a selective cyclic esterification to form chiral α-fluorolactone bearing vicinal stereogenic centers.

Synthesis of 3,3-disubstituted allyl isoindolinones via Pd-catalyzed decarboxylative allylic alkylation

Herein, we report a mild palladium-catalyzed decarboxylative allylic alkylation of allyl ester-substituted isoindolinone substrates to afford a variety of 3,3-disubstituted isoindolinone derivatives. The decarboxylative coupling reaction tolerates a range of functional groups, including ketones and alkenyl halides, and does not require protection of the isoindolinone nitrogen. Additionally, the reaction was found to proceed in near-quantitative yield for most substrates evaluated. Based on the isolation of competing cyclopropane and protonation products, a reaction mechanism is proposed.

NMR spectroscopic characterization of polyhalodisulfides via sulfenyl chloride inverse vulcanization with sulfur monochloride

The preparation of sulfur containing polymers from inexpensive, commodity sulfur base chemicals is an emerging field of polymer chemistry as a route to consume elemental sulfur generated from fossil fuel refining. Recently a new process, termed, sulfenyl chloride inverse vulcanization has been developed that exploits the high reactivity and miscibility of sulfur monochloride, (S2Cl2) with a broad range of allylic monomers to prepare soluble, high molar mass linear polymers, segmented block copolymers and crosslinked thermosets with greater synthetic precision than achieved using classical inverse vulcanization with elemental sulfur. However, the ring-opening of episulfonium intermediates from this polymerization can proceed via Markovnikov, anti-Markovnikov, or alternative pathways resulting in complex regioisomeric microstructures, particularly when used with allylic ester monomers. Hence, to accelerate structural characterization of this new class of polyhalodisulfides prepared by the sulfenyl chloride inverse vulcanization process, we report on a detailed structural characterization to quantify the molar composition of regioisomeric units in these materials using NMR spectroscopy, focusing on sulfenyl chloride additions to allylic benzoate substrates. We report on a general methodology using one- and two-dimensional NMR spectroscopic techniques to enable direct integration of 2D NMR spectroscopic cross peaks to quantify the molar composition of regioisomeric units in 1,3-diallyl isophthalate (DAI) polymerized with S2Cl2, along with detailed studies on model compound reactions to detail the analytical methodology.

Rhodium-Catalyzed Asymmetric Synthesis of 1,2-Disubstituted Allylic Fluorides.

Although there are many methods for the asymmetric synthesis of monosubstituted allylic fluorides, construction of enantioenriched 1,2-disubstituted allylic fluorides has not been reported. To address this gap, we report an enantioselective synthesis of 1,2-disubstituted allylic fluorides using chiral diene-ligated rhodium catalyst, Et3 N ⋅ 3HF as a source of fluoride, and Morita Baylis Hillman (MBH) trichloroacetimidates. Kinetic studies show that one enantiomer of racemic MBH substrate reacts faster than the other. Computational studies reveal that both syn and anti π-allyl complexes are formed upon ionization of allylic substrate, and the syn complexes are slightly energetically favorable. This is in contrast to our previous observation for formation of monosubstituted π-allyl intermediates, in which the syn π-allyl conformation is strongly preferred. In addition, the presence of an electron-withdrawing group at C2 position of racemic MBH substrate renders 1,2-disubstituted π-allyl intermediate formation endergonic and reversible. To compare, formation of monosubstituted π-allyl intermediates was exergonic and irreversible. DFT calculations and kinetic studies support a dynamic kinetic asymmetric transformation process wherein the rate of isomerization of the 1,2-disubstituted π-allylrhodium complexes is faster than that of fluoride addition onto the more reactive intermediate. The 1,2-disubstituted allylic fluorides were obtained in good yields, enantioselectivity, and branched selectivity.

Rhodium‐Catalyzed Asymmetric Synthesis of 1,2‐Disubstituted Allylic Fluorides

AbstractAlthough there are many methods for the asymmetric synthesis of monosubstituted allylic fluorides, construction of enantioenriched 1,2‐disubstituted allylic fluorides has not been reported. To address this gap, we report an enantioselective synthesis of 1,2‐disubstituted allylic fluorides using chiral diene‐ligated rhodium catalyst, Et3N ⋅ 3HF as a source of fluoride, and Morita Baylis Hillman (MBH) trichloroacetimidates. Kinetic studies show that one enantiomer of racemic MBH substrate reacts faster than the other. Computational studies reveal that both syn and anti π‐allyl complexes are formed upon ionization of allylic substrate, and the syn complexes are slightly energetically favorable. This is in contrast to our previous observation for formation of monosubstituted π‐allyl intermediates, in which the syn π‐allyl conformation is strongly preferred. In addition, the presence of an electron‐withdrawing group at C2 position of racemic MBH substrate renders 1,2‐disubstituted π‐allyl intermediate formation endergonic and reversible. To compare, formation of monosubstituted π‐allyl intermediates was exergonic and irreversible. DFT calculations and kinetic studies support a dynamic kinetic asymmetric transformation process wherein the rate of isomerization of the 1,2‐disubstituted π‐allylrhodium complexes is faster than that of fluoride addition onto the more reactive intermediate. The 1,2‐disubstituted allylic fluorides were obtained in good yields, enantioselectivity, and branched selectivity.

Desymmetrization of Geminal Difluoromethylenes using a Palladium/Copper/Lithium Ternary System for the Stereodivergent Synthesis of Fluorinated Amino Acids

AbstractFluorinated amino acids and related peptides/proteins have been found widespread applications in pharmaceutical and agricultural compounds. However, strategies for introducing a C−F bond into amino acids in an enantioselective manner are still limited and no such asymmetric catalysis strategy has been reported. Herein, we have successfully developed a Pd/Cu/Li ternary system for stereodivergent synthesis of chiral fluorinated amino acids. This method involves a sequential desymmetrization of geminal difluoromethylenes and allylic substitution with amino acid Schiff bases via Pd/Li and Pd/Cu dual activation, respectively. A series of non‐natural amino acids bearing a chiral allylic/benzylic fluorine motif are easily synthesized in high yields with excellent regio‐, diastereo‐, and enantioselectivities (up to >20 : 1 dr and >99 % ee). A density functional theory (DFT) study revealed the F−Cu interaction of the allylic substrate and the Cu catalyst significantly influence the stereoselectivity.

Desymmetrization of Geminal Difluoromethylenes using a Palladium/Copper/Lithium Ternary System for the Stereodivergent Synthesis of Fluorinated Amino Acids.

Fluorinated amino acids and related peptides/proteins have been found widespread applications in pharmaceutical and agricultural compounds. However, strategies for introducing a C-F bond into amino acids in an enantioselective manner are still limited and no such asymmetric catalysis strategy has been reported. Herein, we have successfully developed a Pd/Cu/Li ternary system for stereodivergent synthesis of chiral fluorinated amino acids. This method involves a sequential desymmetrization of geminal difluoromethylenes and allylic substitution with amino acid Schiff bases via Pd/Li and Pd/Cu dual activation, respectively. A series of non-natural amino acids bearing a chiral allylic/benzylic fluorine motif are easily synthesized in high yields with excellent regio-, diastereo-, and enantioselectivities (up to >20 : 1 dr and >99 % ee). A density functional theory (DFT) study revealed the F-Cu interaction of the allylic substrate and the Cu catalyst significantly influence the stereoselectivity.

Scope and Mechanistic Probe into Asymmetric Synthesis of α-Trisubstituted-α-Tertiary Amines by Rhodium Catalysis.

Asymmetric reactions that convert racemic mixtures into enantioenriched amines are of significant importance due to the prevalence of amines in pharmaceuticals, with about 60% of drug candidates containing tertiary amines. Although transition-metal catalyzed allylic substitution processes have been developed to provide access to enantioenriched α-disubstituted allylic amines, enantioselective synthesis of sterically demanding α-tertiary amines with a tetrasubstituted carbon stereocenter remains a major challenge. Herein, we report a chiral diene-ligated rhodium-catalyzed asymmetric substitution of racemic tertiary allylic trichloroacetimidates with aliphatic secondary amines to afford α-trisubstituted-α-tertiary amines. Mechanistic investigation is conducted using synergistic experimental and computational studies. Density functional theory calculations show that the chiral diene-ligated rhodium promotes the ionization of tertiary allylic substrates to form both anti and syn π-allyl intermediates. The anti π-allyl pathway proceeds through a higher energy than the syn π-allyl pathway. The rate of conversion of the less reactive π-allyl intermediate to the more reactive isomer via π-σ-π interconversion was faster than the rate of nucleophilic attack onto the more reactive intermediate. These data imply that the Curtin-Hammett conditions are met in the amination reaction, leading to dynamic kinetic asymmetric transformation. Computational studies also show that hydrogen bonding interactions between β-oxygen of allylic substrate and amine-NH greatly assist the delivery of amine nucleophile onto more hindered internal carbon of the π-allyl intermediate. The synthetic utility of the current methodology is showcased by efficient preparation of α-trisubstituted-α-tertiary amines featuring pharmaceutically relevant secondary amine cores with good yields and excellent selectivities (branched-linear >99:1, up to 99% enantiomeric excess).

Asymmetric Allylic Substitution‐Isomerization for the Modular Synthesis of Axially Chiral N‐Vinylquinazolinones

AbstractAxially chiral N‐substituted quinazolinones are important bioactive molecules, which are presented in many synthetic drugs. However, most strategies toward their atroposelective synthesis are mainly limited to the axially chiral arylquinazolinone frameworks. The development of modular synthetic methods to access diverse quinazolinone‐based atropisomers remains scarce and challenging. Herein, we report the regio‐ and atroposelective synthesis of axially chiral N‐vinylquinazolinones via the strategy of asymmetric allylic substitution‐isomerization. The catalysis system utilized both asymmetric transition‐metal catalysis and organocatalysis to efficiently afford trisubstituted and tetrasubstituted N‐vinylquinazolinone atropisomers, respectively. With the meticulous design of β‐substituted allylic substrates, both Z‐ and E‐tetrasubstituted axially chiral N‐vinylquinazolinones were obtained in good yields and high enantioselectivities.

Asymmetric Allylic Substitution-Isomerization for the Modular Synthesis of Axially Chiral N-Vinylquinazolinones.

Axially chiral N-substituted quinazolinones are important bioactive molecules, which are presented in many synthetic drugs. However, most strategies toward their atroposelective synthesis are mainly limited to the axially chiral arylquinazolinone frameworks. The development of modular synthetic methods to access diverse quinazolinone-based atropisomers remains scarce and challenging. Herein, we report the regio- and atroposelective synthesis of axially chiral N-vinylquinazolinones via the strategy of asymmetric allylic substitution-isomerization. The catalysis system utilized both asymmetric transition-metal catalysis and organocatalysis to efficiently afford trisubstituted or tetrasubstituted N-vinylquinazolinone atropisomers, respectively. With the meticulous design of β-substituted allylic substrates, configurationally stable Z- and E-tetrasubstituted axially chiral N-vinylquinazolinones were obtained in good yields and high enantioselectivities.

Multicomponent Domino Reaction for Concise Access to 2-Amino-Substituted 1,3,4 Oxadiazoles via Smiles Rearrangement.

A multicomponent domino reaction has been developed for the preparation of N-substituted 2-amino-1,3,4-oxadiazoles directly from various hydrazides (32 examples). The formation of 2-amino-1,3,4-oxadiazole involves the Smiles rearrangement of thiazolidinone, which results in the formation of carbodiimide intermediate that concomitantly undergoes amide-imidic acid tautomerism followed by cyclization. The protocol developed has wide applicability and provides the desired 2-amino-1,3,4-oxadiazole in excellent yields. The GSD studies of NMR spectra of aliphatic substrates (4di, 4dh) revealed the formation of three products, whereas, in the case of allylic and benzylic substrates, thiazolidinones were obtained as the sole products. Furthermore, to elucidate the plausible mechanism, DFT studies were performed affirming carbodiimide as the crucial intermediate for the interconversion of thiazolidinone to oxadiazole.

Allylic and Benzylic Alcohol Coupling Reactions Catalyzed by Lithium-Promoted Manganese Oxides

This study reports a novel methodology for the production of allyl acrylate from allyl alcohol solely as the starting substrate. The reaction reported here utilizes a heterogeneous reusable catalyst based on Li-ion-promoted mesoporous manganese oxide. The reaction conditions are mild (ambient pressure and temperature of 80 °C). The catalytic activity, selectivity, and substrate scope of the reaction are reported (60% yield). The system proposed here is composed of an allylic alcohol substrate, O2 as the oxidant, N-hydroxyphthalimide (NHPI) as the promoter, and trichloro acetonitrile (CCl3CN) as the solvent together with the Li-promoted manganese oxide (surface area >150 m2/g) as the catalyst.

Palladium-Catalyzed C-H Allylation/Annulation Reaction of Amides and Allylic Alcohols: Regioselective Construction of Vinyl-Substituted 3,4-Dihydroisoquinolones.

A palladium-catalyzed highly regioselective C-H allylation/annulation reaction of N-sulfonyl amides with secondary or tertiary allylic alcohols has been developed to construct 3,4-dihydroisoquinolones bearing a synthetically valuable vinyl substituent. This cascade cyclization approach of allylic alcohols involving C-H allylation has not been reported previously. The commercially available allylic alcohol substrates, the only by-product of water, and the used terminal oxidant of O2 provide environmentally benign advantages.

Copper-Catalyzed Visible-Light-Induced Allylic Difluoromethylation of Unactivated Alkenes Using Difluoroacetic Acid.

We herein describe a straightforward allylic difluoromethylation reaction of unactivated alkenes. Compared to cross-couplings of prefunctionalized allylic substrates for the construction of allylic CF2H bonds, this reaction employs readily available alkenes as substrates under mild conditions. Difluoroacetic acid is used as an inexpensive and easy-to-handle source of CF2H radical under visible light irradiation with PIDA. The copper catalyst plays an important role of diverting the reaction pathway toward allylic difluoromethylation as opposed to previously found hydrodifluoromethylation.

KIT-5 Supported Copper (II) Oxide Mesoporous Materials: An Efficient Catalyst for Regioselective Synthesis of 1,4- Disubstituted-1H-1,2,3-Triazoles in Water

We have synthesized copper-incorporated KIT-5 mesoporous materials which were characterized thoroughly by powder XRD, N2-sorption, UV-Vis, HR-SEM & EDS and HR-TEM techniques. The low angle PXRD with theta values of 0.609, 0.660, 0.704 and 0.746 confirmed the mesoporosity of the synthesized materials. In addition, the materials showed type-IV isotherms which are spherical in morphology and fringes with pores of materials supporting the formation of mesoporous materials. The catalytic activity of synthesized materials was also investigated. We have used our materials as catalyst for the synthesis of 1,2,3-triazole derivatives via three component reaction of alkyl/aryl halide, terminal alkynes and sodium azide in water as a solvent. The desired triazole products were obtained in very good yields. This study indicates the importance of Cu element, solid support with uniformity of metal nanoparticles over the materials. The recyclability study with PXRD data of the catalyst confirmed the existence of the mesoporosity of the catalyst after the reaction and the yield decreased marginally from 98 to 91% over three cycles. This reaction has broad substrate scope and is compatible for aliphatic, aromatic, allyl substrates giving high yield of triazole products.

Functional verification and characterization of a type-III geranylgeranyl diphosphate synthase gene from Sporobolomyces pararoseus NGR.

Carotenoids, a group of natural pigments, have strong antioxidant properties and act as precursors to vitamin A, which have garnered attention from industry and researchers. Sporobolomyces pararoseus represents a hyper-producer of carotenoids, mainly including β-carotene, torulene, and torularhodin. Geranylgeranyl diphosphate synthase (GGPPS) is regarded as a key enzyme in the carotenoid biosynthesis pathway. However, the precise nature of the gene encoding GGPPS in S. pararoseus has not been reported yet. Here, we cloned a cDNA copy of the GGPPS protein-encoding gene crtE from S. pararoseus NGR. The crtE full-length genomic DNA and cDNA are 1,722 and 1,134 bp, respectively, which consist of 9 exons and 8 introns. This gene encodes 377 amino acids protein with a predicted molecular mass of 42.59 kDa and a PI of 5.66. Identification of the crtE gene encoding a functional GGPPS was performed using heterologous complementation detection in Escherichia coli. In vitro enzymatic activity experiments showed that CrtE utilized farnesyl diphosphate (FPP) as an allylic substrate for the condensation reaction with isopentenyl diphosphate (IPP), generating more of the unique product GGPP compared to other allylic substrates. The predicted CrtE 3D-model was analyzed in comparison with yeast GGPPS. The condensation reaction occurs in the cavity of the subunit, and three bulky amino acids (Tyr110, Phe111, and His141) below the cavity prevent further extension of the product. Our findings provide a new source of genes for carotenoid genetic engineering.

Stereoretentive regio‐ und enantioselektive Allylierung von Isoxazolinonen per planar chiralem Palladacyclus‐Katalysator

The catalytic allylic substitution is one of the most important tools in asymmetric synthesis to form C-C bonds in an enantioselective way. While high efficiency was previously accomplished in terms of enantio- and regiocontrol using different catalyst types, a strong general limitation is a very pronounced preference for the formation of allylic substitution products with ( E )-configured C=C double bonds. Herein, we report that with a planar chiral palladacycle catalyst a diastereospecific reaction outcome is achieved using isoxazolinones and allylic imidates as substrates, thus maintaining the C=C double bond geometry of the allylic substrates in the highly enantioenriched products. DFT calculations show that the reactions proceed via an S N 2 mechanism and not via π-allyl Pd complexes. Crucial for the high control is the stabilization of the allylic fragment in the S N 2 transition state by π-interactions with the phenyl substituents of the pentaphenylferrocenyl catalyst core.

Stereoretentive Regio- and Enantioselective Allylation of Isoxazolinones by a Planar Chiral Palladacycle Catalyst.

The catalytic allylic substitution is one of the most important tools in asymmetric synthesis to form C-C bonds in an enantioselective way. While high efficiency was previously accomplished in terms of enantio- and regiocontrol using different catalyst types, a strong general limitation is a very pronounced preference for the formation of allylic substitution products with (E)-configured C=C double bonds. Herein, we report that with a planar chiral palladacycle catalyst a diastereospecific reaction outcome is achieved using isoxazolinones and allylic imidates as substrates, thus maintaining the C=C double bond geometry of the allylic substrates in the highly enantioenriched products. DFT calculations show that the reactions proceed via an SN 2 mechanism and not via π-allyl Pd complexes. Crucial for the high control is the stabilization of the allylic fragment in the SN 2 transition state by π-interactions with the phenyl substituents of the pentaphenylferrocenyl catalyst core.

Recent Advances in the Synthesis of Five-Membered Cyclic Carbonates and Carbamates from Allylic or Propargylic Substrates and CO2

The organic carbamates and carbonates are highly desirable compounds that have found a wide range of applications in drug design, medicinal chemistry, material science, and the polymer industry. The development of new catalytic carbonate and carbamate forming reactions, which employ carbon dioxide as a cheap, green, abundant, and easily available reagent, would thus represent an ideal substitution for existing methods. In this review, the advancements in the catalytic conversion of allylic and propargylic alcohols and amines to corresponding five-membered cyclic carbonates and carbamates are summarized. Both the metal- and the organocatalyzed methods are reviewed, as well as the proposed mechanisms and key intermediates of the illustrated carbonate and carbamate forming reactions.

Recent Advances in the Catalytic Umpolung Carboxylation of Allylic Alcohol Derivatives with Carbon Dioxide

AbstractAllylic alcohols and their derivatives (e. g. halides, acetates, and pivalates) are readily available organic compounds that are frequently employed in organic synthesis, and especially in Tsuji‐Trost‐type allylic substitution reactions. These allylic substrates add oxidatively to transition metals such as Pd to form π‐allyl metal species, which can act as suitable electrophiles for several nucleophilic counterparts. However, under reductive conditions, the π‐allyl metal species instantly become nucleophilic and react with various electrophiles including the rather stable CO2, which is an abundant, inexpensive, non‐toxic, and renewable carbon source in organic synthesis. When CO2 is incorporated in allylic compounds, synthetically useful β,γ‐unsaturated carboxylic acid derivatives are obtained exclusively. In this review, we focus on the recent advances in such catalytic umpolung carboxylations of allyl alcohols, acetates, pivalates, and halides with CO2 under thermal, photochemical, and electrochemical conditions.