Allylic Derivatives Research Articles

Carbene-Catalyzed α,γ-Deuteration of Enals under Oxidative Conditions

Organic compounds with deuterated allyl groups are very attractive for drug entities to enhance pharmacokinetic properties, since allylic C–H bonds are prone to metabolic oxidation and the deuterated versions can be less prone to such metabolism. However, direct deuteration at allylic C–H moieties is still a challenge. Few examples have been reported by transition-metal catalysis and no such reports have been documented in an organocatalytic fashion. Herein, a carbene-catalyzed C–H deuteration of enal at allylic C(sp3) and C(sp2) centers is disclosed. Addition of the carbene catalyst to the aldehyde moiety of enals to eventually activate the α- and γ-carbon atom under oxidative conditions is critical to achieve high deuterium incorporation. Key mechanistic steps of our reaction include carbene catalyst addition, azolium ester formation, remote γ-carbon activation, reversible α- and γ-carbon enolization, and iterative H/D exchanges. The reaction is performed under mild conditions using D2O as the deuterium source to efficiently afford α,γ-deuterated 2-alkenoic acids and their derivatives in good to excellent yields and high deuterium incorporation. These labeled products containing carbonyl and allyl bifunctionalities are valuable building blocks for further transformations, eventually leading to otherwise challenging labeled targets including deuterated allylic derivatives, aliphatic derivatives and polydeuterated drugs (e.g., Ibuprofen). The convenient and scalable synthesis has application potential for materials and pharmaceuticals.

Iron-Catalyzed Asymmetric Hydrosilylation of Vinylcyclopropanes via Stereospecific C-C Bond Cleavage.

SummaryAn iron-catalyzed highly anti-Markovnikov selective, enantioselective hydrosilylation of vinylcyclopropanes with PhSiH3 was reported for the preparation of valuable chiral allylic silanes via stereospecific C-C bond cleavage. Simultaneously, difficultly prepared chiral VCPs could be also obtained with moderate to excellent enantioselectivity via this kinetic resolution pathway. The chiral Z-allylic silanes could be converted to various chiral allylic derivatives. A possible mechanism via an iron-silyl species was proposed based on experimental and computational studies.

Pseudo‐Stereodivergent Synthesis of Enantioenriched Tetrasubstituted Alkenes by Cascade 1,3‐Oxo‐Allylation/Cope Rearrangement

AbstractThe catalytic diastereodivergent construction of stereoisomers having two or more stereogenic centers has been extensively studied. In contrast, the switchable introduction of another stereogenic element, that is, Z/E configuration involving a polysubstituted alkene group, into the optically active stereoisomers, has not been recognized yet. Disclosed here is the pseudo‐stereodivergent synthesis of highly enantioenriched tetrasubstituted alkene architectures from isatin‐based Morita–Baylis–Hillman carbonates and allylic derivatives, under the cooperative catalysis of a tertiary amine and a chiral iridium complex. The success of the switchable construction of the tetrasubstituted alkene motif relies on the diastereodivergent 1,3‐oxo‐allylation reaction between N‐allylic ylides and chiral π‐allyliridium complex intermediates by ligand and substrate control, followed by the stereoselective concerted 3,3‐Cope rearrangement process.

Pseudo-Stereodivergent Synthesis of Enantioenriched Tetrasubstituted Alkenes by Cascade 1,3-Oxo-Allylation/Cope Rearrangement.

The catalytic diastereodivergent construction of stereoisomers having two or more stereogenic centers has been extensively studied. In contrast, the switchable introduction of another stereogenic element, that is, Z/E configuration involving a polysubstituted alkene group, into the optically active stereoisomers, has not been recognized yet. Disclosed here is the pseudo-stereodivergent synthesis of highly enantioenriched tetrasubstituted alkene architectures from isatin-based Morita-Baylis-Hillman carbonates and allylic derivatives, under the cooperative catalysis of a tertiary amine and a chiral iridium complex. The success of the switchable construction of the tetrasubstituted alkene motif relies on the diastereodivergent 1,3-oxo-allylation reaction between N-allylic ylides and chiral π-allyliridium complex intermediates by ligand and substrate control, followed by the stereoselective concerted 3,3-Cope rearrangement process.

A-type doubly linked proanthocyanidin trimer and other metabolites from Canthium venosum fruits, and their biological activities

Phytochemical investigation of Canthium venosum fruits led to the isolation of a new doubly linked A-type proanthocyanidin trimer: epicatechin-(2β→O→7, 4β →8)-catechin-(5→O→2β, 6→4β)-epicatechin [venosumtannin A-1 (1)], along with twenty known compounds 2-21. Allyl (9a) and acetyl (9b) derivatives of 9 were prepared. The structures of compounds were established using comprehensive spectroscopic analysis including 1D NMR, 2D NMR (COSY, HMQC, HMBC, and NOESY) and circular dichroism (CD), and by comparison with the corresponding literature data. The antioxidant, cytotoxic, acetylcholinesterase and antibacterial activities of some of the isolated compounds were investigated. In the acetylcholinesterase inhibitory activity test, compounds 2 and 9 (IC50: 0.03 ± 1.22 × 10−3 and 0.04 ± 1.23 × 10−3μM) were more active than the references (eserine and tacrine; IC50: 0.77 ± 1.84 × 10−3 and 0.15 ± 1.04 × 10−3 μM respectively).

Construction of allylic amino acid derivatives through a catalytic asymmetric allylic alkylation of azlactones with vinyl cyclopropanes

A simple and concise asymmetric allylic alkylation of azlactones was developed for direct construction of quaternary amino acid derivatives. Electrophilic synthons vinyl propanes were used in the presence of Pd catalyst under mild conditions, which afforded the desired quaternary allylic amino acid derivatives in good to excellent yields with a high level of stereoselectivity.

3,3-Sigmatropic Shifts of Allyl Group Along Cyclopentadiene Ring Perimeter

Reversible non-degenerate 3,3-sigmatropic shifts of the allyl group along the perimeter of the five-membered ring occurring with energy barriers ΔG°≠ = 28.5–30.2 kcal/mol (o-dichlorobenzene-d4) have been detected in the allyl derivatives of 5-methyl-1,2,3,4-tetramethoxycarbonylcyclopentadiene by NMR method. Using DFT B3LYP/6-311++G(d,p) method, it has been shown that degenerate migrations of the allyl group in the related 5-allyl-1,2,3,4,5-pentamethoxycarbonylcyclopentadiene should occur via 3,3-sigmatropic shift through transition states with conformation of a six-membered ring (chair or boat, with close barriers ΔG°≠ = 27.4 or 27.7 kcal/mol, respectively). The simulated higher barrier of alternative 1,5-sigmatropic shifts of the allyl group (ΔG°≠ = 30.8 kcal/mol) indicates the energy preference of the migrations via 3,3-shifts.

Selective Synthesis of Z-Cinnamyl Ethers and Cinnamyl Alcohols through Visible Light-Promoted Photocatalytic E to Z Isomerization.

A photocatalytic E to Z isomerization of alkenes using an iridium photosensitizer under mild reaction conditions is disclosed. This method provides scalable and efficient access to Z-cinnamyl ether and allylic alcohol derivatives in high yields with excellent stereoselectivity. Importantly, this method also provides a powerful strategy for the selective synthesis of Z-magnolol and honokiol derivatives possessing potential biological activity.

Palladium-catalyzed regio- and stereoselective access to allyl ureas/carbamates: facile synthesis of imidazolidinones and oxazepinones.

Typically, transition metal catalysis enforces the stereodefined outcome of a reaction. Here we disclose the palladium-catalyzed regio- and stereoselective access to allylic ureas/carbamates and their further exploitation to diverse cyclic structures under operationally simple reaction conditions. This protocol features palladium-catalyzed decarboxylative amidation of highly modular VECs with good to excellent yield, minimal waste production, wide substrate scope, and low catalyst loading. In follow-up chemistry, we demonstrated the debenzylation of vinylic imidazolidinones to N-hydroxycyclic ureas and regioselective derivatization towards the facile synthesis of halohydrins and oxiranes under mild reaction conditions in good to excellent yields.

Annulative Allylic Alkylation Reactions between Dual Electrophiles and Dual Nucleophiles: Applications in Complex Molecule Synthesis.

Metal-catalyzed allylic alkylation reactions between dual nucleophiles and dual electrophiles represent a powerful set of methods for the synthesis of small-, medium-, and even large-sized rings. Using this strategy, a handful of simple allylic diol derivatives can be transformed into a broad array of complex carbo- and heterocycles of varying ring sizes in just a single step. Because of their ability to rapidly generate complexity, annulative allylic alkylation reactions between dual nucleophiles and dual electrophiles have been extensively employed in the total synthesis of both natural products and pharmaceutical compounds.

Copper(I) π-coordination compounds with allyl derivatives of disubstituted pseudothiohydantoin: synthesis, structure investigation and nonlinear optical features

The present work is directed towards preparation by means of alternating current electrochemical synthesis, structural, and optical property characterization of Cu(I) π-coordination compounds [Cu(papt)NO3] (1), [Cu2(papt)2Cl2] (2), [Cu2(papt)2Br2] (3), [Cu2(eapt)2Cl2] (4), and [Cu2(eapt)2Br2] (5) with disubstituted pseudothiohydantoins, (2Z)-2-(phenylimino)-3-allyl-1,3-thiazolidin-4-one (papt) and (2Z)-2-[(2-hydroxyethyl)imino]-3-allyl-1,3-thiazolidin-4-one (eapt). All coordination compounds crystallize in the centrosymmetric monoclinic P21/n space group, 2 and 3, as well as 4 and 5 are isostructural to each other. Cu(I) in all the structures have trigonal–pyramidal environment formed by N-imino and allyl C = C double bond of the chelate organic ligand and two oxygens of NO3– in 1 or two halides in 2–5. Crystal packing of 2 and 4 were analyzed using energy framework computational analysis to examine differences in crystal structures of papt- and eapt-based coordination compounds, which could be explained by the difference in weak interactions of phenyl and 2-hydroxyethyl groups. The third-order nonlinear optical features for 1 and 2 are studied at 1064 nm generated by a nanosecond pulsed Nd:YAG laser.

Antimicrobial Activity of Naturally Occurring Phenols and Derivatives Against Biofilm and Planktonic Bacteria.

Biofilm-forming bacteria present formidable challenges across diverse settings, and there is a need for new antimicrobial agents that are both environmentally acceptable and relatively potent against microorganisms in the biofilm state. The antimicrobial activity of three naturally occurring, low molecular weight, phenols, and their derivatives were evaluated against planktonic and biofilm Staphylococcus epidermidis and Pseudomonas aeruginosa. The structure activity relationships of eugenol, thymol, carvacrol, and their corresponding 2- and 4-allyl, 2-methallyl, and 2- and 4-n-propyl derivatives were evaluated. Allyl derivatives showed a consistent increased potency with both killing and inhibiting planktonic cells but they exhibited a decrease in potency against biofilms. This result underscores the importance of using biofilm assays to develop structure-activity relationships when the end target is biofilm.

Electrophilic Amination of Allylic Boranes with Azodicarboxylates: Synthesis of α,α-Disubstituted Allylic Amine Derivatives

The electrophilic amination of allylic boranes, which are prepared from allenes and 9-borabicyclo[3.3.1]nonane (9-BBN), with azodicarboxylates as an aminating reagent is reported. 9-BBN-based allyl...

Functionalized 1,3-Thiazolidin-4-Ones from 2-Oxo-Acenaphthoquinylidene- and [2.2]Paracyclophanylidene-Thiosemicarbazones.

The reactions of dialkyl acetylenedicarboxylates with various 2-oxo-acenaphthoquinylidene- and 4-acetyl[2.2]paracyclophanylidene-thiosemicarbazones were investigated. Using simple experimental procedures, 1,3-Thiazolidin-4-ones derived from acenaphthequinone or [2.2]paracyclophane were obtained as major products in good yields. In the case of allyl derivative of acenaphthoquinylidene-thiosemicarbazones, a complex structure of tetramethyl 5-(2-(((Z,E)-N-allyl-N′-(2-oxoacenaphthylen-1(2H)-ylidene)carbamohydrazonoyl)thio)-1,2,3-tris-(methoxycarbonyl)-cyclopropyl)-4-methoxy-7-oxabicyclo[2.2.1]hepta-2,5-diene-1,2,3,6-tetracarboxylate was formed. Single crystal X-ray analysis was used as an efficient tool to confirm the structure of the synthesized compounds as well as different spectroscopic data (1H-NMR, 13C-NMR, 2D-NMR, mass spectrometry and elemental analysis). The mechanism of the obtained products was discussed.

Synthesis and halocyclization of 3-cyano-4,6-dimethyl-2-pyridone allyl derivatives

The sequence of condensation, alkylation, and halocyclization reactions during the synthesis of the target 2,3-dihydro[1,3]oxazolo[3,2-a]-pyridinium salts was investigated. The effect of basic catalysis on the chemoselectivity of the reaction of malononitrile with acetylacetone has been revealed. In neutral media, the selectivity of the formation of 3-cyano-4,6-dimethyl-2-pyridone increases. The presence of Et3N, on the other hand, leads to the formation of side products. Allylation of 3-cyano-4,6-dimethyl-2-pyridone proceeds with the formation of regioisomeric 1-allyl-3-cyano-4,6-dimethyl-2-pyridone and 2-allyl-3-cyano-4,6-dimethyloxypyridine in a 3:1 ratio, while the high chemoselectivity of halocyclization of allyl derivatives with iodine or bromine results in practically quantitative yields of 2,3-dihydro[1,3]oxazolo[3,2-a]pyridinium salts.

Synthesis of the N-methyl Derivatives of 2-Aminothiazol-4(5H)-one and Their Interactions with 11βHSD1-Molecular Modeling and in Vitro Studies.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme that affects the body's cortisol levels. The inhibition of its activity can be used in the treatment of Cushing's syndrome, metabolic syndrome and type 2 diabetes. In this study, we synthesized new derivatives of 2-(methylamino)thiazol-4(5H)-one and tested their activity towards inhibition of 11β-HSD1 and its isoform - 11β-HSD2. The results were compared with the previously tested allyl derivatives. We found out that methyl derivatives are weaker inhibitors of 11β-HSD1 in comparison to their allyl analogs. Due to significant differences in the activity of the compounds, molecular modeling was performed, which was aimed at comparing the interactions between 11β-HSD1 and ligands differing by substituent at the amine group (allyl vs. methyl). Modeling showed that the absence of the allyl group can lead to the rotation of whole ligand molecule which affects its interaction with the enzyme.

The first copper(I) halide p-complexes with allyl derivatives of urea and parabanic acid

The first copper(I) halide p-complexes with allyl derivatives of urea and parabanic acid

C-6α- vs C-7α-Substituted Steroidal Aromatase Inhibitors: Which Is Better? Synthesis, Biochemical Evaluation, Docking Studies, and Structure-Activity Relationships.

C-6α and C-7α androstanes were studied to disclose which position among them is more convenient to functionalize to reach superior aromatase inhibition. In the first series, the study of C-6 versus C-7 methyl derivatives led to the very active compound 9 with IC50 of 0.06 μM and Ki = 0.025 μM (competitive inhibition). In the second series, the study of C-6 versus C-7 allyl derivatives led to the best aromatase inhibitor 13 of this work with IC50 of 0.055 μM and Ki = 0.0225 μM (irreversible inhibition). Beyond these findings, it was concluded that position C-6α is better to functionalize than C-7α, except when there is a C-4 substituent simultaneously. In addition, the methyl group was the best substituent, followed by the allyl group and next by the hydroxyl group. To rationalize the structure-activity relationship of the best inhibitor 13, molecular modeling studies were carried out.

Solvent-free synthesis and characterization of allyl chitosan derivatives.

The solvent-free synthesis of allyl-substituted chitosan derivatives through reactive co-extrusion of chitosan powder with allyl bromide at shear deformation was performed. For the structural characterization, FTIR and NMR methods were employed. The results were confirmed by chemical analysis. The total content of allyl substituents from 5 to 50 per 100 chitosan units as a function of the component ratio in the reactive mixtures was revealed. Carrying out the reaction without any additives leads to the selective formation of N-alkylated derivatives, whereas in the presence of alkali the ethers of chitosan were preferentially formed. The results suggest that the proposed approach allows significantly higher yield of products to be obtained at high process speeds and significantly lower reagent consumption as compared with the liquid-phase synthesis in organic medium. The synthesized unsaturated derivatives are promising photosensitive components for use in laser stereolithography for fabrication of three-dimensional biocompatible structures with well-defined architectonics.

Synthesis of tri-substituted allyl alcoholsviaa copper/iron co-catalyzed cascade perfluoroalkylation/rearrangement of aryl propynyl ethers

A copper/iron co-catalyzed fluoroalkylation of aryl propynyl ethers for the synthesis of perfluoroalkylated tri-substituted allyl alcohol derivatives is reported.