Wadsworth Emmons Reaction Research Articles

Synthesis of 5-(4-Formylphenyl)barbituric Acid to Access Enolizable Chromophoric Barbituric Acids

AbstractBarbituric acids mono-substituted at the 5-position show keto–enol tautomerism. In the keto form, conjugation to an aryl substituent is interrupted due to the sp³-hybridized carbon atom at the 5-position of barbituric acid. The enol form generates a conjugated π-system to the aryl substituent and acts as an electron-donating group. If the aryl substituent is electron-deficient, a push-pull system is generated that shows typical UV/Vis absorption. These types of compounds are difficult to access synthetically due to their intrinsic convertibility. The synthesis of barbituric acids with a 4-formylphenyl functionality at the 5-position is reported. This compound, 5-(4-formylphenyl)barbituric acid, could be used to introduce extended π-systems with electron-withdrawing groups in great variety by simple condensation reactions. We demonstrate this by a Horner–Wadsworth–Emmons reaction that forms the enolizable dye (E)-5-(4-(4-nitrostyryl)phenyl)barbituric acid.

Wadsworth–Emmons Reaction by Using the Fluorapatite Catalyst: Kinetic Studies

Wadsworth–Emmons reaction was successfully carried out by using the fluorapatite (FAP) catalyst. The reaction of 2-methoxybenzaldehyde and triethylphosphonoacetate using FAP afforded α,β-unsaturated ester with 100% conversion and 80% selectivity. A kinetic model was validated at different temperatures by Langmuir–Hinshelwood–Hougen–Watson (LHHW), and the absence of mass transfer resistance was verified by the Weisz Prater criterion. The effect of different catalysts, temperature, catalyst loading, solvent, mole ratio, and speed of stirring was studied. The FAP catalyst was characterized by Fourier transform infrared spectroscopy, Brunauer–Emmett–Teller method, nitrogen adsorption–desorption, transmission electron microscopy, energy-dispersive X-ray spectroscopy, temperature programmed desorption (TPD-NH3), X-ray diffraction, and X-ray photoelectron spectroscopy. The FAP catalyst was found to be stable up to three recycles with no loss in activity.

Front Cover: Homemade Solution of NaOD in D 2 O: Applications in the Field of Stilbene‐ d 1 Synthesis (Asian J. Org. Chem. 3/2023)

Although NaOD in D2O is a valuable chemical reagent to prepare the deuterium-incorporated products, it costs high. The cover picture shows that the simple and cost-effective preparation of NaOD in D2O from D2O and t-BuONa was accomplished based on the salting-out effect. The homemade NaOD in D2O was used for the one-pot synthesis of mono-deuterated trans-stilbene (stilbene-d1) in the aqueous Horner–Wadsworth–Emmons reaction. The mono-deuterated trans-stilbenes were used to synthesize various deuterated compounds without a loss in the D content. More information can be found in the Research Article by Yoshinari Sawama et al.

Synthesis of New Azetidine and Oxetane Amino Acid Derivatives through Aza-Michael Addition of NH-Heterocycles with Methyl 2-(Azetidin- or Oxetan-3-Ylidene)Acetates.

In this paper, a simple and efficient synthetic route for the preparation of new heterocyclic amino acid derivatives containing azetidine and oxetane rings was described. The starting (N-Boc-azetidin-3-ylidene)acetate was obtained from (N-Boc)azetidin-3-one by the DBU-catalysed Horner-Wadsworth-Emmons reaction, followed by aza-Michael addition with NH-heterocycles to yield the target functionalised 3-substituted 3-(acetoxymethyl)azetidines. Methyl 2-(oxetan-3-ylidene)acetate was obtained in a similar manner, which was further treated with various (N-Boc-cycloaminyl)amines to yield the target 3-substituted 3-(acetoxymethyl)oxetane compounds. The synthesis and diversification of novel heterocyclic amino acid derivatives were achieved through the Suzuki-Miyaura cross-coupling from the corresponding brominated pyrazole-azetidine hybrid with boronic acids. The structures of the novel heterocyclic compounds were confirmed via 1H-, 13C-, 15N-, and 19F-NMR spectroscopy, as well as HRMS investigations.

Horner-Wadsworth-Emmons reaction as an excellent tool in the synthesis of fluoro-containing biologically important compounds.

Selective introduction of a double bond motif into a multifunctional organic compound is always a big challenge. The Horner-Wadsworth-Emmons reaction is one of the most reliable, simple, and stereoselective olefination methods, widely used in organic chemistry. To the best of our knowledge, no review article on the application of HWE reaction in the synthesis of fluoroorganic compounds with direct biological interest has been published in recent years. The importance of the HWE reaction should be emphasised due to its simplicity and stereoselectivity. Under mild conditions and in one step, valuable compounds can be obtained. The HWE reaction is primarily a great tool in the synthesis of fluoroolefins that are, among others, peptide bond mimetics. Therefore, it can serve as an indispensable approach to access peptide bioisosteres and, consequently, analogues of numerous enzyme inhibitors. The protocol may be utilized to obtain florinated vinylphosphonate, vinylsulfone or sulfonate derivatives, which exhibit biological activity. In this review article, we would like to summarize the HWE reaction output of the last 12 years (since 2010).

Synthesis of 2′-O-[3-(N-methylsulfamoyl)propan-1-yl]ribothymidine as a potentially applicable 2′-modified nucleoside for antisense oligonucleotides

A synthetic scheme was developed to derive a modified ribothymidine bearing a 3-(N-methylsulfamoyl)propyl group on 2′-oxygen (TMSP). For synthesis initiation, a nucleophilic attack of 1,2-ethanediol on 5′-protected 2,2′-anhydro-ribothymidine was performed to selectively modify the 2′-position. After protection of the 3′-hydroxy group, the hydroxyethyl group was oxidized to the aldehyde, which was coupled with isobutyl (diethoxyphosphinyl)methanesulfonate through the Horner–Wadsworth–Emmons reaction to yield the sulfonate intermediate. The intermediate was further converted to the desired TMSP. Using the phosphoramidite units derived from nucleosides, we synthesized oligonucleotides incorporating TMSP. Oligonucleotides modified with TMSP were found to have duplex stability, resistance toward 3′-exonuclease digestion, and antisense activity comparable to that of the oligonucleotide modified with a previously reported 2′-O-methylcarbamoylethyl group. Based on these results and the generality of the synthetic scheme, 2′-O-sulfamoylalkyl modification is expected to be used for the modulation of the properties of oligonucleotides by changing the substituents on the nitrogen, enabling the oligonucleotides to possess suitable properties for antisense oligonucleotides.

Design and Synthesis of New α-hydroxy β-fluoro/β-trifluoromethyl and Unsaturated Phosphonates from Carbohydrate-Derived Building Blocks via Pudovik and Horner-Wadsworth-Emmons Reactions.

Herein, we present the application of fluorinated carbohydrate-derived building blocks for α-hydroxy β-fluoro/β-trifluoromethyl and unsaturated phosphonates synthesis. Pudovik and Horner–Wadsworth–Emmons reactions were applied to achieve this goal. The proposed pathway of the key reactions is supported by the experimental results, as well as quantum chemical calculations. The structure of the products was established by spectroscopic (1D, 2D NMR) and spectrometric (MS) techniques. Based on our data received, we claim that the progress of the Pudovik and HWE reactions is significantly influenced by the acidic protons present in the molecules as assessed by pKa values of the reagent.

Total Synthesis of (+)‐Alstonlarsine A

An enantioselective total synthesis of (+)-alstonlarsine A (1), a monoterpenoid indole alkaloid possessing a unique pentacyclic skeleton as well as a rare biological activity, is achieved. The key step is an efficient domino sequence, comprising enamine formation followed by an inverse-electron-demand intramolecular dearomative Diels–Alder cycloaddition for the construction of 9-azatricyclo[4.3.1.03,8]decane core. The key intermediate for this domino sequence was synthesized by a newly developed methodology, relying on indole C(2)-H bond functionalization, combined with intramolecular Horner–Wadsworth–Emmons reaction. This tactical combination offers a new general entry into other (privileged) tricyclic frameworks possessing indole ring fused to 6-, 7- or 8-membered rings.

One-Pot O2-Oxidation and the Horner-Wadsworth-Emmons Reaction of Primary Alcohols for the Synthesis of (Z)-α,β-Unsaturated Esters.

We developed one-pot oxidation/olefination procedures of primary alcohols giving Z-α,β-unsaturated esters 3. TEMPO-(CuCl or CuBr2)-(2,2'-bipyridine) (1:1:1) catalyzed O2 oxidation of primary alcohols in the presence of Z-selective Horner-Wadsworth-Emmons reagent 1b and K3PO4 or NaH gave 3 with Z/E = 84:16 to 96:4 in high yields. A stepwise reaction was also developed. After TEMPO-CuBr2-(2,2'-bipyridine)-K3PO4 (1:1:1:1) catalyzed O2 oxidation of alcohols in MeCN, the resulting mixture was treated with a THF solution of 1b and t-BuOK at -78 °C to 0 °C, giving 3 with higher selectivity (Z/E = 91:9 to 99:1).

Sonosensitized Aggregation-Induced Emission Dots with Capacities of Immunogenic Cell Death Induction and Multivalent Blocking of Programmed Cell Death-Ligand 1 for Amplified Antitumor Immunotherapy

Sonosensitized Aggregation-Induced Emission Dots with Capacities of Immunogenic Cell Death Induction and Multivalent Blocking of Programmed Cell Death-Ligand 1 for Amplified Antitumor Immunotherapy

New fluorescent tetraphenylporphyrin-based dendrimers with alkene-linked fluorenyl antennae designed for oxygen sensitization

The design of porphyrin-based dendrimers featuring conjugated fluorenyl dendrons via alkene spacers allows evaluating the importance of the role of these spacers on the optical properties of interest. In the continuation of previous studies, a second-generation porphyrin-based dendrimer was synthesized and metalated by Zn(II) along with its known first-generation homologue. The targeted free-base porphyrin was obtained by repetitively cycling a Michaelis–Arbuzov reaction and a Horner–Wadsworth–Emmons reaction to construct the desired vinyl-containing dendrons. After metalation by Zn(II), meso-tetraphenylporphyrin-cored dendrimers with eight (ZnTPP-D1) and sixteen (ZnTPP-D2) fluorenyl arms at their periphery were eventually isolated. These species allow evaluating the influence of the central metal and of the 1,2-alkyne for 1,2-alkene exchange on fluorescence, oxygen photosensitization, and two-photon absorption. Such structure–property relationships are currently needed for the design of optimal dendrimeric photosensitizers allowing combined two-photon-based photodynamic therapy (2P-PDT) and imaging.

Overexpression of SRO_3163, a homolog of Streptomyces antibiotic regulatory protein, induces the production of novel cyclohexene-containing enamide in Streptomyces rochei.

Streptomyces antibiotic regulatory proteins (SARPs) are well characterized as transcriptional activators for secondary metabolites in Streptomyces species. Streptomyces rochei 7434AN4 harbors 15 SARP genes, among which 3 were located on a giant linear plasmid pSLA2-L and others were on the chromosome. Some SARP genes were cloned into an integrative thiostrepton-inducible vector pIJ8600, and their recombinants were cultivated. The recombinant of SARP gene, SRO_3163, accumulated a UV-active compound YM3163-A, which was not detected in the parent strain and other SARP recombinants. Its molecular formula was established to be C8H11NO. Extensive NMR analysis revealed that YM3163-A is a novel enamide, 2-(cyclohex-2-en-1-ylidene)acetamide, and its structure was confirmed by chemical synthesis including Horner-Wadsworth-Emmons reaction and ammonolysis.

A Straightforward, Purification-Free Procedure for the Synthesis of Ando and Still–Gennari Type Phosphonates

Abstract Z-Selective Still–Gennari and Ando modifications of the typically E-selective Horner–Wadsworth–Emmons reaction are highly valuable synthetic tools in organic chemistry. These procedures are based on application of bis(2,2,2-trifluoroethyl) phosphonates or diaryl phosphonates, respectively, for the olefination of carbonyl groups. In our research, we present an improved, straightforward, purification-free procedure for the synthesis of these reagents. The key step of our procedure is the reaction of phosphonic dichlorides with the appropriate sodium alkoxides, which results in 52–97% isolated yields of the desired products on a gram scale. The whole three-step process is performed in one pot. Most importantly, the product is obtained in over 95% purity after simple extraction, avoiding column chromatography and distillation. Moreover, we present the synthesis of a novel Still–Gennari type reagent, bis(1,1,1,3,3,3-hexafluoroisopropyl) phosphonates, which may exhibit improved Z-selectivity in Still–Gennari olefinations.

Asymmetric total synthesis of (–)-rossinone A

The asymmetric total synthesis of (–)-rossinone A, a meroterpene exhibiting a range of pharmacologically important biological activities, has been accomplished for the first time from geraniol by a concise eight-step sequence that involves the Horner–Wadsworth–Emmons reaction of an aldehyde derived from a geranylated hydroquinone intermediate with a chiral phosphonate prepared via the highly diastereoselective Davis oxidation of a known oxazolidinone derivative.

Synthesis and photoluminescence properties of fluorine‐containing poly(phenylene vinylene) bearing hexafluorocyclopentene‐fused phenanthrene unit

AbstractThe intramolecular oxidative photocyclization of 1,2‐diarylhexafluorocyclopentene (1) under light irradiation (λ = 365 nm) provided hexafluorocyclopentene‐fused phenanthrene with formyl groups (2) in moderate yield. The copolymerization of 2 with tetraethyl(2,5‐bis(dodecyloxy)‐1,4‐phenylene)bis(methylene)diphosphonate by the Horner–Wadsworth–Emmons reaction gave a fluorine‐containing poly(phenylene vinylene), Polymer‐2, in 41% yield. For comparison, a diphenylethene‐type copolymer, Polymer‐1, was also prepared analogously. The number‐average molecular weights of Polymer‐1 and Polymer‐2 were 8900 and 3300 g mol−1, respectively. The copolymers showed high thermal stability, as revealed by their thermogravimetric analysis. UV–visible spectra of the copolymers in CHCl3 showed π–π* transition peaks at around 420 nm, and the peaks shifted to longer wavelengths by ca 10 nm for samples in film form. The photoluminescence spectra of Polymer‐1 and Polymer‐2 exhibited peaks at 542 and 560 nm in CHCl3, respectively, whereas the photoluminescence intensity of Polymer‐2 was very low in the solid state, presumably owing to the partial aggregation of the polymer molecules. © 2021 Society of Industrial Chemistry.

Total Synthesis of 6-Hydroxymetatacarboline-d Discovered from Mycena metata via the Pictet-Spengler Reaction Followed by the Horner-Wadsworth-Emmons Reaction.

Total synthesis of a new β-carboline alkaloid, 6-hydroxymetatacarboline-d, which was isolated from fruiting bodies of Mycena metata was accomplished in 14 steps. The synthetic strategy features the Pictet–Spengler reaction to construct the tricyclic core followed by amide coupling and the Horner–Wadsworth–Emmons reaction.

Efficient synthesis of vinylene-linked conjugated porous networks via the Horner-Wadsworth-Emmons reaction for photocatalytic hydrogen evolution.

A simple, yet efficient synthetic approach for the construction of vinylene-linked conjugated porous networks was developed. Based on the Horner-Wadsworth-Emmons reaction, the condensation polymerization for the formation of an sp2 carbon-linkage can be achieved at room temperature. The resulting vinylene-linked frameworks exhibit a promising porous nature with the best surface area of up to 1373 m2 g-1. Their intrinsic conjugated architectures and semiconducting properties lead to photocatalytic evolution of hydrogen from water under visible light irradiation. This new synthesis method provides a facile means to prepare attractive sp2 carbon linked porous organic frameworks.

Synthesis of Vinylene‐Linked Two‐Dimensional Conjugated Polymers via the Horner–Wadsworth–Emmons Reaction

In this work, we demonstrate the first synthesis of vinylene‐linked 2D CPs, namely, 2D poly(phenylenequinoxalinevinylene)s 2D‐PPQV1 and 2D‐PPQV2, via the Horner–Wadsworth–Emmons (HWE) reaction of C 2‐symmetric 1,4‐bis(diethylphosphonomethyl)benzene or 4,4′‐bis(diethylphosphonomethyl)biphenyl with C 3‐symmetric 2,3,8,9,14,15‐hexa(4‐formylphenyl)diquinoxalino[2,3‐a:2′,3′‐c]phenazine as monomers. Density functional theory (DFT) simulations unveil the crucial role of the initial reversible C−C single bond formation for the synthesis of crystalline 2D CPs. Powder X‐ray diffraction (PXRD) studies and nitrogen adsorption‐desorption measurements demonstrate the formation of proclaimed crystalline, dual‐pore structures with surface areas of up to 440 m2 g−1. More importantly, the optoelectronic properties of the obtained 2D‐PPQV1 (Eg=2.2 eV) and 2D‐PPQV2 (Eg=2.2 eV) are compared with those of cyano‐vinylene‐linked 2D‐CN‐PPQV1 (Eg=2.4 eV) produced by the Knoevenagel reaction and imine‐linked 2D COF analog (2D‐C=N‐PPQV1, Eg=2.3 eV), unambiguously proving the superior conjugation of the vinylene‐linked 2D CPs using the HWE reaction.

Development of Manufacturing Processes for the Carboxylic Acid Key Intermediate of Lusutrombopag: One-Pot Reaction Process of Formylation and the Horner–Wadsworth–Emmons Reaction

We describe the development of a one-pot preparation process of (E)-3,5-dichloro-4-(3-ethoxy-2-methyl-3-oxoprop-1-en-1-yl)benzoic acid (3), which is a key carboxylic acid intermediate of lusutrombopag. This one-pot reaction process is composed of lithiation of 3,5-dichlorobenzoic acid with lithium diisopropylamide (LDA), formylation using N-formylmorpholine, followed by olefination employing the Horner–Wadsworth–Emmons reaction with triethyl 2-phosphonopropionate. This method enabled kilogram-scale manufacturing of carboxylic acid 3, a key intermediate of lusutrombopag with high purity, together with a reduced number of steps, improvement of yield, and avoidance of a cumbersome procedure for isolation of the intermediate.

Still–Gennari Olefination and its Applications in Organic Synthesis

AbstractThe Still–Gennari olefination is a widely applied modification of the Horner–Wadsworth–Emmons reaction, allowing access to Z‐olefins by carbonyl group transformation. Its synthetic utility is undoubtedly of great significance for organic chemistry, as can be illustrated by the number of citations of the original report by W. C. Still and C. Gennari which up to date has been cited over 1000 times. In 2008 Nobel prize winner Ei‐ichi Negishi indicated the Still–Gennari olefination as one of the crucial methods for tolefin synthesis, complementary to palladium‐catalyzed alkenylations. Surprisingly, so far there is no review concerning this popular and valuable transformation. Therefore, we aim to comprehensively systematize achievements in this field and to present the scope of applications of the Still–Gennari olefination along with recent examples in the total synthesis of biologically active compounds. Our review is intended to be of interest for the general chemical community as well as to be a helpful source of information for synthetic organic chemists.magnified image