Mitsunobu Reagents Research Articles

Diphenoxytriphenylphosphorane: A potent carbohydrate cyclodehydration reagent

Methyl α(and β)-D-3,4-anhydro-tagatofuranosides are important synthetic building blocks as they undergo regioselective ring-opening to afford exclusively products with the D-fructo configuration. Previous attempts to prepare these compounds from the corresponding methyl D-fructofuranosides under standard Mitsunobu conditions have led to an undesired 9:1 mixture of tagato and psico oxiranes. We now report that in the presence of added phenol, the tagato product is formed exclusively and in quantitative yield under extremely mild conditions. Similarly, both D- and L-methyl arabinofuranosides, gave the corresponding methyl 2,3-anhydro-D-lyxofuranosides and methyl 2,3-anhydro-L-lyxofuranosides in quantitative yields using this modified Mitsunobu protocol. The mechanism of this reaction appears to involve the intermediate formation of diphenoxytriphenylphosphorane, which acts as a selective Mitsunobu reagent for oxirane formation from fructo and arabino furanosides as well as trans-diaxial pyranoside diols such as those in levoglucosan. An unusual Mitsunobu-induced anomerisation reaction is also reported.

A new “Mitsunobu homocoupling” reaction using aldol adducts of kojic acid

In this study, we attempted to carry out the Mitsunobu 1,4-elimination using the kojic acid analog 3, which carries a hydroxymethyl group on C-6 introduced by aldol condensation, to obtain an effective Michael acceptor 4. To the ethyl acetate solution of 3 and Ph3P, diisopropyl azodicarboxylate was added quickly at 0 °C, resulting in the immediate generation of a yellow precipitate. NMR, mass spectrometry, and X-ray crystal structure analyses allowed to identify the precipitate as a diastereomeric/racemic mixture of dimeric compounds of 4. The dimerization reaction was hypothesized to occur through two major steps: (i) intramolecular dehydration of 3 by Mitsunobu reagents and (ii) homocoupling of the dehydration product 4 to form a new trans-carbon–carbon double bond. Presumably, the enol ether moiety of 4 acts as an electron donor and immediately attacks the α,β-unsaturated carbonyl group of another molecule via a reaction that can be dubbed “Mitsunobu homocoupling.”

Synthesis of Benzoxazole‐2‐carboxylate Derivatives: Electronic‐ and Position‐effect of Functional Groups and Computational Modeling of the Selectivity for Oxazole Ring

AbstractIn this study, Mitsunobu reagent, DEAD (diethyl azodicarboxylate) and PPh3, and ethyl‐oxalamide derivatives of 2‐aminophenol were reacted under mild reaction conditions. As a result of the cyclization reaction, benzoxazole derivatives bearing an ester group in the C‐2 position were obtained in a one‐pot protocol. It was observed that the electron‐donating groups at the C‐5 position and the electron‐withdrawing groups at the C‐6 position of the benzene ring increased the yield of the cyclic product. It was found that the cyclization does not occur when the carboxylic acid group is substituted in the benzene ring. The cyclization reaction we performed preferred the 5‐endo‐trig reaction instead of the 6‐exo‐trig. This experimental result was examined in detail with density functional theory (DFT) calculations as well. A computational exploration is presented herein that elucidates the detailed mechanism for Huisgen zwitterion‘s reaction with ethyl‐oxalamide derivatives of 2‐aminophenol. Potential alternative mechanisms were modeled with DFT calculations via CPCM/M06‐2X/6‐311++G(d,p)//B3LYP/6‐31+G(d,p) level method in tetrahydrofuran to understand shed light on the mechanism. Our computational results are in good agreement with experimental findings that benzoxazole derivatives are the sole products in this reaction.

Synthesis of 18O-labelled alcohols from unlabelled alcohols.

The synthesis of primary, secondary and tertiary 18O-enriched alcohols from readily available 16O-alcohols via a Mitsunobu esterification and hydrolysis is described. The method is further exemplified in the labelling of the active pharmaceutical ingredient, dropropizine and is shown to be tolerant of modern, separation friendly Mitsunobu reagents.

Development of Mitsunobu Reagents Recyclable by Aerobic Oxidation and the Application to Catalytic Mitsunobu Reactions

Development of Mitsunobu Reagents Recyclable by Aerobic Oxidation and the Application to Catalytic Mitsunobu Reactions

Rapid and Efficient Synthesis of 11C‐Labeled Benzimidazolones Using [11C]Carbon Dioxide

Abstract[11C]Carbon dioxide is an attractive synthon for the labeling of positron emission tomography (PET) tracers for subsequent use in biomedical research and drug development. In this study, [11C]CO2 was used for direct 11C‐labeling of a set of cyclic aromatic ureas starting from their corresponding ortho‐phenylenediamines, BEMP (2‐tert‐butylimino‐2‐diethylamino‐1,3‐dimethylperhydro‐1,3,2‐diazaphosphorine) as fixation base, and Mitsunobu reagents (DBAD, nBu3P) for the intramolecular cyclization. The procedure is rapid (6 minutes total synthesis time), mild (proceeds at room temperature) and provided a set of 11C‐benzimidazolones in good to excellent radiochemical yields. As a final testament to the utility of this method, the beta‐adrenoceptor PET ligand [11C]CGP12177, was successfully prepared using the optimized conditions.

In My Element: Sulfur

The In My Element series celebrates the personal accounts from Chemistry – A European Journal Editorial Board members for the 2019 International Year of the Periodic Table. In this contribution, Tien-Yau Luh gives his story on sulfur. I never “loved” smelly sulfur compounds, but have always admired the versatility of sulfur chemistry. In the 1980s, we worked on organometallics to mimic desulfurization by Raney nickel and oil refining hydrotreatment. My first Ph.D. student, Zhi-Jie Ni, joined the Chinese University of Hong Kong in 1986. He was more synthetically oriented and had just learned cross-coupling from Kumada's seminar in Shanghai. Quite quickly, he discovered the nickel-catalyzed olefination of benzylic and allylic dithioacetals under Kumada conditions. Silyl-substituted styrenes and dienes could be obtained conveniently using this method. Meanwhile, Lam Lung Yeung unearthed Mo(CO)6-promoted desulfurdimerization of dithiolanes. These discoveries led us to work systematically on the conversion of two C−S bonds in dithioacetals into two C−C bonds. Ping-Fan Yang furnished geminal dimethylation using a bidendate phosphine ligand. After I moved back to Taiwan in 1988, Ken-Tsung Wong invented chelation-assisted, nickel-catalyzed olefination of aliphatic dithioacetals. Sulfur and carbon have similar electronegativities, and thus, Hsian-Rong Tseng and Chi-Fa Lee found that the propargylic dithioacetal serves as a propyne-1,3-zwitterion sython. This strategy offers a one-pot annulation of substituted furans and pyrroles. Chi-Wei Chen used the Mitsunobu reagent to eliminate β-thioalkoxyalcohols (obtained from dithioacetals). The reaction could then be extended for the selective synthesis of oligodiacetylenes. Our group members’ endeavor have shaped the dithioacetal group as a “pet” functionality in our laboratory. Position Professor Emeritus and Distinguished Chair Professor E-mail [email protected] Homepage https://www.ch.ntu.edu.tw/english/faculty/?id=tyluh&lang=en Education B.Sc. National Taiwan University (1967 and Taipei) Ph.D. University of Chicago (1974, Leon M. Stock, Chemistry of Cubane, Chicago) Postdoctoral positions (1974-76, Paul G. Gassman, Minneapolis) Notable awards Academic Award, Chemical Society Located in Taipei, 2012, JSPS Fellow, 2010, National Chair Award, Ministry of Education, 1999-2002, Ministry of Education Award for the Outstanding Research in Science, 1998, Outstanding Scholar Award, Foundation for the Advancement of Outstanding Scholarship, 1995-2000, Executive Yuan′s Outstanding Award on Science and Technology, 1994 Research interests Organometallics in organic and polymer synthesis, and chemistry of materials Hobbies Hiking, museums, calligraphy The Luh research group.

Regioselective formation of 1,2,4-triazoles by the reaction of amidrazones in the presence of diethyl azodicarboxylate and catalyzed by triethylamine.

A general method for the synthesis of 1,3,5-trisubstituted 1,2,4-triazoles has been developed from reaction of amidrazones with ethyl azodicarboxylate and triethylamine (Mitsunobu reagent) in EtOH. This highly regioselective one-pot process provides rapid access to highly diverse triazoles. The reaction was explained, based on Mitsunobu reagent oxidizing ethanol to acetaldehyde, which would then react with amidrazones to give the substituted 3-methyltriazoles. A [2 + 3] cycloaddition reaction between two oxidized forms of amidrazones produced the second type of triazoles. X-ray structure analyses proved the structure of each type of product.

Systematic Evaluation of 2-Arylazocarboxylates and 2-Arylazocarboxamides as Mitsunobu Reagents.

2-Arylazocarboxylate and 2-arylazocarboxamide derivatives can serve as replacements of typical Mitsunobu reagents such as diethyl azodicarboxylate. A systematic investigation of the reactivity and physical properties of those azo compounds has revealed that they have an excellent ability as Mitsunobu reagents. These reagents show similar or superior reactivity as compared to the known azo reagents and are applicable to the broad scope of substrates. p Ka and steric effects of substrates have been investigated, and the limitation of the Mitsunobu reaction can be overcome by choosing suitable reagents from the library of 2-arylazocarboxylate and 2-aryl azocarboxamide derivatives. Convenient recovery of azo reagents is available by one-pot iron-catalyzed aerobic oxidation, for example. SC-DSC analysis of representative 2-arylazocarboxylate and 2-arylazocarboxamide derivatives has shown high thermal stability, indicating that these azo reagents possess lower chemical hazard compared with typical azo reagents.

A new approach to arylhydrazides via the reaction of the Mitsunobu reagent with arynes: further application to access diverse nitrogen-containing heterocycles in one pot

A new route to arylhydrazides involving the reaction of two highly active intermediates, the 1,3-zwitterion generated in situ from the Mitsunobu reagent and arynes, under mild conditions has been developed.

ChemInform Abstract: Advances and Mechanistic Insight on the Catalytic Mitsunobu Reaction Using Recyclable Azo Reagents.

AbstractEthyl 2‐arylazocarboxylates are described as useful Mitsunobu reagents applied in catalytic amounts only.

Chromatography-free, Mitsunobu-triggered heterocyclizations of salicylhydroxamic acids to 3-hydroxybenzisoxazoles

The Mitsunobu reaction has become one of the most powerful tools to alkylate acidic pronucleophiles. A significant caveat of Mitsunobu chemistry, however, is that the reaction mixture is often plagued with purification problems owing to the phosphine oxide and hydrazine dicarboxylate by-products. In addition to the development of more readily separable Mitsunobu reagents, the product’s physicochemical properties may be exploited to facilitate purification. In this regard, we present a swift and efficient preparation of 3-hydroxybenzisoxazoles by the Mitsunobu-triggered heterocyclizations of salicylhydroxamic acids, which can be isolated by an acid–base work-up. As expected, a range of functional groups was compatible with the chemistry.

ChemInform Abstract: Nonsymmetrical Azocarbonamide Carboxylates as Effective Mitsunobu Reagents.

A family of nonsymmetrical Mitsunobu reagents possessing both dialkyl amide and ester substituents was developed. These new reagents were readily prepared in a single pot from inexpensive, commercially available materials by using a scalable and environmentally friendly procedure. They were shown to exhibit activity parallel to that of diethyl azodicarboxylate/diisopropyl azodicarboxylate in a wide variety of Mitsunobu reactions. Importantly, the acyl hydrazine reaction byproducts were readily separable from the crude mixture by standard aqueous workup. In addition, the discovery of effective nonsymmetrical Mitsunobu reagents offers new directions for the ongoing development of this important reaction.

Corrigendum: Recyclable Mitsunobu Reagents: Catalytic Mitsunobu Reactions with an Iron Catalyst and Atmospheric Oxygen

Corrigendum: Recyclable Mitsunobu Reagents: Catalytic Mitsunobu Reactions with an Iron Catalyst and Atmospheric Oxygen

ChemInform Abstract: The Use of a Mitsunobu Reagent for the Formation of Heterocycles: A Simple Method for the Preparation of 3‐Alkyl‐5‐aryl‐1,3,4‐oxadiazol‐2(3H)‐ones from Carboxylic Acids.

AbstractThe reaction proceeds smoothly when Mitsunobu reagents with smaller alkyl groups are used.

Nonsymmetrical Azocarbonamide Carboxylates as Effective Mitsunobu Reagents

AbstractA family of nonsymmetrical Mitsunobu reagents possessing both dialkyl amide and ester substituents was developed. These new reagents were readily prepared in a single pot from inexpensive, commercially available materials by using a scalable and environmentally friendly procedure. They were shown to exhibit activity parallel to that of diethyl azodicarboxylate/diisopropyl azodicarboxylate in a wide variety of Mitsunobu reactions. Importantly, the acyl hydrazine reaction byproducts were readily separable from the crude mixture by standard aqueous workup. In addition, the discovery of effective nonsymmetrical Mitsunobu reagents offers new directions for the ongoing development of this important reaction.

Direct Coupling of Cs2CO3and Alcohols for the Synthesis of Dimethyl, Diethyl, and Various Dialkyl Carbonates

Dimethyl carbonate (DMC) has been used in synthetic organic chemistry as a low-toxicity and versatile methylating and carbonylating agent. In industrial processes, DMC is widely used as a fuel additive, electrolyte for lithium ion batteries, and monomer for polycarbonate and polyurethane synthesis. Therefore, an efficient and high-yield synthesis for DMC has been actively investigated. Reaction conditions typically involve either carbon monoxide (CO) or derivatives (e.g., phosgene), or carbon dioxide (CO2) or derivatives (e.g., inorganic carbonates or organic cyclic carbonates). Due to the toxicity and flammability of CO and phosgene, the more environmentally benign and sustainable carbon sources CO2 and derivatives have been actively employed for production of DMC and related acyclic carbonates. The DMC and acyclic carbonate syntheses that have been reported include: 1) transesterification of cyclic carbonates derived from oxirane and CO2; 2) dehydrative condensation of alcohols with CO2; 3) reactions between alkyl halide and metal carbonates; 4) reactions between alcohol, alkyl halide, and CO2; and 5) reactions between alcohol and CO2 in the presence of condensing agents. Other than transesterification of cyclic carbonates, DMC is generated from alcohols or alkyl halide. In terms of chemical cost, use of an alcohol without an extra step for alkyl halide preparation appears more desirable; however, direct coupling of alcohols with CO2 or metal carbonates is challenging. In dehydrative condensation of alcohols with CO2, very efficient dehydrating reagents and metal catalysts are necessary to drive the reaction equilibrium to the product. In direct coupling of alcohols with CO2, alcohol-activation reagents such as the Mitsunobu reagent are required. According to Saito et al., dichloromethane, a common organic solvent, has been used as an alcohol-activating reagent for synthesis of various aliphatic carbonates in the presence of CO2 and Cs2CO3 (base), although synthesis of DMC has not been reported using dichloromethane. In the present study, we used dibromomethane (CH2Br2) as an alcohol-activating reagent and solvent. Using CH2Br2 and an ionic liquid, direct coupling of alcohols with Cs2CO3 in the absence of CO2 was achieved. Using Cs2CO3-mediated conditions, various aliphatic carbonates, including DMC and diethyl carbonate (DEC), were prepared with good yields. Optimization of the synthesis of carbonate 1 is summarized in Table 1. Reaction of cinnamyl alcohol and Cs2CO3 in a mixture of dichloromethane (CH2Cl2) and 1-butyl-3-methylimidazolium hexafluorophosphate (bmimPF6) was carried out at 70 C. Even in the absence of CO2, carbonate 1 was formed with 71% yield (entry 1). In this reaction, Cs2CO3

The use of a Mitsunobu reagent for the formation of heterocycles: a simple method for the preparation of 3-alkyl-5-aryl-1,3,4-oxadiazol-2(3H)-ones from carboxylic acids.

The reaction of carboxylic acids with Mitsunobu reagents, prepared by the reaction of triphenylphosphine with dialkyl azodicarboxylates, followed by heating at 180-190 °C under solvent-free conditions, afforded 3-alkyl-5-aryl-1,3,4-oxadiazol-2(3H)-ones. This facile and convenient method readily provides the 1,3,4-oxadiazolone ring systems in good yields using a one-pot protocol starting from the corresponding carboxylic acids. It was also demonstrated that the presence of a catalytic base facilitates the final ring closure forming the 1,3,4-oxadiazol-2(3H)-one.

ChemInform Abstract: Recyclable Mitsunobu Reagents: Catalytic Mitsunobu Reactions with an Iron Catalyst and Atmospheric Oxygen.

Aerobic recycling: A catalytic amount of a hydrazine reagent is sufficient to promote Mitsunobu reactions in the presence of triphenylphosphine, an iron catalyst, and air. The active form of the catalyst, an azo species, can be readily generated by iron-catalyzed aerobic oxidation. MS = molecular sieves, Pc = phthalocyanine.

Ionic Liquid Based Vilsmeier Reagent as a Substitute for Mitsunobu Reagent: Direct Conversion of Alcohols into Different Compounds under Ionic Liquid Conditions

The ionic liquid based methylchloroiminium chloride reagent (Vilsmeier reagent) derived from DMF-like multipurpose functional ionic liquid has been used as an efficient and reusable reagent for Mitsunobu reaction. Variety of different alcohols has been converted into different classes of compounds under ionic liquid conditions. The present system offers a competitive and better alternative to routine Mitsunobu protocol.