Use of the Mitsunobu reaction in the synthesis of orthogonally protected α,β-diaminopropionic acids

Orthogonally protected α,β-diaminopropionic acids have been synthesised in good yields by the reaction of N-trityl l-serine esters with N-substituted sulfonamides under Mitsunobu reaction conditions (DEAD, PPh₃, THF). The best isolated yields were obtained when N-Boc p-toluenesulfonamide was used as the nitrogen nucleophile precursor in the Mitsunobu reaction. Subsequently, the N-trityl group was efficiently replaced with the more stable allyloxycarbonyl (alloc) group.     

Di-p-nitrobenzyl azodicarboxylate (DNAD): an alternative azo-reagent for the Mitsunobu reaction

Di-p-nitrobenzyl azodicarboxylate is prepared in 83.6% yield in two steps as a bright yellow solid, which can be used as an azo-reagent in the Mitsunobu reaction. When a chiral secondary alcohol was used, sufficient configurational inversion of alcohol occurred under Mitsunobu conditions. That the hydrazine produced from DNAD is semisoluble in some solvents such as THF and CH₂Cl₂ makes it separated easily from the reaction mixture just via filtration. Then the recovered hydrazine compound can be re-exposed to oxidant to produce DNAD. Because DNAD is more stable than DIAD at ambient temperatures and allows easy separation, it is a good alternative azo-reagent for the Mitsunobu reaction.     

An efficient synthesis of optically active 3-amino-3-alkyl-2-oxetanones

An efficient two-step synthesis of p-toluenesulfonic acid salts of optically active 3-amino-3-alkyl-2-oxetanones is reported that involves cyclization of N-Boc-α-alkylserines under Mitsunobu reaction conditions followed by deprotection of the amino group with trifluoroacetic acid in the presence of anhydrous p-toluenesulfonic acid.     

An unexpected migration of O-silyl group under Mitsunobu reaction conditions

A 1,4 O→O silyl migration followed by nucleophilic substitution with phthalimide was observed under Mitsunobu reaction conditions. This one step secondary alcohol protection and primary alcohol substitution with N-nucleophiles was extended to a variety of 2-hydroxyethyl trialkylsilylether derivatives. A possible mechanism has been postulated based on the pK_a values of the alcohol and nucleophile. The present one-pot silyl migration and substitution reaction might find application in the stereoselective synthesis of novel iminosugar derived anti diabetic agents.     

Influence of conjugation of donor and acceptor on the properties of hydrogen bonds of Cis and trans isomers

Cis and trans, and syn and anti. isomers are studied by IR and NMR in acetonitrile-d₃ solutions. Cis and syn isomers form completely intramolecular N⁺H…N⇌N…H⁺N bonds. They show, however, nearly no proton polarizability since the donor and acceptor are electronically conjugated. The trans and anti isomers form intermolecular N⁺H…N⇌N…H⁺N bonds showing large proton polarizability.     

N-(ethoxycarbonyl)ferrocenecarboxamide: Synthesis and use as the pronucleophile in the Mitsunobu reaction

The title compound has been synthesized in the reaction of ferrocene with ethoxycarbonyl isocyanate in methanesulfonic acid. It has been found that it undergoes N-alkylation with benzyl alcohols under classical Mitsunobu conditions (PPh₃/DEAD). However, in the reaction with cholesterol and stigmasterol O-alkylation with inversion of configuration occurred (confirmed by hydrolysis of the product obtained from cholesterol to epicholesterol). The structure of the product obtained from p-nitrobenzyl alcohol was determined by X-ray diffraction.     

Construction of 1H-indazoles from ortho-aminobenzoximes by the Mitsunobu reaction

Recently, there has been an upsurge in the occurrence of the indazole motif in drug discovery. Accordingly, newer, milder and more efficient routes towards their synthesis have emerged in the literature. We recently reported the Mitsunobu-triggered cyclodehydration of salicylaldoximes to transient 1,2-benzisoxazoles, and salicylhydroxamic acids to their corresponding 3-hydroxybenzisoxazoles. We hypothesized subjecting ortho-aminobenzoximes to Mitsunobu conditions will likewise induce a cyclodehydration to deliver the corresponding 1H-indazoles. Indeed, secondary anilines afforded the predicted N¹-substituted 1H-indazoles, and primary anilines, after activation with a Boc group, furnished the N¹-Boc 1H-indazoles in good to excellent yields. This work further expands the chemical repertoire of the Mitsunobu reaction, representing its unprecedented use in the construction of the 1H-indazole nucleus.     

Decomposition of meta- and para-phenylphenol during ozonation process

The decomposition of meta-phenylphenol (m-PP) and para-phenylphenol (p-PP) in a heterogeneous gas-liquid system using ozone was investigated. The influence of different reaction parameters such as ozone and PP isomers concentration as well as pH and temperature of the reaction mixture on the PP decay rate was determined. The second-order rate constants for the direct reaction of molecular ozone, determined in a homogeneous system, were (5.85 ± 0.35) × 10² M^?1 s^?1 and (8.90 ± 0.33) × 10² M^?1 s^?1 for m-PP and p-PP, respectively. The rate constants for the reaction of m-PP and p-PP with ozone increased with increasing pH. The reaction rate constants with ozone were found to be (1.75 ± 0.02) × 10⁹ M^?1 s^?1 and (1.86 ± 0.02) × 10⁹ M^?1 s^?1 for m-PP and p-PP anions, respectively.     

Stereoselective anti-SN2′ Mitsunobu reaction of α-hydroxy-α-alkenylsilanes

A novel silyl group-directed anti-S_N2′ reaction of allylic alcohols under Mitsunobu reaction conditions is described. The Mitsunobu reaction of α-hydroxy-α-alkenylsilanes with a TBS or TIPS group gave the anti-S_N2′ product, in which regio- and stereochemical outcomes of the reaction depended on the steric bulkiness of the silyl group.     

Synthesis and structural studies of N-(p-toluenesulfonyl)-amino acid 3,5-di-tert-butyl-2-phenolamides

This paper describes the synthesis and structural studies of N-(p-toluenesulfonyl)-amino acid 3,5-di-tert-butyl-2-phenolamides by ¹H, ¹³C, and ¹⁵N. The presence of intra- and intermolecular hydrogen bonds were studied by variable temperature NMR spectroscopy. The molecular structure of two amides in the solid state was determined by X-ray diffraction experiments. The results show that tert-butyl substituents in the phenolic ring have important effects in the nature of hydrogen bonds and conformation of these amides. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:114–120, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10223     

The preparation of conducting polyaniline�Csilver and poly(p-phenylenediamine)�Csilver nanocomposites in liquid and frozen reaction mixtures

The oxidation of aniline with silver nitrate in 1?mol?L^?1 acetic acid at 20?°C yielded a composite of two conducting components, polyaniline and silver; the acceleration with 1?mol% of p-phenylenediamine is needed for efficient synthesis. The yield and molecular weight increased when aniline was copolymerized with 10?mol% p-phenylenediamine. Such product displayed metallic conductivity below 180?K and semiconductor type above this temperature. As the result, the conductivity was the same at 100 and 300?K. The oxidation of p-phenylenediamine alone with silver nitrate also produced a conducting composite having the conductivity of 1,750?S cm^?1 despite the assumed nonconductivity of poly(p-phenylenediamine). The present study demonstrates that all oxidations proceeded also in frozen reaction mixtures at ?24?°C, i.e., in the solid state. In most cases, molecular weights of polymer component increased, the conductivity of composites with silver improved, to 2,990?S?cm^?1 for poly(p-phenylenediamine)?Csilver, and remained high after deprotonation with 1?mol?L^?1 ammonium hydroxide.     

Selective O-alkylations with glycol chlorohydrins via the Mitsunobu reaction. A versatile route to calix[4]- and 1,1′-binaphthocrowns

Selective monoalkylation of p-tert-butylcalix[4]arene and BINOL with oligoethylene glycol chlorohydrins was achieved under the Mitsunobu protocol using DEAD/TPP. The method provides a simple access to ether precursors capable of cyclising to various crowns.     

Regioselective alkylation of the exocyclic nitrogen of adenine and adenosine by the Mitsunobu reaction

A novel synthetic route to N⁶-substitution of adenine is presented, employing the Mitsunobu reaction as the key step. A range of primary and secondary alcohols all coupled in very good to excellent yields within 30 min at 45 °C, offering a milder alternative to the traditional nucleophilic aromatic substitution of 6-chloropurine. The utility of this protocol is further demonstrated by its application to the syntheses of N⁶,N⁹-di-substituted adenines, including the potent and selective A₁ adenosine receptor agonist N⁶-cyclopentyladenosine.     

An expedient route to p-tert-butylthiacalix[4]arene 1,3-diethers via Mitsunobu reactions

Regioselective distal dialkylation of p-tert-butylthiacalix[4]arene with alcohols was performed under the Mitsunobu protocol using the DEAD/TPP system. The method provides a versatile tool for obtaining 1,3-diethers with different functional groups in the alkyl chains.     

Mitsunobu reactions of aliphatic alcohols and bulky phenols

Alkylation of hydrazinedicarboxylate (a Mitsunobu by-product) is not a notable problem in common Mitsunobu alkyl aryl etherification reactions. Good yields can be obtained with a wide range of solvents. However, this side reaction can cause yield reduction for the reactions of sterically hindered phenols and primary alcohols. To suppress the side reaction, solvent effect was investigated. It was found that hydrazinedicarboxylate is about five times less soluble in diethyl ether than in THF, and the yields are improved for ortho-substituted phenols of a wide range of steric hindrance using diethyl ether as the solvent instead of THF which is the more commonly used for Mitsunobu reactions.     

Reaction rate of crosslinkings by using a metallated polymer. II. Intermolecular and intramolecular crosslinkings at the second state

Lithium-metallated styrene–p-benzylstyrene copolymer was reacted with the branched polymer with chlorine groups at the pendant chain ends (multifunctional branched polymer) in tetrahydrofuran (THF) at 25°C. The rate constant was estimated from the changes in the concentration of metallated polymer by using photometrical measurements. The various reaction conditions were chosen and it became clear that the rate constants of intermolecular (k₂₀) and intramolecular (k_3intra) crosslinkings were derived separately at the second stage. k₂₀ showed a constant value in spite of the molecular weight of crosslinker chains and was about equal to the rate constant of the grafting. The rate of intramolecular crosslinking at the second stage increased with decreasing the molecular weight of pendant chains of multifunctional branched polymer.     

Reaction rate of crosslinkings by using metallated polymer. I. Grafting and intramolecular crosslinkings at the first stage

Lithium-metallated styrene–p-benzylstyrene copolymer was reacted with chlorine-terminated polystyrene as a crosslinker polymer in tetrahydrofuran (THF) at 25°C. The rate constant was estimated from the changes in the concentration of metallated polymer by using photometrical measurements. The various reaction conditions were chosen and it became clear that the rate constants of grafting (k₁) and intramolecular crosslinkings (k_2intra) were gotten separately at the first stage. As a result, k_2intra showed larger values than k₁ and decreased with increasing degree of polymerization of crosslinker polymers.     

A practical large scale chemical synthesis of chiral glycines

(R)- and (S)-[2-²H]glycine of high chiral purity were synthesized in large quantities in ≈ 40% overall yield from readily available starting materials via a totally chemical procedure. Reduction of either [1-²H]-furfural or [1-²H]-4-methoxybenzaldehyde with either (+) or (-)-B-isopinocampheyl-9-borabicyclo[3.3.1]nonane gave chiral arylmethyl alcohols which were converted into their respective phthaloyl amino derivatives of the opposite configuration at the methylene carbon via the Mitsunobu reaction. The aromatic groups were oxidatively unmasked to give their corresponding glycine derivatives by either ozone or ruthenium tetraoxide oxidation.     

Author index to volume 53

The triplet-state EPR spectra of photosynthetic bacteria reported in the literature exhibit a unique spin polarization pattern, previously attributed to intermolecular processes such as electron transfer. We show here that another, purely intramolecular, model can also account for the observed spin polarization. New experimental results, obtained for a porphyrin triplet state, are used to illustrate the proposed interpretation.