Dicyclopentyl azodicarboxylate(DCpAD):A new alternative azo-reagent for the Mitsunobu reaction

Dicyciopentyl azodicarboxylate is introduced as a new azo-reagent which can be conveniently prepared in two steps and be used in the Mitsunobu reaction.Though there are no distinct difference of reactivity between DCpAD and DEAD,the former is a more preferable azo-reagent for its stability.     

Impurity annihilation: chromatography-free parallel Mitsunobu reactions

Mitsunobu reaction of an alcohol ROH with a carboxylic acid, phthalimide, or N-hydroxyphthalimide (NuH) using DNAD (4) and (diphenylphosphino)polystyrene (11) gave the products RNu. Ring-opening metathetic polymerization of the side product DNADH(2) (3) using Cl(2)(Cy(3)P)(2)Ru=CHPh (13) and filtration, to remove poly(DNADH(2)), (diphenylphosphino)polystyrene 11, its oxide, and its adduct with excess DNAD, gave RNu (43-100%, 86-96% purity) without recourse to chromatography.     

Synthesis of amino terminated semifluorinated long-chain alkanethiols

The α,ω-diiodoperfluorooctane is added to undecyl-10-en-1-ol through AIBN initiation yielding the monoadduct in good yield (1,2-dichloroethane, 52%). This is added to N-allylphthalimide (AIBN initiation, 1,2-dichloroethane, 81%). The resulting diiodo compound is hydrodeiodinated with Bu₃SnH (toluene, 70%) and the alcohol function is converted to thioacetate through the Mitsunobu reaction (PPh₃, DIAD, THF, 75%). The two protecting groups, phthalimide and thioacetate, are removed with hydrazine to give the expected amino terminated semifluorinated long-chain alkanethiol (ethanol, 80%). This compound has been designed in order to form mixed fluorinated self-assembled monolayers (SAMs) with semifluorinated long-chain alkanethiol giving access to a new platform system for biosensors. Similar results are reported starting from the α,ω-diiodoperfluorohexane.     

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.     

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.     

Tetrazine Assists Reduction of Water by Phosphines: Application in the Mitsunobu Reaction

Reaction of 3,6‐disubstituted‐1,2,4,5‐tetrazines with water and PEt₃ forms the corresponding 1,4‐dihydrotetrazine and OPEt₃. Thus PEt₃, as a stoichiometric reductant, reduces water, and the resulting two reducing equivalents serve to doubly hydrogenate the tetrazine. A variety of possible initial interactions between electron‐deficient tetrazine and electron‐rich PR₃, including a charge transfer complex, were evaluated by density functional calculations which revealed that the energy of all these make them spectroscopically undetectable at equilibrium, but one of these is nevertheless suggested as the intermediate in the observed redox reaction. The relationship of this to the Mitsunobu reaction, which absorbs the components of water evolved in the conversion of alcohol and carboxylic acid to ester, with desirable inversion at the alcohol carbon, is discussed. This enables a modified Mitsunobu reaction, with tetrazine replacing EtO₂CN=NCO₂Et (DEAD), which has the advantage that dihydrotetrazine can be recycled to tetrazine by oxidation with O₂, something impossible with the hydrogenated DEAD. For this tetrazine version, a betaine‐like intermediate is undetectable, but its protonated form is characterized, including by X‐ray structure and NMR spectroscopy.     

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.     

2-(Prenyloxymethyl)benzoyl (POMB) group: a new temporary protecting group removable by intramolecular cyclization

2-(Prenyloxymethyl)benzoates can be prepared from alcohols and readily available 2-(prenyloxymethyl)benzoic acid by standard acylation techniques or by Mitsunobu reaction with inversion of configuration. The POMB group can be cleaved first by oxidative removal of the prenyl group with DDQ followed by lactonization with expulsion of the alcohol catalyzed by Yb(OTf)₃. These reaction conditions are compatible with the presence of a large number of common protecting groups.     

The First Mitsunobu Protocol for Efficient Synthesis of α-Acyloxyphosphonates Using 4,4′-Azopyridine

Abstract

This is the first report on applying the Mitsunobu protocol for the synthesis of various α-acyloxyphosphonates using 4,4′-azopyridine and PPh₃ with diverse aromatic and aliphatic carboxylic acids. Under these conditions, diethyl azodicarboxylate (DEAD) as the traditional reagent for Mitsunobu reaction is not efficient. The insoluble pyridine hydrazine byproduct can be simply isolated and recycled to its azopyridine by an oxidation reaction and reused again.

[Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental resource: Characterization data of compounds 3a–3z2 and NMR spectra.]

GRAPHICAL ABSTRACT      

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.     

Stereospecific synthesis of chiral tertiary alkyl-aryl ethers via Mitsunobu reaction with complete inversion of configuration

Mitsunobu reaction of chiral tertiary alcohol (S)-2 with phenol 3 provides the desired ether (R)-1 in moderate yields at elevated temperatures (80-100°C). The S_N2 displacement pathway is evident by complete inversion of the (S)-alcohol to (R)-ether.     

Easily prepared azopyridines as potent and recyclable reagents for facile esterification reactions. An efficient modified mitsunobu reaction

The 2,2'-, 3,3'-, and 4,4'-azopyridines (azpy) and their alkyl pyridinium ionic liquids were studied as a new class of electron-deficient reagents for Mitsunobu esterification reactions. Among these compounds, 4,4'-azopyridine was found to be the most suitable one for esterification and thioesterification reactions. This new reagent promises to provide general and complementary solutions for separation problems in Mitsunobu reactions without restricting the reaction scope and facilitates the isolation of its hydrazine byproduct. The pyridine hydrazine byproduct can be simply recycled to its azopyridine by an oxidation reaction.     

An unusual acetonide group migration

Treatment of (2S,3R)-2,3-O-isopropyliden-4-penten-1,2,3-triol mesylate with uracil, K₂CO₃ did not provide the product of S_N2 displacement, but an interesting acetonide group migration product 8. The structure of 8 was secured by spectral analysis and single crystal X-ray analysis. The desired product 2 could be ultimately obtained by Mitsunobu reaction of the alcohol 6 with 3-N-benzoyl uracil followed by basic hydrolysis.     

The breaking and mending of porphyrins: reductive coupling of secochlorin bisaldehydes

The reaction of free base or Ni(II) complex secochlorin bisaldehydes 4H₂ and 4Ni regenerates the ultimate starting material of the bisaldehydes, meso-tetraphenylporphyrin 2H₂ and 2Ni, respectively. Depending on the reaction conditions employed (hydrazine hydrate in pyridine at reflux or hydrazine hydrate activated with sulfur in the presence of aqueous NaOH at ambient temperature), either porphyrin 2H₂ is formed together with known dihydroxymorpholinochlorin 9H₂ or known 2-hydroxychlorin 8H₂. Two different reaction pathways for the hydrazine reaction can be derived, either involving the formation of a meso-tetraphenyl-1,4,5-triazepinoporphyrin that loses spontaneously N₂ or a Wolff-Kishner-type pathway that also involves an intramolecular aldol-type reaction. Neither reaction is synthetically useful but both highlight in an impressive fashion the high thermodynamic stability of porphyrins. They also bring the ‘breaking and mending of porphyrin’ strategy to its ultimate conclusion by regenerating the starting porphyrin.     

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.     

Capture-ROMP-release: application for the synthesis of O-alkylhydroxylamines

[reaction: see text] A new capture-ROMP-release method for chromatography-free purification of N-hydroxysuccinimde Mitsunobu reactions is described. The Mitsunobu reaction captures a variety of alcohols onto a norbornenyl N-hydroxysuccinimide monomer. Subjection of the resulting crude reaction mixture to ROM-polymerization generates a polymer that can be precipitated with methanol and filtered from the Mitsunobu byproducts. Treatment of the polymer with hydrazine releases the substrate from the water-soluble polymer, producing a variety of O-alkylhydroxylamines with good purity.     

Stereodefined synthesis of the four possible stereoisomers of 5,18-diHETE

Because of the structural similarity between 5,18-diHETE and anti-inflammatory resolvin E2, synthesis of 5,18-diHETE was studied. Methyl (R)-3-hydroxyvalerate was converted to the (R)-C9–C20 phosphonium salt via alkylation of the derived iodide with propargyl alcohol dianion and subsequent Castro-Stephens coupling. The (S)-enantiomer was prepared via Mitsunobu inversion. The (R)- and (S)-enantiomers of the γ-TMS-propargylic alcohol corresponding to the C1–C7 part were constructed by asymmetric hydrogen transfer reaction and converted to the (R)- and (S)-enals by adding the aldehyde carbon using the reaction of the derived TMS-epoxide with Et₂AlCN followed by hydride reduction. The (R)-enantiomer of the C1–C8 enal was coupled with the (R)-C9–C20 phosphonium salt by Wittig reaction, and the functional group in the product was transformed to afford 5R,18R-diHETE stereoselectively. Other stereoisomers were synthesized as well.     

A synthesis of the γ-secretase inhibitor BMS-708163

A concise, convergent racemic synthesis of BMS-708163 is reported. Two fragments consisting of N-4-chlorophenylsulfonyl-3,3,3-trifluorpropylglycine and a 1,2,4-oxadiazole derivative of 2-fluorobenzyl alcohol were prepared in separate pots and then coupled together via a Mitsunobu reaction. Since a convenient chiral synthesis of optically pure (d)-3,3,3-trifluoropropyl glycine methyl ester was developed using Schöllkopf reagent alkylation, this methodology can also be adopted for the enantioselective synthesis of BMS-708163.     

A divergent synthesis of d- and l-carbocyclic 4′-fluoro-2′,3′-dideoxynucleosides as potential antiviral agents

d- and l-Carbocyclic 4′-fluoro-2′,3′-dideoxynucleosides have been synthesized from 2, which can be conveniently prepared from 1,2:5,6-di-O-isopropylidene-d-mannitol 1 in eight steps. Ruthenium-catalyzed ring-closing metathesis has been employed in the synthesis of d-nucleosides, whereas the l-series have been obtained through an intramolecular nucleophilic substitution reaction. The Mitsunobu condensation was used as a general tool for the synthesis of both purine and pyrimidine nucleosides.     

Convergent synthesis of panclicin-D via intramolecular SN2 displacement approach

A convergent enantioselective synthesis of panclicin-D has been reported from simple octanal using syn aldol reaction via intramolecular S_N2 displacement reaction for the first time towards the construction of anti-β-lactones in panclicin-D. The key steps involved are C-allylation, asymmetric aldolization under Crimmins condition, intramolecular S_N2 displacement, and Mitsunobu esterification reaction.