The Hendrickson reagent and the Mitsunobu reaction: a mechanistic study

The alkoxytriphenylphosphonium ion intermediate of the Mitsunobu reaction can be generated using the Hendrickson reagent, triphenylphosphonium anhydride trifluoromethanesulfonate, 1. Strangely, while the reagent 1 can be used in place of the Mitsunobu reagents (triphenylphosphine and a dialkylazodicarboxylate) for the esterification of primary alcohols, secondary alcohols such as menthol undergo elimination. Evidence is presented to show that this unexpected result is due to the presence of trialkylammonium triflate salts. Such salts lead to a dramatic decrease in the rate of esterification relative to competing elimination. The Mitsunobu esterification of menthol with p-nitrobenzoic acid was re-examined and the occurrence of elimination reported for the first time. The presence of traces of tetrabutylammonium triflate led to a dramatic reduction in the yield of inverted ester and a corresponding increase in the yield of anti elimination product 2-menthene. The mechanism of the Mitsunobu reaction is discussed in the light of the dramatic salt effect on both the rate and outcome of the reaction and the possible involvement of ion pair clustering. In contrast, use of the reagent 1 resulted in syn elimination to give a 1:2 mixture of 2- and 3-menthenes. Finally, 1 and sodium azide can be used to convert a primary alcohol into an azide in high yield. There was no reaction under Mitsunobu conditions.     

Organocatalytic Mitsunobu reactions

A catalytic Mitsunobu reaction system is described in which the azo reagent is used as an organocatalyst and iodosobenzene diacetate is used as the stoichiometric oxidant. In this system, iodosobenzene diacetate oxidizes the formed hydrazine byproduct to regenerate the azo reagent. Yields obtained in the catalytic reactions using a variety of carboxylic acids and alcohols were slightly lower than those obtained from corresponding stoichiometric reactions. Both primary and secondary alcohols can be used as substrates in this reaction system, with the secondary alcohols affording products with inverted stereochemistry at the carbinol center.     

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.     

Mechanistic study of the Mitsunobu reaction

The Mitsunobu reaction occurs typically with inversion of configuration in secondary alcohol derivatives. In this paper, a mechanistic explanation for lactonizations of hindered alcohols under Mitsunobu conditions with retention is proposed. This involves the intermediacy of an acyloxyphosphonium salt followed by acyl transfer to the alcohol.     

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.     

Synthesis and reactivity profiles of phosphinated poly(alkyl aryl ether) dendrimers

Poly(alkyl aryl ether) dendrimers were utilized to synthesize a series of new triphenylphosphine functionalized dendrimers. Zero, first, second and third generation dendrimers, carrying 3, 6, 12 and 24 triphenylphosphine units, were prepared and characterized. The new triphenylphosphine containing dendrimers were assessed for their reactivity profiles and in this instance, the dendrimers were used as reagents to mediate Mitsunobu etherification reaction between phenol and various primary, secondary and benzylic alcohols. In addition, dendritic poly-phenols were also tested in an O-benzylation reaction. A monomeric methoxy group attached triphenylphosphine acted as a control for comparison of reactivity profiles of dendrimers. It was observed that the etherification reaction was mediated efficiently by the dendritic reagent, and in addition, the dendritic phosphine oxide reagents could be recovered quantitatively by precipitation methods. The recovered dendritic phosphine oxides were reduced subsequently to the corresponding phosphines and used as reagents for the Mitsunobu reaction, repetitively.     

Solid-phase synthesis of a library of hydroxyproline derivatives

The synthesis of a library of N-alkylated O-arylated hydroxyproline derivatives has been achieved on solid phase. The choice of O-protection and the optimization of the Mitsunobu reaction involving a secondary alcohol were key to the success of this synthesis. First, acylation of resin-bound amines with N-Fmoc-O-THP-hydroxyproline was accomplished readily. Subsequent deprotection of the Fmoc and reductive amination with different aldehydes resulted in the tertiary amine intermediate. The deprotection of the THP group by p-toluenesulfonic acid was followed by a Mitsunobu reaction with a series of phenols. Finally, the products were cleaved from the resin using trifluoroacetic acid to produce a 10 200 member library.     

New Synthesis of 1,1-Substituted Hydrazines by Alkylation of N-Acyl- or N-alkyloxycarbonylaminophthalimide Using the Mitsunobu Protocol

N-acyl- and N-alkoxycarbonylaminophthalimides are prepared using a convenient reaction and are efficiently used as acid partners in Mitsunobu reaction. This reaction allows them to be alkylated by primary, secondary or benzyl groups. Comparison of the reactivities and pK(a) values of these N-substituted aminophthalimides suggest that the success of the Mitsunobu reaction in this case seems to be governed more by steric than by electronic effects. A final dephthaloylation step results in an efficient method for the preparation of 1,1-substituted hydrazines.     

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.     

Deracemization of 1,2-diol monotosylate derivatives by a combination of enzymatic hydrolysis with the Mitsunobu inversion using polymer-bound triphenylphosphine

The deracemization of 1,2-diol monotosylate derivatives is achieved by the sequential combination of enzymatic hydrolysis and Mitsunobu inversion using a polymer-bound triphenylphosphine. After the lipase-catalysed hydrolysis of the racemic 2-acetoxyhexyl tosylate, the subsequent Mitsunobu reaction without separation causes an inversion of the resulting (R)-alcohol to give the (S)-enantiomer of the acetate as a single product. In particular, the reaction using the polymer-bound triphenylphosphine also proceeds smoothly, and the product is easily separated by filtration from the polymer-bound reagent and its by-products. This deracemization process is applicable to the preparation of several optically active 1,2-diol monotosylates.     

N-isopropylidene-N'-2-nitrobenzenesulfonyl hydrazine, a reagent for reduction of alcohols via the corresponding monoalkyl diazenes

The reagent N-isopropylidene-N'-2-nitrobenzenesulfonyl hydrazine (IPNBSH) is used in the reduction of alcohols via the loss of dinitrogen from transiently formed monoalkyl diazene intermediates accessed by sequential Mitsunobu displacement, hydrolysis, and fragmentation under mild reaction conditions.     

A new supported reagent for the parallel synthesis of primary and secondary O-alkyl hydroxylamines through a base-catalyzed Mitsunobu reaction

The growing field of applications of O-alkyl hydroxylamines in medicinal chemistry and chemical biology has motivated the search for a parallel synthesis. A solid-phase approach based on the alkylation by alcohols of a new supported N-hydroxyphthalimide reagent using a Mitsunobu reaction followed by methylaminolysis has been optimized. This study points out the importance of the linker and a specific base effect for the Mitsunobu reaction. A large variety of alcohols can be used to give with moderate to high yields diverse O-alkyl hydroxylamines in high purity.     

New Synthetic Approach for the Incorporation of 3,2-Hydroxypyridinone (HOPO) Ligands: Synthesis of Structurally Diverse Poly HOPO Chelators

The HOPO sulfonamide reagent, 3, was prepared from commercial 2,3-dihydroxypyridine in four steps in good yields. Sulfonamide 3 readily underwent selective alkylation with dibromides in the presence of base or could be coupled to alcohols using Mitsunobu conditions. The utility of this nucleophilic HOPO reagent was demonstrated by the synthesis some tris and tetraHOPO chelators. This approach for tethering HOPO ligands is unique and flexible as shown by the preparation of HOPO/iminocarboxylic acid chelator 17.     

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.     

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      

Enantioselective synthesis of oseltamivir phosphate

The key steps in the enantioselective synthesis of Tamiflu include an asymmetric Diels-Alder reaction, Mitsunobu inversion using Fukuyama modified Weinreb reagent, carbamate directed epoxidation. Epoxide opening with trimethylsilyl azide furnished a 3:1 mixture of regioisomers that converged to afford the same aziridine. Attempted preparation of the unsaturated ester regioselectively using 2-iodoxybenzoic acid (IBX) following Nicolaou’s protocol failed. The unsaturated ester was prepared by phenylselenylation followed by selenoxide elimination.     

Synthesis of N,N-Diethylbenzamides via a Nonclassical Mitsunobu Reaction

The use of the Mitsunobu reaction for the synthesis of N,N-diethylbenzamides affords ortho-, meta-, and para-substituted benzamides containing both electron-donating and electron-withdrawing groups. While the preparation of numerous functional groups has been efficiently demonstrated employing the Mitsunobu reaction, our methodology represents the first application of the Mitsunobu reaction for the construction of benzamides using benzoic acid and amine starting materials. Moreover, this synthetic transformation is believed to proceed via a nonclassical mechanism involving the existence of an acyloxyphosphonium ion.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]     

Construction of Vicinal Quaternary Stereogenic Centers by Enantioselective Direct Mannich‐Type Reaction Using a Chiral Bis(guanidino)iminophosphorane Catalyst

A novel asymmetric direct Mannich‐type reaction of α‐iminophenylacetate esters with thionolactones, bearing a substituent at the α‐position, as a less acidic pronucleophile was developed. Using bis(guanidino)iminophosphorane as the chiral organosuperbase catalyst, the reaction afforded densely functionalized amino‐acid derivatives having vicinal quaternary stereogenic centers, one of which is an all‐carbon quaternary stereogenic center, in good yield with high diastereo‐ and enantioselectivities.     

Mitsunobu reactions of nucleoside analogs using triisopropyl phosphite-DIAD

Herein, we report the use of triisopropyl phosphite (TIP) as an effective substitute for triphenylphosphine in the Mitsunobu reaction of nucleoside analogs. In addition, the use of triphenyl phosphite as an alternative reagent for the expensive hexamethylphosphorous triamide (HMPT) in the Véliz-Beal bromination protocol is reported.     

Fluorous scavenger for parallel preparation of tertiary sulfonamides leading to secondary amines

Alkylation of secondary sulfonamides by alkyl halides or alcohols (Mitsunobu reaction) is an efficient method for secondary amines preparation. However, its application to parallel chemistry is often difficult due to partial reaction. In this Letter, we propose a fluorous technique to bypass this problem. Thus, o-nitrobenzenesulfonamides were prepared and alkylated in parallel (Fukuyama method) with various alkyl halides or alcohols. Depending on the nature of the alkyl halide or alcohol, this step remained incomplete. A reactive fluorous alkyl iodide was then used to trap the unreacted sulfonamide allowing for a rapid and efficient fluorous solid-phase extraction (FSPE). Some examples of the isolated tertiary sulfonamides were converted in parallel to the corresponding secondary amines with good purity.