Simplification of the Mitsunobu Reaction. Di-<i>p</i>-chlorobenzyl Azodicarboxylate:  A New Azodicarboxylate

Lipshutz, Bruce H.; Chung, David; Rich, Brian; Corral, Ricardo S.

doi:10.1021/ol0618757

Cited by 81 publications

(40 citation statements)

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“…In situ recycling of DEAD that makes it a catalyst is one of the solutions. 6 Total removal of the hydrazinedicarboxylate and the side-products can be performed by polymerization of norbornene units incorporated in the reagent as to be called impurity annihilation.7 Very recently, di-4-chlorobenzyl analogue was reported, 8 where the hydrazinedicarboxylate can be removed by the crystallization. We have made another approach to this issue by molecular design to enable the separation of a hydrazinedicarboxylate by extraction with neutral water.…”

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confidence: 99%

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Di-2-methoxyethyl Azodicarboxylate (DMEAD): An Inexpensive and Separation-friendly Alternative Reagent for the Mitsunobu Reaction

Sügimura¹,

Hagiya²

2007

Chemistry Letters

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Di-2-methoxyethyl azodicarboxylate (DMEAD) was prepared as an alternative of DEAD or DIAD for the Mitsunobu reaction. Removal of the hydrazinedicarboxylate generated from DMEAD becomes much easier owing to the polar and water-soluble property.The Mitsunobu reaction is popular in organic synthesis to introduce an acidic nucleophile (carboxylic acid, phenol, imide, etc.) to an alcoholic function under mild conditions.2 The notable property of this reaction is complete inversion of stereochemistry at the alcoholic function. The original procedure consists of mixing an alcohol and a nucleophile with diethyl azodicarboxylate (DEAD) and triphenylphosphane at ambient temperature.3 This oxidant-reductant combination to cause dehydration in the Mitsunobu reaction is still widely used although diisopropyl azodicarboxylate (DIAD) is also conveniently employed as a more stable analogue of DEAD. A major drawback of this process is formation of two co-products, hydrazinedicarboxylate and phosphane oxide, which must be removed from the reaction mixture to isolate a target compound. Many efforts have been undertaken to solve this issue: e.g., one of the reagents is supported by polymer or solid to perform the separation by filtration, or is attached to an acidic, basic, or fluorous function to allow the separation by extraction into a basic or acidic aqueous layer or into fluorous solvent. These modifications of the original oxidant or reductant are considered to intend a separation-free or separation-friendly process. 4,5 Formation of triphenylphosphane oxide is practically insignificant matter in the separation process due to its facile crystallization in non-polar solvents. In contrast, separation of the other co-product, diethyl or diisopropyl hydrazinedicarboxylate requires highly capable column chromatography to isolate a target compound. One also often faces a problem that several side products of the hydrazinedicarboxylate cannot be removed completely from the product. In situ recycling of DEAD that makes it a catalyst is one of the solutions. 6 Total removal of the hydrazinedicarboxylate and the side-products can be performed by polymerization of norbornene units incorporated in the reagent as to be called impurity annihilation.7 Very recently, di-4-chlorobenzyl analogue was reported, 8 where the hydrazinedicarboxylate can be removed by the crystallization. We have made another approach to this issue by molecular design to enable the separation of a hydrazinedicarboxylate by extraction with neutral water. The preparation cost and handling were also considered to compete with DEAD and DIAD in the commercial source. Di-2-methoxyethyl azodicarboxylate (DMEAD) is a new reagent, which will be detailed in this report.Di-2-dimethoxyethyl hydrazinedicarboxylate (1) was prepared by mixing hydrazine hydrate and 2-methoxyethyl chloroformate in ethanol in the presence of sodium carbonate (72% yield after recrystallization, Scheme 1).9,10 Solubility of 1 is good in chloroform (0.25 g/mL) and ethyl acetate (0.1), but very poor (<0...

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confidence: 99%

“…7 Very recently, di-4-chlorobenzyl analogue was reported, 8 where the hydrazinedicarboxylate can be removed by the crystallization. We have made another approach to this issue by molecular design to enable the separation of a hydrazinedicarboxylate by extraction with neutral water.…”

mentioning

confidence: 99%

Di-2-methoxyethyl Azodicarboxylate (DMEAD): An Inexpensive and Separation-friendly Alternative Reagent for the Mitsunobu Reaction

Sügimura¹,

Hagiya²

2007

Chemistry Letters

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“…[27] The coupling product 8 was obtained in moderate yield, but excel-lent optical purity (99 % ee), accompanied by a small amount of aziridine 9. [28] Even increasing the reaction time to three days did not improve the yield. Subsequent Nmethylation occurred in nearly quantitative yield.…”

Section: Resultsmentioning

confidence: 98%

Syntheses and Evaluation of Simplified Pretubulysin Analogues

2011

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The syntheses of new tubulysin analogues are described, in which the central amino acid, tubuvaline, is replaced by the rather simple building blocks phenyltubuvaline and phenoxytubuvaline. These analogues can be obtained in only two to three steps from easily accessible starting materials. Although the new derivatives are less active than the tubulysins, their activities towards U‐2 OS tumor cells are still in the nanomolar range.

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“…The betaine 8 proved particularly effective for substrates sensitive to phosphines [17,18]. -+ A large number of oxidation-reduction systems that facilitate the isolation of the product from the reaction mixture have also been proposed [7,19].…”

Section: The General Characteristics and Certain Aspects Of The Mechamentioning

confidence: 99%

The Mitsunobu reaction in the chemistry of nitrogen-containing heterocyclic compounds. The formation of heterocyclic systems (review)

Голанцов

Карчава

Yurovskaya

2008

Chem Heterocycl Comp

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Methods for the design of nitrogen-containing heterocyclic systems involving the formation of C-N bonds under the conditions of the Mitsunobu reaction are discussed.The Mitsunobu reaction [1][2][3][4] is the reaction of compounds containing a mobile hydrogen atom HX with alcohols in the presence of a reagent system consisting of an azodicarboxylic ester and a phosphine PR 1 3 . This reaction results in the formation of an alkylation product RX accompanied by oxidation of the phosphine PR 1 3 to phosphine oxide R 1 3 P=O and reduction of the azodicarboxylic ester to the corresponding hydrazine.The reaction takes place under very mild conditions and usually at room temperature. If a chiral secondary alcohol ROH is used, the reaction is usually stereospecific and is accompanied by inversion of the configuration at the asymmetric carbon atom of the alcohol [1-3].From the moment of the first report [5] the Mitsunobu reaction became a powerful tool in synthetic organic chemistry and found widespread use in the synthesis of various heterocyclic compounds, optically active substances, steroids, alkaloids, carbohydrates, and nucleosides [1][2][3][4]6]. In particular, in a number of cases the Mitsunobu reaction has made it possible to synthesize new physiologically active compounds or to put forward new highly effective approaches to synthesis. Several reviews have been devoted to the Mitsunobu reaction [1-4, 6, 7]. Data on the use of the Mitsunobu reaction in the synthesis of alkaloids were reviewed in [6]. Various experimental techniques that make it possible to simplify the isolation of the products of the Mitsunobu reaction RX from the reaction mixture, including the use of reagents attached to a polymer support, were discussed in [7]. _______ * Dedicated to Afanasi Andreevich Akhrem on his 95th birthday. _________________________________________________________________________________________

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Simplification of the Mitsunobu Reaction. Di-p-chlorobenzyl Azodicarboxylate: A New Azodicarboxylate

Abstract: Di-p-chlorobenzyl azodicarboxylate (DCAD) is introduced as a novel, stable, solid alternative to DEAD and DIAD for a variety of Mitsunobu couplings. DCAD/Ph(3)P-mediated reactions in CH(2)Cl(2) generate a readily separable hydrazine byproduct. [reaction: see text]

Cited by 81 publications

References 14 publications

Di-2-methoxyethyl Azodicarboxylate (DMEAD): An Inexpensive and Separation-friendly Alternative Reagent for the Mitsunobu Reaction

Di-2-methoxyethyl Azodicarboxylate (DMEAD): An Inexpensive and Separation-friendly Alternative Reagent for the Mitsunobu Reaction

Syntheses and Evaluation of Simplified Pretubulysin Analogues

The Mitsunobu reaction in the chemistry of nitrogen-containing heterocyclic compounds. The formation of heterocyclic systems (review)

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