DEAD diethyl Mitsunobu

The Mitsunobu esterification of carboxylic acids with alcohols in the presence of Ph3P and DEAD (diethyl azodicarboxylate) occurs under neutral conditions and provides the corresponding esters in high yields. 

The conversion of an alcohol to an amine can be achieved in a one-pot reaction the alcohol 1 is treated with hydrazoic azid (HN3), excess triphenylphosphine and diethyl azodicarboxylate (DEAD). The initial Mitsunobu product, the azide 14, further reacts with excess triphenylphosphine to give an iminophosphorane 15. Subsequent hydrolytic cleavage of 15 yields the amine—e.g. as hydrochloride 16 ... 

Cydization of P-hydroxy-a-amino esters under Mitsunobu reaction conditions is an alternative approach to aziridine-2-carboxylic esters [6b, 13-16], In this case the P-hydroxy group is activated by a phosphorus reagent. Treatment of Boc-a-Me-D-Ser-OMe 13 (Scheme 3.5) with triphenylphosphine and diethyl azodicarboxylate (DEAD), for example, gave a-methyl aziridinecarboxylic acid methyl ester 14 in 85% yield [15]. In addition to PPh3/DEAD [13b, 15], several other reagent combi-... 

A unique preparation of 2,3 5,6-di-O-isopropylidene-a-D-mannofuran-osyl fluoride (45) utilizing the Mitsunobu reaction [diethyl azodicarboxy-late (DEAD)-triphenylphosphine in the presence of EtjO BFi ii this case] has been reported (see Table 1). 

Benzisoxazoles and isoxazoles are also accessible in excellent yields by intramolecular Mitsunobu reaction or related reactions of o-hydroxy- or a-hydroxyoximes ° . Thus, treatment of oxime 208 in the presence of diethyl azodicarboxylate (DEAD) and PPhs in THE leads to benzisoxazoles 209 (equation 91). ... 

Treatment of y-nitro alcohols with diethyl azodicarboxylate DEAD and triphenylphos-phine affords nitrocyclopropanes with inversion of configuration at the a-carbon via the intramolecular Mitsunobu reaction involving carbon nucleophiles stabilized by the nitro group (equation 16)28. The reaction works best with nitro compounds (pA"a < 17) and is not applicable to the sulfonyl derivatives (pATa 25). 

Mitsunobu conditions [triphenylphosphine/diethyl azodicarboxylate (DEAD)]7 and triphenylphosphite methiochde [(PhO)3P+MeI ] or dihalides [(PhO)3P + XX-j8 have been successfully applied to the synthesis of halogeno sugars. 

Fig. 2.33. Mitsunobu inversion a typical substrate, the reagents, and products (possible preparation of the substrate Figure 2.27). "DEAD" stands for diethyl-azodicarboxylate.

Several examples of reactions of allyl alcohols under Mitsunobu reaction conditions using diethyl azodicarboxylate (DEAD) and triphenyl phosphine giving allyl amines are known. An example is the reaction of the steroid 5 with azide nucleophiles under Mitsunobu reaction conditions, giving the corresponding azide 6 in 63 % yield (Eq. (3)) [5]. The reaction is regioselective with inversion of the configuration and no SN2/ substitution is observed. 

Relatively acidic indoles such as 44 can be alkylated on nitrogen using an alcohol and diethyl azodicarboxylate (DEAD), i.e. Mitsunobu reaction conditions (Scheme 11). 

One of the most widely used procedures for dehydrative coupling and cyclization reactions is the Mitsunobu reaction in which the components are treated with triphenylphosphine and diethyl azodicarboxylate (DEAD, EtOaC—N=N—COiEt). The overall equation for reaction of an alcohol 67 with an acid 68 to form the ester 69 is as shown and the active species is the zwitterionic... 

Macrolactonization can also be achieved by the Mitsunobu reaction [44] with inversion of the configuration of the alcohol. The reaction principle and mechanism are demonstrated in Scheme 24. Addition of triphenylphosphine to diethyl azodicarboxylate (DEAD, 73) forms a quaternary phosphonium salt 74, which is protonated by hydroxy acid 11, followed by phosphorus transfer from nitrogen to oxygen yielding the alkoxyphosphonium salt 76 and diethyl hydrazinedicarboxy-late 75. Then, an intramolecular Sn2 displacement of the important intermediate 76 results in the formation of the lactone 15 and triphenylphosphine oxide. 

An example of an alcohol activation method is the Mitsunobu reaction. This reaction is performed by slow addition of the seco-acid alcohol to a mixture of diethyl azodicarboxylate (DEAD) and PPhs in toluene or THF. In the mechanism, the key intermediate is an alkoxyphosphonium cation, which is formed by DEAD and PPhs in situ. The macrolactone is formed by an intramolecular Sn2 reaction of this intermediate via an attack of the carboxylate moiety and therefore the reaction proceeds with inversion of the configuration at C-co. 

The Mitsunobu procedure, which uses diethyl azodicarboxylate (DEAD) or diisopropyl azodi-carboxylate (DIAD) to react with PPh3 and alcohols providing configuration-inversed substitution products via alkoxytriphenylphosphonium ion intermediates (O Scheme 28), presents another route for introducing halogen atoms into carbohydrates [48]. 

In the Mitsunobu reaction, a chiral 2° alcohol and a carboxylic acid are converted to an ester with clean inversion at the electrophilic C. The reaction requires PI13P and Et02CN=NC02Et (diethyl azodicarboxylate, DEAD). It is usually carried out by adding DEAD slowly to a mixture of the alcohol, PI13P, and the nucleophile in its protonated form. 

Scheme 3.23 The Mitsunobu reaction with fluorous condensation reagents [24] enables the simple purification of the reaction product and recycling of the reagents TPP (49) and DEAD (52). ( TPP = fluorous triphenylphosphine TPPO = fluorous triphenylphosphine oxide DEAD = fluorous diethyl diazodicarboxylate DCEH = fluorous dicarboxyethoxyhydrazine).

Holzer and Plagens (97H309) (Scheme 24) studied the alkylation of pyrazol-3-ones 62 and of the tautomeric pyrazol-3-one 78a-d/pyrazol-5-ol 79a d mixtures by applying the Mitsunobu reaction [triphenylphosphine, diethyl azodicarboxylate (DEAD), alcohol, solvent]. The reactions were performed in various solvents. Using methanol as the alkylating agent the reaction of 62 in dichloromethane or THF,... 

Mitsunobu et al. [46] reported an efficient macrolactonization using diethyl azodicarboxylate (DEAD) and Ph3P. In the case of (o-hydroxy acids having a secondary alcohol, this cyclization takes place with inversion of the configuration of the alcohol. In the total synthesis of latrunculin A (82) and B, the Mitsunobu reaction was used for the macrolactonization of the seco-acid 81 with inversion of the secondary alcohol [47]. 

Theil et al. developed a method for chemoenzymatic synthesis of both enantiomers of cispentacin [89]. frans-2-Hydroxymethylcyclopentanol, obtained by the sodium borohydride reduction of ethyl 2-oxocyclopentanecarboxylate, was monosilylated with tert-butyldimethylsilyl (TBDMS) chloride to afford 55. Lipase PS-catalysed transesterification with vinyl acetate in /erf-butyl methyl ether furnished the ester 56 and the alcohol 57. The deacetylated 58 was obtained by the Mitsunobu reaction with phthalimide, triphenylphosphine and diethyl azodicarboxylate (DEAD) to furnish the cis oriented 59 with inversion of configuration (not retention as mentioned in the original article) (Scheme 9). Desilylation, Jones oxidation and subsequent deprotection with aqueous methylamine gave the ( R,2S) enantiomer 5 [89]. The (15, 2/f) enantiomer was prepared by the same route from the silyl alcohol 57. 

Diethyl azodicarboxylate (Et02C-N=N-C02Et, DEAD) is a key reagent in the Mitsunobu reaction (sec. 2.7.A.ii) and has also been used for macrolactonization. Reaction of 230 with DEAD gave 15% of 231 in White s synthesis of the antibiotic vermiculine. ... 

In recent years, the Mitsunobu reaction has been studied extensively in solution and has found many useful applications. In an effort to overcome many of the problems associated with solution synthesis, the use of highly loaded triphenylphosphine polystyrene-derived resin represents a simple solution to the problem of purification. Thus, reaction of a series of alcohols of type 67 with carboxylic acids in the presence of diethyl azodicarboxylate (DEAD) and PS-PPhj in THF between 0°C and room temperature resulted in the clean formation of the expected esters of type 68. 5 Filtration through a plug of AljO, gave the essentially pure products in high yields (70-90%). 

Another possibility for substituting flie hydroxyl group by a nucleophile is the Mitsunobu reaction (31,32). In this case, the alcohol is linked to the nucleophile using diethyl azodicarboxylate (DEAD) and Iriphenylphosphine. This reaction was applied to the allylic alcohols [5a,b] (from mefliyl oleate) (Eq. 13, Table 3) and [2] (from methyl 10-undecenoate) (Eq. 14, Table 4). 

This reaction was initially reported by Fukuyama and co-workers in 1995. It is a two-step conversion of primary amines into secondary amines via ortho-nitrobenzenesulfonation in conjunction with the Mitsunobu Reaction and subsequent removal of the o-nitrobenzenesulfonyl group by thiophenol. Therefore, this reaction is generally known as the Fukuyama amine synthesis. In addition, it is also referred to as the Fukuyama-Mitsunobu A -alkylation," Fukuyama-Mitsunobu alkylation, Fukuyama-Mitsunobu condition, Fukuyama-Mitsunobu procedure, or Fukuyama-Mitsunobu Reaction. In this reaction, the o-nitrobenzenesulfonyl-protected amine is alkylated with alcohol in the presence of PPhs and diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), and the deprotection occurs in a very mild condition (almost neutral ). The o-nitrobenzenesulfonyl group is simply called the Fukuyama sulfonamide protecting groupThis reaction has become a versatile method... 

This reaction was first reported by Mitsunobu in 1967. It is the alkylation of compounds with active protons by using primary or secondary alcohols as the alkylating agents in combination with triphenylphosphine and diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), to form molecules like esters, ethers, thioethers, and amines. Therefore, this reaction is generally known as the Mitsunobu reaction or Mitsunobu coupling. In addition, the specific reaction for forming esters by means of DEAD (or DIAD) and PPhs is generally referred to as the Mitsunobu esterification." Occasionally, the Mitsunobu reaction is also called the Mitsunobu transformation (for the conversion of alcohol into amines) or Mitsunobu cyclizafion (for the formation of cyclic compounds). Because of its intrinsic features of stereospecificity, as well as its occurrence in neutral media and at room temperature without a prerequisite activation of alcohol, this reaction has been extensively studied and used to synthesize a variety of compounds since 1970. 

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