Diethyl azodicarboxylate Mitsunobu reaction

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 ... 

The Mitsunobu reaction was also applied to the synthesis of [ 1,2,4]triaz-ino[4,5-n]indoles (84AG517). Thus, reaction of the 2-acylindoles 127 with sodium borohydride in methanol or with lithium aluminium hydride in tetrahydrofuran gave the corresponding alcohols 128. Their cyclization with diethyl azodicarboxylate in the presence of triphenyl-phosphine gave the triazinoindoles 129. Acid treatment of the latter afforded 130 (Scheme 30). 

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-... 

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). ... 

The role of the diethyl azodicarboxylate is to activate the triphenylphosphine toward nucleophilic attack by the alcohol. In the course of the reaction, the N=N double bond is reduced. As will be discussed subsequently, this method is applicable for activation of alcohols to attack by other nucleophiles in addition to halide ions. The activation of alcohols to nucleophilic attack by the triphenylphosphine-diethyl azodicarboxylate combination is called the Mitsunobu reaction. 

Diphenylphosphoryl azide reacts with alcohols in the presence of triphenylphosphine and diethyl azodicarboxylate.45 Hydrazoic acid, HN3, can also serve as the azide ion source under these conditions.46 These reactions are examples of the Mitsunobu reaction discussed earlier. 

N-Alkyl amides or imides can also be prepared starting from alcohols by treatment of the latter with equimolar amounts of the amide or imide, Ph3P, and diethyl azodicarboxylate (EtOOCN=NCOOEt) at room temperature (the Mitsunobu reaction, see p. 396).925... 

Intermolecular and intramolecular nucleophilic substitution of an alcoholic hydroxy group by the triphenylphosphine/dialkyl azodicarboxylate redox system is widely used in the synthesis and transformation of natural products and is known in organic chemistry as the Mitsunobu reaction.1951 This reaction starts with formation of the zwitterionic phosphonium adduct 19 (Scheme 9) from triphenylphosphine and diethyl (or diisopropyl) azodicarbox-... 

A remarkable stereospecific dehydrative alkylation of (3-disulfones was reported by Falck et al. [406] under Mitsunobu conditions (triethyl phosphine, diethyl azodicarboxylate). The synthesis of a pheromone component of the lesser tea tortrix emphasizes some of the possibilities offered by coupling this reaction with further uses of the sulfone functionality. In the present case, monodesulfonylation with lithium naphthalenide (-78°C, 5 min), in situ alkylation (-78 to 23°C, 1 h), and Li-naphthalene cleavage of the second sulfonyl group (—78°C, 5 min) yielded in a one-pot procedure a THP ether which was converted into the sought after pheromone through direct acetylation. 

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). 

Tosylation with inversion.1 The reaction of a secondary alcohol with zinc tosylate, diethyl azodicarboxylate, and triphenylphosphine (Mitsunobu inversion, 5, 728) leads to the inverted tosylate in about 80-95% yield. Lithium tosylate is less effective. The reaction is sensitive to steric hindrance. 

When esterification is achieved under the Mitsunobu conditions (diethyl azodicarboxylate, Ph3P), only esters at positions 6 and 6 are produced, and isolation of the 6-monoester, which is formed faster is possible. Thus diesters can be efficiently prepared.97 99 In this type of reaction, when the carboxylic acid is... 

OH - —NTfCHj. Primary or secondary alcohols are converted to protected secondary amines by this triflamide under Mitsunobu conditions (triphenylphos-phine, diethyl azodicarboxylate) in 70-86% yield. The reaction proceeds with inversion, and is useful for preparation of optically active secondary amines. 

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... 

Previously documented methods for menthol inversion under standard Mitsunobu conditions (benzoic acid, PPha, diethyl azodicarboxylate) result in low yields4 (27%). More effective methods have been reported using extended reaction periods in refluxing toluene via a formic acid/N,N -dicyclohexylcarbodiimide-mediated transformation5 (20-92 hr, 80%). For hindered alcohols in general, representative methods for inverting alcohol stereochemistry necessitate conversion of the alcohol to... 

MITSUNOBU REACTION Triphenylphos-phine-Diethyl azodicarboxylate. 

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. 

A preformed complex of diethyl azodicarboxylate/PhsP activates primary and secondary alcohols sufficiently for SN2-type reactions with LiF (Scheme 33). This Mitsunobu procedure is a rare example of a reaction useful with all four halogens. 

Walden inversion, on the other hand, is observed in the reaction of alkanols with diethyl azodicarboxylate, triphenylphosphine and HN3 (c/. the Mitsunobu reaction).There is also some interest in the Pd-catalyzed transformation of allyl acetates into the corresponding azido derivatives. Primary amines can be generated in a one-pot procedure without isolation of these azides, by further treatment with PhsP and subsequent hydrolysis (Scheme 45). 

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