Phosphines Mitsunobu reaction

The Mitsunobu reaction was applied to the synthesis of pyrrolo[l,2-d [, 2,4]triazines from pyrrole derivative 71. Thus reduction of 71 gave alcohol 72, which on treatment with diethylazodicarboxylate and triphenyl phosphine gave 74 via the open chain intermediate 73. Hydrolysis of 74 gave 75 (84AG517) (Scheme 18). 

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). 

Iodination reagents combined with aryl phosphines and imidazole can also effect reductive conversion of diols to alkenes. One such combination is 2,4,5-triiodoimidazole, imidazole, and triphenylphosphine.215 These reagent combinations are believed to give oxyphosphonium intermediates which then serve as leaving groups, forming triphenylphosphine oxide as in the Mitsunobu reaction (see Section 3.2.4). The iodide serves as both a... 

Bifunctional reagents have recently been used to facilitate separations in the Mitsunobu reaction.39 Mitsunobu products are often hard to separate from excess reagents and byproducts, including phosphines and phosphine oxides. The tagged phosphine 21 and azodicarboxylate 22 and the byproducts formed from these are converted to the carboxylic acid forms by treatment with trifluoroacetic acid (TFA) at the end of the reaction. The excess reagents and byproducts could then be captured on an ion exchange resin for convenient removal. 

Employing the Mitsunobu reaction with diisopropyl azodicarboxylate and triphenyl-phosphine, aminoacylserine (in contrast to aminoacylthreonine) is converted into (ami-noacyl)oxazolidine-2-carboxylic acid. 54 By the same procedure a/Zo-threonine peptides are converted into the oxazoline derivatives, whilst the threonine peptides are apparently converted into the aziridines in good yields. 86 ... 

Alternatively, alkyl aryl ethers can be prepared from support-bound aliphatic alcohols by Mitsunobu etherification with phenols (Table 7.13). In this variant of the Mit-sunobu reaction, the presence of residual methanol or ethanol is less critical than in the etherification of support-bound phenols, because no dialkyl ethers can be generated by the Mitsunobu reaction. For this reason, good results will also be obtained if the reaction mixture is allowed to warm upon mixing DEAD and the phosphine. Both triphenyl- and tributylphosphine can be used as the phosphine component. Tributyl-phosphine is a liquid and generally does not give rise to insoluble precipitates. This reagent must, however, be handled with care because it readily ignites in air when absorbed on paper. 

The Mitsunobu reaction is usually only suitable for the alkylation of negatively charged nucleophiles rather than for the alkylation of amines, and only a few examples of such reactions (mainly intramolecular N-alkylations or N-benzylations) have been reported (Entry 15, Table 10.2). Halides, however, are very efficiently alkylated under Mitsunobu conditions, and it has been found that the treatment of resin-bound ammonium iodides with benzylic alcohols, a phosphine, and an azodicarboxylate leads to clean benzylation of the amine (Entry 9, Table 10.3). Unfortunately, alkylations with aliphatic alcohols do not proceed under these conditions. The latter can, however, also be used to alkylate resin-bound aliphatic amines when (cyanomethyl)-phosphonium iodides [R3P-CH2CN+][r] are used as coupling reagents [62]. These reagents convert aliphatic alcohols into alkyl iodides, which then alkylate the amine (Entry 10, Table 10.3). 

MITSUNOBU REACTION. Intcrnioleculur dehydration reaction occurring between alcohols and acidic components on treatment with diethyl azodtearboxylate and triphcnyl phosphine under mild neutral conditions. The reaction exhibits stereospecilicity and regional and functional selectivity. 

This reaction is somewhat similar to the Mitsunobu Reaction, where the combination of a phosphine, a diazo compound as a coupling reagent, and a nucleophile are used to invert the stereochemistry of an alcohol or displace it. 

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. 

So how does the Mitsunobu reaction work The first step involves neither the alcohol nor the nucleophile. The phosphine adds to the weak N-N n bond to give an anion stabilized by one of the ester groups. 

Diols are directly converted into oxiranes with Ph3P or other phosphines in the presence of diisopropyl azodicarboxylate (Mitsunobu reaction). Simple alkenes can be converted into nonracemic epoxides in high yields and with excellent ee values via a two-step sequence of asymmetric dihydroxylation and Mitsunobu cyclodehydration of the intermediate diol (Scheme 18) <20010L2513>. These reactions give best results using electron-poor alkenes . 

Curran, D. P., Dandapani, S. Fluorous nucleophilic substitution of alcohols and reagents for use therein, specifically, perfluoroalkyl-containing phosphines and azodicarboxylates as polyfluorinated reagents for the Mitsunobu reaction, 2002-US26045 2003016246, 2003 (University of Pittsburgh, USA). 

Watanabe, T., Gridnev, I. D., Imamoto, T. Synthesis of a new enantiomerically pure P-chiral phosphine and its use in probing the mechanism of the Mitsunobu reaction. Chirality 2000,12, 346-351. 

Inversion of the configuration of an alcohol by cesium carboxylate has also been demonstrated. This Mitsunobu-type reaction is sometimes more convenient than the classical phosphine-based reaction. Although a small amount of the E2 elimination reaction also occurs, carboxylation of the mesylate of the alcohol proceeds perfectly with inversion of configuration (Scheme 2.28) [44]. 

Figure 6.32 Successes and failure of carbonate protection in an attempt to make aryl P-mannobiosides. The formation of the cyclic orthocarbonate must be entirely due to the complex phosphine oxide leaving group in the Mitsunobu reaction, since 4,6-di-O-acetyl-a-D-mannopyranosyl bromide 2,3-carbonate gave the expected aryl P-mannosides on reaction -with phenoxides. ...

Conventional reagents that cannot easily be removed by solid-phase extraction may be tagged in such a way that extraction by scavenger resins becomes possible. For example, for Mitsunobu reactions phosphines and azodicarboxylic acid derivatives of types 3 and 4... 

Epoxides. Reaction pathways for the Mitsunobu reaction to convert l,l-diaryl-2-phenylethanediols to epoxides are phosphine-dependent. Retention of configuration at the secondary carbinolic center is observed in reaction mediated by PhsP-DIAD, while mote electron-rich phosphines (e.g., BU3P) favor products with inversion of configuration. ... 

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