Mitsunobu reaction, azides

The major application of the Mitsunobu reaction is the conversion of a chiral secondary alcohol 1 into an ester 3 with concomitant inversion of configuration at the secondary carbon center. In a second step the ester can be hydrolyzed to yield the inverted alcohol 4, which is enantiomeric to 1. By using appropriate nucleophiles, alcohols can be converted to other classes of compounds—e.g. azides, amines or ethers. 

The synthesis of 6-azidomethyl-S,6,7,8-tetrahydropterin 108 has been carried out from 106 via the intermediate 107 using the Mitsunobu reaction with diphenylphosphoryl azide followed by deprotection <95MI09 %CA(124)232123>. 

Diphenylphosphoryl azide reacts with alcohols in the presence of triphenylphosphine and DEAD.76 Hydrazoic acid, HN3, can also serve as the azide ion source under these conditions.77 These reactions are examples of the Mitsunobu reaction. 

In another approach, 2-(alkylamino)alcohol is employed as starting material for aziridine syntheses with the aid of dihalogenophosphoranes (70BCJ1185). Intramolecular transformation of 3-azidopropyloxirane 73 results in a simultaneous formation of a condensed aziridino[l,2-a]pyrrol-idine system (Scheme 39). The azide group is first transformed into imino-phosphorane 74, the nucleophilic N atom cleaves the oxirane to form betaine 75 [as in the Mitsunobu reaction (81S1)], and the phosphorus is shifted from N to O and then eliminated as phosphane oxide under simultaneous cyclization to bicyclic 76 (89JA7500). 

In 1991, Duncia et al. reported on the synthesis of 1,5-disubstituted tetrazoles from secondary amides and azidotrimethylsilane under the conditions of the Mitsunobu reaction <1996CHEC-II(4)621>. The Mitsunobu protocol was successfully applied to the conversion of AT(cyanoethyl)amide into tetrazole 510. The tetrazole ring in this event forms by the cyclization of an imidoyl azide (not shown in the scheme) whose precursor is the phosphonium imidate 509 (Scheme 67) <2000JME488>. 

Note that alkyl azides are potentially explosive. This and the simpler reaction conditions involved is one reason why the reaction described above is mainly carried out as a Mitsunobu reaction. In this method the alkanol is reacted with diethyl diazenedicarboxylate, triphenylphosphane and hydra-zoic acid in a one-pot reaction. The reaction also proceeds with inversion and affords the amine directly because the intermediate azide is reduced by excess triphenylphosphane in situ. 

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. 

Alcohols and alkenes react with HN3 to give alkyl azides, which in the course of reaction rearrange in the same way as discussed in reaction 18-14. The Mitsunobu reaction (10-17) can be used to convert alcohols to alkyl azides, and an alternative reagent for azides, (PhO)2PON3, for use in the Mitsunobu is now available. ° ... 

The nature of the nucleophile is critical when considering the Mitsunobu reaction as a means of introducing amine functionalities. Because of the proton transfer components illustrated in the reaction mechanism, only acidic nitrogens can be introduced. The most common nitrogen nucleophiles include phthahmide, hydrazoic acid and zinc azide [62]. Once placed, phthahmides are easily converted to amines utihzing hydrazine [6]. Moreover, azides are easily reduced to amines under numerous conditions [32]. Schemes 6.32 and 6.33 illustrate the application of this chemistry to nucleosides [63] and pyranosides [64], respectively. 

SCHEME 6.33 The Mitsunobu reaction can deliver azides to sugars and sugar derivatives. 

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). 

The enantioselective total synthesis of the complex bioactive indole alkaloid enf-WIN 64821 was accomplished by L.E. Overman and co-workers." This natural product is a representative member of the family of the C2-symmetric bispyrrolidinoindoline diketopiperazine alkaloids. The stereospecific incorporation of two C-N bonds was achieved using the Mitsunobu reaction to convert two secondary alcohol functionalities to the corresponding alkyl azides with inversion of configuration. The azides subsequently were reduced to the primary amines and cyclized to the desired ib/s-amidine functionality. 

Isopropylidene-D-erythrose (104) was treated with Wittig reagent to give the olefin 110. This was subjected to a Mitsunobu reaction to afford the azide intermediate 111, whose intramolecular cycloaddition in refluxing benzene produced the bicyclic iminium ion 112. Treatment of 112 with tm-butylamine gave 113, which upon hydroboration using the modification of Schultz method " afforded the acetonides 48 as a major product in addition to 114 (7%). Aqueous acid hydrolysis of 48 afforded 1 in 39% overall yield from 104. 

The Mitsunobu reaction is also the basic step in the synthesis of 65. The starting homochiral hydroxy ester 62 is readily available by yeast-mediated reduction of ethyl 2-oxocyclopentanecarboxylate. Treatment of 62 with hydrazoic acid under Mitsunobu conditions resulted in inversion to the azide 63, which was hydrogenated in the presence of di-ter/-butyl... 

Alkyl azides. The substitution of an alcohol to give the azide is an alternative to the Mitsunobu reaction. 

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