Reactions Mitsunobu

The Mitsunobu reaction [26] with phenols was carried out under standard reaction conditions. 

This reaction proceeded very well, and only the SN -reaction product was obtained. To determine the Z-/E-ratio of the final product, NOE-experiments were used, these showing that only the E-product was formed. 

The Mitsunobu reaction, discovered by Mitsunobu in the late 1960s, has become one of the most widely used reactions in organic chemistry. The reaction has become the standard method for the inversion of secondary alcohols, the conversion of alcohols into amines and sulfides, and many other applications. New uses for this versatile reaction continue to be developed. The Mitsunobu reaction, due to its mild reaction conditions, has found wide application in total synthesis, and heterocyclic and medicinal chemistry. Since the Mitsunobu reaction has been extensively reviewed during the last thirty years, this chapter will focus primarily on applications of the Mitsunobu reaction during the last fifteen years. This review will cover recent examples for the various uses of the Mitsunobu reaction and introduce several new applications of the reaction. Recently developed phosphine and azadicarboxylate reagents will be covered as well. 

The currently accepted mechanism, which is based primarily on experimental results, is outlined below. The reaction begins with the nucleophilic attack of triphenylphosphine, on the N=N double bond of diethylazadicarboxylate (DEAD) to form betaine intermediate 1. Crich and others have determined 

Extensive work has been carried out on the standard Mitsunobu reaction. Generally, the reaction is carried out according to two extreme approaches. 

The commercially available diethyl azadicarboxylate like reagents are listed below. DEAD (4) and DIAD (5) are by far the most frequently used. The methyl (6), benzyl (7) and terr-butyl (8) analogs of the most commonly used reagents are also known, but used much less frequently. Bis-(2,2,2-trichloroethyl)azadicarboxylate, another commercially available compound, has also been reported, but applications thereof appear to be very limited. ADDP, l,r-(azodicarbonyl)-dipiperidine (10), was first reported by Tsunoda. This reagent appears be useful for more difficult Mitsunobu reactions related reagents in which the piperidine moiety has been replaced by morpholine or A-methyl piperazine are also known. These reagents and the reduced hydrazine products thereof can often be precipitated out by the addition of hexanes to Ae reaction mixture additionally, treatment with mild acid can be useful in the removal of the A-methyl piperidine reagent. 

Diethyl azadicarboxylate Diisopropyl azadicarboxylate Dimethylazadicarboxylate (DEAD) (4) (DIAD) (5) (DMAD) (6) 

In the Mitsunobu esterification reaction, an alcohol can be converted to a carboxylate ester as indicated in (12.338). Conversions to an azide, an iodide and other compounds has also been carried out with this kind of reaction involving Ph3P -i- EtOOCN=NCOOEt. 

ROH + PhjP + EtOOCN=NCOOEt--- PhjPtOR) + EtOOCN-NHCOOEt 

The conversion of 79 to 80 illustrates what improbably the most common application of the Mitsunobu reaction, inverting the stereogenic center of a chiral alcohol (the problem described in sec. 2.7.A.i). The alcohol is first converted to an ester in most cases, however, because that reaction is more efficient than using the free alcohol. Formation of 80 proceeded with inversion of the (R)-alcohol and isolation of the (5)-alcohol requires only hydrolysis of the ester, as mentioned above. 

Chapter 2. Acids, Bases, Functional Group Exchanges 

Another modification illustrates two features that can be useful in synthesis. When 83 was treated with triphenylphosphine and DEAD (Bn is benzyl), cyclization o urred to give benzoxepin (84) in 87% yield. This shows that Mitsunobu conditions can be used for intramolecular reactions and also that an alcohol can be coupled with another OH unit. This transformation was used by Yamaguchi in a synthesis of radulanins.  

The Mitsunobu reaction is a clever and highly useful exploitation of the Sn2 reaction that allows one to control the stereochemistry of a given stereogenic center (see Chap. 6). It also allows one to correct the stereochemistry if an alcohol is produced that has the opposite stereochemistry from that desired. 

The Sn2 Reaction. Normal Sn2 reactions were illustrated in the previous sections. In general, allylic halides react faster with nucleophiles than do simple alkyl halides (see above) because the Jt bond can 

Many strategies in organic synthesis involve inversion of a stereo center in order to reach the target molecule. In the era of modem chemistry, the most widely used reaction when alcohols are involved is the Mitsunobu reaction. In general, the hydroxyl function is activated with dialkyl azodicarboxylate/Ph3P reagent, after which reaction with a nucleophile occurs via an Sn2 mechanism with inversion of configuration. 

---

A very mild and efficient synthesis of N-substituted -lactams uses the Mitsunobu reaction (see section 2.6.2) for the ring closure of seryl dipeptides protected at the terminal N as 4,5-diphenyloxazol-2(3f/)-one ( Ox ) derivatives (see section 2,6.3)... 

In the olivanic acid series of carbapenems the ( )-acetamidoethenyl grouping can be isomerised to the (Z)-isomer (19) (22) and reaction with hypobromous acid provides a bromohydrin that fragments to give a thiol of type (20) when R = H, SO H, or COCH. The thiol is not isolated but can react to provide new alkyl or alkenyl C-2 substituents (28). In the case of the nonsulfated olivanic acids, inversion of the stereochemistry at the 8(3)-hydroxyl group by way of a Mitsunobu reaction affords an entry to the 8(R)-thienamycin series (29). An alternative method for introducing new sulfur substituents makes use of a displacement reaction of a carbapenem (3)-oxide with a thiol (30). Microbial deacylation of the acylamino group in PS-5 (5) has... 

The Mitsunobu reaction is usually used to introduce an ester with inversion of configuration. The use of this methodology on an anomeric hydroxyl was found to give only the /3-benzoate, whereas other methods gave mixtures of anomers. Improved yields are obtained in the Mitsunobu esterification when p-nitrobenzoic acid is used as the nucleophile/ Bis(dimethylamino) azodicarboxylate as an activating agent was... 

The Mitsunobu reaction is used to convert an alcohol and an acid into an ester by the formation of an activated alcohol (Ph3P, diethyl diazodicar-boxylate), which then undergoes displacement with inversion by the carboxylate. Although this reaction works very well, it suffers from the fact that large quantities of by-products are produced, which generally require removal by chromatography. 

Primary alcohols may be phosphorylated by use of the Mitsunobu reaction (Ph, , DEAD, HBF4, Pyr). Of several salts examined, the potassium salt of the phosphate was the best. 

The Wenker aziridine synthesis entails the treatment of a P-amino alcohol 1 with sulfuric acid to give P-aminoethyl sulfate ester 2 which is subsequently treated with base to afford aziridine 3. Before the discovery of the Mitsunobu reaction, wbicb transforms an amino alcohol into an aziridine in one step under very mild conditions, the Wenker reaction was one of the most convenient methods for aziridine synthesis. However, due to the involvement of strong acid and then strong base, its utility has been limited to substrates without labile functionalities. 

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. 

In summary the Mitsunobu reaction can be described as a condensation of an alcohol 1 and a nucleophile—NuH—11, where the reagent triphenylphosphine is oxidized to triphenylphosphine oxide and the azodicarboxylate reagent 12 is reduced to a hydrazine derivative 13 ... 

Suitable starting materials for the Mitsunobu reaction are primary and secondary alcohols. Tertiary alcohols are less suitable since these are bad substrates for a SN2-mechanism. 

Michael addition/elimination 256 Mitsunobu glycosidation 543 ff. Mitsunobu reaction 259, 5291,... 

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). 

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-... 

Scheme 29 Tandem benzannulation-Mitsunobu reaction of a chiral decalin-derived carbene complex...

A similar tandem Dotz-Mitsunobu reaction has been reported starting from a l,6-methano[10]annulene carbene complex, but no conclusion could be reached on the influence of the chiral information regarding the stereoselective course of the reaction since the chromium fragment could not be kept coordinated to the benzannulation product [47]. 

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>. 

Until now, the most efficient approach to synthesize Freidinger lactams 147 started from a resin-bound cinnamylamine 144. A Fukuyama-Mitsunobu reaction to 145 followed by sulfonamide cleavage and a consecutive appropriate acylation built up the diene 146, which underwent ring-closing metathesis involving Grubb s catalyst 123 to generate the desired lactams 147 (Scheme 27, Table 5) [35d]. 

---