Mitsunobu reaction dehydration

Another interesting class of five-membered aromatic heterocycles has recently been published by Tron et al. [54]. These compounds have biological activity in the nM range. An example of the formation of these furazan (1,2,5-oxadiazole) derivatives is shown in Scheme 9. The diol 50 was oxidized to the diketone 51 using TEMPO and sodium hypochlorite. Transformation to the bisoxime 52 was performed in an excess of hydroxylamine hydrochloride and pyridine at high temperature for several days. Basic dehydration of 52 formed two products (53a and b). A Mitsunobu reaction was then employed using toluene as solvent to form compound 53b in 24% yield. 

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. 

The Mitsunobu reaction of perhydropyrido[l,2-a]pyrazine-l,4-dione 230 at ambient temperature gave dehydrated product 231 in 15% yield. When the reaction was carried out with excess PBu3 and diethyl azodicar-boxylate at 40 °C the incipient 231 spontaneously underwent enolization and tautomerization, [4+2] aza-Diels-Alder reaction to provide a 2.4 1 mixture of diastereomers 232 and 233 (07T6124). No reaction occurred when isolated 231 was treated under similar conditions. 

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... 

In the total syntheses of squamocin A and squamocin D, acetogenins from Annonaceae, a double cyciization has been demonstrated to be feasible for the assembly of bis-tetrahydrofuran motifs (Equation 71) <2000EJ01889>. Intramolecular dehydration to afford tetrahydrofurans can efficiently be carried out by the Mitsunobu reaction <2003JOC4422> and a cationic platinum-catalyzed dehydration <2005SL152>. 

Mitsunobu reaction as well as by mesylation and subsequent base treatment failed, the secondary alcohol was inverted by oxidation with pyridinium dichromate and successive reduction with sodium borohydride. The inverted alcohol 454 was protected as an acetate and the acetonide was removed by acid treatment to enable conformational flexibility. Persilylation of triol 455 was succeeded by acetate cleavage with guanidine. Alcohol 456 was deprotonated to assist lactonization. Mild and short treatment with aqueous hydrogen fluoride allowed selective cleavage of the secondary silyl ether. Dehydration of the alcohol 457 was achieved by Tshugaejf vesLCtion. The final steps toward corianin (21) were deprotection of the tertiary alcohols of 458 and epoxidation with peracid. This alternative corianin synthesis needed 34 steps in 0.13% overall yield. 

Grochowski, E., Hilton, B. D., Kupper, R. J., Michejda, C. J. Mechanism of the triphenylphosphine and diethyl azodicarboxylate induced dehydration reactions (Mitsunobu reaction). The central role of pentavalent phosphorus intermediates. J. Am. Chem. Soc. 1982,104, 6876-6877. 

The enantioselective synthesis of monoprotected fra 5-2,5-pyrrolidine dialcohol 1119, a potentially useful intermediate for the construction of pyrrolizidine alkaloids, uses ( S)-malic acid as the chiral source and radical cyclization to fabricate the heterocycle (Scheme 164) [236]. The crucial intermediate 1112 is prepared from acetonide 454b by a Mitsunobu reaction of 1110 with oxazolidine-2,4-dione, resulting in inversion of configuration at the hydroxyl-bearing carbon. Reduction of the 4-carbonyl group of heterocycle 1111 with sodium borohydride followed by dehydration of the resulting alcohol furnishes 1112. 

Thus, thromboxane 82 (177) was first converted into the 1,15-macrolide (178) which, after dehydration to (179), was elaborated into the bromohydrin (I80). A modified Mitsunobu reaction with (180) next produced the 10-bromothromboxane A2 derivative (I8la)... 

In a similar manner, acid labile compounds can be sufficiently sensitive to the carboxylic acids used in the Mitsunobu reaction that dehydration or other degradation pathways can become competitive. In a particularly sensitive case, dihydroxyvitamin-Ds related triol 38 was... 

The Mitsunobu reaction can be employed as a dehydration method. In a synthetic approach towards broad-spectrum -lactamase inhibitors of the trinem class, the Mitsunobu reaction was utilised to introduce an exocyclic double bond (245). Other traditional dehydration methods did not work for this particular substrate. 

Reaction with Di- and Polyols. Although intermolecular dehydration between two molecules of alcohols to afford acyclic ethers usually does not occur with the DEAD-TPP system, intramolecular cyclization of diols to produce three to seven-membered ethers is a common and high yielding reaction. Contrary to an early report, 1,3-propanediol does not form oxetane. Oxetanes can be formed, however, using the trimethyl phosphite modification of the Mitsunobu reaction. The reaction of (5)-1,2-propanediol and ( )-l,4-pentanediol with DEAD and TPP affords the corresponding cyclic ethers with 80-87% retention of stereochemistry at the chiral carbon, while (5)-phenyl-1,2-ethanediol affords racemic styrene oxide. In contrast to the reaction of the same 1,2-diols with benzoic acid (eq 4), oxyphos-phonium salts (25a) and (25b) have been postulated as key intermediates in the present reaction (eq 20). ... 

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. 

There are two good ways to do this. Dehydration of alkyl nitrocompounds 68, either with PhNCO or with Ph3P and DEAD (Et02C-N=N-C02Et) in a Mitsunobu elimination gives nitrile oxides 69, as does the 1,3-elimination of HC1 from chloro-oximes 70. In the next section we shall show only the nitrile oxide but you should recall that it is generated in the reaction mixture by one of these reactions. 

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