Mitsunobu reaction

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Mitsunobu reaction
Named after Oyo Mitsunobu
Reaction type Coupling reaction
Identifiers
Organic Chemistry Portal mitsunobu-reaction
RSC ontology ID RXNO:0000034

The Mitsunobu reaction is an organic reaction that converts an alcohol into a variety of functional groups, such as an ester, using triphenylphosphine and an azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD).[1] The alcohol undergoes an inversion of stereochemistry. It was discovered by Oyo Mitsunobu (1934–2003).

The Mitsunobu reaction

Several reviews have been published.[2][3][4][5][6]

Reaction mechanism[edit]

The reaction mechanism of the Mitsunobu reaction is fairly complex. The identity of intermediates and the roles they play has been the subject of debate.

Initially, the triphenyl phosphine (2) makes a nucleophilic attack upon diethyl azodicarboxylate (1) producing a betaine intermediate 3, which deprotonates the carboxylic acid (4) to form the ion pair 5. DEAD itself deprotonates the alcohol (6) forming an alkoxide that can form the key oxyphosphonium ion 8. The ratio and interconversion of intermediates 811 depend on the carboxylic acid pKa and the solvent polarity.[7][8][9] Although several phosphorus intermediates are present, the attack of the carboxylate anion upon intermediate 8 is the only productive pathway forming the desired product 12 and triphenylphosphine oxide (13).

The mechanism of the Mitsunobu reaction

Hughes et al. have found that the formation of the ion pair 5 is very fast. The formation of the oxyphosphonium intermediate 8 is slow and facilitated by the alkoxide. Therefore, the overall rate of reaction is controlled by carboxylate basicity and solvation.[10]

Order of addition of reagents[edit]

The order of addition of the reagents of the Mitsunobu reaction can be important. Typically, one dissolves the alcohol, the carboxylic acid, and triphenylphosphine in tetrahydrofuran or other suitable solvent (e.g. diethyl ether), cool to 0 °C using an ice-bath, slowly add the DEAD dissolved in THF, then stir at room temperature for several hours. If this is unsuccessful, then preforming the betaine may give better results. To preform the betaine, add DEAD to triphenylphosphine in tetrahydrofuran at 0 °C, followed by the addition of the alcohol and finally the acid.[11]

Variations[edit]

Other nucleophilic functional groups[edit]

Many other functional groups can serve as nucleophiles besides carboxylic acids. For the reaction to be successful, the nucleophile must have a pKa less than 15.

Nucleophile Product
hydrazoic acid alkyl azide
imide substituted imide[12]
phenol alkyl aryl ether (discovered independently [13][14])
sulfonamide substituted sulfonamide[15]

Modifications[edit]

Several modifications to the original reagent combination have been developed in order to simplify the separation of the product and avoid production of so much chemical waste. One variation of the Mitsunobu Reaction uses resin-bound triphenylphoshine and uses di-tert-butylazodicarboxylate instead of DEAD. The oxidized triphenylphosphine resin can be removed by filtration, and the di-tert-butylazodicarboxylate byproduct is removed by treatment with trifluoroacetic acid.[16] Bruce H. Lipshutz has developed an alternative to DEAD, Di-(4-chlorobenzyl)azodicarboxylate (DCAD) where the hydrazine by-product can be easily removed by filtration and recycled back to DCAD.[17]

A modification has also been reported in which DEAD can be used in catalytic versus stoichiometric quantities, however this procedure requires the use of stoichiometric (diacetoxyiodo)benzene to oxidise the hydrazine by-product back to DEAD.[18]

Phosphorane reagents[edit]

(Cyanomethylene) trialkylphosphorane

Tsunoda et al. have shown that one can combine the triphenylphosphine and the diethyl azodicarboxylate into one reagent: a phosphorane ylide. Both (cyanomethylene)trimethylphosphorane (CMMP, R = Me) and (cyanomethylene)tributylphosphorane (CMBP, R = Bu) have proven particularly effective.[19]

The mechanism of the phosphorane variant of the Mitsunobu reaction

The ylide acts as both the reducing agent and the base. The byproducts are acetonitrile (6) and the trialkylphosphine oxide (8).

Uses[edit]

The Mitsunobu reaction has been applied in the synthesis of aryl ethers:[20]

Mitsunobu reaction Application

With these particular reactants the conversion with DEAD fails because the phenol is only weakly acidic. Instead the related 1,1'-(azodicarbonyl)dipiperidine (ADDP) is used of which the betaine intermediate is a stronger base. The phosphine is a polymer-supported triphenylphosphine (PS-PPh3).

The reaction has been used to synthesize quinine, colchicine, sarain, morphine, stigmatellin, eudistomin, oseltamivir, strychnine, and nupharamine.[21]

The mitsunobu reaction has also been used to label the oxygen atom in alcohols for isotope effect measurements. In the mechanism above, notice that the oxygen in the product ester comes from the carboxylic acid moiety, unlike Fisher esterification where the oxygen in the ester comes from the alcohol moiety. This means that if the ester is formed using a carboxylic acid moiety labeled with oxygen-18, cleaving the ester will re-produce the starting alcohol, but bearing the heavy oxygen atom from the carboxylic acid. [22]

References[edit]

  1. ^ Mitsunobu, O.; Yamada, Y. (1967). "Preparation of Esters of Carboxylic and Phosphoric Acid via Quaternary Phosphonium Salts". Bulletin of the Chemical Society of Japan. 40 (10): 2380–2382. doi:10.1246/bcsj.40.2380. 
  2. ^ Mitsunobu, O. (1981). "The Use of Diethyl Azodicarboxylate and Triphenylphosphine in Synthesis and Transformation of Natural Products". Synthesis. 1981 (1): 1–28. doi:10.1055/s-1981-29317. 
  3. ^ Castro, B. R. (1983). "Replacement of Alcoholic Hydroxy Groups by Halogens and Other Nucleophiles via Oxyphosphonium Intermediates". Organic Reactions. 29: 1–162. doi:10.1002/0471264180.or029.01. ISBN 9780471264187. 
  4. ^ Hughes, D. L. (1992). "The Mitsunobu Reaction". Organic Reactions. 42: 335–656. doi:10.1002/0471264180.or042.02. ISBN 9780471264187. 
  5. ^ Hughes, D. L. (1996). "Progress in the Mitsunobu Reaction. A Review". Organic Preparations and Procedures International. 28 (2): 127–164. doi:10.1080/00304949609356516. 
  6. ^ Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.; Kumar, K. V. P. P. (2009). "Mitsunobu and Related Reactions: Advances and Applications". Chemical Reviews. 109 (6): 2551–2651. doi:10.1021/cr800278z. PMID 19382806. 
  7. ^ Grochowski, E.; Hilton, B. D.; Kupper, R. J.; Michejda, C. J. (1982). "Mechanism of the triphenylphosphine and diethyl azodicarboxylate induced dehydration reactions (Mitsunobu reaction). The central role of pentavalent phosphorus intermediates". Journal of the American Chemical Society. 104 (24): 6876–6877. doi:10.1021/ja00388a110. 
  8. ^ Camp, D.; Jenkins, I. D. (1989). "The mechanism of the Mitsunobu esterification reaction. Part I. The involvement of phosphoranes and oxyphosphonium salts". The Journal of Organic Chemistry. 54 (13): 3045–3049. doi:10.1021/jo00274a016. 
  9. ^ Camp, D.; Jenkins, I. D. (1989). "The mechanism of the Mitsunobu esterification reaction. Part II. The involvement of (acyloxy)alkoxyphosphoranes". The Journal of Organic Chemistry. 54 (13): 3049–3054. doi:10.1021/jo00274a017. 
  10. ^ Hughes, D. L.; Reamer, R. A.; Bergan, J. J.; Grabowski, E. J. J. (1988). "A mechanistic study of the Mitsunobu esterification reaction". Journal of the American Chemical Society. 110 (19): 6487–6491. doi:10.1021/ja00227a032. 
  11. ^ Volante, R. (1981). "A new, highly efficient method for the conversion of alcohols to thiolesters and thiols". Tetrahedron Letters. 22 (33): 3119–3122. doi:10.1016/S0040-4039(01)81842-6. 
  12. ^ Hegedus, L. S.; Holden, M. S.; McKearin, J. M. (1984). "cis-N-TOSYL-3-METHYL-2-AZABICYCLO[3.3.0]OCT-3-ENE". Org. Synth. 62: 48.  ; Coll. Vol., 7, p. 501 
  13. ^ Manhas, Maghar S.; Hoffman,, W. H.; Lal, Bansi; Bose, Ajay K. (1975). "Steroids. Part X. A convenient synthesis of alkyl aryl ethers". J. Chem. Soc., Perkin Trans. 1: 461–463. doi:10.1039/P19750000461. 
  14. ^ Bittner, Shmuel; Assaf, Yonit (1975). "Use of activated alcohols in the formation of aryl ethers". Chemistry & Industry (London, United Kingdom) (6): 281. 
  15. ^ Kurosawa, W.; Kan, T.; Fukuyama, T. (2002). "PREPARATION OF SECONDARY AMINES FROM PRIMARY AMINES VIA 2-NITROBENZENESULFONAMIDES: N-(4-METHOXYBENZYL)-3-PHENYLPROPYLAMINE". Org. Synth. 79: 186.  ; Coll. Vol., 10, p. 482 .
  16. ^ Pelletier, J. C.; Kincaid, S. (2000). "Mitsunobu reaction modifications allowing product isolation without chromatography: application to a small parallel library". Tetrahedron Letters. 41 (6): 797–800. doi:10.1016/S0040-4039(99)02214-5. 
  17. ^ Lipshutz, B. H.; Chung, D. W.; Rich. B.; Corral, R. (2006). "Simplification of the Mitsunobu Reaction. Di-p-chlorobenzyl Azodicarboxylate: A New Azodicarboxylate". Organic Letters. 8 (22): 5069–5072. doi:10.1021/ol0618757. PMID 17048845. 
  18. ^ But, T. Y.; Toy, P. H. (2006). "Organocatalytic Mitsunobu Reactions". Journal of the American Chemical Society. 128 (30): 9636–9637. doi:10.1021/ja063141v. PMID 16866510. 
  19. ^ Tsunoda, T.; Nagino, C.; Oguri, M.; Itô, S. (1996). "Mitsunobu-type alkylation with active methine compounds". Tetrahedron Letters. 37 (14): 2459–2462. doi:10.1016/0040-4039(96)00318-8. 
  20. ^ Humphries, P. S.; Do, Q. -Q. T.; Wilhite, D. M. (2006). "ADDP and PS-PPh3: an efficient Mitsunobu protocol for the preparation of pyridine ether PPAR agonists". Beilstein Journal of Organic Chemistry. 2 (21): 21. doi:10.1186/1860-5397-2-21. PMC 1705810free to read. PMID 17076898. 
  21. ^ Mitsunobu Reaction at SynArchive Accessed April 26, 2014
  22. ^ [1] "Altered Transition State for the Reaction of an RNA Model Catalyzed by a Dinuclear Zinc(II) Catalyst" Humphry, Iyer, Iranzo, Morrow, Richard, Paneth, Hengge Journal of the American Chemical Society 2008: 17858-17866

See also[edit]