Mitsunobu reaction
The Mitsunobu reaction is an organic chemical reaction to derivatize alcohols . It was discovered by Oyo Mitsunobu (1934-2003) and named after him.
It enables the transformation of alcohols to esters , ethers , amines and thioethers using the reagents triphenylphosphine and diethylazodicarboxylate (DEAD), diisopropylazodicarboxylate (DIAD) or tetramethylazodicarboxamide (TMAD).
If the hydroxy group is located at a stereogenic center of the molecule, such secondary alcohols react in the Mitsunobu reaction with inversion at the stereocenter. In this way, the Mitsunobu benzoylation of the hydroxyl group, followed by the hydrolysis of the ester obtained in this way, can be used in natural product chemistry for the targeted inversion of secondary , chiral alcohols. In this context one speaks of a Mitsunobu inversion .
mechanism
In the initial step, the triphenylphosphine (2) attacks the diethylazodicarboxylate (1) and a betaine (3) is formed as an intermediate . This betaine deprotonates the carboxylic acid and an ion pair (4) is formed. The alcohol, which is in the ( R ) configuration, attacks this intermediate stage and an alcohol triphenylphosphonium ion (5) is formed. This is now attacked by the carboxylate ion via an SN2 mechanism and the ester (6) is formed by splitting off triphenylphosphine oxide , which is now in the ( S ) configuration. An inversion has taken place. The driving force behind this reaction is the formation of the very stable phosphorus - oxygen bond.
The order in which the reagents are added is important in the Mitsunobu reaction. The alcohol, the carboxylic acid and the triphenylphosphine are usually dissolved in an ethereal solvent such as diethyl ether or tetrahydrofuran (THF) and the diazodicarboxylate is added at 0 ° C. A variant in the case of unsuccessful Mitsunobu reactions consists of a solution of the diazodicarboxylate and phosphine at 0 ° C. to which the alcohol and the carboxylic acid are added one after the other.
variants
A number of other functional groups can be prepared from alcohols in this way, depending on the nucleophile. The nucleophile must, however, have a pKa value of less than 15.
| Nucleophile | product |
|---|---|
| Hydrazoic acid | Alkyl azides (after reduction amines) |
| Imide | Substituted imides |
| Phenols | Phenyl alkyl ethers |
| Sulfonamides | Substituted sulfonamides |
Web links
- The Mitsunobu Reaction (PDF; 37 kB) by Kevin Jantzi ( Memento from May 1, 2003 in the Internet Archive )
literature
- O. Mitsunobu: The Use of Diethyl Azodicarboxylate and Triphenylphosphine in Synthesis and Transformation of Natural Products , Synthesis , 1981 , 1-28.
- BR Castro: In Org.React. 1983 , 29 , 1.
- DL Hughes: In Org.React. 1992 , 42 , 335-656.
- DL Hughes: In Org. Prep. 1996 , 28 , 127-164.
Individual evidence
- ↑ O. Mitsunobu, Y. Yamada: In Bull. Chem. Soc. Japan , 1967 , 40 , 2380-2382.
- ^ László Kürti and Barbara Czakó .: Strategic Applications of Named Reactions in Organic Synthesis: Background and Detailed Mechanisms , Elsevier Academic Press, 2005, pp. 294-295, ISBN 978-0-12-429785-2 .
- ^ R. Volante: In Tetrahedron Lett. , 1981 , 22 , 3119.
- ↑ Hegedus, LS; Holden, MS; McKearin, JM: cis -N-Tosyl-3-methyl-2-azabicyclo [3.3.0] oct-3-ene In: Organic Syntheses . 62, 1984, p. 48, doi : 10.15227 / orgsyn.062.0048 ; Coll. Vol. 7, 1990, p. 501 ( PDF ).
- ↑ Kurosawa, W .; Kan, T .; Fukuyama, T .: Preparation of secondary amines from primary amines via 2-Nitrobenzenesulfonamides: N- (4-Methoxybenzyl) -3-Phenylpropylamine In: Organic Syntheses . 79, 2002, p. 186, doi : 10.15227 / orgsyn.079.0186 ; Coll. Vol. 10, 2004, p. 482 ( PDF ).