Mitsunobu Reaction

The Mitsunobu reaction is a unique dehydration-condensation reaction between alcohols and various nucleophiles using the redox system comprised of diethyl azodicarboxylate (DEAD) and triphenylphosphine (TPP).1) The reactions proceed under mild conditions, and a wide variety of compounds can be used as nucleophiles, for example, carboxylic acids, active methylenes, imides, thiols, etc. The reaction between secondary alcohols and nucleophiles yields products with Walden inversion. The Mitsunobu reaction has been used widely in organic synthesis. Due to its utility, efforts have been made to expand application of the Mitsunobu reaction, and modified reactions have been reported.2) For example, by using azodicarboxamides instead of azodicarboxylates the Mitsunobu reaction is being applied to weak-acidity nucleophiles with a higher pKa value.3) Methods have also been reported for the easy removal of phosphine oxide, a reaction by-product, by utilizing phosphines which have an intramolecular basic component4) and diphenylphosphino polystyrene resin.5)

In 1994, Tsunoda and co-workers reported a new Mitsunobu reagent, cyanomethylenetributylphosphorane 1.6) This reagent alone can achieve the functions of DEAD and TPP. It is shown to be very effective in the reaction of secondary alcohols and active methylene of pKa value above 23.4. Accordingly, 1 is a reagent which increases the usefulness of the Mitsunobu reaction.

Azodicarboxylates & Amides

Phosphines

Modified New Mitsunobu Reaction (Tsunoda Reagent)

Azodicarboxylates & Amides

A1051 A1051 A1458 A1458 A1332 A1332
A0776 A0776
A1051 1,1'-(Azodicarbonyl)dipiperidine
A1458 1,1'-Azobis(N,N-dimethylformamide)
A1332 Bis(2,2,2-trichloroethyl) Azodicarboxylate
A0776 Dibenzyl Azodicarboxylate (40% in Dichloromethane, ca. 1.7mol/L)
Page Top

Phosphines

D2478 D2478 D2766 D2766 D2411 D2411
D1019 D1019 D2471 D2471 I0583 I0583
P1843 P1843 T0503 T0503 T1912 T1912
T0361 T0361 T1005 T1005 T0519 T0519
D2478 4-(Dimethylamino)phenyldiphenylphosphine
D2766 4-Diphenylphosphinomethyl Polystyrene Resin cross-linked with 2% DVB (200-400mesh) (0.5-1.0mmol/g)
D2411 Dicyclohexylphenylphosphine
D1019 Diethylphenylphosphine
D2471 Diphenyl-2-pyridylphosphine
I0583 Isopropyldiphenylphosphine
P1843 Phenoxydiphenylphosphine
T0503 Tri-n-octylphosphine
T1912 Tri-tert-butylphosphine
T0361 Tributylphosphine
T1005 Trihexylphosphine
T0519 Triphenylphosphine
Page Top

Modified New Mitsunobu Reaction (Tsunoda Reagent)

C1500 C1500
C1500 Cyanomethylenetributylphosphorane
Page Top

On exposure to heat, impact, friction, etc., derivatives of azodicarboxylic acid are prone to highly exothermic reaction or explosive decomposition. Sufficient safety measures, such as usage of safety shield, wearing of protective equipment, and extreme caution should be taken, when using this compound, from the opening up to the disposal of the reagents.

Literature

1) O. Mitsunobu, Synthesis, 1981, 1 [DOI].
2) S. Ito, Yakugaku Zasshi (J. Pharm. Soc. Jpn.), 2001, 121, 567 [DOI]; T. Onozawa. TCIMAIL, 1999, number 104, 10.
3) T. Tsunoda, Y. Yamamiya, S. Ito, Tetrahedron Lett., 1993, 34, 1639 [DOI]; T. Tsunoda, J. Otsuka, Y. Yamamiya, S. Ito, Chem. Lett., 1994, 539 [DOI]; S. Ito, T. Tsunoda, Pure & Appl. Chem., 1994, 66, 2071 [DOI]; T. Tsunoda, Y. Yamamiya, Y. Kawamura, S. Ito, Tetrahedron Lett., 1995, 36, 2529 [DOI]; K. Tahara, T. Onozawa, Yuki Gosei Kagaku Kyokaishi (J. Synth. Org. Chem. Jpn.), 1999, 57, 633.
4) L. D. Arnold, H. I. Assil, J. C. Vederas, J. Am. Chem. Soc., 1989, 111, 3973 [DOI]; A. R. Tunoori, D. Dutta, G. I. Georg, Tetrahedron Lett., 1998, 39, 8751 [DOI].
5) R. A. Amos, R. W. Emblidge, N. Havens, J. Org. Chem., 1983, 48, 3598 [DOI].
6) T. Tsunoda, M. Nagaku, C. Nagino, Y. Kawamura, F. Ozaki, H. Hiroki, S. Ito, Tetrahedron Lett., 1995, 36, 2531 [DOI]; T. Tsunoda, F. Ozaki, N. Shirakata, Y. Tamaoka, H. Yamamoto, S. Ito, Tetrahedron Lett., 1996, 37, 2463 [DOI].

Page Top
kdjoad0000003vsp