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Mitsunobu Coupling between Tetrahydrophthalimide and 4-Pentyn-1-ol; N-alkyl maleimides

SyntheticPage 435
DOI: 10.1039/SP435
Submitted Jul 05, 2010, published Jul 05, 2010
Kara Cubbage (kara.cubbage@bristol.ac.uk)
A contribution from Kevin Booker-Milburn Group, Bristol

			Reaction Scheme: Mitsunobu Coupling between <SPAN class=csm-chemical-name id=csm1285440321342 title=Tetrahydrophthalimide>Tetrahydrophthalimide</SPAN> and <SPAN class=csm-chemical-name id=csm1285440262664 title=4-Pentyn-1-ol>4-Pentyn-1-ol</SPAN>

Chemicals Used

3,4,5,6-Tetrahydrophthalimide: CAS 4720-86-9 (Acros)
4-Pentyn-1-ol: CAS 5390-04-5 (Acros)
Triphenylphosphine: CAS 603-35-0 (Sigma-Aldrich)
Diisopropyl azodicarboxylate: CAS 2446-83-5 (Alfa Aesar)
Tetrahydrofuran (anhydrous)


A solution of PPh3 (1.05 eq, 21 mmol, 5.50 g) in anhydrous THF (100 mL) was cooled to -78oC using an actone/CO2 low temperature bath. To this cooled solution was added DIAD (1.04 eq, 20.8 mmol, 4.20 g, 4.04 mL) to give a yellow solution. The reaction was stirred for 1 hr at -78oC and under N2, after which time a white precipitate was observed. To this suspension was added the 4-pentyn-1-ol (1.25 eq, 25.4 mmol, 2.13 g, 2.32 mL) and the reaction was stirred for a further 20 min at -78oC. After this time 3,4,5,6-tetrahydrophthalimide (1.0 eq, 20.0 mmol, 3.00 g) was added in one portion, the reaction was stirred at -78oC for 1 hr before allowing to warm to RT. On warming to RT the precipitate was observed to disappear. Stirring at RT was continued for 16 hrs. The THF was removed in vacuo and the crude oil then redissoved in minimal Et2O (approx. 10 mL). This solution was cooled in the freezer for 2 hrs before filtering under vacuum to remove precipitated triphenylphosphine oxide (Nb. if precipitation does not occur, scratching the vessels glass will encourage the process). The filtrate was concentrated in vacuo and purified by column chromatography (SiO2, 10% EtOAc/Petrol) to give a colourless oil (4.28 g, 99%). 

Author's Comments

This Mitsunobu procedure has been used with a variety of different alkyl alcohols, maleimide nucleophile and on varying scales (1 - 75 mmol). Yields range from 75-99%. The only example where the reaction has failed in my hands has been when coupling 3,4,5,6-tetrahydrophthalimide to methyl 6-hydroxyhex-2-ynoate.


Rf: 0.20 (20% Et20/Petrol); 1H NMR (CDCl3, 400 MHz) 3.58 (2H, t, J = 7.1 Hz, NCH2), 2.33 (4H, m, CH2CH2C=C), 2.21 (2H, td, J = 7.1, 2.7 Hz, CH2=CH), 1.96 (1H, t, J = 2.7 Hz, CH), 1.82 (2H, quin, J = 7.1 Hz, NCH2CH2).

Lead Reference

C. Roscini; K. L. Cubbage; M. Berry; A. J. Orr-Ewing; K. I. Booker-Milburn; Angew. Chem. Int. Ed. 2009, 48, 8716. doi:10.1002/anie.200904059

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Keywords: alcohols, alkenes, alkynes, Imide, Maleimide, Mitsunobu, nucleophilic, substitution

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