Solid phase synthesis of 2-aminobutadienes using a piperazine linker

Tetrahedron Letters

Volumn 38, Issue 40, 1997, Pages 7111-7114

  Hird, Nicholas W ^a   Irie, Kazuyuki ^b   Nagai, Katsunori ^b  

^a GLAXOSMITHKLINE   (United Kingdom)

^b TAKEDA PHARMACEUTICAL COMPANY LIMITED   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

1,3 BUTADIENE DERIVATIVE;

ARTICLE; DRUG SYNTHESIS; IN VITRO STUDY; REACTION ANALYSIS; TECHNIQUE;

EID: 0030756775     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(97)01633-X     Document Type: Article

References (11)

1. Hermkens, P. H. H.; Ottenheijm, H. C. J., Rees, D. Tetrahedron 1996, 52, 4527.
2. Bicknell, A.J. and Hird, N.W. Bioorganic and Medicinal Chemistry Lett. 1996, 6, 2441.
3. Krohn, K. Angew. Chem. Int. Ed. Engl. 1993, 32, 1582.
4. Barluenga, J.; Merino, I., Palacios, F. Tetrahedron Lett 1990, 32, 6713.
5. Ketones have previously been synthesised on solid support by use of a Weinreb amide linker Dinh, T.; Armstrong, R. W. Tetrahedron Lett 1996, 37, 1161.
6. Procedure: A suspension of Merrifield resin (50 mmol, 1.13 mmol/g) and piperazine (250 mmol) in dioxane (500 ml) was heated to 70 °C for 16 h. The resin was removed by filtration and washed successively with dioxane, dioxane-1N NaOH, dioxane-water, dioxane and methanol then dried under vacuum. The product resin was suspended in anhydrous dichloromethane, then propargyltriphenyl phosphine (150 mmol) was added and the mixture was shaken for 3 h. The resin was then washed with dichloromethane and THF. Elemental analysis of the product gave N 2.10%, Br 5.88% (theoretical N 2.13%, Br 6.07%).
7. Enders, D.; Meyer, O., Raabe, G., Runsink, J. Synthesis 1994, 66.
8. Typical Procedure: resin 1 (0.16 mmol) was suspended in dry benzene (20 ml) in a round bottom flask under argon and 15 ml of solvent was distilled off. The remainder was removed under a gentle stream of argon, then the resin was re-suspended in anhydrous THF and cooled to 0°C . Potassium tert-butoxide (2.5eq., 1 M in THF) mixture was added, and the mixture stirred for 5 min resulting in the formation of bright red-orange coloured resin. Aldehyde (10 eq.) was added dropwise and the mixture was refluxed for 16h after which the resin was filtered and washed successively with methanol, THF, dioxane and ether (each 3×10 ml) and dried under high vacuum. The resin was cleaved by suspension in trifluoroacetic acid/ dichloromethane (3:97) for 10 min, followed by washing with dichloromethane.
9. 1H NMR and MS as: (formula presented)
10. 3 2.41(3 H, s), 5.5 (1 H, d, J=15.5 Hz), 5.5 (1 H, d, J=15.5 Hz),
11. ™ is a modular robotic synthesiser developed by the Myriad Consortium and The Technology Partnership. The synthesis protocol included in situ azeotropic resin drying