A Cleaner Approach to Solid-Supported Radical Chemistry: Application of Hypophosphite Salts to Intramolecular C-C Bond Formation on the Solid-Phase

Abstract

The application of hypophosphite salts to solid-supported radical chemistry has been explored. EPHP-mediated intramolecular cyclisations have been shown to give good yield of cyclised products on JandaJel^® resin.

solid-phase - cyclizations - radical reactions

References

1 Jasperse CP. Curran DP. Fevig TL. Chem. Rev.  1991,  91:  1237 

2a Routledge A. Abell C. Balasubramanian S. Synlett  1997,  61 

2b Miyabe H. Tanaka H. Naito T. Tetrahedron Lett.  1999,  40:  8387 

2c Berteina S. DeMesmaeker A. Tetrahedron Lett.  1998,  39:  5759 

3 Yallapragada PR. Vig PJS. Kodavanti PRS. Desaiah D. J. Toxicol. Environ. Health  1991,  34:  229 

4 Chatgilialoglu C. Griller D. Lesage M. J. Org. Chem.  1988,  53:  3641 

5a Barton DHR. Jang DO. Jaszberenyi JC. Tetrahedron Lett.  1992,  33:  5709 

5b Graham SR. Murphy JA. Coates D. Tetrahedron Lett.  1999,  40:  2415 

6 Yorimitsu H. Shinokubo H. Oshima K. Bull. Chem. Soc. Jpn.  2001,  74:  225 

7 Kita Y. Nambu H. Ramesh NG. Anilkumar G. Matsugi M. Org. Lett.  2001,  3:  1157 

8 Rano TA. Chapman KT. Tetrahedron Lett.  1995,  36:  3789 

9

Carboxypolystyrene resin loaded with 1a (100 mg, 0.063 mmol) was suspended in anhyd degassed toluene (1 mL), EPHP (225 mg, 1.26 mmol) and AIBN (10 mg, 0.06 mmol) were added, and then the reaction mixture was heated under reflux for 4 h. The resin was washed with DMF (3 × 5 mL), THF (3 × 5 mL), THF-H₂O (1:1, 3 × 5 mL), THF (3 × 5 mL), CH₂Cl₂ (3 × 5 mL) then dried under vacuum for 48 h.

10

Resin was suspended in THF-MeOH (4:1), excess MeONa was added and the reaction mixture was agitated for 24 h. The resin was filtered off and the solution was eluted through a plug of ion exchange resin (Dowex 50W-X8 H⁺) then analysed by HPLC on a Alltech econosil Si column eluting with hexane-i-PrOH (0-5 min 100% hexane, 5-35 min gradient 0-30% i-PrOH): iodoether 2, 18.4 min; benzyl ether 3, 17.3 min; benzofuran 4, 19.9 min; 220 nm detection.

11

2,2′-azobis(2-amidinopropane) dihydrochloride, a water soluble azo radical initiator.

12

The stepwise solid-phase synthesis (Scheme [1] ) could not be applied to NovaSyn^® TG carboxy resin as reaction with cis-butan-1,4-diol resulted in extensive cross-linking of the resin.

13

NovaSyn ^® TG resin loaded with 1b (100 mg, 0.015 mmol) was suspended in degassed solvent (0.25 mL), EPHP (54 mg, 0.30 mmol) and AIBN (2.5 mg, 0.015 mmol) or V-50 (4 mg, 0.015 mmol) were added then the reaction mixture was heated under reflux for 18 h. The resin was washed with THF (3 × 5 mL), THF-H₂O (1:1, 3 × 5 mL), THF (3 × 5 mL), CH₂Cl₂ (3 × 5 mL) then dried under vacuum for 48 h.

14

Carboxy-functionalised resins were either commercially available (HypoGel^®) or synthesized from commercially available amino functionalised resin by reaction with glutaric anhydride (JandaJel^®, ArgoGel^® and ArgoPore^®).

15

The reactions were performed on 100 mg of resin and the amount of solvent used in the reaction was dependent on the loading of the resin (100 mg of resin with 1 mmol g^-1 loading = 1.5 mL solvent for reaction), 1 equiv of initiator added at t = 0 h and t = 24 h.