The [4 + 2] Addition of Singlet Oxygen to Thebaine:  New Access to Highly Functionalized Morphine Derivatives via Opioid Endoperoxides

• Published in: Journal of organic chemistry 2000-07, Vol.65 (15), p.4671-4678
• Main Authors: López, Dolores, Quiñoá, Emilio, Riguera, Ricardo
• Format: Article
• Language: English
• Subjects: Benzofurans - chemical synthesis; Benzofurans - chemistry; Benzofurans - metabolism; Codeine - analogs & derivatives; Codeine - chemical synthesis; Codeine - chemistry; Light; Magnetic Resonance Spectroscopy; Mercury; Morphine Derivatives - chemical synthesis; Morphine Derivatives - chemistry; Narcotics - chemistry; Narcotics - metabolism; Oxidants - chemistry; Oxidants - metabolism; Oxycodone - analogs & derivatives; Oxycodone - chemical synthesis; Oxycodone - chemistry; Oxygen - chemistry; Oxygen - metabolism; Peroxides - chemistry; Peroxides - metabolism; Photochemistry; Singlet Oxygen; Thebaine - chemistry; Thebaine - metabolism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo000288a

The photooxidation of thebaine (3) with a sun lamp affords two main products:  hydrodibenzofuran 10 (major) and benzofuran 11 (minor). The latter compound becomes predominant if a Hg lamp is used instead of a sun lamp. The formation of 10 proceeds via an endoperoxide intermediate that undergoes oxidation at the nitrogen atom. Protection of the nitrogen either by protonation or quaternization prevents its oxidation and thus the photooxidation of 3 in acid media constitutes a one-pot procedure for the preparation of 14-hydroxycodeinone 35. Photooxidation of the thebaine ammonium salt 31 allows the isolation in good yields of the corresponding to thebaine endoperoxide 32. The selective protection and reduction of the keto, aldehyde, and olefinic groups of hydrodibenzofuran 10 allowed the preparation of several diol and keto alcohol derivatives. This is the first report on the use of photooxidation to functionalize thebaine at C(6) and C(14) and also the first on the isolation of opioid endoperoxides.