J. Org. Chem. 1982,47, 2907-2910
2907
Photooxygenation and Other Oxidation Reactions of 2,3-Dehydro-1-nitrosopiperidine Richard H. Smith, Jr.,l Marilyn B. Kroeger-Koepke, and Christopher J. Michejda* Chemical Carcinogenesis Program, National Cancer Institute-Frederick Cancer Research Facility, Frederick, Maryland 21 701 Received March 1, 1982
The N-nitroso enamine, 2,3-dehydro-l-nitrosopiperidine(l),reacted with oxygen in a light-catalyzed reaction (2). The nitro enamine 2 was also formed when to form a novel oxidation product, 2,3-dehydro-3-nitropiperidine 1 was oxidized with m-chloroperbenzoicacid or with iodosobenzene. The reaction involves the photodissociation of the N-N bond of 1, followed by the oxidation of the nitric oxide so produced to nitrogen dioxide. The latter combines with the enaminyl radical to form 2, after a prototropic hydrogen shift. It was shown that the photooxygenation does not involve singlet oxygen, although it is catalyzed by polymer-bound Rose Bengal. It (4) and 3-(hydroxyimino)-l,2-dehydropiperidine (3) were not was also shown that l-nitro-2,3-dehydropiperidine intermediates in the photooxygenation. Microsome-catalyzed oxidation of 1 did not lead to 2, but a new metabolite (6), was detected. of 1, l-nitroso-4-hydroxy-2,3-dehydropiperidine, We have recently reported several procedures for the preparation of a,@-unsaturatednitrosamines,2 and some of their reaction^.^ We also investigated4the carcinogenic properties of one member of this class of compound, 2,3dehydro-1-nitrosopiperidine(1). In an effort to understand the chemistry of 1, which, in turn, may be helpful to the understanding of its metabolic reactions, we investigated several oxidation reactions of the compound. This paper concerns itself with some of these reactions, particularly the photooxygenation reaction.
Results Photooxygenation Reactions. Compound 1 is photolabile. Thus, storage of solutions of 1 in dichloromethane, under normal laboratory light conditions, resulted in a gradual disappearance of the compound and the formation of new, crystalline material. I t was determined that the reaction required light and the presence of oxygen. The structure of the product was shown to be 2 by NMR ('H and 13C) and high-resolution mass spectrometry and IR and UV spectroscopy (see Experimental Section).
0+ I
NO
1
QNO2
I
H
2
The ambient light reaction was slow (13% conversion after 7 days); consequently most of the experiments reported herein were carried out with a high-intensity incandescent lamp. The photoreaction in the absence of oxygen did not give 2, although photolysis did occur to form the oxime 3 as the only identifiable product. Compound 3 could not be photooxygenated to 2 under our conditions, although it could be converted in low yield to 2 with m-chloroperbenzoic acid. Moreover, the N-nitramine 4, which was detected as a very minor product (> k(rearrangement),and epimerization approached an equilibrium in which (+)-catechin predominated over (+)-epicatechin. Near pH 11 and at elevated temperatures, k(epimerization)was only slightly greater than k(rearrangement),and the rapid, irreversible formation of catechinic acid under these conditions determined product composition. Both the epimerization of catechin and its rearrangement to catechinic acid can be rationalized in terms of a quinone methide intermediate (4). Condensed tannins from conifer bark are polyflavanoids containing flavan-3-01 repeat units such as (+)-catechin [ 1; (2R,3S)-3,3',4',5,7-pentahydroxyflavan]and (-)-epicatechin [(2R,3R)-3,3',4',5,7-pentahydroxyflavan] linked between C-4 of one unit and either C-6 or C-8 of the next unit? The possibility of using these subunits in polymers cross-linked with formaldehyde or methylolated phenol has been considered as a means of improving the adhesive properties of phenol-formaldehyde resins, but the results have been generally d i ~ a p p o i n t i n g . ~ A primary concern in the design of polymeric systems derived from catechins is the instability of these flavanoids toward epimerization and rearrangement. Epimerization of 1 in hot water or dilute caustic solution to (+)-epicatechin (2) is ~ e l l - k n o w n and, , ~ more recently, it was shown by Sears et al.e that 1 undergoes rearrangement to catechinic acid (3) in hot alkaline solution. The quinone methide 4 suggested by Mehta and Whalley' is a logical intermediate in both processes (see Scheme I). Because these competitive reactions could potentially interfere with tannin extraction from plant material and with resin (1) (a) Taken in part from the Ph.D. thesis of P.K., Oregon State University, 1980. (b) Paper 1575, Forest Research Laboratory, School of Forestry, Oregon State University. (2)(a) Forest Research Laboratory. (b) To whom correspondence should be addressed, at Georgia-Pacific Corp., Decatur, GA 30035. (c) Department of Chemistry. (3) Roux, D. G. Phytochemistry 1972, 11, 1219. (4) Hemingway, R. W. "CompleteTree Utilization of Southern Pine"; MacMillin, C. W., Ed.; Forest Products Research Society: Madison WI, 1978; pp 443-457. (5) Freudenberg, K.; B6hme, 0.;Purrman, L. Eer. Dtsch. Chem. Ges. E 1922, 55, 1734. Freudenberg, K.; Purrman, L. Justus Liebigs Ann. Chem. 1924,437, 274. (6) Sears, K. D.; Casebier, R. L.; Hergert, H. L.; Stout, G . H.; McCandlish, L. E. J. Org. Chem. 1974, 39, 3244. (7) Mehta, P. P.; Whalley, W. E. J . Chem. SOC.1963, 5327.
Scheme I
OH
OH
4
I
0
M
HO
OH
HO'
2
3
synthesis based on flavanoids, it was important to determine their relative rates over a range of p H and temperature. We report the results of kinetic studies (a) on the epimerization of 1 to 2 and of (-)-epicatechin to (-)catechin and (b) on the rearrangement of 1 and 2 to 3. These studies were conducted in aqueous solution over the pH range 5.4-11.0 and a t temperatures from 34 to 100 "C.
Results Catechin, epicatechin, and catechinic acid can readily be resolved by high-pressure liquid chromatography (HPLC); this permits an accurate assay by measurement of peak area. A preliminary survey with 1 and 2 revealed
0022-3263/82/1947-2910$01.25/00 1982 American Chemical Society
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