C(6)-alkylation of 3-hydroxypiperidine via reductive and homolytic cleavage of N,S-acetals

Synlett

Volumn , Issue 14, 2004, Pages 2636-2638

  Bartels, Marc ^a   Zapico, Julian ^a   Gallagher, Timothy ^a  

^a UNIVERSITY OF BRISTOL   (United Kingdom)

Author keywords

Alkylation; Anodic oxidation; Piperidines; Radical

Indexed keywords

3 PIPERIDINOL; ACETAL DERIVATIVE; CARBON; LITHIUM DERIVATIVE; LITHIUM NAPHTHALENIDE; N CARBOXYMETHYL 3 HYDROXYPIPERIDINE; PIPERIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ALKYLATION; ARTICLE; CHEMICAL REACTION; CHEMICAL STRUCTURE; OXIDATION; REACTION ANALYSIS; REDUCTION;

EID: 9644282969     PISSN: 09365214     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-2004-832846     Document Type: Article

References (27)

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6. (b) For earlier work which incorrectly assigned the regiochemistry of the lithiation of 1, see: Pandey, G.; Chakrabarti, D. Tetrahedron Lett. 1996, 37, 2285.
7. See also: Pandey, G.; Lakshmalah, G. Synlett 1994, 277.
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11. (c) Barren, A. T.; Pilipauskas, D. J. Org. Chem. 1991, 56, 2787.
12. (d) Shono, T.; Matsumura, Y.; Tsubata, K. J. Am. Chem. Soc. 1981, 103, 1172.
13. (e) Shono, T.; Hamaguchi, H.; Matsumura, Y. J. Am. Chem. Soc. 1975, 97, 4264.
14. The anodic oxidation of N-carboxymethyl 3-hydroxy-pyrrolidine has been described and exploited for the synthesis of pyrrolizidine alkaloids: (a) Thaning, M.; Wistrand, L.-G. Acta Chem. Scand. 1989, 55, 290.
15. (b) A 1:1 mixture of regioisomers was obtained, analogous to oxidation of 6 leading to 7a and 7b. See: Thaning, M.; Wistrand, L.-G. J. Org. Chem. 1990, 55, 1406.
16. (a) Chiba, T.; Takata, Y. J. Org. Chem. 1977, 42, 2973.
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18. (c) Ross, S. D.; Finkelstein, M.; Petersen, R. C. J. Am. Chem. Soc. 1966, 88, 4657.
19. 4) and concentrated in vacuo and the residue was purified by flash chromatography (hexane-EtOAc 3:2) to afford 2-phenylthio-N-carbomethoxy-3-hydroxy-piperidine (8b, 275 mg, 19%) as a mixture of diastereo-isomers and as colorless oil. Continued elution gave 2-phenylthio-N-carbomethoxy-5-hydroxypiperidine (8a, 880 mg, 61%) as a mixture of diastereoisomers and as a colorless oil.
20. 3): δ = 156.4, 155.5, 135.0, 134.6, 133.3, 132.9, 129.3, 129.0, 128.9, 127.5, 72.2, 70.7, 69.3, 67.3, 52.9, 52.4, 39.3, 38.3, 29.4, 23.9, 23.4. Compound 8b also gave satisfactory HRMS data.
21. ax is a useful diagnostic probe for cis/trans stereochemistry in this and related disubstituted piperidines.10
22. (a) Plehiers, M.; Hootelé, C. Can. J. Chem. 1996, 74, 2444.
23. (b) Herdeis, C.; Held, W. A.; Kirfel, A.; Schwabenländer, F. Liebigs Ann. Chem. 1995, 1295.
24. (c) Shono, T.; Matsumura, Y.; Onomura, O.; Sato, M. J. Org. Chem. 1988, 55, 4118.
25. N,S-Acetal 8a also provided access to the corresponding N-acyl imimium ion under Lewis acid-mediated conditions. Accordingly, reaction of 8a with allyl trimethylsilane in the presence of TMSOTf gave 10a as a 6:1 mixture of cis and trans isomer in a combined yield of 77%. Note that under these conditions, cis-10a predominated.
26. Radical addition adducts 10d-f were obtained as approx. 1:1 mixtures of cis and trans isomers which were separable by chromatography. Styrene is generally a poor trap for nucleophilic radicals, and the major byproduct in this case was 6.
27. The N,Se-acetal corresponding to 8a is generated from 7a,b under similar conditions to those used for 8a and 8b and has also been used as a source of a nucleophilic α-aza radical by C-Se homolysis to provide 10d-f in similar yields to those obtained from 8a. The use of an N,Se-acetal as a source of nucleophilic radical reactivity adjacent to nitrogen within a pyrrolidine framework has been described. See: Barrett, A. G. M.; Pilipauskas, D. J. Org. Chem. 1991, 56, 2787.