A practical, efficient synthesis of 1,1-dioxo-hexahydro-1#-thiopyran-4- carbaldehyde

Organic Process Research and Development

Volumn 12, Issue 5, 2008, Pages 892-895

  Bio, Matthew M ^a   Hansen, Karl B ^a   Gipson, John ^a  

^a AMGEN INC   (United States)

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Indexed keywords

EID: 58149114902     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op800108s     Document Type: Article

References (20)

1. (a) Carlon, E.; Draper, R. W.; Friary, R. Org. Prep. Proced. Int. 1977, 9, 94-96. A longer and far less efficient synthesis of 2 is also known:
2. (b) Cockburn, W. F.; McKay, A. F. J. Am. Chem. Soc. 1954, 76, 5703. While the aldehyde has appeared as a reagent in a few published articles, we have not found a reported synthesis.
3. The diacid is an observed intermediate in this reaction, suggesting that a simple hydrolysis - decarboxylation mechanism is operative as opposed to a plausible pathway to 2 via ketene.
4. Volumes here is used according to the convention: mL of 6 N HCl/g of 1.
5. 2 solution of 5 obtained can be used directly in the oxidation step with no change in reaction performance.
6. Parikh, J. R.; Doering, W. von E. J. Am. Chem. Soc. 1967, 89, 5505-5507.
7. Crystallization of the aldehyde following oxidation was complicated by the pyridine, DMSO, and oxidation byproducts.
8. Order addition proved important here. Addition of ethanol prior to water led to the formation of the diethylacetal from which the aldehyde could only be recovered by hydrolysis with aqueous acid.
9. A reductive animation directly with an aldehyde bisulfite adduct was demonstrated: Ragan, J. A.; am Ende, D. J.; Brenek, S. J.; Eisenbeis, S. A.; Singer, R. A. , Tickner, D. L.; Teixeira, J. J., Jr.; Vanderplas, B. C.; Weston, N. Org. Process Res. Dev. 2003, 7, 155-160.
10. Jencks, W. P.; Young, P. R. J. Am. Chem. Soc. 1978, 100, 1228-1235.
11. A non-aqueous method for regeneration of aldehydes from bisulfite adducts has been reported: Kjell, D. P.; Slattery, B. J.; Semo, M. J. J. Org. Chem. 1999, 64, 5722-5724, While this method was successful for regenerating aldehyde 3, it was ultimately not used due to the acidic nature of the conditions which complicated isolation of our aldehyde (vide infra).
12. The polymerization is most likely an acid-catalyzed process and variable due to variable amounts of acid present during the crystallization and in the resulting solid. That no polymer is observed in aldehyde isolated under basic conditions supports this conclusion.
13. 2 solution of aldehyde obtained out of the oxidation step. For many applications this solution of aldehyde can be used directly. Alternatively, the bisulfite adduct is obtained in 42% overall yield, and the crystalline aldehyde may be recovered from bisulfite with 35% overall yield from divinylsulfone.
14. 4 aqueous and MeCN at 1.5 mL/min. with a gradient of 10% MeCN to 70% MeCN over 7 min.
15. Antifoam 204 is a Sigma-Aldrich product. It was used to suppress foaming during the decarboxylation reaction.
16. Reaction progress was monitored by LC/MS fitted Zorbax SB-C8 4.6 mm × 75 mm, 3.5 μm column eluted at 1 mL/min with water and MeCN each containing 0.1% AcOH on a gradient of 10% MeCN to 90% MeCN over 9 min. The starting material 1 is detected at 4.11 min and the product 2 at 1.49 min by evaporative light scattering detector at 40°C. During the course of the reaction 1 is rapidly hydrolyzed to the corresponding diacid which is then slowly converted to 2 as observed by LC/MS.
17. The aldehyde 3, alcohol 5 and carboxylic acid 2 were analyzed by GC using the following method. HP-5 column at 100°C initial temp, ramp to 325 at 25°C per min., constant flow = 1.3 mL/min., split ratio = 10:1, hydrogen as carrier gas, retention times: 3 = 4.31, 5 = 4.95, 2 = 5.32 min.
18. 1H NMR may be used to monitor conversion.
19. 3.
20. 2 after extended drying under dry nitrogen. The stability of the aldehyde isolated from the basic bisulfite break described is in stark contrast to the rapid decomposition observed for crystalline aldehyde isolated from acidic bisulfite break procedures which often decomposed >30% in a matter of days at ambient temperature.