Transfer Hydrogenations of Alkenes with Formate on Pd/C: Synthesis of Dihydrocinchona Alkaloids

Abstract

Protocols for preparative (1–80 gram scale) transfer hydrogenations of alkenes over a palladium on carbon catalyst using formic acid/ammonium formate as hydrogen donor are presented. Cinchona alkaloids have been converted to their dihydro derivatives in >94% yield.

Key words

alkaloids - alkenes - catalysis - hydrogen transfer - hydrogenation - palladium

• References

• 1 Nylander PN. Hydrogenation Methods . Academic Press; Orlando: 1985
• 2 Smith MB, March J. March’s Advanced Organic Chemistry . 6th ed. Wiley; Hoboken: 2007: 1053
• 3 Mozingo R. Org. Synth. 1946; 26: 77
• 4 Johnstone RA. W, Wilby AH, Entwistle ID. Chem. Rev. 1985; 85: 129
• 5 Cortese NA, Heck RF. J. Org. Chem. 1978; 43: 3985
• 6 Ram S, Ehrenkaufer RE. Synthesis 1988; 91
• 7 Paryzek Z, Koenig H, Tabaczka B. Synthesis 2003; 2023
• 8 For a versatile homogeneous transfer hydrogenation using Pd(OAc)₂/Pt-Bu₃ as catalyst at the 1 mmol scale, see: Brunel JM. Synlett 2007; 330
• 9a Hintermann L, Schmitz M, Englert U. Angew. Chem. Int. Ed. 2007; 46: 5164 ; Angew. Chem. 2007, 119, 5256
• 9b Hintermann L, Dittmer C. Eur. J. Org. Chem. 2012; 5573
• 9c Hintermann L, Ackerstaff J, Boeck F. Chem. Eur. J. 2013; 19: 2311
• 10a Hintermann L, Schmitz M. Adv. Synth. Catal. 2008; 350: 1469
• 10b Hintermann L, Schmitz M, Maltsev OV, Naumov P. Synthesis 2013; 45: 308

Hydrogenation of the alkaloids in dilute H₂SO₄ with PdCl₂ and H₂ close to regular pressure has been described:
• 11a Heidelberger M, Jacobs WA. J. Am. Chem. Soc. 1919; 41: 817
• 11b Vereinigte Chininfabriken Zimmer & Co., German Patent DE 252136, 1912 ; Chem. Abstr. 1913, 7, 2678.
• 12 Exner C, Pfaltz A, Studer M, Blaser H.-U. Adv. Synth. Catal. 2003; 345: 1253
• 13 Transfer hydrogenation of cinchonine (1 g scale) with a freshly ordered 10% Pd/C catalyst (67 mg, 1:15 ratio; Alfa Aesar) gave a 87% yield within 36 h; with freshly ordered 5% Pd/C catalyst (67 mg, 1:15 ratio; Alfa Aesar), a 94% yield was obtained within 22 h. Thus, the higher metal content did not translate to higher catalytic activity.
• 14 Individual student results for dihydrocinchonidine: scale and yield: 4.0 g (98%), 5.0 g (93%), 10.0 g (88%).
• 15 Guillen F, Rivard M, Toffano M, Legros J.-Y, Daran J.-C, Fiaud J.-C. Tetrahedron 2002; 58: 5895
• 16 Zumbansen K, Döhring A, List B. Adv. Synth. Catal. 2010; 352: 1135
• 17a Sharma A, Kumar V, Sinha AK. Adv. Synth. Catal. 2006; 348: 354
• 17b Viviano M, Glasnov TN, Reichart B, Tekautz G, Kappe CO. Org. Process Res. Dev. 2011; 15: 858
• 18 Straub TS. J. Chem. Educ. 1991; 68: 1048