Synthesis and Characterization of β‐Trifluoromethyl‐Substituted Pyrrolidines

Abstract

A practical synthetic approach to the construction of a library of three isomeric/homologous β‐trifluoromethyl‐substituted pyrrolidines is disclosed. All products were prepared in multigram quantities from a common precursor. The key synthetic step was a [3+2] cycloaddition reaction. The influence of the trifluoromethyl group on the physicochemical characteristics of the pyrrolidine fragment was studied.

Comparative effects of trifluoromethyl- and methyl-group substitutions in proline

“…These reductions are 4.6-4.9 pK a units at positions 2 and 5 and 2.2 units at positions 3 and 4. The magnitudes of the effects are similar to those previously described for trifluoromethylated pyrrolidines 60 and morpholines. 61 Notably, for the free amino acid, the C-terminal carboxyl-group remains ionized over the entire pH range of the ammonium protonation transition.…”

Synthesis of Spirocyclic Pyrrolidines: Advanced Building Blocks for Drug Discovery

“…[11] In the present study,w ew anted to extend this strategy towards other spirocycles. In fact, all three-(5, 6), four-(2, 7-10), five- (11)(12)(13), six-(4, [14][15][16][17][18][19][20], and seven-membered-ring (21)a lkenes gave the desired spirocyclic products in good to excellent yields. Only startingm aterial wasr ecovered from the reactionm ixture.…”

“…[18] Oxidation of alcohol 29 with Py·SO 3 ,f ollowedb y treatment of the intermediate aldehyde with morph-DAST, gave compound 32.A cidic cleavage of the N-Boc group completed the synthesis of difluoromethylated pyrrolidine 33. N-Boc protection (29)a nd treatment with morpholinosulfur trifluoride (morph-DAST) gave pyrrolidine 30.A cidic cleavage of the N-Boc group furnished the fluoromethyl pyrrolidine 31 (Scheme 4).…”

Synthesis of Trifluoromethyl‐Substituted 3‐Azabicyclo[n.1.0]alkanes: Advanced Building Blocks for Drug Discovery

“…We next cleaved the N ‐Boc group in 10 by HCl/methanol to afford 4‐(trifluoromethyl)pyrrolidine ( 11· HCl). During the last decade, amine 11 has become popular in both drug discovery and agrochemistry projects,20 but we only recently comprehensively described its synthesis 21,9b…”