D‐Glucosamine in iron‐catalysed cross‐coupling reactions of Grignards with allylic and vinylic bromides: application to the synthesis of a key sitagliptin precursor

Abstract

A sustainable D-glucosamine ligand is successfully introduced into iron-catalysed C-C cross-coupling reactions for the first time. The Fe(acac) 2 /D-glucosamine·HCl/Et 3 N catalytic system was effective at 5 mol% loading in coupling reactions of Grignard reagents with organic bromides. Moderate to high efficiency was achieved with preserved stereochemistry when allyl (Csp 3 ) or alkenyl (Csp 2 ) bromides were coupled with phenylmagnesium (Csp 2 ) or benzylmagnesium (Csp 3 ) bromides. The catalytic system developed was also successfully applied for the novel and economic preparation of a Michael-acceptor-like starting material used in an alternative synthesis of the drug sitagliptin, a known blockbuster for the treatment of type II diabetes mellitus.

Iron‐Catalyzed Cross‐Couplings in the Synthesis of Pharmaceuticals: In Pursuit of Sustainability

“…[9,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] In 2015, Casar and co-workers reported d-glucosamine as an ew ligand for iron-catalyzed crosscouplings of aryl and benzyl Grignard reagents with allyl and alkenyl bromides (Scheme 18). [63] Theu se of biocompatible ligands [64] in sustainable iron catalysis holds significant promise for future developments.…”

Efficient and Convenient Synthetic Routes for Sitagliptin Impurities

“…It follows lengthier procedure and involves reduction of acid 9 to alcohol 16 and subsequent oxidation by employing NaOCl and TEMPO to furnish aldehyde 17 followed by Doebner modification of Knoevenagel condensation reaction to furnish alkene 19 , which was further coupled with triazole 6 to afford alkene impurity IV. Other elegant method for synthesis of alkene impurity involves cobalt‐catalyzed cross‐coupling of methyl 4‐bromocrotonate with Grignard reagent by using sarcosine as a ligand –. Reported synthesis of enantiomer involves enantioselective catalytic allylic amination of olefin 20 by using Pd(TFA) 2 catalyst and chiral ligand 22 , the reaction time for this conversion is 7 days (Scheme c) .…”

Use of Monosaccharides in Metal-Catalyzed Coupling Reactions

“…Triethylamine (5 mol %) was added to deprotonate the ligand and thus increase its solubility in THF. 32 Moderate yields of substituted alkenes 12 were obtained from allylic bromides 10, and good yields of the sp 3 -hybridized products 13 were obtained from alkenyl bromides 11. D-glucosamine was shown to improve the yield in palladium-catalyzed Mizoroki-Heck reactions of aryl halides (Scheme 5).…”