Direct Asymmetric Mannich‐Type Reaction of α‐Isocyanoacetates with Ketimines using Cinchona Alkaloid/Copper(II) Catalysts

Abstract

The enantioselective direct Mannich-type reaction of ketimines with α-isocyanoacetates has been developed. Excellent yields and enantioselectivity were observed for the reaction of various ketimines and α-isocyanoacetates using cinchona alkaloid/Cu(OTf)2 and a base. Both enantiomers of the products could be obtained by using pseudoenantiomeric chiral catalysts. This process offers an efficient route for the synthesis of α,β-diamino acids.

Catalytic diastereo- and enantioselective additions of versatile allyl groups to N–H ketimines

“…The absolute stereochemistry of the product was confirmed through X-ray structure of primary alcohol 9b . It merits note that catalytic enantioselective enolate additions to N -activated ketimines (e.g., N -phosphinoylketimines 36,37 or those derived from α-ketoesters 38 or diethyl ketomalonate 39 ) are limited in scope (see the Supplementary Information for additional references). …”

Picolinamides as Effective Ligands for Copper‐Catalysed Aryl Ether Formation: Structure–Activity Relationships, Substrate Scope and Mechanistic Investigations

“…Also, picolinamide‐derived substrates are nowadays widely used as coordinating substrates in group‐directed CH bond activation, due to their favourable coordination to the metal centre 36–38. Reports recently appeared on the use of picolinamides as ligands in Cu‐catalysed synthesis of biphenyls, [39] and as chiral ligands in asymmetric Mannich‐type reactions 40. To our knowledge, however, no reports have appeared in the literature on the use of such ligands for Cu‐catalysed CO bond formation.…”

“…[36][37][38] Reports recently appeared on the use of picolinamides as ligands in Cu-catalysed synthesis of biphenyls, [39] and as chiral ligands in asymmetric Mannich-type reactions. [40] To our knowledge, however, no reports have appeared in the literature on the use of such ligands for Cu-catalysed CÀ O bond formation. Herein we report the use of N-arylpicolinamide ligands for the synthesis of aryl ethers.…”

Catalytic Asymmetric Mannich‐Type Reaction of N‐Alkylidene‐α‐Aminoacetonitrile with Ketimines

“…We selected the Mannich‐type reaction of N ‐(9‐fluorenylidene)‐α‐aminoacetonitrile ( 1 ) with N ‐(diphenylthiophosphinoyl)ketimines as a rational and formidable objective because 1) both nitrile and thiophosphinoyl functionalities can be activated by a soft Lewis acid; 2) direct catalytic asymmetric addition of in situ generated nucleophiles to ketimines is underdeveloped; and 3) densely functionalized α,β‐diamino nitriles bearing consecutive tetra‐ and trisubstituted stereogenic centers are produced. Recent advances in ester‐based pronucleophiles have enabled the direct catalytic asymmetric addition of α‐ N ‐functionalized (α‐isothiocyanato and α‐isocyano) esters 4 to N ‐Dpp‐ketimines 5 13 to afford the analogous α,β‐diamino esters with concomitant intramolecular cyclization to thioureas 6 or imidazolines 7 (Scheme ) 14–16. These reactions were largely limited to aromatic ketimines, and the excessive stability of the thiourea and imidazoline products complicated further elaboration.…”