Asymmetric organocatalytic decarboxylative Mannich reaction using β-keto acids: A new protocol for the synthesis of chiral β-amino ketones

Abstract

SummaryThe first decarboxylative Mannich reaction employing β-keto acids, catalyzed by cinchonine-derived bifunctional thiourea catalyst has been described. The desired β-amino ketones were obtained in excellent yields and with moderate to good enantioselectivities.

Efficient synthesis of β’-amino-α,β-unsaturated ketones

“…This versatile synthon has been extensively used in the construction of β-amino acids [2], β-amino alcohols [3], and homoallylic amines [4–5], and can serve as building blocks for the preparation of nitrogen-containing molecules often found in medicinal chemistry [6–10]. Thus, the development of efficient and stereoselective reactions for a useful approach to chiral β-amino ketones is still of importance.…”

“…Thus, the development of efficient and stereoselective reactions for a useful approach to chiral β-amino ketones is still of importance. One of the most powerful approaches is the Mannich reaction, which can be conducted under different protocols in which the stereoselectivity of the reaction can be introduced through the use of a chiral catalyst [9–10] (Lewis acid, Brønsted acids, L-proline, Cinchona alkaloids derivatives, thioureas, etc. ), or by the addition of chiral amines to α,β-unsaturated esters [11–12] or the reaction of chiral imines with enolates derived from Weinreb amides [13–14].…”

Ni-catalyzed asymmetric decarboxylative Mannich reaction for the synthesis of β-trifluoromethyl-β-amino ketones

“…1 In particular, the pharmaceutical industry critically depends on the methodological developments in 15 fluorine chemistry for the design of more selective and potent new drugs. 2 One of these areas is the synthesis of polyfunctional fluorinated derivatives possessing keto/hydroxy/amino groups.…”

“…For the substrates with para-substituted phenyl group 2b-2j, either electronic properties or steric bulk of the substituent had almost no noticeable effect on the diastereoselectivity of the reactions. For example, product 3g, bearing bulky iso-propyl group was also isolated as diastereomerically pure compound in 15 quantitative chemical yield. The reactions with the substrates containing meta-substituted phenyl ring, also could proceed smoothly resulting in a bit lower chemical yields (3k-3m).…”

Copper‐Catalyzed One‐Pot Denitrogenative–Dehydrogenative–Decarboxylative Coupling of β‐Ketoacids with Trifluorodiazoethane: Facile Access to Trifluoromethylated Aldol Products

“…The use of other copper complexes resulted in a slight lower yield (entries 2-5). The solvent was found to have an important effect on the reactivity (entries [6][7][8][9][10][11]). Among the solvents tested, the mixed solvent system was found to be the best choice for this cross-coupling reaction (entry 10).…”