Design and synthesis of amide-based hydrogen bond donor-acceptor-donor organocatalysts for conjugate addition

Abstract

Organocatalysis has emerged as an appealing strategy for addressing important synthetic challenges in chemistry. In this thesis, a new class of amide-based hydrogen bond donor-acceptor-donor (HB-DAD) organocatalysts has been developed as efficient organocatalysts for conjugate addition of benzylidene barbiturates. Through mechanistic studies, a good correlation between binding constants of hydrogen bonding and reaction rates has been found to support the substrate activation mode. A modular approach to identify essential moieties in the organocatalysts for substrate activation has been employed. A series of amide-based HB-DAD organocatalysts 1a-1c, 2a-2c, 3a-3b and 4a with tunable functionalities including [1] nitrogen-heterocyclic ring as hydrogen bond acceptor (HBA), [2] nitrogen-hydrogen bond (N-H bond) as hydrogen bond donor (HBD), and [3] electron-withdrawing activator (A) to increase the acidity of the N-H bond have been constructed. Systematic screening of organocatalysts 1a-1c, 2a-2c, 3a-3b and 4a in catalyzing conjugate addition of benzylidene barbiturates has been performed. We have found that organocatalyst 1a (featuring para-chloro-pyrimidine as the HBA, N-H as the HBD and trifluoroacetyl group as the activator) is able to activate the substrates through complementary DAD-ADA hydrogen bonding resulting in reaction rate enhancement. Organocatalyst 1a together with other newly developed HB-DAD organocatalysts 1c, 2a and 2c were found to be efficient in catalyzing conjugate addition of 2-methylfuran to benzylidene barbiturates in dichoromethane at room temperature. Using 20 mol% of organocatalysts, a two-fold reaction rate enhancement in conjugate addition of furans to barbiturates was obtained with good isolated yield (up to 70 %). In particular, benzylidene barbiturates bearing aliphatic ether and thioether substituents were most significantly activated by the organocatalysts. Mechanistic studies of the amide-based HB-DAD catalyzed conjugate addition have been conducted. Using 1H NMR spectroscopy, pseudo first-order kinetic studies were conducted. The rate constant (k = 1.48x10⁻³ s⁻¹, R² = 0.95, krel = 2.22) of 1a in catalyzing conjugate addition of benzylidene barbiturates was obtained. Hence, the role of the trifluoroacetylamide as HBD and activator in 1a has been supported by reaction rate enhancement in the conjugate addition of benzylidene barbiturates. By UV/vis titration experiments, high binding constants (up to K = 8936 M-1, R² = 0.95, ΔG = -22.5 kJ/mol) of the amide-based HB-DAD organocatalysts with benzylidene barbiturate chromophores in dichloromethane were obtained. The excellent correlation (R² = 0.92) between the binding constants and reaction rate constants of amide-based HB-DAD organocatalysts provides support for HB-DAD as the activation moiety in organocatalysis. In addition, adjustable electrophilic substrate control in the conjugate addition of benzylidene barbiturates has been realized. On the basis of the above findings, rational design and synthesis of C₂-symmetric chiral amide-based HB-DAD organocatalysts, 10a-10f, have been achieved. Using chiral organocatalysts 10a-10f, asymmetric conjugate addition of dibenzoylmethane to maleimide in dichloromethane at room temperature has been performed. Adducts were obtained in excellent isolated yield (up to 90 %) with enantioselectivities of 8-15 %ee indicating the feasibility of catalyst-to-product chirality transfer.