Multicomponent domino reactions (MDRs) serve as a rapid and efficient tool for the synthesis of versatile heterocycles, particularly those containing structural diversity and complexity, by a one-pot operation. These reactions can dramatically reduce the generation of chemical wastes, costs of starting materials, and the use of energy and manpower. Moreover, the reaction period can be substantially shortened. This Review covers recent advances on multicomponent domino reactions for the construction of five-, six-, and seven-membered heterocyclic skeletons and their multicyclic derivatives.

The new asymmetric catalytic Strecker reaction of achiral N-phosphonyl imines has been established. Excellent enantioselectivity (95.2-99.7%ee) and yields (89-97%) have been achieved by using primary free natural amino acids as catalysts and Et 2 AlCN as nucleophile. This work also presents the novel use of non-volatile and inexpensive Et 2 AlCN in asymmetric catalysis. The Nphosphonyl protecting group enabled simple product purification to be achieved simply by washing the crude products with hexane. It can also be readily cleaved and recycled under mild condition to give a quantitative recovery of N, N′-bis(naphthalen-1-ylmethyl)ethane-1,2-diamine. A new mechanism was proposed for this reaction and was supported by experimental observations.

Flash vacuum pyrolysis studies of substituted 6-acetoxy-2,4-cyclohexadienones (3 and 10) from 300 to 500 °C provide strong experimental evidence that direct [3,5]-sigmatropic rearrangements in these molecules are favored over the more familiar [3,3]-sigmatropic rearrangements. The preference holds when the results are extrapolated to 0.0% conversion, indicating that this is a concerted process. Pyrolysis of 6,6-diacetoxy-2-methyl-2,4-cyclohexadienone (9) at 350 °C gives a modest yield of the initial [3,5]-sigmatropic rearrangement product, 2,6-diacetoxy-6-methyl-2,4-cyclohexadienone (11). Qualitative arguments and electronic structure theory calculations are in agreement that the lowest energy pathway for each [3,5]-sigmatropic rearrangement is via an allowed, concerted pseudopericyclic transition state. The crystal structures of compounds 3, 9, and 10 prefigure these transition states. The selectivity for the [3,5] products increases with an increasing temperature. This unexpected selectivity is explained by a concerted, intramolecular, and pseudopericyclic transition state (TS-5) that forms a tetrahedral interemediate (ortho-acid ester 4'), followed by similar ring openings to isomeric phenols, which shifts the equilibrium toward the phenols from the [3,5] (but not the [3,3]) products.

The asymmetric catalytic Strecker reaction of achiral N-phosphonyl imines with Et(2)AlCN has been established. Both free amino alcohols and BINOLs have been proven to be effective catalysts to afford excellent enantioselectivities and yields. The N-phosphonyl group can be readily cleaved under mild conditions and enable purification of crude products by simple washing with hexane. The cleaved N,N-dialkyl diamine auxiliary can be recovered quantitatively via n-BuOH extraction. The scope for both N-phosphonyl imines and catalysts was vastly studied for this new catalytic system.

Analogues of amino methylisoxazole propionic acid (AMPA), were prepared from a common intermediate 12, including lipophilic analogues using lateral metalation and electrophilic quenching, and were evaluated at System xc−. Both the 5-naphthylethyl-(16) and 5-naphthylmethoxymethyl-(17) analogues adopt an E-conformation in the solid state, yet while the former has robust binding at System xc−, the latter is virtually devoid of activity. The most potent analogues were amino acid naphthyl-ACPA 7g, and hydrazone carboxylic acid, 11e Y=Y′=3,5-(CF3)2, which both inhibited glutamate up-take by the System xc− transporter with comparable potency to the endogenous substrate cystine, whereas in contrast the closed isoxazolo[3,4-d] pyridazinones 13 have significantly lower activity. A preliminary pharmacophore model has been constructed to provide insight into the analogue structure-activity relationships.