The steric and electronic requirements have been investigated for the synthesis of 2,3-dihydro-4(1H)-quinolinones by the tandem Michael-S_NAr reaction. Substrates bearing a single methyl group at the β-enone carbon gave excellent yields of the title compounds from both the E and Z isomers with X═H or NO₂. Substrates with β,β-dimethyl substitution at the Michael terminus gave low yields of heterocyclic products in molecules having monoactivated S_NAr aromatic acceptor rings (X═H) and very good yields for diactivated systems (X═NO₂). For these hindered substrates, success in the final cyclization hinges on the ability of the aromatic acceptor to capture the pendant nitrogen nucleophile of the initial Michael adduct before this intermediate can revert to starting materials.

A tandem imine addition-S_NAr annulation reaction has been developed as a new approach to the synthesis of 4-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylic esters. A series of these structures has been generated by reacting selected imines with tert-butyl 2-fluoro-5-nitrobenzoylacetate. Structural variations in the final products are accomplished by changing the substituents on the imine and the alkyl group of the ester. The title compounds are isolated as their enols in 55–97% yield without the need for added base or catalysts. The synthesis of the starting materials as well as mechanistic studies and further synthetic conversions of the products are presented.

A series of N-substituted 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate esters has been prepared in two steps from ethyl 2-(2-chloronicotinoyl)acetate. Treatment of the β-ketoester with N,N-dimethylformamide dimethyl acetal in N,N-dimethylformamide (DMF) gave a 95% yield of the 2-dimethylaminomethylene derivative. Subsequent reaction of this β-enaminone with primary amines in DMF at 120^oC for 24 h then afforded the target compounds in 47–82% yields by a tandem S_NAr-addition-elimination reaction. Synthetic and procedural details as well as a mechanistic rationale are presented.

(±)-6-Alkyl-2,4-diaminopyrimidine-based inhibitors of bacterial dihydrofolate reductase (DHFR) have been prepared and evaluated for biological potency against Bacillus anthracis and Staphylococcus aureus. Biological studies revealed attenuated activity relative to earlier structures lacking substitution at C6 of the diaminopyrimidine moiety, though minimum inhibitory concentration (MIC) values are in the 0.125–8 μg mL⁻¹ range for both organisms. This effect was rationalized from three- dimensional X-ray structure studies that indicate the presence of a side pocket containing two water molecules adjacent to the main binding pocket. Because of the hydrophobic nature of the substitutions at C6, the main interactions are with protein residues Leu 20 and Leu 28. These interactions lead to a minor conformational change in the protein, which opens the pocket containing these water molecules such that it becomes continuous with the main binding pocket. These water molecules are reported to play a critical role in the catalytic reaction, highlighting a new area for inhibitor expansion within the limited architectural variation at the catalytic site of bacterial DHFR.

An efficient synthesis of (±)-2-monosubstituted and (±)-2,2-disubstituted 2,3-dihydro-4(1H)-quinazolinones has been developed using a dissolving metal reduction-condensative cyclization strategy. Treatment of 2-nitrobenzamide and an aldehyde or ketone with iron powder in refluxing acetic acid affords high yields of the title compounds. More complex ring systems are available by incorporating additional reactive functionality γ to the carbonyl of the aldehyde or ketone substrate. The scope and limitations of the process along with optimized procedural details are presented. The same target molecules are also accessible by reaction of 2-aminobenzamide with aldehydes and ketones in refluxing acetic acid. J. Heterocyclic Chem., (2011).

An efficient synthesis of (±)-2-aryl-2,3-dihydro-4(1H)-quinolinones has been developed from chalcones prepared from 2′-nitroacetophenone and a series of substituted benzaldehydes. The cyclization sequence is initiated by reduction of the nitro group under dissolving metal conditions using iron powder in concentrated hydrochloric acid. Milder conditions, using acetic acid or acetic acid–phosphoric acid as the reaction medium, were less satisfactory. Procedural details as well as a mechanistic discussion and reaction optimization studies are presented. J. Heterocyclic Chem., (2011).

The ethyl 1,4-dihydro-4-oxo-3-quinolinecarboxylate ring structure, important in several drug compounds, has been prepared in two steps from ethyl 2-(2-fluorobenzoyl)acetate. Treatment of this β-ketoester with N,N-dimethylformamide dimethyl acetal gives a 97% yield of the 2-dimethylaminomethylene derivative. Reaction of this β-enaminone with primary amines in N,N-dimethylformamide at 140°C for 48 h then affords the 1,4-dihydro-4-oxo-3-quinolinecarboxylate esters in 60–74% yields by a tandem addition-elimination-S_NAr reaction. The synthesis of the starting material as well as procedural details and a mechanistic scenario are presented. J. Heterocyclic Chem., (2011).

A tandem reductive amination-S_NAr reaction has been developed for the synthesis of 6-nitro-1,2,3,4-tetrahydroquinolines. Treatment of 4-(2-fluoro-5-nitrophenyl)-2-butanone or 3-(2-fluoro-5-nitrophenyl)-propanal with primary amines and sodium cyanoborohydride in methanol at room temperature provided good to excellent yields of the substituted tetrahydroquinolines. The reaction proceeded best with the ketone substrate using primary amines that were unbranched at the α-carbon. The aldehyde also produced the target heterocycles, but these were accompanied by 10-15% of the uncyclized side chain reductive amination products.

Treatment of 2-fluoro-5-nitrobenzyl bromide with active methylene compounds in the presence of excess potassium carbonate in acetone leads to the formation of highly functionalized 4H-1-benzopyrans by a tandem S_N2-S_NAr reaction sequence. The reaction works well with β-keto esters, β-keto sulfones, β-keto phosphine oxides, β-keto phosphonates and β-keto nitriles. The reaction is simple to perform and affords products in 50-92% yields.

Benzo-fused heterocyclic and carbocyclic systems have been synthesized by intramolecular S_NAr and tandem S_N2-S_NAr reactions. Treatment of 3-(2-fluoro-5-nitrophenyl)-1-propanol with sodium hydride in N,N-dimethylformamide gave 6-nitrochroman in 80% yield by an intramolecular S_NAr reaction. Treatment of 2-(3-bromopropyl)-1-fluoro-4-nitrobenzene with benzylamine in N,N-dimethylformamide gave 1-benzyl-6-nitrotetrahydroquinoline in 98% yield by a tandem S_N2-S_NAr reaction. Finally, in a similar process, reaction of this same bromide with dimethyl malonate under basic conditions gave 1,1-bis(methoxycarbonyl)-6-nitro-1,2,3,4-tetrahydronaphthalene in 80% yield. Further studies exploring ring size effects are also presented.