A diastereoselective synthesis of 1-methyl-2-alkyl- and 2-alkyl-1,2,3,4-tetrahydroquinoline-4-carboxylic esters has been developed from methyl (2-nitrophenyl)acetate (1). The method involves alkylation of 1 with an allylic halide, ozonolysis of the double bond, and catalytic hydrogenation. The final hydrogenation initiates a tandem sequence involving (1) reduction of the aromatic nitro group, (2) condensation of the aniline or hydroxylamine(8) nitrogen with the side chain carbonyl, (3) reduction of the resulting nitrogen intermediate, and (4) reductive amination of the tetrahydroquinoline with formaldehyde produced in the ozonolysis to give a methyl (+/-)-1-methyl-2-alkyl-1,2,3,4-tetrahydroquinoline-4-carboxylate. Removal of the formaldehyde prior to hydrogenation gives the simple (+/-)-2-alkyl derivatives. The products are isolated in high yield as single diastereomers having the C-2 alkyl group cis to the C-4 carboxylic ester. The reaction has been extended to the synthesis of tricyclic structures with similar high diastereoselection.

No abstract

A tandem reduction‐reductive amination reaction has been applied to the synthesis of 3,4‐dihydro‐2H‐1,4‐benzoxazines and 1‐acetyl‐1,2,3,4‐tetrahydroquinoxalines. The nitroketones required for the benzoxazine ring closures were prepared by (A) alkylation of the anion derived from 2‐nitrophenol with an allylic halide or (B) nucleophilic aromatic substitution of an allylic alkoxide on 2‐fluoro‐1‐nitrobenzene followed by ozonolysis. Precursors for the quinoxalines were prepared by alkylation of the anion of 2‐nitroacetanilide with an allylic halide followed by ozonolysis. Catalytic hydrogenation of the nitroketones using 5% palladium‐on‐carbon in methanol then gave the target heterocycles by a reduction‐reductive amination sequence. The N‐methyl derivatives for both ring systems were easily prepared by adding 5‐10 equivalents of aqueous formaldehyde prior to the reduction. The dihydrobenzoxazines were isolated in high yield following purification by chromatographic methods; tetrahydroquinoxalines were isolated in a similar manner and possessed differentiated functionality on the two nitrogens.

A two-step diastereoselective synthesis of linear-fused tricyclic nitrogen heterocycles has been developed from cyclic β-ketoesters. The cyclization substrates are readily prepared by alkylation of the methyl 2-oxocycloalkanecarboxylates with 2-nitrobenzyl bromide. Hydrogenation of these substrates initiates a reaction sequence involving (1) reduction of the aromatic nitro group, (2) condensation of the resulting hydroxylamine or aniline nitrogen with the cycloalkanone and (3) reduction of the imine. The products are isolated in high yield as single diastereomers having the trans-fused ring junction. The observed selectivity is rationalized in terms of a steric effect imposed by the ester group in the final reductive amination step which directs the incoming hydrogen to the opposite face of the molecule. By comparison, reductive cyclizations of substrates lacking the stereodirecting ester group give mixtures of cis and trans products with a preference for the cis-fused heterocycle.