[b,e]azepin-6-one are described using a tandem reductionlactamization sequence. Precursors for these ring systems are available in 1-3 steps using nucleophilic aromatic substitution and Ullmann coupling methodology. Direct reduction-lactamization of these compounds using iron powder in acetic acid at 115° affords the target heterocycles in 90% yield.

No abstract

A diastereoselective synthesis of 1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline-5-carboxylic esters has been developed using a tandem reduction-double reductive amination reaction. The nitro dicarbonyl cyclization substrates were synthesized by alkylation of methyl (2-nitrophenyl)acetate with 2-bromomethyl-1,5-hexadiene derivatives, followed by ozonolysis. Catalytic hydrogenation of each substrate gave the target heterocycle, along with a deacylated product and an adduct resulting from capture of the intermediate hydroxylamine by the side chain carbonyls. The product ratio varied dramatically with the catalyst and the hydrogen pressure. Cyclization to the title compounds was highly diastereoselective, producing each hexahydropyrrolo[1,2-a]-quinoline as a single stereoisomer with the all-cis geometry. The competing processes have not been observed in previous heterocyclization studies but can be attributed to greater strain in the system, which slows the final ring closure.

The tandem reductive amination-S N Ar reaction sequence has recently been reported for the efficient synthesis of 1,2,3,4-tetrahydroquinolines. 1 As part of our effort to develop new routes to biologically active heterocyclic compounds having diverse substitution, we wished to extend this methodology to the synthesis of tetrahydroquinolines and tetrahydroquinoxalines bearing carboxyl groups on the saturated ring, and possibly to dihydrobenzoxazines as well. 2 In the tetrahydroquinoline series, this would provide compounds that have been shown to have useful activities in the treatment of inflammatory diseases such as asthma. 3 Tetrahydroquinoxaline derivatives have been shown to express useful activity as anticancer drugs 4 and cell adhesion agents. 5 Dihydrobenzoxazines have demonstrated activity as antihypertensives 6 and neuroprotective agents. 7 The substrates for this annulation reaction are trisubstituted aromatic systems bearing a 3-oxo side-chain at C1, a F (or Cl) at C2 and a NO 2 group at C5. We expected that the electronic nature of the atom linking the 3-oxo side chain to the ring would be critical to the success of the final S N Ar ring closure. While the alkyl side-chain of the tetrahydroquinoline precursors should not pose a problem, the alkylamino group in the tetrahydroquinoxaline precursors and the alkoxy side chain required to prepare dihydrobenzoxazines would deactivate the ring toward the final S N Ar cyclization. In the tetrahydroquinoxaline precursors, the electron donating character of the nitrogen could be decreased by protecting it as a carbamate. Derivatization, however, would not be possible in the case of the dihydrobenzoxazine precursors and we anticipated difficulties in the ring closure step using these substrates.The synthesis of the cyclization substrates is shown in Scheme 1. The tetrahydroquinoline precursors were prepared from methyl 2-fluoro-5-nitrophenylacetate obtained by esterification of the corresponding acid; 8 the tetrahydroquinoxaline precursors were