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Our research is focused on the development of tandem reaction sequences for the synthesis of compounds having potential drug activity. Tandem reactions are processes where an initial transformation generates an intermediate that can react with other molecules or, more often, with functional groups built into the same molecule. This allows for the efficient preparation of complex molecular structures with a high degree of selectivity. Tandem reactions are generating considerable interest since they accomplish several reactions in a single laboratory operation. This increases synthetic efficiency and also creates less chemical waste, making them prime examples of "green" chemistry. Application of these methods to drug synthesis could potentially decrease the cost and environmental impact of producing these compounds. Over the past 5 years, our work has involved the development of processes that use the nitro group as a latent amine. Aromatic nitro compounds are readily available and easily purified. They are stable to non-reducing conditions and do not have a basic nitrogen to interfere with other chemical transformations. Thus, we have found them to be useful in the construction of complex heterocyclic systems using tandem reaction strategies. Substrates incorporating a nitroaromatic moiety have been designed with a reactive group positioned to capture the amino (or hydroxylamino) group formed upon reduction of the aromatic nitro group. Reduction is most effectively accomplished using dissolving metal or catalytic hydrogenation conditions. To date, we have developed schemes involving reduction-Michael addition, reduction-addition-elimination, reduction-reductive amination and reduction-double reductive amination. Several of these transformations are remarkably diastereoselective and, thus, we are working to adapt them to the synthesis of enantiomerically pure heterocyclic compounds. Some of our recent accomplishments are outlined below. A diastereoselective synthesis of (±)-2-alkyl-1,2,3,4-tetrahydroquinoline-4-carboxylic esters has been developed from methyl 2-nitrophenylacetate (1). Alkylation of 1 with a series of allylic halides followed by ozonolysis yielded cyclization substrates 2. Catalytic hydrogenation of these substrates under 3 atm H2 resulted in reduction of the nitro group and reductive amination of the intermediate aniline (or hydroxylamine) with the side chain carbonyl group. The entire process proceeded in 75-85% yields to give exclusively the diastereomer having the C2 alkyl and the C4 ester groups cis. The method is illustrated below for the synthesis of a tricyclic heterocycle (1 —> 3). In this case, the reaction involves reduction of the nitro group and two sequential reductive aminations. The C4 ester serves as a stereodirecting group by sterically blocking one face of the molecule and directing the addition of hydrogen to the opposite side of the final imine intermediate to give the cis arrangement of substituents in the product. Extension of this work has led to an enantioselective version of this reaction. We have also prepared (±)-2-alkyl-2,3,4,5-tetrahydro-1H-1-benzazepine-5-carboxylic esters using this strategy. The selectivity in these seven-membered cyclizations was somewhat reduced, however, due to increased conformational mobility in the system and greater distance between the C5 ester and the site of the reductive amination.
Finally, we have extended the use of these reductive cyclizations to the high yield preparation of 6- and 7-membered rings containing multiple heteroatoms. The synthesis of precursors 4 to the 6-membered heterocycles 5 was straightforward; however, some effort was required to prepare precursors 6 (X = N-COCH3) for the 7-membered analogues 7. These cyclizations are summarized below.
In the course of our investigations, we encountered two reaction schemes that exhibited a pressure and/or catalyst dependence. The first study was focused on the synthesis of 1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline-5-carboxylic esters (e.g. 9) by a tandem reduction-double reductive amination reaction. Catalytic reduction of 8 under 3 atm H2 using 5% palladium-on-carbon gave 9 (36%) along with a substantial quantity of the cyclized decarbonylation product 10 (29%) and a small amount of the cyclic hemiacetal 11 (3%) resulting from capture of the intermediate hydroxylamine by the side chain carbonyl. Repeating the reaction using 5% platinum-on-carbon suppressed formation of the decarbonylation product but gave 9 in only 24% yield and 11 as the major product in 50% yield. Lowering the pressure to 1 atm with 5% palladium-on-carbon gave a larger proportion of the decarbonylation product 10 (37%). Finally, when the reaction was rerun under 5 atm H2 using 5% palladium-on-carbon, the yield of the desired product 9 was dramatically improved to 66%, while 10 and 11 were each produced in ≤ 5% yield. Thus, the palladium catalyst promotes decarbonylation at low pressures while the reductive cyclization predominates at elevated pressures. The preferential formation of hemiacetal 11 with the platinum catalyst suggests that platinum does not efficiently reduce the nitro group, particularly in the second stage where the N-O bond of the intermediate hydroxylamine must be cleaved. The hydroxylamine, thus, has time to attack the side chain aldehyde to form the hemiacetal. As in earlier work, product 9 was produced with high diastereoselectivity for the cis stereoisomer.
In the second scheme, 2-(2-nitrobenzyl)-substituted β-keto esters 12 were subjected to cyclization under catalytic hydrogenation conditions and found to give products that were also highly dependent on catalyst and hydrogen pressure. Hydrogenation of 12 over 5% palladium-on-carbon under 4 atm H2 produced complex mixtures of products that included 1,2,3,4-tetrahydroquinolines 13 (minor) and quinoline 14 (major). At 1 atm H2 pressure, the same reactions gave mixtures containing tetrahydroquinolines 13 (minor) and 1,4-dihydroquinoline 15 (major). These observations are in accord with literature reports describing disproportionation reactions promoted by palladium-based catalysts. Furthermore, control experiments demonstrated that disproportionation occurs in 15 to give 13 and 14 under our reaction conditions. Finally, when substrates 12 were hydrogenated using 5% platinum-on-carbon under 4 atm H2, the desired cis- and trans-(±)-2-alkyl-1,2,3,4-tetrahydroquinoline-3-carboxylic esters 13 were isolated as the exclusive products in 74-86% yields, with the cis stereoisomer predominating by ≥ 13:1. This result extends an earlier report by others in the carbocyclic series and establishes platinum as the catalyst of choice in reductions of heterocyclic substrates prone to aromatization.
A simple and efficient diastereoselective synthesis of linear-fused tricyclic nitrogen heterocycles has been developed from methyl 2-oxocycloalkanecarboxylates. Substrates such as 16 were readily prepared by alkylation of the β-keto esters with 2-nitrobenzyl bromide. Hydrogenation of these substrates under 4 atm H2 then initiated a tandem reduction-reductive amination sequence to close the ring. The products (e.g. 17) were isolated in high yield as single diastereomers having the trans-fused rings. By comparison, reductive cyclizations of substrates lacking the ester group gave mixtures of isomers with a preference for the cis ring junction. The selectivity of the final ring closure was rationalized in terms of a steric effect whereby the bridgehead ester group blocks one face of the molecule and forces the addition of hydrogen from the opposite side to give the trans product.
More recently, our work has focused on the use of nucleophilic aromatic substitutions in tandem reaction sequences to prepare heterocyclic compounds. We have, thus, generated a number of substrates that incorporate a 2-fluoro-5-nitrophenyl substituent on a carbon chain terminated by an alcohol, alkyl halide, aldehyde or ketone. From these precursors, we have successfully prepared benzo-fused oxygen, carbon and nitrogen ring systems. Alcohol substrates, such as 18, were prepared and treated with sodium hydride to give the benzo-fused oxygen heterocycles 19 by an intramolecular nucleophilic aromatic substitution (SNAr) reaction. The method was found to be general for the closure of 6 and 7-membered rings giving ca. 80% yields in each case. Attempts to close the 5-membered ring, however, gave intermolecular reaction and degradation of the substrate.
Bromide 20, prepared from alcohol 18, provided an entry to carbocyclic and nitrogen heterocyclic rings by a tandem SN2-SNAr sequence. Treatment of 20 with dimethyl malonate in the presence of excess sodium hydride yielded dimethyl 6-nitro-1,2,3,4-tetrahydronaphthalene-1,1-dicarboxylate (21) in 80% yield. Treatment of this same bromide with benzylamine resulted in the formation of the 1-benzyl-6-nitro-1,2,3,4-tetrahydroquinoline (22) in 98% yield. Low temperature experiments in the heterocycle series indicated that the SN2 reaction initiates the sequence. Attempts to extend the scope of this synthesis, however, have revealed that this approach to benzo-fused nitrogen heterocycles is limited to the formation of 6-membered rings, with 5- and 7-membered rings both formed in < 40% yields . DFT calculations suggest that ring strain alone is not the primary factor limiting these ring closures. The major limitation arises in the final SNAr ring closure. Once the initial SN2 reaction occurs, the tethered nucleophilic center must be able to achieve the correct orientation for SNAr addition from above (or below) the plane of the ring. In the 5-membered transition state, the chain linking the nucleophile to the aromatic ring is too short to permit approach of the nucleophile with the correct trajectory, while the side chain in the 7-membered transition state must fold into a more ordered conformation to achieve the proper angle for addition to the aromatic ring. A further problem in the 5-membered precursors is the tendency of the substrates to undergo elimination to give the styrene derivative in the presence of the basic nucleophile.
A variant of this reaction was discovered in our attempt to prepare substrates with a ketone group on the side chain. Treatment of the 2-fluoro-5-nitrobenzyl bromide (23) with the anion derived from tert-butyl acetoacetate (24) led to the formation of the highly substituted 4H-1-benzopyran derivative 25 by an SN2-SNAr sequence. This process appears to be general for active methylene substrates such as β-keto esters, sulfones, phosphine oxides, phosphonates esters and nitriles, which give initial alkylation at carbon. β-Diketones, however, generally gave O-alkylation under our reaction conditions while activated ketones, such as phenylacetone and deoxybenzoin gave monoalkylation without subsequent ring closure.
Finally, we have successfully developed a tandem reductive amination-SNAr sequence for use in the synthesis of nitrogen heterocycles. Reaction of the 4-(2-fluoro-5-nitrophenyl)-2-butanone (26) with benzylamine in methanol in the presence of sodium cyanoborohydride afforded the 1-benzyl-6-nitro-1,2,3,4-tetrahydroquinoline (27) in 98% yield. The reaction proceeds equally well for aldehyde and ketone substrates, providing nearly quantitative yields with primary amines. Yields, however, were lower using more sterically hindered amines branched at the carbon α to nitrogen. We are currently working to evaluate this procedure for the preparation of 5- and 7-membered rings as well as targets incorporating more than one heteroatom.
Recent Publications
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