Octahydroacridines, synthesis

A highly diasteieoselective synthesis of substituted 1,2,3,4,4a,9,9a, 10-octahydroacridines 95 with five stereogenic centers has been achieved by domino imine condensation/intramolecular polar [4ti + 2k] cycloaddition of anilines and oo-unsaturated aldehydes 94 <96JPR(338)468>. 

Schulte, J. L. Laschat, S. Kotila, S. Hecht, J. Frohlich, R. Wibbeling, B. Synthesis of j 6-(octahydroacridine)chromiumtricarbonyl complexes with non-polar tails via molecular sieves-catalyzed cydization of N-arylimines and subsequent diastereoselective complexa-tion. Heterocydes 1996, 43, 2713-2724. 

An approach directed towards the synthesis of more complex octahydroacri-dines has been described by Beifuss and his coworkers very recently. Starting from aniline 3-48, the reactive N-aryl iminium ions 3-50 and 3-51 were generated by reaction with a diastereomeric mixture of the aldehyde 3-49. These intermediates underwent a cationic [4++2] cycloaddition via an exo-E-anti transition state to give the octahydroacridines 3-52 and 3-53 as only products out of 16 possible stereoisomers (Fig. 3-16). The cislfrans-ratio as well as the ( -configuration of the dienophilic double bond were completely retained during the... 

This chapter illustrates torand synthesis with the preparation of unsubstituted torand 1 by the route developed for synthesis of tributyltorand 2.1,6,7 The synthesis of 1 is two steps shorter than that of 2 because commercially available 1,2,3,4,5,6,7,8-octahydroacridine, 5, replaces the 9-butyl derivative, which is prepared in two steps.11,12 Many of the intermediates could also be... 

In Scheme 6.1, outlining the synthesis of torand 1, each of the numbered arrows corresponds to one of the eleven protocols. This approach to 1 sequentially combines three octahydroacridine subunits, whereas the previously... 

Synthesis of 5-benzylidene-1,2,3,4,5,6,7,8-octahydroacridin-4-ol hydrobromide (Structure 7, Scheme 6.4)... 

Diketone 12 must be condensed with a third, doubly functionalized octahydroacridine unit in the last step of the torand synthesis (cf Scheme 6.1). The following protocols (8-10) describe the three-step synthesis of torand precursor 15 from octahydroacridine 5. The reagents involved in these three steps are shown in Scheme 6.11. According to Protocol 8, octahydroacridine is condensed with benzaldehyde in the presence of acetic anhydride,24 as in the second stage of Protocol 2 (cf Scheme 6.3). The crystalline product 13 precipitates from the reaction mixture in high yield and purity. Ozonolysis of 13 (Protocol 9) is conducted by the method described in Protocol 7 for conversion of 11 to diketone 12 (cf. Scheme 6.10) and the same precautions apply. The product diketone 1425 requires no further purification after removal of benzaldehyde by trituration with diethyl ether. The third octahydroacridine unit is then readied for torand cyclization in Protocol 10 by condensing diketone 14 with Bredereck s reagent, r-butoxybis(dimethylamino)methane,26 which is commercially available. The bis[p-(dimethylamino)]enone product 15 is easily purified by precipitation from ether/dichloromethane. 

Jacob, R.G., Perin, G., Botteselle, G.V., and Lenardao, E.J. 2003. Clean and atom-economic synthesis of octahydroacridines Apphcation to essential oil of citroneUa. Tetrahedron Letters, 44 6809-12. 

Yen and co-workers [155] have described a one-pot MCR for the synthesis of 4,5-dibenzylidene octahydroacridines 107 in high yields. A tandem reaction was performed with three equivalents of an aromatic aldehyde and two equivalents of 4-alkylcyclohexanone in NH4OAC/ACOH applying a domestic microwave oven. Except for one example, most of the reported compounds were obtained in moderate to good yields (Scheme 83). 

Wang Q-F, Yen GC (2008) Efficient synthesis of diarylidene octahydroacridines by one-pot multi-component tandem reactions. Cent Eur J Chem 6 404-409... 

Octahydroacridine and its derivatives are of great interest as they play an important role in the preparation of alkaloids, dyes, drugs and other biologically active compounds. Conventional synthesis methods so far reported in literature are multistep and homogeneously catalyzed and require tedious work-up procedures. 

Several zeolites (HY, H-Beta, H-ZSM-5) and the mesoporous material MCM-41 were found to catalyze the one-pot synthesis of octahydroacridine from the low cost compounds cyclohexanone, formaldehyde and ammonia [56]. 

Conditions a mixture of cyclohexanone, formaldehyde and ammonia (molar ratio 2 1 3) is fed from the top to a fixed bed reactor containing the catalyst, with WIISV- at temperatures of 250 - 350 °C and at atmospheric pressure. Product analysis by GC-MS and NMR. The new zeolite-catalyzed synthesis of octahydroacridine represents an eco-friendly and simple method. 

Two other interesting reports on IMFIDA reactions describe the application of solvent-free, solid-support catalyzed microwave technology. Indeed, as mentioned previously in Scheme 11.2, the IMHDA reaction for synthesis of octahydroacridine 6 was efficiently catalyzed by Si02/ZnCl2 under microwave irradiation conditions [36]. In another example (Scheme 11.10), sesamol 31 and 3-methyl-2-butenal 32 reacted to provide 35, under basic KIO-K clay-catalyzed solvent-free microwave conditions. The IMHDA reaction of o-quinone methine 34 produced the expected chromene 35 in 84% yield within 8 min. Conventional heating conditions at 110 °C (K10-K+, 60 min) were longer and provided the desired product 35 in an equivalent 91% yield but with 9% of another, unidentified product (Scheme 11.10) [34b]. 

Octahydroacridines are tetrahydroquinoline core structures with potentially interesting biological properties. An elegant example for their synthesis in a one-pot strategy was published by J0rgensen and coworkers [97]. The transformation... 

By introducing chiral information into the substrate, a diastereo- and enantioselective preparation of 1,2,3,4-tetrahydroquinolines is possible. Jprgensen therefore combined an organocatalytic Michael addition (not shown) with a Povarov reaction in a one-pot process to achieve good selectivities in the synthesis of octahydroacridines 527 (Scheme 13.119) [199]. 

The highly efficient and stereoselective synthesis of octahydroacridines in one pot from the reaction of citronellal and amines with a catalytic amount of BiCl3 at 0 °C in acetonitrile was described. The product formation involves the intramolecular hetero Diels-Alder reaction of N-arylimines, generated in situ, from the citronellal and amines. The temperature of the reaction medium plays a key role in determination of the trans/cis ratio (Equation 21) [39]. 

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