J . Org. Chem. 2001, 66, 1525-1527
1525
Sch em e 1
Syn th esis of
1,2,3,4,5,6,7,8-Octa h yd r oa cr id in e via
Con d en sa tion of Cycloh exa n on e w ith
F or m a ld eh yd e
Michelle L. Pilato, Vincent J . Catalano, and
Thomas W. Bell*
Department of Chemistry, University of Nevada, Reno,
Nevada 89557-0020
Sch em e 2
twb@unr.edu
Received November 27, 2000
In tr od u ction
Several hydrogen-bonding receptors and polydentate
ligands have been synthesized from 1,2,3,4,5,6,7,8-oc-
tahydroacridine (1)1 and from 9-substituted 1,2,3,4,5,6,7,8-
octahydroacridines.2 Because 1 is a valuable starting
material of limited commercial availability, we have
undertaken its large scale synthesis. Of the many
methods for the preparation of 1,3 the two-step process
outlined in Scheme 1 was chosen on the basis of the
successful large scale synthesis of 9-butyl-1,2,3,4,5,6,7,8-
octahydroacridine (2).4 Currently, the most efficient
methods for the synthesis of 1 require three steps (51-
71% overall)3b,d,k and involve the low melting intermedi-
ate, 2,2′-methylenebiscyclohexanone (5) (Scheme 2). This
compound and its high-melting isomer, 2-hydroxytricyclo-
[7.3.1.02,7]tridecan-13-one (3), have also been the subject
of several synthetic5 and stereochemical6 studies. Re-
ported herein are the optimization of the synthesis of 3,
its conversion to 1, and the structure of a new hexacyclic
compound encountered along the way.
Resu lts a n d Discu ssion
The formation of 3 begins with aldol condensation
between cyclohexanone and formaldehyde and elimina-
tion of water to form 2-methylenecyclohexanone. Michael
addition of cyclohexanone enolate gives 2,2′-methylenebis-
cyclohexanone (5) as a mixture of meso and d,l isomers.
Finally, intramolecular aldol condensation provides com-
pound 3. The configuration of 3 was assigned as shown
in Scheme 1, on the basis of the NMR and crystal-
lographic data published for the 8-methyl derivative.6f
Any stereoisomer of 5 or 3 could be used in the
preparation of 1, as retro-aldol reaction occurs under the
conditions for the formation of 1. Our goal was to develop
a reproducible protocol for the preparation and isolation
of 5 or 3 on a large scale, with reasonable purity and
yield, using variations of known procedures.5 When the
condensation was performed with aqueous formaldehyde,5c
vacuum distillation (bp 139-148 °C, 0.7 mm) gave a
stereoisomeric mixture of 1,5-diketones (5) in low yield
(<20%).
* Fax: (775) 784-6804.
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1992, 1-12. (c) Hegde, V.; Hung, C.-Y.; Madbukar, P.; Cunningham,
R.; Ho¨pfner, T.; Thummel, R. P. J . Am. Chem. Soc. 1993, 115, 872-
878. (d) Taffarel, E.; Chirayil, S.; Thummel, R. P. J . Org. Chem. 1994,
59, 823-828. (e) Kelly-Rowley, A. M.; Lynch, V. M.; Anslyn, E. V. J .
Am. Chem. Soc. 1995, 117, 3438-3447. (f) Keuper, R.; Risch, N. Liebigs
Ann. 1996, 717-723. (g) Tidswell, J . L.; Bell, T. W. In Macrocycle
Synthesis: A Practical Approach; Parker, D., Ed.; Oxford University
Press: New York, 1996; pp 119-143.
(2) (a) Kneeland, D. M.; Ariga, K.; Lynch, V. M.; Huang, C.-Y.;
Anslyn, E. V. J . Am. Chem. Soc. 1993, 115, 10042-10055. (b) Bell, T.
W.; Cragg, P. J .; Drew, M. G. B.; Firestone, A.; Kwok, A. D.-I.; Liu, J .;
Ludwig, R. T.; Papoulis, A. T. Pure Appl. Chem. 1993, 65, 361-366.
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A. B. Pure Appl. Chem. 1998, 70, 2371-2377. (g) Bejan, E.; Fontenas,
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1999, 2485-2490. (h) Sasaki, I.; Daran, J .-C.; Balavoine, G. G. A.
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The patented procedure of Becke and Wick5b for the
synthesis of 5 involves the addition of a basic methanolic
solution of paraformaldehyde to a solution of cyclohex-
anone in methanol. By this method we were able to
obtain only the desired product 3 as a white solid (mp
166-168 °C, lit.5c 166-168 °C), again in poor yield (20-
50%). It was noticed that a higher-melting side product
(mp 200-202 °C) was also formed under these conditions.
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10.1021/jo005746u CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/17/2001