Alcohol oxidation and aldol condensation during base-catalyzed reaction of primary alcohols with 1-chloroanthraquinone

Article abstract of DOI:10.1016/S0040-4039(00)01142-4

When chloroanthraquinone is treated with primary alcohols under basic conditions, the notoriously low yields observed for substitution result in part from oxidation of the alcohol followed by aldol condensation. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01142-4

Tetrahedron Letters 41 (2000) 6705±6708
Alcohol oxidation and aldol condensation during
base-catalyzed reaction of primary alcohols with
1-chloroanthraquinone
Hossein Shabany, Ernesto Abel, John P. Evans, Ian M. McRobbie
and George W. Gokel*
Bioorganic Chemistry Program and Department of Molecular Biology & Pharmacology,
Washington University School of Medicine, 660 South Euclid Ave., Campus Box 8103, St. Louis, MO 63110, USA
Received 9 May 2000; revised 29 June 2000; accepted 30 June 2000
Abstract
When chloroanthraquinone is treated with primary alcohols under basic conditions, the notoriously low
yields observed for substitution result in part from oxidation of the alcohol followed by aldol condensation.
# 2000 Elsevier Science Ltd. All rights reserved.
Anthraquinone is an intriguing but complex organic residue.1 Its three fused rings make it a
potential building block in supramolecular chemistry that has a planar span, between the 2- and
6-positions, of >10 A.2 It has two carbonyl groups directly opposite each other and it is reducible
by one- or two-electron transfer to the radical anion or to the dianion, respectively. The anthra-
quinone residue has been incorporated into crown ethers,3 podands,4 cryptands,5 cyclodextrins,6
¯uorescent sensors7 and molecular (cyclophane) receptors,8 and even into an `organic super-
structure'.9 Some of this work has recently been reviewed.10 Furthermore, certain anthraquinones
occur in nature and the proteins involved in their synthesis from polyketides are under study.11
A limitation in the approach to these novel and interesting molecules has been the lack of
appropriate synthetic methodology. Of course, important synthetic methods have been developed
in connection with tetracycline12 syntheses, but much of this elegant work deals with ring
construction13 rather than skeletal modi®cation.
Attempts to prepare relatively simple anthraquinone-substituted podands and lariat ethers met
with substantial diculties. Simple alkylation reactions of 1-hydroxyanthraquinone proved not
to be easy and nucleophilic aromatic substitution reactions of electron-de®cient chloroanthra-
quinone were poor yielding or a€orded only intractable mixtures of product and by-products,
although substitution by methoxide ion was reported to be successful.14 The application of phase
* Corresponding author. Tel: +1-314-362-9297; fax: +1-314-362-9298; e-mail: ggokel@molecool.wustl.edu
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01142-4

6706
transfer catalysis also proved useful.15 In the pragmatic sense, we solved the general problem of
synthetic access by development of a podand-catalyzed substitution reaction (see Scheme 1). This
approach permitted the syntheses of a variety of 1-alkoxyanthraquinones.16 It was thought that
the podands were serving both as nucleophiles and as leaving groups, enhancing nucleophilic
aromatic substitution. Additional study showed17 that certain alkynes could function as catalysts
for the same reaction that was e€ected by podands. Enhancement of leaving group ability
(podand relative to chloride) could not account for this catalytic ecacy and the mode of action
of alkynes in this process remains obscure.
Scheme 1.
Recent work related to our own e€orts18 has demonstrated that modest yields and dehalo-
genation can occur with 1,8-dichloroanthraquinone as well as with 1-chloroanthraquinone. We
now present evidence that suggests the intervention of a more complex mechanism than we at ®rst
envisioned. This process involves redox chemistry, by which the alkanols are converted into
aldehydes. Once formed, the aldehydes self-condense under the basic reaction conditions to
a€ord aldol products.
When 1-chloroanthraquinone (5 mmol) was heated for 6 h with 1-hexanol (solvent, 50 ml) at
160ꢀC in the presence of K2CO3 (4 equiv.), three major products were isolated. 1-Hexyloxyan-
thraquinone (3a, n=5), the expected substitution product, was isolated in 10% yield. The major
product of the reaction is anthraquinone (2a, n=5, 45%). Habata and co-workers18 have
postulated that dehalogenation in their NaH/alcohol/dichloroanthraquinone systems occurs by
direct hydride substitution. The base used in the present studies is K2CO3 and there is no obvious
source of hydride. A third product, shown in Scheme 2 as compound 4a, was isolated in 26%
yield. The latter is the product of aldol condensation of hexanal followed by dehydration.
Compound 4a (n=5) is an aldehyde and its 2,4-dinitrophenylhydrazone derivative was found to
melt at 130±132ꢀC.19 For comparison, when n-dodecanol (50 ml) was heated with K2CO3 (4
equiv.) at 160ꢀC in the absence of 1-chloroanthraquinone, no aldol product was detected by TLC.
When anthraquinone rather than 1-chloroanthraquinone was present or when no K2CO3 was
used, no ether or other product was isolated. Thus, base, 1-chloroanthraquinone and alcohol are
all required for the aldol product to be isolated.
It seemed surprising that the aldehyde chemistry is so prominent and there is no evidence for
the corresponding carboxylic acid. The reaction mixture is basic and the product is isolated by
short path (Kugelrohr) distillation followed by isolation of the aldol condensation products as

6707
Scheme 2.
their 2,4-dinitrophenylhydrazone derivatives. The alcohols studied here were used in part because
their condensation products have already been fully characterized. Any carboxylic acid remaining
after the reaction would be present as its potassium salt. This would probably precipitate, would
certainly not distill, and does not move on the TLC plates used in this study. Its presence would
therefore be undetected.
A series of experiments was conducted in an e€ort to gain additional insight into this process.
It was decided to use n-dodecanol as the nucleophile and as the solvent. Two variants were
prepared: CH3(CH2)11OD and CH3(CH2)10CD2OH. The former was prepared by titration of n-
dodecanol with 1 equiv. of n-butyllithium in hexanes followed by careful quenching with D2O.
The latter was prepared by LiAlD4 reduction of methyl dodecanoate. When 1-chloroan-
thraquinone (5 mmol) was treated with K2CO3 (20 mmol) in n-dodecanol (6 h, 160ꢀC),
compounds 2a (n=11, 39%), 3a (9%) and 4a (42%) were obtained. When the corresponding
reaction was done using CH3(CH2)11OD, similar yields of identical products were obtained.
Thus, no deuterium incorporation was observed in either case. In contrast, when
CH3(CH2)10CD2OH was used as solvent, compound 4b was obtained (b-double bond and aldehyde
hydrogen atoms both deuterated). As expected, NMR analysis showed that anthraquinyl ether 3b
was deuterated at the methylene group adjacent to oxygen. In both cases, deuterium substitution
1
was determined by H NMR analysis. The presence of deuterium was con®rmed by mass
spectrometric analyses. In no case was 1-deuterioanthraquinone detected either by NMR or mass
spectrometry.
It seems reasonable to assume that the poor yields in alkanol substitutions are due to competing
oxidation and condensation. We previously reported that phenols give much higher yields in the
substitution reaction than do aliphatic alcohols. No obvious mechanism exists for the
formation of an aldehyde from phenol. It was also found that podands, even short-chained ones,
substituted 1-chloroanthraquinone in much better yield than do alkanols. Likewise, alkynols, but
not alkenols, gave good yields of substitution products (corresponding to 1). In the former case,
reaction was best when the triple bond was closest to the hydroxyl group. Yields declined more or
less monotonically as the triple bond was moved down the carbon chain.
We demonstrate in the present study that substitution reactions in 1-chloranthraquinone
derivatives may lead to oxidation of alkanol nucleophiles by a previously unknown mechanism

6708
that involves hydride transfer. The generality of the oxidation is demonstrated for several simple
alkanols and the mechanism is considered in light of observations presented in other work, which
comport with the postulates presented here.
Acknowledgements
We thank the NIH (GM-36262) and the NSF (CHE-9805840) for grants that supported this
work. We are also grateful to Professor Rudolph E. K. Winter (University of Missouri at St.
Louis) for assistance with the GC±MS studies.
References
1. (a) The Chemistry of the Functional Groups; Patai, S., Ed. The chemistry of quinonoid compounds. John Wiley:
New York, 1974. (b) Muller, E.; Bayer, O. Methoden der Organischen Chemie, Band VII/3c, Anthrachinone,
Anthrone; Georg Thieme Verlag: Stuttgart, 1979. (c) Zollinger, H. Color Chemistry, Syntheses, Properties and
Applications of Organic Dyes and Pigments; VCH: Weinheim, 1987.
2. Abel, E.; Castro, R.; McRobbie, I.; Barbour, L.; Atwood, J. L.; Kaifer, A. E.; Gokel, G. W. Supramol. Chem.
1998, 9, 199±202.
3. (a) Maruyama, K.; Sohmiya, H.; Tsukube, H. Tetrahedron Lett. 1985, 3583. (b) Maruyama, K.; Sohmiya, H.;
Tsukube, H. J. Chem. Soc., Perkin Trans. 1 1986, 2069. (c) Echagoyen, L.; Gustowski, D. A.; Gatto, V. J.; Gokel,
G. W. J. Chem. Soc., Chem. Commun. 1986, 220±223. (d) Ozeki, E.; Kimura, S.; Imanishi, Y. J. Chem. Soc., Chem.
Commun. 1988, 1353. (e) Echagoyen, L. E.; Yoo, H. K.; Gatto, V. J.; Gokel, G. W.; Echagoyen, L. J. Am. Chem.
Soc. 1989, 111, 2440±2443. (f) Ossowski, T.; Schneider, H. Chem. Ber. 1990, 123, 1673.
4. (a) Gustowski, D. A.; Delgado, M.; Gatto, M.; Echagoyen, L.; Gokel, G. W. Tetrahedron Lett. 1986, 3487±3490.
(b) Echeverria, L.; Delgado, M.; Gatto, V. J.; Gokel, G. W.; Echagoyen, L. J. Am. Chem. Soc. 1986, 108, 6825±
6826. (c) Delgado, M.; Gustowski, D. A.; Yoo, H. K.; Gatto, V. J.; Gokel, G. W.; Echagoyen, L. J. Am. Chem.
Soc. 1988, 110, 119±123. (d) Kim, H.; Schall, O. F.; Fang, J.; Trafton, J. E.; Lu, T.; Atwood, J. L.; Gokel, G. W.
J. Phys. Org. Chem. 1992, 5, 482. (e) Silva, D. J.; Kahne, D.; Kraml, C. M. J. Am. Chem. Soc. 1994, 116, 2641.
5. Chen, Z.; Schall, O. F.; Alcala, M.; Li, Y.; Gokel, G. W.; Echagoyen, L. J. Am. Chem. Soc. 1992, 114, 444±451.
6. Aquino, A. M.; Abelt, C. J.; Berger, K. L.; Darragh, C. M.; Kelley, S. E.; Cossette, M. V. J. Am. Chem. Soc. 1990,
112, 5819.
7. DeSilva, A. P.; Sandanayake, K. R. A. S. Tetrahedron Lett. 1991, 32, 421.
8. Haeg, M. E.; Whitlock, B. J.; Whitlock Jr., H. W. J. Am. Chem. Soc. 1989, 111, 692.
9. Otsuki, J.; Oya, T.; Lee, S.-H.; Araki, K. J. Chem. Soc., Chem. Commun. 1995, 2193.
10. Bouas-Laurent, H.; Desvergne, J.-P.; Fages, F.; Marsau, P. In Frontiers in Supramolecular Organic Chemistry and
Photochemistry; Schnieder, H.-J.; Durr, H., Eds. Anthraceno-crown ether and cryptands, cation-directed
photophysics and photochemistry. VCH: Weinheim, 1991; p. 265.
11. Bartel, P. L.; Zhu, C.; Lampel, J. S.; Dosch, D. C.; Connors, N. C.; Strohl, W. R.; Beale Jr., J. M.; Floss, H. G.
J. Bacteriol. 1990, 172, 4816±4826.
12. Sum, P.-E.; Sum, F.-W.; Projan, S. J. Curr. Pharm. Des. 1998, 4, 119±132.
13. Krohn, K. Tetrahedron 1990, 46, 291.
14. Ignatov, V. A.; Shein, S.; Novosibirsk, M. Izv. Sib. Otd. Akad. Nauk SSSR, Ser. Khim. Nauk 1967, 1, 122±125
(Chem. Abstr. 67, 107862).
15. Seguchi, K.; Ozasa, A. Yukagaku 1982, 31, 609±611.
16. Lu, T.; Yoo, H. K.; Zhang, H.; Bott, S.; Atwood, J. L.; Echagoyen, L.; Gokel, G. W. J. Org. Chem. 1990, 55,
2269±2270.
17. Fang, J.; Lu, T.; Kim, H.; Delgado, I.; Geo€roy, P.; Atwood, J. L.; Gokel, G. W. J. Org. Chem. 1991, 56, 7059±
7065.
18. Habata, Y.; Bradshaw, J. S.; Nelson, R. W.; Izatt, R. M. Tetrahedron 1997, 53, 4179.
19. McElvain, S. M.; Degginger, E. R.; Behun, J. D. J. Am. Chem. Soc. 1954, 76, 5736±5739.