Synthesis of phenanthrenes from formylbenzoquinone

Article abstract of DOI:10.1016/S0040-4039(02)01026-2

Phenanthrenes are synthesized by condensation of formylbenzoquinone with a substituted toluene followed by O-methylation and cyclization using the phosphazine base P₄-tBu.

Full text of DOI:10.1016/S0040-4039(02)01026-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5319–5321
Synthesis of phenanthrenes from formylbenzoquinone
George A. Kraus,* Kim Hoover and Ning Zhang
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Received 19 March 2002; revised 23 March 2002; accepted 28 May 2002
Abstract—Phenanthrenes are synthesized by condensation of formylbenzoquinone with a substituted toluene followed by
O-methylation and cyclization using the phosphazine base P4-tBu. © 2002 Elsevier Science Ltd. All rights reserved.
Functionalized phenanthrenes are useful intermediates
for natural product synthesis.1 Natural products such
as tetrangulol (1),2 denbinobin (2),3 and bungone B (3)4
contain an oxidized phenanthrene subunit.
and co-workers developed a clever intramolecular
cyclization using base and light.9 Kraus and Melekhov
recently synthesized phenanthrenes via a Lewis acid-
mediated cyclization reaction.10
Many phenanthrenes are prepared by photochemical
cyclizations of stilbenes. Both Mallory and Giles have
demonstrated that certain stilbenes undergo photocy-
clization in the presence of oxidizing agents to afford
phenanthrene dimethyl ethers.5 Snieckus and co-work-
ers have synthesized phenanthrenes via an innovative
approach involving directed ortho metalation followed
by a palladium-catalyzed cyclization.6 Catellani has
synthesized phenanthrenes via a palladium-mediated
bis-addition to aryl acetylenes.7 Ramana has synthe-
In the reaction sequence that we have developed,
formylbenzoquinone reacts with a substituted toluene
near ambient temperature. The resulting hydroquinone
is O-methylated and then converted into the phenan-
threne using the hindered phosphazine base P4-tBu.
This sequence is illustrated below. Deprotonation,
cyclization and dehydration occur in a one-pot reaction
to generate the phenanthrene structure.
This methodology affords a straightforward and novel
synthesis of highly substituted phenanthrenes. Initially,
we prepared formylbenzoquinone from the hydro-
sized phenanthrenes by
a tandem intermolecular
acylation/intramolecular acylation strategy.8 DeKoning
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01026-2

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G. A. Kraus et al. / Tetrahedron Letters 43 (2002) 5319–5321
quinone using silver oxide in benzene at ambient tem-
perature.11 The reaction product was filtered through
Celite and immediately reacted with the substituted
toluene 4 and stannic chloride at 0°C to room tempera-
ture.12 The yields of purified product were modest
despite variations in temperature, Lewis acid and reac-
tion time.
potassium tert-butoxide and light. With adduct 5, the
use of both reagents returned recovered starting mate-
rial. We had previously employed the hindered phos-
phazine base P4-tBu in
a
novel synthesis of
benzofurans.15 The reaction of adduct 5 with P4-tBu
generated the phenanthrene cleanly in good yield at
100°C.16 The results of cyclizations using P4-tBu are
collated in Table 2. This reaction has been successfully
conducted on scales ranging from 1 to 10 mmol.
We then tried the oxidation of 2,5-dihydroxybenzalde-
hyde using DDQ according to the method of Bruce.13
This method afforded a quinone that was much more
pure than that produced by the silver oxide method.
Formylbenzoquinone generated from the reaction with
DDQ reacted with the substituted toluenes 4 and tri-
fluoroacetic acid to provide adducts in improved yields.
The best yields were obtained using no Lewis acid and
simply extending the reaction time. The yields of the
products are shown below in Table 1.
The procedure described above represents a mild and
efficient method for the regiochemical construction of
highly substituted phenanthrenes.17 The phosphazine
cyclization is compatible with a variety of substituents.
This methodology will be applied to the total synthesis
of denbinobin and bungone B.
Acknowledgements
With a good preparation of the adducts 5, we next
focused on the cyclization. Magnus and co-workers had
previously reported the synthesis of phenanthrenols
from biphenyl esters using lithium diisopropylamide.14
DeKoning had reported a related cyclization using
We thank the Environmental Protection Agency and
Iowa State University for partial support of this
research.
Table 1. Reactions using formylbenzoquinone prepared
from DDQ
References
1. (a) Floyd, A. J.; Dyke, S. F.; Ward, S. E. Chem. Rev.
1976, 76, 509–562; (b) Bruce, J. M.; Heatley, F.; Ryles, R.
G.; Scrivens, J. H. J. Chem. Soc., Perkin 2 1980, 860.
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L.-T. J. Nat. Prod. 2001, 64, 1084–1086.
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R1
R2
R3
R4
% Yield
5. (a) Mallory, F. B.; Mallory, C. W. In Organic Reactions;
Dauben, W. G., Ed.; Wiley: New York, 1984; p. 30; (b)
Giles, R. G. F.; Sargent, M. V. J. Chem. Soc., Perkin
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H
CH3
H
H
H
CH3
CH3
CH3
OCH3
OCH3
H
H
H
H
H
H
H
CH3
OCH3
CH3
75 (29% with Ag2O)
58 (23% with Ag2O)
67 (21% with Ag2O)
60
51 (24% with Ag2O)
Table 2. Cyclizations using P4-tBu
8. Ramana, M. M. V.; Potnis, P. V. Synthesis 1996, 1090–
1092.
9. De Koning, C. B.; Michael, J. P.; Rousseau, A. L.
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Chem. Soc., Perkin 2 1980, 860.
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OCH3
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14. (a) Magnus, P.; Eisenbeis, S. A.; Magnus, N. A. J. Chem.
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5321
16. One example of this transformation using silver oxide to
generate formylbenzoquinone and P4-tBu to make the
phenanthrene has been reported as part of a synthesis of
tetrangulol: Kraus, G. A.; Zhang, N.; Melekhov, A.;
Jensen, J. Synlett 2001, 521.
and dried. The product was purified by sgc (50:1 H:EA).
The hydroquinone was then dissolved in acetone and
Me2SO4 and K2CO3 were added. This reaction was boiled
for 24 h and allowed to cool. The mixture was filtered and
the acetone was removed. The solid was then dissolved in
ether and washed with 1N NaOH solution once and
extracted with ether twice. The combined ether layers were
washed with brine twice and dried over MgSO4. The crude
product was then purified by sgc (10:1 H:EA).
The hydroquinone dimethyl ether was placed in an argon-
flushed sealable tube with benzene and 1.05 equiv. of
P4-tBu (purchased from Fluka) and heated in an oil bath
to 100°C for 24 h. The solvent was evaporated and the
crude product was purified by sgc (100:1 H:EA).
17. Representative example:
DDQ method: The quinine was prepared by combining
equimolar amounts of 2,5-dihydroxybenzaldehyde and
DDQ in a 100 mL flask in about 50 mL of dry benzene.
This was allowed to react at rt for 16 h. The benzene was
evaporated and the crude product was re-dissolved in Et2O.
This was allowed to react with 4 for 24 h. The crude
product was poured onto ice and extracted three times with
ethyl acetate. The organic layer was washed once with brine