An expeditious one pot synthesis of dibenzo[a,g]fluorene

Article abstract of DOI:10.1081/SCC-100105115

A convenient one-pot synthesis of dibenzo[a,g]fluorene via enolate alkylation and cyclodehydration-aromatisation route has been developed.

Full text of DOI:10.1081/SCC-100105115

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AN EXPEDITIOUS ONE POT SYNTHESIS OF
DIBENZO[a,g]FLUORENE
Bimal K. Banik a , Chhanda Mukhopadhyay a & Frederick F. Becker a
a Department of Molecular Pathology , The University of Texas, M.D. Anderson Cancer
Center , Box-89, 1515 Holcombe Blvd., Houston, TX, 77030, U.S.A.
Published online: 09 Nov 2006.
To cite this article: Bimal K. Banik , Chhanda Mukhopadhyay & Frederick F. Becker (2001) AN EXPEDITIOUS ONE POT
SYNTHESIS OF DIBENZO[a,g]FLUORENE, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 31:16, 2399-2403, DOI: 10.1081/SCC-100105115
To link to this article: http://dx.doi.org/10.1081/SCC-100105115
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SYNTHETIC COMMUNICATIONS, 31(16), 2399–2403 (2001)
AN EXPEDITIOUS ONE POT SYNTHESIS
OF DIBENZO[a,g]FLUORENE
Bimal K. Banik,* Chhanda Mukhopadhyay,
and Frederick F. Becker
The University of Texas, M.D. Anderson Cancer Center,
Department of Molecular Pathology, Box-89, 1515 Holcombe
Blvd., Houston, TX 77030, USA
ABSTRACT
A convenient one-pot synthesis of dibenzo[a,g]fluorene via
enolate alkylation and cyclodehydration-aromatisation route
has been developed.
Synthesis of polycyclic aromatic ring systems by various methodology
has been the subject of extensive investigation for many years.1 The
carcinogenic properties of such compounds have been explained by advan-
cing different mechanisms.2 We observed from a prior study that suitably
substituted chrysene derivatives act on the cancer cell as membrane stabiliz-
ing agents.3 Recently, we also demonstrated the anti-tumor effects of
structurally complex, angular dibenzofluorene [a,g] polycyclic systems (for
example, 3) with a very reactive bridged methylene group.4 Diamide 3 was
prepared through a series of reactions starting from the hydrocarbon 1a.
Hydrocarbon 1a on nitration gave 1b which on reduction produced the
amino compound 1c. Coupling reaction of 1c with the acid 2 in the presence
of isobutyl chloroformate afforded the diamide 3 (Scheme 1).
*Corresponding author. E-mail: banik@mdanderson.org
2399
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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BANIK, MUKHOPADHYAY, AND BECKER
Scheme 1.
Synthesis of the hydrocarbon 1a required for this study in pure
and adequate quantities by following the method of Harvey et al.5 proved
difficult to us. Harvey et al. synthesized the hydrocarbon 1a from b-tetralone
4 through a series of steps. For this reason, we became interested in devel-
oping a new synthetic method for the preparation of hydrofluorene deriva-
tives. This paper describes a simple and convenient one pot method6 for the
synthesis of dibenzo[a,g]fluorene.
Environmentally benign chemistry is one of the attractive areas of
chemical research. Disposal of solvents and chemical waste are matters
of concern to the pharmaceutical manufacturer. Generally, chemical syn-
thesis of any target molecule requires multi-step operation. Thus, to execute
the synthesis of even a simple organic compound, extraction and purifica-
tion either by chromatography or by crystallization are essential. For this
reason, atom economy by Trost7 can play a significant role. Combination of
multi-step sequence into a fewer number of step or in an one pot can nicely
fit into Trost’s atom economy.
The enolate alkylation8 and cyclization method has been used for the
construction of multi-cyclic ring systems. But, surprisingly, the use of this
method in the annulation of polycyclic non-alternate hydrocarbon has never
been explored. We envisioned that enolate alkylation of the ketone and
cyclization-aromatisation route in a one pot operation could be a viable

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alternative of the existing method.5 Towards this goal we treated b-tetralone
(4) with sodium hydride using benzene as solvent at À10 to À20ꢀC, reacted
the enolate with 2-bromomethylnaphthalene (5) at the same temperature,
neutralized and then benzene was evaporated under reduced pressure. The
residue was refluxed with 10% methane sulfonic acid-dichloroethane for
12 h and obtained the hydrocarbon in 35% yield after purification9
(Scheme 2). The entire procedure required only one extraction and a
simple filtration through a column for the isolation of the final product.
Using the method (enamine formation, alkylation of the enamine, cycliza-
tion and aromatisation) by Harvey et al.,5 we required three weeks to
produce the same amount of compound as this process required isolations
at each stage either through distillation or extraction-chromatography.
Scheme 2.
In conclusion, we have demonstrated here a simple one-pot synthesis
of dibenzofluorene, some of the derivatives of which have potent anticancer
activities.4
EXPERIMENTAL
A typical experimental procedure is as follows: To NaH (50% disper-
sion in oil, 0.068 mol) in benzene (10 mL) at À10ꢀC to À20ꢀC were added
dropwise a solution of ketone 4 (0.034 mol) in benzene (10 mL). The
immediate appearance of the deep blue color indicated the formation of
the sodium enolate. The mixture was kept at the same temperature for
30 min and then bromomethylnaphthalene 5 (0.034 mol) in benzene
(10 mL) was added to it. The temperature was slowly allowed to rise to
room temperature and stirring was continued for 2 h. The reaction mixture
was cooled in ice and excess NaH was decomposed by careful addition of
methane sulfonic acid. Benzene was removed under reduced pressure,
methane sulfonic acid-1,2-dichloroethane (100 mL, 10%, v/v) was added
to the residue and the mixture was refluxed for 12 h. The reaction mixture
was then poured into crushed ice, the dichloroethane layer was collected,

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BANIK, MUKHOPADHYAY, AND BECKER
washed with sodium bicarbonate (5%), brine, dried (Na2SO4) and solvent
was evaporated. The crude product was purified by filtration through a
short column of silica gel using hexanes as eluant. The isolated yield of
the product was 35%; mp 175ꢀC (lit.5 mp 174–175ꢀC).
ACKNOWLEDGMENTS
We are grateful for the funds from the Hubert L. and Olive Stringer
Chair for the partial support of this research.
REFERENCES
1. For example, see: Harvey, R.G. Polycyclic Aromatic Hydrocarbons,
Wiley-VCH, 1997.
2. (a) Di Raddo, P.; Chan, T.H. J. Org. Chem. 1982, 47, 1427.
(b) Sami, S.M.; Dorr, R.T.; Alberts, D.S.; Remers, W.A. J. Med. Chem.
1993, 36, 765. (c) Bair, K.W.; Tuttle, R.L.; Knick, V.C.; Cory, M.;
McKee, D.D. J. Med. Chem. 1990, 33, 2385.
3. Becker, F.F.; Banik, B.K. Bioorganic & Med. Chem. Lett. 1998, 8, 2877.
For an example, see: Jorgensen, K.; Ipsen, J.H. Biochem. Biophys. Acta
1991, 1062, 227.
4. Becker, F.F.; Mukhopadhyay, C.; Hackfeld, L.; Banik, I.; Banik, B.K.
Bioorg. & Med. Chem. 2000, 000. For the synthesis of dibenzfluorenone,
see: Banik, B.K.; Mukhopadhyay, C.; Venkatraman, M.S.; Becker, F.F.
Tetrahedron Lett. 1998, 39, 7247. Also see: Banik, B.K.; Ghatak, A.;
Mukhopadhyay, C.; Becker, F.F. J. Chem. Res (s) 2000, 108.
5. Harvey, R.G.; Pataki, J.; Cortez, C.; DiRaddo, P.; Yang, C. J. Org.
Chem. 1991, 56, 1210.
6. For some recent examples of one pot synthesis, see: (a) Minuti, L.;
Taticchi, V.; Gacs-Baitz, E.; Marrocchi, A. Tetrahedron 1998, 54,
10891. (b) Oguz, U.; Akkaya, E.U. J. Org. Chem. 1998, 63, 6059.
(c) Banik, B.K.; Manhas, M.S.; Robb, E.W.; Bose, A.K. Heterocycles
1997, 44, 405. (d) Froyen, P.; Juvvik, P. Tetrahedron Lett. 1995, 36,
9555. (e) Banik, B.K.; Manhas, M.S.; Newaz, S.N.; Bose, A.K.
Bioorganic & Med. Chem. Lett. 1993, 3, 2363.
7. Trost, B.M. Science 1991, 254, 1471.
8. For some references of enolate alkylation with sodium hydride, see: (a)
Zook, H.D.; Kelley, W.L.; Posey, I.Y. J. Org. Chem. 1968, 33, 3477. (b)
House, H.O. In Modern Synthetic Reactions (second edition), chapter 9,
W. A. Benzamin, INC, 1972.

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9. Suitably substituted ketones can be aromatised by cyclodehydration-
aromatisation path. For an example see: Ghosh, S.; Banik, B.K.;
Ghatak, U.R. J. Chem. Soc., Perkin Trans 1 1991, 3195.
Received in the USA November 6, 2000

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