An efficient and scalable synthesis of substituted phenanthrenequinones by intramolecular Friedel-Crafts reaction of imidazolies

Article abstract of DOI:10.1021/ol071261h

An efficient synthesis of 9,10-phenanthrenequinones is described. The two carbonyl groups were introduced by an orthosetective intermolecular Friedel-Crafts reaction of 3-methoxyphenol with ethyl chlorooxoacetate. The formation of a biaryl bond by Suzuki-

Full text of DOI:10.1021/ol071261h

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4103-4106
An Efficient and Scalable Synthesis of
Substituted Phenanthrenequinones by
Intramolecular Friedel
of Imidazolides
−Crafts Reaction
Naoki Yoshikawa,*,† Austin Doyle,† Lushi Tan,† Jerry A. Murry,† Atsushi Akao,‡
Masashi Kawasaki,‡ and Kimihiko Sato‡
Department of Process Research, Merck Research Laboratories, Merck & Co., Inc.,
Rahway, New Jersey 07065, and Process Research, Merck Banyu TSK,
Merck Research Laboratories, 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan
naoki_yoshikawa@merck.com
Received May 29, 2007
ABSTRACT
An efficient synthesis of 9,10-phenanthrenequinones is described. The two carbonyl groups were introduced by an orthoselective intermolecular
Friedel Crafts reaction of 3-methoxyphenol with ethyl chlorooxoacetate. The formation of a biaryl bond by Suzuki Miyaura coupling reaction,
followed by the hydrolysis of the ester, gave a biaryloxoacetic acid. Treatment of this acid with CDI gave the corresponding imidazolide. The
−
−
ring closure to the desired phenanthrenequinone was accomplished by intramolecular Friedel
TiCl4.
−Crafts reaction of the imidazolide promoted by
9,10-Phenanthrenequinones have been studied in many
scientific fields, including photochemistry, analytical chem-
istry, physical chemistry, and bioorganic chemistry, due to
their unique properties. The simple 9,10-phenanthrene-
quinone has been found by Smith et al. to act as a redox-
dependent receptor for the selective recognition of urea and
amide derivatives.1 Urbanek et al. have recently identified
that a number of substituted 9,10-phenanthrenequinones are
highly potent inhibitors of the protein tyrosine phosphatase
(PTP) CD45 and the selective inhibition was achieved by
structural modification of the phenanthrenequinone.2 CD45
is a family of transmembrane PTPs that are expressed
exclusively by hematopoetic cells; therefore, the development
of the inhibitors has received increased interest. The deriva-
tives of phenanthrenequinone have also been studied for their
interaction with DNA. Barton et al. have demonstrated that
the metal complexes of 9,10-phenanthrenequinone diimine,
which is readily prepared from 9,10-phenanthrenequinone,
showed sequence-specific recognition of DNA3 and have
(2) Urbanek, R. A.; Suchard, S. J.; Steelman, G. B.; Knappenberger, K.
S.; Sygowski, L. A.; Veale, C. A.; Chapdelaine, M. J. J. Med. Chem. 2001,
44, 1777.
(3) (a) Pyle, A. M.; Rehmann, J. P.; Meshoyrer, R.; Kumar, C. V.; Turro,
N. J.; Barton, J. K. J. Am. Chem. Soc. 1989, 111, 3051. (b) Sitlani, A.;
Barton, J. K. Biochemistry 1994, 33, 12100.
† Merck Research Laboratories, Rahway, New Jersey.
‡ Merck Research Laboratories, Tsukuba, Ibaraki, Japan.
(1) Ge, Y.; Lilienthal, R. R.; Smith, D. K. J. Am. Chem. Soc. 1996, 118,
3976.
10.1021/ol071261h CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/20/2007

recently applied it to the development of artificial nucleases
for shape-selective DNA photo cleavage.4 The metal com-
plexes of phenanthrenequinone thiosemicarbazone were
studied as potential anticancer agents.5
5. The benzoylformic acid derivatives 5 would be prepared
by a Friedel-Crafts type acylation of aromatic compounds
6 with 7. The development of a regio- and chemoselective
method to install the oxalyl group to 6 seemed to be critical
in order to attain an efficient overall process. First of all,
the conventional Friedel-Crafts reaction of 6 with 7
promoted by AlCl3 was examined; however, it gave 5 as a
mixture of ortho- and parasubstituted regioisomers. To
circumvent this problem, we were interested in the use of
unprotected phenols for the regiospecific acylation with the
aid of the strong coordinative capability of the free hydroxyl
group. Piccolo et al. had reported the orthoselective acylation
of phenols in the presence of Lewis acids.16 Although most
examples reported therein were the BCl3-promoted acylation
of regular acid chloride such as benzoyl chloride, they
described one example of TiCl4-mediated acylation using
methyl chlorooxoacetate as the acylating reagent. Inspired
by this report, we started to examine the orthoselective
acylation of phenols.
Most of the syntheses of phenanthrenequinones have
involved the oxidation of the corresponding phenanthrenes.6
This oxidation is, however, often performed using toxic
heavy metals such as chromium. The phenanthrenequinone
core has also been constructed directly using various
methods, i.e., the cyclization of benzil derivatives using
potassium graphite7 or transition metals8 and the benzoin/
acyloin type condensation of functionalized biphenyls.9-11
Another approach is to prepare 9-phenanthrols and oxidize
them to 9,10-phenanthrenequinones. 9-Phenanthrols have
been prepared by the benzoin condensation of 2,2′-dialde-
hydobiphenyls,12 the photocyclization of benzoin deriva-
tives,13 and the anionic cyclization of 2-amido-2′-methyl-
biphenyls.14 FusonandTalbotthavedescribedthat2-biphenylyl-
glyoxal cyclized to 9,10-dihydroxyphenanthrene by treatment
with aluminum chloride; however, the chemical yield was
only 40%.15
We were pleased to find that the Friedel-Crafts reaction
of 3-methoxyphenol (8, Scheme 2) with ethyl chlorooxo-
Herein we report a novel strategy for the synthesis of
phenanthrenequinones (1, Scheme 1) by the intramolecular
Scheme 2. Synthesis of Biaryloxalic Acid by Intermolecular
Friedel-Crafts Reaction and Suzuki-Miyaura Coupling
Reaction
Scheme 1. Retrosynthetic Analysis
Friedel-Crafts type reaction of biaryloxoacetic acid deriva-
tives (2). The biaryl bond was expected to be formed by a
cross-coupling reaction of 4 and benzoylformic acid esters
(4) (a) Sitlani, A.; Long, E. C.; Pyle, A. M.; Barton, J. K. J. Am. Chem.
Soc. 1992, 114, 2303. (b) Fitzsimons, M. P.; Barton, J. K. J. Am. Chem.
Soc. 1997, 119, 3379.
(5) Afrasiabi, Z.; Sinn, E.; Padhye, S.; Dutta, S.; Padhye, S.; Newton,
C.; Anson, C. E.; Powell, A. K. J. Inorg. Biochem. 2003, 95, 306.
(6) For a review of phenanthrene syntheses, see: Floyd, A. J.; Dyke, S.
F.; Ward, S. E. Chem. ReV. 1976, 76, 509.
acetate proceeded smoothly even at -78 °C by using TiCl4
as promoter. The ortho position of the phenol was selectively
acylated to produce 9 in 94% yield. The para-acylated
compound or the corresponding ester (oxygen acylation) was
not obtained at all. The crude product after aqueous work
up was pure enough and used for the subsequent step without
(7) Tamarkin, D.; Benny, D.; Rabonovitz, M. Angew. Chem., Int. Ed.
Engl. 1984, 23, 642.
(8) Mohr, B.; Enkelmann, V.; Wegner, G. J. Org. Chem. 1994, 59, 635.
(9) Mihelic, E. L.; Wilt, M. H. U.S. Patent 3014049, 1960; Chem. Abstr.
1962, 56, 8657.
(10) Wittig, G.; Zimmermann, H. Chem. Ber. 1953, 85, 629.
(11) Tamarkin, D.; Rabinovitz, M. J. Org. Chem. 1987, 52, 3472.
(12) (a) Mayer, F. Chem. Ber. 1914, 47, 406. (b) Enders, D.; Niemeier,
O. Synlett 2004, 2111.
(13) (a) Lantos, I. Tetrahedron Lett. 1978, 19, 2761. (b) Togashi, D.
M.; Nicodem, D. E.; Marchiori, R.; De, F. C.; Marchiori, M. L. P. Synth.
Commun. 1998, 28, 1051.
(14) (a) Fu, J.-m.; Sharp, M. J.; Snieckus, V. Tetrahedron Lett. 1988,
29, 5459. (b) Fu, J.-m.; Snieckus, V. Can. J. Chem. 2000, 78, 905.
(15) Fuson, R. C.; Talbott, R. L. J. Org. Chem. 1961, 26, 2674.
(16) Piccolo, O.; Filippini, L.; Tinucci, L.; Valoti, E.; Citterio, A.
Tetrahedron 1986, 42, 885.
4104
Org. Lett., Vol. 9, No. 21, 2007

purification. The triflation of the hydroxyl group was
performed by using Tf2O and Et3N in CH2Cl2 to afford the
corresponding triflate (10) in quantitative yield. The biaryl
bond was formed by Suzuki-Miyaura coupling reaction of
10 with 3-chlorophenylboronic acid catalyzed by PdCl2(dppf)
in the presence of K3PO4 in refluxing THF to afford biaryl
11 in 91% yield. The ester was readily hydrolyzed by
aqueous NaOH to give benzoylformic acid 12 in 99% yield.
Although these two steps once afforded an excellent yield,
the process suffered from poor reproducibility, presumably
due to varied particle sizes of K3PO4 and the presence of
different amounts of boronic acid anhydrides. This issue was
circumvented by employing an aqueous biphasic condition.
The triflate was treated with the same boronic acid and the
same catalyst in DME-H2O in the presence of K2CO3 as
base. The reaction was gradually heated to 60 °C to effect
the coupling step and then to 80 °C for the ester hydrolysis
to afford acid 12 in 91% yield with good reproducibility.
The crude 12 was used for the subsequent cyclization step
without further purification.
Table 1. Synthesis of Phenanthrenequinones with Different
Substituents
With the oxalyl group installed at the desired position,
the formation of the phenanthrene skeleton was examined
by the intramolecular Friedel-Crafts type reaction (Scheme
3). First of all, the direct cyclization of the acid (12) was
Scheme 3. Cyclization
observed, the reaction produced no phenanthrenequinones,
giving rise to a complex mixture. An attempt to convert the
carboxylic acid to the corresponding acid chloride (15) by
treatment with thionyl chloride resulted in the formation of
an unidentified byproduct. On the other hand, the treatment
of the same acid (12) with thionyl chloride in the presence
of benzotriazole18 cleanly produced the corresponding ben-
1
zotriazolide (16), whose structure was judged by H NMR.
The resulting benzotriazolide, which was stable at 20 °C,
rapidly underwent a cyclization reaction upon activation of
the carbonyl group by treatment with TiCl4 to afford the
attempted by using a mixture of H3PO4 and trifluoroacetic
anhydride.17 Although rapid consumption of the acid was
(17) Veeramaneni, V. R.; Pal, M.; Yeleswarapu, K. R. Tetrahedron 2003,
59, 3283.
(18) Chaudhari, S. S.; Akamanchi, K. G. Synlett 1999, 1763.
Org. Lett., Vol. 9, No. 21, 2007
4105

desired phenanthrenequinone (13) in 80% yield (2 steps from
12). The other regioisomer (14) was formed in 3%. Although
this result was encouraging for us, there was a safety concern
about the use of benzotriazole on a large scale. Thus, we
examined the use of 1,1′-carbonyldiimidazole (CDI) as an
alternative reagent. Using a similar procedure, the phenan-
threnequinone (13) was obtained in an improved yield (85%)
with a slightly better selectivity (regioisomer ∼2%).
The process to prepare 13 from 10 has been demonstrated
in a large scale (>20 kg) with an overall yield of 77%. No
purification or isolation of intermediates was necessary, and
the final phenanthrenequinone (13) was isolated by simple
crystallization. Using triflate 10 as the starting material, the
present process has been extended to the synthesis of other
substituted phenanthrenequinones using different boronic
acids (Scheme 4 and Table 1).
82%) from these boronic acids. The efficiency of the
cyclization was not as good when 4-methoxyphenylboronic
acid and phenylboronic acid were used. The yields of the
phenanthrenequinones from triflate 10 were 42% and 44%,
respectively. Although 2,3-difluorophenylboronic acid, which
has an electron deficient aromatic ring, had a significantly
lower reactivity in the cyclization, we were able to obtain
the corresponding phenanthrenequinone (22) in 61% (from
10) after an extended reaction time. Boronic acids with
electron deficient aromatic ring such as 3-formylphenyl-
boronic acid failed to give the corresponding phenanthrene-
quinones.
In summary, a Friedel-Crafts type acylation has proven
to be effective to construct the phenanthrenequinone skeleton
for the first time. The substrates for the cyclization were
synthesized through an orthoselective Friedel-Crafts
acylation of 3-methoxyphenol with ethyl chlorooxoacetate
promoted by TiCl4, followed by a Suzuki-Miyaura coupling
and hydrolysis. The method can be applied to boronic acids
with nonelectron-deficient aromatic ring. Further studies to
exploit this methodology using other phenols are currently
underway.
Scheme 4. Improved One-Pot Process for the
Suzuki-Miyaura Coupling and Hydrolysis
Acknowledgment. We thank Kevin Belyk (MRL, Rah-
way) for the early development of the Suzuki coupling step,
Dr. Chie Kadowaki (Merck Banyu TSK), Toshiyuki Ohno
(Merck Banyu TSK), and Nobuya Satake (Merck Banyu
TSK) for process optimization, and Robert Reamer (MRL,
Rahway) for NMR analyses of relevant compounds. We are
also grateful to Dr. Shinji Kato (Merck Banyu TSK) and
Dr. Nobuyoshi Yasuda (MRL, Rahway) for fruitful discus-
sions.
The Suzuki-Miyaura coupling and hydrolysis steps
proceeded well for all boronic acids, giving the corresponding
carboxylic acids. The crude acids were again subjected to
the subsequent cyclization step without further purification.
When boronic acids having a π-donor at the 3-position were
employed, the cyclization tended to proceed more rapidly
and cleanly (Table 1). The phenanthrenequinones (13, 20,
and 21) were generally obtained in excellent yields (70-
Supporting Information Available: Experimental pro-
cedures and spectral data of products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL071261H
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Org. Lett., Vol. 9, No. 21, 2007