Rediscovering the double friedel-crafts acylation: An expedient entry to phenanthrene-9,10-diones

Article abstract of DOI:10.1055/s-0032-1318481

The double Friedel-Crafts acylation of readily accessible biaryls with oxalyl chloride delivers the respective phenanthrene-9,10-diones, providing an alternative to the traditional methods, which require harsh oxidizing conditions and multistep sequences.

Full text of DOI:10.1055/s-0032-1318481

LETTER
▌951
lRetteerdiscovering the Double Friedel–Crafts Acylation: An Expedient Entry to
Phenanthrene-9,10-diones
Rediscovering the Double Friedel–Crafts A
a
cylation
a
b
a,c
a
Institute of Organic Chemistry (IOC), Karlsruher Institute of Technology (KIT), Fritz-Haber-Weg 6, Campus Süd, Geb. 30.42,
76131 Karlsruhe, Germany
Fax +49(721)60848581; E-mail: kye.masters@kit.edu; E-mail: stefan.braese@kit.edu
b
c
Zoological Institute, Cell and Developmental Biology, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany
School of Chemistry, Physics and Mechanical Engineering, Faculty of Science and Engineering, Queensland University of Technology,
GPO Box 2434, Brisbane, Queensland 4001, Australia
Received: 19.01.2013; Accepted after revision: 26.02.2013
2
f
plex involved in colon and other cancers. This biosyn-
thetic pathway has also been shown to affect the Wnt-
targeted gene transcription signaling pathway, which
Abstract: The double Friedel–Crafts acylation of readily accessi-
ble biaryls with oxalyl chloride delivers the respective phenan-
threne-9,10-diones, providing an alternative to the traditional
methods, which require harsh oxidizing conditions and multistep leads to stem cell self-renewal.3
sequences. This simple method allows the synthesis of various sym-
Several close structural analogues of murrayaquinone ex-
metrical and non-symmetrical targets, and is even effective for the
synthesis of the parent ring system from (unactivated) biphenyl.
ist in the fungal and plant kingdoms; piloquinone (4) was
4a–c
isolated from Streptomyces pilosus.
Haloquinone (5)
Key words: cyclization, electrophilic aromatic, substitution, fused-
ring systems, Friedel–Crafts acylation, phenanthrene-9,10-diones
has been isolated from Streptomyces venezuelae ssp. xan-
thophaeus and is shown to be a potent antibiotic against
4d,e
halobacteria. Biruloquinone (8) has also been isolated
4f
from the lichen Parmeliu birulue and the fungus Myco-
In 1911, Liebermann described the Friedel–Crafts acyla-
tion of 4,4′-dimethylbiphenyl (1, Scheme 1) with oxalyl
4g
sphaerella rubella. Manniorthoquinone (9) has also
been isolated from the stem bark of Neoboutonia mannii
chloride to produce 2,7-dimethylphenanthrene-9,10-di-
4h
Benth (Euphorbiaceae). Lastly, a tetracyclic compound,
1
one (2). Despite the nature of this reagent as a concise C
2
9,10-dione-3,4-methylenedioxy-8-methoxy-9,10-dihydro-
synthon to install the diketo bridge of phenenthrene-9,10-
dione cores, it has since remained essentially unexploited
for this purpose by the synthetic community for the last
century.
phenanthrinic acid (10) was isolated from the roots of
4i
Peucedanum praeruptorum Dunn.
The putative synthetic route to murrayaquinone was re-
quired to be extremely modular in nature, as the intention
was to synthesize a variety of substituted analogues for
testing in a β-catenin screen and establishment of struc-
ture-activity relationships around the core. Initially un-
aware of the precedent from Liebermann, we speculated
that the 1,2-diketo functionality might be conveniently in-
stalled in one step by double-electrophilic aromatic sub-
stitution upon biaryl substrates, which are extremely
facile to synthesize in a modular sense via a variety of
well-established transition-metal-catalyzed techniques.
We reasoned that from a variety of functionalized aryl
species, both symmetrical and asymmetrical combina-
tions of arenes could be converted in just two steps into a
large variety of tricyclic core (phenanthrene-9,10-dione)
products (Scheme 2).
O
O
(
ClCO)2,
AlCl3
1
2
Scheme 1 Liebermann’s synthesis of 2,7-dimethylphenanthrene-
,10-dione in 19111
9
We were asked by an academic colleague to devise a nov-
el synthetic route to the phenanthrene-dione-containing
core of murrayaquinone (3), a natural product with multi-
ple bioactivities first isolated from Streptomyces mur-
2
a
rayamaensis, and later from a further two Streptomyces
2b
species. It has been shown to be orally bioavailable as an
antibacterial agent against Mycoplasma and Trepanone-
ma sp., to have low oral toxicity in mice, and to inhibit
hepatitis C virus proteinase.2 It furthermore possesses
promising inhibition on the formation of the Tcf and β-
catenin complex, an established oncogenic protein com-
R4
R2
R2
O
Cl
R3
R1
R1
O
O
X1
Cl
O
c–e
+
X2
R3
R3
coupling
double
Friedel–Crafts
R1
R2
R4
R4
SYNLETT 2013, 24, 0951–0954
Advanced online publication: 05.04.2013
Scheme 2 Concise and highly modular pathway to phenanthrene-
,10-diones from functionalized arenes via coupling and double
Friedel–Crafts acylation of the resulting biaryls
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
9
DOI: 10.1055/s-0032-1318481; Art ID: ST-2013-B0064-L
Georg Thieme Verlag Stuttgart · New York
©

952
N. Crosta et al.
LETTER
OH
O
OH
OH
OH
OH
bility of the double Friedel–Crafts acylation reaction with
a variety of easily accessed substrates (Scheme 3).
O
O
O
O
MeO
OMe
MeO
OMe
O
O
conditions
a: 3%
b: 0%
O
O
O
OH
c: 51%
O
murrayaquinone (3)
piloquinone (4)
haloquinone (5)
MeO
Me
OMe
Me
MeO
OMe
1
1
12
CO2H
Me
OH
O
OH
OH
2
) double
Me
Me Me
O
Friedel–Crafts
acylation
O
O
conditions
1
) coupling
a: 14 0%, 15 35%
b: 14 0%, 15 0%
c: 14 0%, 15 0%
(
many possibilities)
+
O
O
a
OH
R
R
Me
Br
Me
Me
Me Me
Me
1
3
14
15
general structure 6
modular approach 7
OMe
Br
Br
OMe
OH
O
OH
O
CO2H
O
O
O
O
O
conditions
a–c: no reaction
O
O
O
O
O
Br
OMe
OMe
OH MeO
OMe
OMe
1
6
17
R3
R3
9,10-dione-3,4-
manniortho-
methylenedioxy-8-methoxy-
biruloquinone (8)
quinone (9) 9,10-dihydrophenanthrinic acid (10)
O
O
conditions
d: 19 complex mixture
e: 21 no rxn
Figure 1 Proposed key disconnections to synthesize the phenan-
threne-9,10-dione core of murrayaquinone and related products
Phenanthrene-9,10-diones are found as the cores of nu-
merous biologically active natural products, and deriva-
tives of this motif are frequently the focus of medicinal
R3
R3
1
8: R = t-Bu
20: R = CO Me
19: R = t-Bu
21: R = CO Me
5
a
chemistry programs. They are also able to perform se-
quence-specific recognition of DNA,5 which may be
utilized to effect the photo-induced cleavage of DNA
strands.5 Nonetheless, the existing synthetic methods to-
wards these compounds all suffer from severe practical
drawbacks. Syntheses can be grouped into two categories,
starting either from phenanthrenes and involve the use of
strong acids and oxidizing agents, or by way of less direct
synthetic intermediates, which typically feature numerous
2
2
b,c
R1
R2
MeO
MeO
conditions
d,e
b
O
O
a: 23a: 0%, 23b: 41%, 23c: 5%
c: 23a: 4%, 23b: 37%, 23c: 4%
b
3a: R / = OMe, R2/4 = H
1 3
2
23b: R / = OMe, R2/3 = H
1 4
R3
R1
R4
23c: R / = H, R2/4 = OMe
1 3
22
R2
6
sequential steps. We present herein a simple and effec-
conditions
f: 24a: 73%
f: 24b: 63%
tive method for the synthesis of the phenanthrene-9,10-di-
one core and derivatives.
O
O
2
3a
or
3b
2
Examination of literature methodology for the synthesis
of the phenanthrene-9,10-dione core revealed that, with a
few exceptions,6 virtually all existing syntheses of this
core involve multistep sequences from phenanthrenes,
typically via ene-enol oxidation or cis-dihydroxylation
4a: R1/3 = OH, R2/4 = H
24b: R1/4 = OH, R2/3 = H
2
R3
R4
d,e
Scheme 3 The double Friedel–Crafts acylation of symmetrical bi-
aryls with oxalyl chloride. Reagents and conditions: (a) oxalyl chlo-
ride (1.2 equiv), aluminium trichloride (1.2 equiv), CH Cl (0.1 M),
2
2
6
followed by further oxidation steps. One or both of these
r.t., 15 h; (b) oxalyl chloride (1.2 equiv), aluminium trichloride (1.2
steps are typically performed under extremely harsh con- equiv), triflic acid (1.2 equiv), CH Cl (0.1 M), r.t., 15 h; (c) oxalyl
2
2
chloride (1.5 equiv), aluminium trichloride (1.2 equiv), ClCH CH Cl
ditions, with multiple equivalents of toxic metals and nox-
ious oxidants, and high temperatures. Furthermore, these
conditions are unsuitable for the presence of many func-
tional groups and sensitive substituents, and thus not suit-
2
2
(0.1 M), 60 °C, 15 h; (d) oxalyl chloride (3.0 equiv), aluminium tri-
chloride (3.0 equiv), CH Cl (0.1 M), r.t., 1 h; (e) as in d, but for 72 h;
2
2
a
(
f) boron tribromide, CH Cl , 0 ºC to r.t., 12 h. Product 14 was ob-
2 2
served in the crude reaction mixture, but decomposed during
b
able for modular synthetic strategies. Sensing an chromatography on silica gel. Products 23a and 23c were not sepa-
opportunity for improvement of the synthetic options rable by chromatography on silica gel.
available to the chemist, we decided to explore the feasi-
Synlett 2013, 24, 951–954
© Georg Thieme Verlag Stuttgart · New York

LETTER
Rediscovering the Double Friedel–Crafts Acylation
953
Symmetrical biaryl species 18, 20 and 23 (Scheme 3) volved in autoimmune diseases and transplant-organ re-
were commercially available, whilst 11 and 13 were syn- jection, and interference with metabolic processes
1
3d
thesized in good yields by oxidative homocoupling of the mediated by redox-cycling of this substrate in vivo.
II
boronic acids with catalytic Pd and molecular dioxygen
7
(
from air atmosphere) as the final electron acceptor. Bia-
ryls 11, 13, 16, 18, 20 and 22 were then exposed to oxalyl
8
chloride under typical Friedel–Crafts conditions, furnish-
O
O
ing the corresponding phenanthrene-9,10-diones 12 (from
1), 15 (from 13), 19 (from 18), 21 (from 20) and 23a–c
+
1
(
from 22). Phenanthrenediones 19 and 21 were not ob-
tained, despite both blocking of the para positions in each,
and the active direction to the ortho positions (driven by
sterics in the case of 18, and electronics in the case of 20).
25
26 conditions
a: 7%
27 conditions
a: 40%
O
b: 22%
2
b: 73%
In the case of 15, this compound resulted from the reac- Scheme 4 Synthesis of unsubstituted phenanthrene-9,10-dione. Re-
agents and conditions: (a) oxalyl chloride (2.0 equiv), substrate, then
tion of 13 with oxalyl chloride, which was possibly then
aluminium trichloride (2.0 equiv), ClCH CH Cl, 60 °C, 15 h; (b) ox-
2
2
decarbonylated by aluminium salts under the reaction
alyl chloride (3.0 equiv), aluminium trichloride (3.0 equiv), CH Cl
9
2
2
conditions. Dibromo-substituted biaryl 16, which would
slow addition of substrate in CH Cl , r.t., 15 h.
2
2
have constituted an optimal intermediate for further cou-
pling or halogen-metal exchange and reaction with elec-
trophiles, was unfortunately not observed to undergo the
double Friedel–Crafts reaction to 17, more than likely due
The reaction of biphenyl (25) with oxalyl chloride in the
presence of aluminium trichloride gave a mixture of two
co-eluting compounds which were ultimately separated
via repeated preferential crystallization of 1,2-di([1,1′-bi-
phenyl]-4-yl)ethane-1,2-dione (27, 40% yield) from chlo-
roform with acetonitrile as an anti-solvent. The mother
liquor was found to contain the desired product (26), albe-
it in a low yield (7%). When the reaction was repeated
with slow addition of the substrate over one hour, the
yield of the monomeric product was substantially in-
creased (22%). The linear dimer 27 has been previously
reported from a synthetic procedure under related condi-
1
0
to the deactivating affect of the halo substituents. At-
tempts to promote more conversion of substrate 16 via al-
ternative Lewis acid mediators (BCl , AlBr , and AlI )
3
3
3
were unsuccessful, giving largely the demethylated sub-
strate, especially in the case of AlI , as were the efforts to
3
increase the reactivity of the system through the combina-
tion of a strong protic acid (trifluoromethanesulfonic acid,
TfOH) with aluminium trichloride, which has been previ-
1
1
ously reported to be successful in some cases. It has ad-
ditionally been reported that the latter conditions enhance
the reversible nature of the Friedel–Crafts acylation,
1
4
tions.
which we sought to exploit in order to enhance the In conclusion, we have extended the century-old Lieber-
regioselectivity profile of the reaction of 22 to 23a–c, mann phenanthrene synthesis to a number of new sub-
which again was not successful. Nonetheless, demethyl- strates and have shown that some simple derivatives have
1
5
ation of 23a and 23b with boron tribromide easily gave biological activities. Currently we are exploring this
the respective diphenolic products. Compounds 23a, 23b, chemistry towards the total synthesis of murrayaquinone
24a and 24b were tested for their ability to stimulate the which should be available using this approach.
Wnt transcription pathway versus haloquinone (5, Figure
1
) with DMSO as a control, and were found to exhibit ap-
Acknowledgment
1
2
proximately equal molar activity (Table 1).
K.-S. M. would like to thank the Alexander von Humboldt Founda-
tion for their generous funding and support.
Table 1 Stimulation of β-Catenin in vitro
Compound
Activity
DMSO
5
23a
23b
24a
24b
References and Notes
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0.6
0.1
80
48
87
43
111
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©
Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 951–954

954
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(
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(2 × C), 158.7 (C), 145.6 (C), 142.0 (C), 131.0 (CH), 129.9
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Synlett 2013, 24, 951–954
© Georg Thieme Verlag Stuttgart · New York