Synthesis of fluorenone and anthraquinone derivatives from aryl- and aroyl-substituted propiolates

Article abstract of DOI:10.1021/ol4023276

Fluorenone derivatives were generated from aryl-substituted propiolates via a cobalt-catalyzed Diels-Alder reaction/DDQ-oxidation and Friedel-Crafts-type cyclization. Several functional groups are tolerated, and good to excellent overall yields (up to 89%) could be achieved. For the synthesis of anthraquinone derivatives, aroyl-substituted propiolates were applied in a zinc iodide catalyzed Diels-Alder reaction with 1,3-dienes. The subsequent DDQ oxidation and Friedel-Crafts-type cyclization led to symmetrical as well as some unsymmetrical anthraquinones in good to excellent yields of up to 87% over the three-step reaction sequence.

Full text of DOI:10.1021/ol4023276

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Synthesis of Fluorenone and
Anthraquinone Derivatives from
Aryl- and Aroyl-Substituted Propiolates
€
Florian Punner, Justin Schieven, and Gerhard Hilt*
€
Fachbereich Chemie, Philipps-Universitat Marburg, Hans-Meerwein-Str.,
35043 Marburg, Germany
hilt@chemie.uni-marburg.de
Received August 14, 2013
ABSTRACT
Fluorenone derivatives were generated from aryl-substituted propiolates via a cobalt-catalyzed DielsꢀAlder reaction/DDQ-oxidation and Friedelꢀ
Crafts-type cyclization. Several functional groups are tolerated, and good to excellent overall yields (up to 89%) could be achieved. For the synthesis of
anthraquinone derivatives, aroyl-substituted propiolates were applied in a zinc iodide catalyzed DielsꢀAlder reaction with 1,3-dienes. The subsequent
DDQ oxidation and FriedelꢀCrafts-type cyclization led to symmetrical as well as some unsymmetrical anthraquinones in good to excellent yields of up to
87% over the three-step reaction sequence.
Fluorenone and anthraquinone moieties can be found in
nature as part of natural products,1 and many applications
of fluorenone- and anthraquinone-type materials appear
in material chemistry and related sciences. The syntheses of
fluorenones and anthraquinones are well documented, and
several synthetic approaches exist with different scope and
limitations, such as the double FriedelꢀCrafts-type cycli-
zations of phthalic anhydride2 and thermal DielsꢀAlder
reactions of naphthoquinones.3 Most recently, CꢀH acti-
vation of diarylketones to fluorenones4 and biomimetic
synthesis via cyclization reactions of appropriate polyke-
tides toward anthraquinones were also reported.5
Based on our cobalt-catalyzed DielsꢀAlder reactions of
alkyneswith1,3-dienes,6 weinvestigatedthe possibilities of
using an aryl-substituted propiolate (1) as a synthon for an
€
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r
10.1021/ol4023276
XXXX American Chemical Society

aroyl moiety to generate fluorenones (3) and aroyl-
substituted propiolates (2) to generate anthraquinones of
type 4 (Figure 1).7
starting materials in the cobalt-catalyzed DielsꢀAlder
reaction. Following the same reaction sequence of oxida-
tion and FriedelꢀCrafts-type cyclization, fluoreneone de-
rivatives of type 60 were obtained. The results of this three
step reaction sequence are summarized in Table 1.
Scheme 2. Synthesis of Fuorenones (6) via Cobalt-Catalyzed
DielsꢀAlder/DDQ Oxidation/FriedelꢀCrafts Reaction
Sequence
Figure 1. Retrosynthetic approach toward fluorenones (3) and
anthraquinones (4).
For the synthesis of starting materials of type 1(Scheme1),
a Negishi cross-coupling of the corresponding aryl iodide
with methyl propiolate gave the desired materials in ex-
cellent yields (90ꢀ96%, see Supporting Information (SI)).8
The synthesis of the aroyl-substituted starting materials
of type 2 was realized by addition of the deprotonated
propiolate ester to various aldehydes9 and subsequent
oxidation of the propargylic alcohol to the corresponding
ketone. This sequence could be realized in up to 84% yield
over two steps (see SI).
The synthesis of the fluorenone derivatives could be
accomplished in good to excellent yields. The cobalt-
catalyzed DielsꢀAlder reaction could be realized with
1,3-butadiene to afford fluorenone (6a) in an excellent
overall yield of 89% over three steps (entry 1). Also, 2,3-
dimethyl-1,3-butadiene was applied successfully, leading
to the 3,4-dimethyl-substitution pattern in one of the rings
of the fluorenones (entries 2ꢀ6). Moreover, the alternative
route applying 2-alkynyl benzoates (10) for the synthesis of
other fluorenone derivatives (entries 7ꢀ10) could be rea-
lized with good success. Thereby, fluorenones were gener-
ated under the same reaction conditions to achieve other
substitution patterns.
Scheme 1. Synthesis of the Aryl- (1) and Aroyl-Substituted
Propiolates (2)
The FriedelꢀCrafts-type cyclization proves to be pro-
blematic for several substrates when concentrated sulfuric
acid was used. In some cases (entries 3, 8, 9) polypho-
sphoric acid with mechanical stirring proved to be advan-
tageous. Only in one case (entry 7) when the derivative
with the hydroxy group was applied the desired product
6g could only be obtained in trace amounts. Interestingly,
the halide substituted aryl-propiolates could be applied
with good success. The functionalized derivatives 6d/6e
were obtained in good yields without any sign of proto-
dehalogenation. Accordingly, similar derivatives can be
envisaged as a platform for the synthesis of more complex
fluorenones.
Encouraged by these results we turned our attention to
the synthesis of anthraquinone-type molecules. Therefore,
we envisaged that alkynols, such as 7 (Scheme 3), would
undergo the cobalt-catalyzed DielsꢀAlder reaction in a
similar fashion and that subsequent oxidation and cycliza-
tion would lead to anthraquinones.
For the synthesis of fluorenones, the aryl-substituted
propiolates of type 1 were reacted with symmetrical 1,3-
dienes such as 1,3-butadiene and 2,3-dimethyl-1,3-buta-
diene applying a cobalt catalyst mixture comprising
CoBr2(dppe), zinc powder, and zinc iodide (Scheme 2).10
The dihydroaromatic intermediates were immediately oxi-
dized with DDQ (2,3-dichloro-5,6-dicyanobenzoquinone)
to afford the corresponding diaryl esters 5 which were then
converted to the desired fluorenones 6 with H2SO4 (concd)
or polyphosphoric acid. Alternatively, we also investigated
the application of alkynyl-substituted benzoates (10) as
(7) For a DielsꢀAlder reaction of aroyl propiolate type starting
ꢀ
materials, see: (a) Khalaf, A.; Gree, D.; Abdallah, H.; Jaber, N.;
ꢀ
Hachem, A.; Gree, R. Tetrahedron 2011, 67, 3881. (b) Thiemann, T.;
Fujii, H.; Ohira, D.; Arima, K.; Li, Y.; Mataka, S. New J. Chem. 2003,
€
27, 1377. (c) Obrecht, D.; Zumbrunn, C.; Muller, K. J. Org. Chem. 1999,
64, 6182. (d) Obrecht, D. Helv. Chim. Acta 1991, 74, 27. (e) Shen, T. Y.;
Whiting, M. C. J. Chem. Soc. 1950, 1772.
(8) Anastasia, L.; Negishi, E. Org. Lett. 2001, 3, 3111.
(9) Crimmins, M. T.; Guise, L. E. Tetrahedron Lett. 1994, 35, 1657.
(10) No conversion was observed in the absence of the cobalt
complex under otherwise identical reaction conditions.
Unfortunately, all attempts to react 7 with 2,3-dimethyl-
1,3-butadiene under the conditions of the previously
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Results for the Cobalt-Catalyzed DielsꢀAlder Reaction/
DDQ Oxidation to 5 and FriedelꢀCrafts Cyclization to 6a
Scheme 3. Attempted Synthesis of the Anthraquinones via
Cobalt-Catalyzed DielsꢀAlder Reaction from Alkynols of
Type 7
and led to the desired cycloaddition product 8 after DDQ
oxidation.
Scheme 4. Synthesis of Anthraquinones (9) via ZnI2-Catalyzed
DielsꢀAlder Reaction/Oxidation/FriedelꢀCrafts Cyclization
However, in control experiments, we realized that, un-
like in the case of the fluorenone synthesis (Scheme 2), the
cobalt catalyst was not necessary for the cycloaddition of 2
to proceed efficiently. Actually, zinc iodide proved to be a
very mild but efficient catalyst for this Lewis acid catalyzed
DielsꢀAlder reaction to proceed. The results of the ZnI2-
catalyzed DielsꢀAlder reaction/DDQ oxidation/Friedelꢀ
Crafts-type cyclization sequence are summarized in
Table 2.
The ZnI2-catalyzed DielsꢀAlder reaction gave good to
excellent yields with 2,3-dimethyl-1,3-butadiene whereas
with 1,3-butadiene (entries 8/9) and 2-methoxy-1,3-buta-
diene (entry 11) only moderate yields could be obtained.11
The acid-promoted cyclization could be realized for most
substrates, while only for the bromo-substituted derivative
9c (entry 3) a low yield was obtained. The cyclization of
the 2- and 4-methoxy derivatives 8c/8e failed completely,
and only decomposition was observed. The cyclization
most likely failed based on the mismatching directing
effects of the carbonyl group as well as of the methoxy
substituent in 8c/8e for the FriedelꢀCrafts-type cycliza-
tion. Accordingly, when the 3-methoxy derivative 8d was
applied, the para-position is activated and the Friedelꢀ
Crafts acylation gave the desired product 9c in 44% yield
which was identical to the previously addressed product.
In that reaction sequence the other possible regioiso-
mere (9d) was also obtained in 9% yield whereas the
application of 8e did not led to product 9d. For the other
dimethoxy- and trimethoxy-substituted derivatives, the
a CoBr2(dppe) (10 mol %), zinc powder (20 mol %), zinc iodide
(20 mol %), alkyne 1 (1.0 equiv), and diene (2.0 equiv), CH2Cl2, 16 h, rt,
then DDQ (1.1 equiv), toluene, rt; unless otherwise noted: concd H2SO4,
rt, 1ꢀ2 h. b Polyphosphoric acid, 2 h, 80 °C. c The product was obtained
as a mixture of 6f and 10 (see below). d Cyclization attempts using H2SO4
or polyphosphoric acid did not lead to the product.
successful conversions with cobalt catalysts failed, leading
only to a number of unidentified side products.
Therefore, we decided to oxidize the propargylic alcohol
before the cycloaddition reaction and to test the aroyl-
substituted propiolate 2 in the cycloaddition process
(Scheme 4). To our delight, this approach was successful
(11) Only up to 15% of the DielsꢀAlder adduct were detectable
by GCMS in the absence of zinc iodide after 24 h at room
temperature.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 2. Results for the Zinc Iodide Catalyzed DielsꢀAlder
Reaction/DDQ Oxidation to 8 and FriedelꢀCrafts Cyclization
to 9a
Scheme 5. Synthesis of 6H-Benzo[c]chromen-6-one 10
FriedelꢀCrafts-type cyclization could be performed
without problems and the desired anthraquinones could
be obtained in good yields.
The presented protocol led to the product 9f which was
isolated from Hedyotis diffusa.12 Also, product 9h can be
found in nature,13 and both products were generated in
short reaction sequences in good overall yields of 59% and
60% respectively.
Finally, we also identified a side product from the
FriedelꢀCrafts-type cyclization for the synthesis of fluo-
renone derivative 6f (Table 1, entry 6). The product was
obtained as an inseperable mixture with the correspond-
ing lactone in low yield. In order to facilitate this reaction
the Lewis acid BBr3 was applied.14 In this case the benzo-
[c]chromen-6-one derivative 10 could be obtained as a
single product in 82% yield (Scheme 5).
In conclusion, we were able to demonstrate that cobalt,
as well as ZnI2-catalyzed DielsꢀAlder reactions of aryl-
and aroyl-substituted propiolates, can be used for the
synthesis of multifunctionalized fluorenone and anthra-
quinone derivatives in short reaction sequences in good
to excellent overall yields. Therefore, interesting func-
tionalized fluorenone and polysubstituted anthraqui-
none derivatives were addressable which can be used
for follow-up transformations. The scopes and some
limitations of the cyclization for both types of products
could be evaluated and, as expected, the more electron-
donating alkyl- or methoxy-groups that are present in
the ring, the more efficient the FriedelꢀCrafts-type
cyclization proceeds. The flexibilty of the synthetic
approach also allows the possibility of circumventing
some limitations imposed by the requirements for the
FriedelꢀCrafts-type cyclization.
Acknowledgment. We thank the Deutsche Forschungs-
gemeinschaft for financial support.
Supporting Information Available. Experimental pro-
cedures and full characterization of the compounds.
This material is available free of charge via the Internet
at http://pubs.acs.org.
(12) Ho, T.-I.; Chen, G.-P.; Lin, Y.-C.; Lin, Y.-M.; Chen, F.-C.
Phytochem. 1986, 25, 1988.
(13) Ramamoorthy, S.; Mudgal, G.; Rajesh, D.; Nawaz Khan, F.;
Vijayakumar, V.; Rajasekaran, C. Nat. Prod. Res. 2009, 23, 1210.
(14) Palencia, H.; Garcia-Jimeneza, F.; Takacsb, J. M. Tetrahedron
Lett. 2004, 45, 3849.
a Unless otherwise noted: zinc iodide (10 mol %), alkyne 2 (1.0 equiv)
and diene (2.0 equiv), CH2Cl2, 16 h, rt, then DDQ (1.1 equiv), toluene, rt;
concd H2SO4, 60 °C. b Cyclization was performed at 120 °C. c DielsꢀAlder
reaction and DDQ oxidation were performed at 40 °C.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX