Synthesis of substituted azafluorenones from dihalogeno diaryl ketones by palladium-catalyzed auto-tandem processes

Article abstract of DOI:10.1039/c4ob01629g

Substituted azafluorenones were synthesized from different dihalogeno diaryl ketones under palladium catalysis by combining either Suzuki or Heck coupling with direct cyclizing arylation. Conditions were identified to allow both auto-tandem processes to p

Full text of DOI:10.1039/c4ob01629g

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Synthesis of substituted azafluorenones from
dihalogeno diaryl ketones by palladium-catalyzed
Cite this: DOI: 10.1039/c4ob01629g
auto-tandem processes†
Received 30th July 2014,
Accepted 2nd September 2014
Nada Marquise,a Vincent Dorcet,b Floris Chevallier*a and Florence Mongin*a
DOI: 10.1039/c4ob01629g
www.rsc.org/obc
Substituted azafluorenones were synthesized from different di-
halogeno diaryl ketones under palladium catalysis by combining
either Suzuki or Heck coupling with direct cyclizing arylation. Con-
ditions were identified to allow both auto-tandem processes
to proceed successfully from 3-(bromobenzoyl)- or 3-benzoyl-
4-bromo-2-chloropyridines, as well as 4-benzoyl-2,3- and
4-benzoyl-2,5-dichloropyridines.
Azafluorenones are compounds endowed with biological pro-
perties, for example in connection with their antifungal,1 anti-
microbial,2 antimalarial,2b,3 and cytotoxic2b,4 activities, or else
for their role in the treatment of neurodegenerative disorders.5
Thus, many studies have been devoted to their synthesis.
Among modern synthetic methods to access them, lithiations6
and multicomponent reactions2d,4a,7 can be cited.
In 2010, Kraus and Kempema developed an approach invol-
ving 2-bromoaryl 3-pyridyl ketones (prepared in two steps by
reaction of 3-pyridyllithiums with 2-bromobenzaldehydes fol-
lowed by oxidation) in intramolecular Heck cyclization reac-
tions.2c In 2013, Ray and co-workers achieved the conversion
within one step of α-aryl-α-(2-bromo-3-pyridyl)methanols to
4-azafluorenones, owing to facile oxidation of the alcohols.8
Recently, we developed an approach9 to azafluorenones
using diaryl ketones bearing a halogen at the 2 position of one
of the aryl groups (prepared by deprotocupration–aroylation10)
in intramolecular direct palladium-catalyzed arylation reac-
tions.11 We thus thought that the presence of an additional
halogen on such diaryl ketones could permit tandem reac-
Scheme 1 Possible syntheses of substituted azafluorenones using pal-
ladium-catalyzed tandem reactions.
tions. Combining cyclization with cross-couplings such as
Suzuki reaction12 could notably afford substituted azafluore-
nones (Scheme 1). We here describe the results of the study.
We first turned our attention to palladium-catalyzed Suzuki
coupling-intramolecular arylation auto-tandem13 reactions
using 2-chloro-3-(halogenobenzoyl)pyridines in order to attain
4-azafluorenones functionalized on their phenyl ring. These
conversions were attempted using a protocol optimized for the
cyclization of 3-benzoyl-2-chloropyridine to 4-azafluorenone.9
Inspired by conditions previously described for the cyclization
of 2-chloro diaryl aniline to carbazole,14 this protocol
employed catalytic amounts of Pd(OAc)2 as the transition
metal source, electron-rich and bulky trialkyl phosphine Cy3P
(Cy = cyclohexyl) as a ligand, K2CO3 as a base, and DMF at
130 °C. Similar conditions being suitable for Suzuki coupling
reactions,12 we thus involved in the process 2-chloro-3-(4-halo-
genobenzoyl)pyridines together with 1 equiv. of different aryl-
boronic acids (Scheme 2). Using phenylboronic acid with 3-(4-
chlorobenzoyl)-2-chloropyridine (1-Cl)10c only led to a mixture
in which the expected 6-phenyl-4-azafluorenone (2a) was
identified (yield < 15%) from a mixture also containing
2-phenyl-3-(4-phenylbenzoyl)pyridine (bis-Suzuki coupling pro-
duct, about 33% yield). In contrast, using the same boronic
acid with 3-(4-bromobenzoyl)-2-chloropyridine (1-Br) afforded
the functionalized tricycle 2a (Fig. 1, left) in 91% yield. By
extending the reaction involving 1-Br to other arylboronic
aChimie et Photonique Moléculaires, Institut des Sciences Chimiques de Rennes,
UMR 6226, Université de Rennes 1 – CNRS, Bâtiment 10A, Case 1003, Campus de
Beaulieu, CS74205, 35042 Rennes Cedex, France.
E-mail: floris.chevallier@univ-rennes1.fr, florence.mongin@univ-rennes1.fr
bCentre de DIFfractométrie X, Institut des Sciences Chimiques de Rennes, UMR 6226,
Université de Rennes 1 – CNRS, Bâtiment 10B, Campus de Beaulieu, CS 74205,
35042 Rennes Cedex, France
†Electronic supplementary information (ESI) available: General procedures,
experimental procedures and compound characterizations, 1H and 13C NMR
spectra of the new compounds, and X-ray crystallographic data. CCDC 1015380
(2a), 1015381 (4a), 1015382 (6a) and 1015383 (9a). For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c4ob01629g
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Fig. 2 ORTEP diagrams (50% probability) of 6a and 9a.
Scheme 2 Palladium-catalyzed Suzuki coupling-intramolecular aryla-
tion from the dihalides 1 and 3. Reaction conditions: Pd(OAc)2 (5 mol%),
Cy3P·HBF4 (10 mol%), K2CO3 (2 equiv.), DMF, 130 °C, 24 h.
Scheme 3 Palladium-catalyzed Suzuki coupling-intramolecular aryla-
tion from the dihalide 6. Reaction conditions: Pd(OAc)2 (5 mol%),
Cy3P·HBF4 (10 mol%), K2CO3 (2 equiv.), DMF, 130 °C, 24 h.
Fig. 1 ORTEP diagrams (50% probability) of 2a and 4a.
acids, 6-(4-hydroxyphenyl)-, 6-(3-thienyl)- and 6-(2-benzo[b]-
thienyl)-4-azafluorenones (2b–d) were isolated in 41, 80 and
60% yield, respectively. GC analysis of the crude mixtures also
showed the presence of diaryl ketones resulting from a Suzuki
coupling on the phenyl ring (without cyclization).
Using 4-hydroxyphenylboronic acid similarly led to the aza-
fluorenone 6b in a moderate 41% yield due to competitive
formation of 2-chloro-3-(3-(4-hydroxyphenyl)benzoyl)pyridine
(Scheme 3).
We next turned our attention to reactions using 2-chloro-3-
benzoylpyridines bearing a second halogen on their pyridine
ring in order to reach 4-azafluorenones differently functiona-
lized. With 3-benzoyl-2,6-dichloropyridine (8),10c using phenyl-
boronic acid showed a favored Suzuki coupling at the pyridine
6 position, furnishing 3-phenyl-4-azafluorenone (9a), which
was identified by X-ray diffraction (Fig. 2, bottom). A moderate
38% yield was noted for the latter, due to competitive for-
mation of 3-benzoyl-2,6-diphenylpyridine (bis-Suzuki coupling
product). Using 3-benzoyl-2,4-dichloropyridine (10-Cl)10c led to
a mixture in which 1-phenyl-2-azafluorenone was identified
(11% yield). As expected,15 Suzuki coupling at the pyridine 2
position was favored, but the formation of 3-benzoyl-4-chloro-
2-phenylpyridine in 12% yield (together with 3-benzoyl-2,4-
diphenylpyridine in 26% yield and 3-benzoyl-2-phenylpyridine
in 3% yield) showed an intermediate coupled product reluc-
tant to cyclizing C–H arylation.
Reacting with phenylboronic acid the 3-(4-bromobenzoyl)-2-
chloropyridine 3, substituted on its pyridine ring by a trifluoro-
methyl electron-withdrawing group, led to competitive cross-
coupling on the pyridine ring. Indeed, the expected phenyl-
substituted 4-azafluorenone 4a (Fig. 1, right) was obtained in a
medium 51% yield due to the competitive formation (17%
yield) of uncyclized 2-phenyl-3-(4-phenylbenzoyl)-6-(trifluoro-
methyl)pyridine (bis-Suzuki coupling product). The formation
of bis-Suzuki coupling product also happens from 1-Br using
the arylboronic acid in excess. These results suggest that
Suzuki cross-coupling reactions are easier than the C–H aryla-
tion giving the azafluorenone.
By carrying out the reaction on 3-(3-bromobenzoyl)-
2-chloropyridine (5) in the presence of phenylboronic acid,
both 7-phenyl-4-azafluorenone (6a, Fig. 2, top, 30% yield) and
2-chloro-3-(3-phenylbenzoyl)pyridine (7a, 41% yield) were iso-
lated, also suggesting a Suzuki coupling prior to cyclization.
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Scheme 5 Palladium-catalyzedSuzukicoupling-intramoleculararylation
from the dihalides 13 and 14. Reaction conditions: Pd(OAc)2 (5 mol%),
Cy3P·HBF4 (10 mol%), K2CO3 (2 equiv.), DMF, 130 °C, 24 h.
Scheme 4 Palladium-catalyzed Suzuki coupling-intramolecular aryla-
tion from the dihalide 10-Br. Reaction conditions: Pd(OAc)2 (5 mol%),
Cy3P·HBF4 (10 mol%), K2CO3 (2 equiv.), DMF, 130 °C, 24 h.
Compared with 3-benzoyl-2,4-dichloropyridine (10-Cl), the
reaction of 3-benzoyl-4-bromo-2-chloropyridine (10-Br) proved
more promising, benefiting from a selective cross-coupling (at
the brominated 4 position of the pyridine ring) (Scheme 4). By
using phenylboronic acid as before, 1-phenyl-4-azafluorenone
(11a) was obtained in 73% yield. Reacting 10-Br with more
electron-rich 4-methoxyphenylboronic acid gave 1-(4-methoxy-
phenyl)-4-azafluorenone (11e) in
a moderate 52% yield;
indeed, 3-benzoyl-2-chloro-4-(4-methoxyphenyl)pyridine (the
coupled product 12e) was also isolated in 24% yield. The use
of methylboronic acid was attempted in order to reach the
structure of onychine, an alkaloid endowed with anticandidal
activity.1a Under the above conditions, the expected tricycle 11f
was isolated in 52% yield. The Suzuki-coupled uncyclized
product and the Suzuki bis-coupled product were also detected
(in 7 and 11% estimated yields, respectively).
Scheme 6 Palladium-catalyzed Heck coupling-intramolecular arylation
attempted from the dihalides 1-Br and 1-I. Reaction conditions: Pd-
(OAc)2 (5 mol%), Cy3P·HBF4 (10 mol%), K2CO3 (2 equiv.), DMF, 130 °C,
24 h.
Since 2,3- and 2,5-dichloropyridines generally react regio-
selectively in Suzuki cross-coupling reactions to afford the
2-functionalized derivatives,16 we took the opportunity of invol-
ving such substrates in the sequence in order to reach 3-aza-
fluorenones. From 4-benzoyl-2,3-dichloropyridine (13)10c and
4-benzoyl-2,5-dichloropyridine (14),10c the expected 4-phenyl-
and 2-phenyl-3-azafluorenones 15 and 16 were respectively syn-
thesized in 70 and 64% yield (Scheme 5).
Finally, we examined the behavior of both 3-(4-bromo-
benzoyl)-2-chloropyridine (1-Br) and 3-(4-iodobenzoyl)-2-
chloropyridine (1-I) in palladium-catalyzed Heck coupling-
intramolecular arylation auto-tandem13 reactions. Reactions of
this type were documented in 2006 by Fagnou and co-workers,
but starting from dihalogenated benzyl phenyl ethers and
amines.17 By using tert-butyl acrylate under the conditions
used before, which can also be suitable conditions for Heck
coupling reactions,18 the expected coupled azafluorenone 17
was obtained in 81% yield from 1-Br whereas 1-I led to the
coupled non-cyclized product 18 (Scheme 6). It is true that an
initial catalyst can be transformed after the first step of the
tandem process,17 thus becoming unsuitable for the second
step, and this could explain why 1-I cannot be converted to 17.
Nevertheless, applying the same reaction conditions to 18 did
not furnish any cyclized product 17 (no conversion). Such a
result suggests that from 1-Br direct arylation could take place
before Heck coupling.
In conclusion, we have developed palladium-catalyzed auto-
tandem processes by which various substituted azafluorenones
can be obtained from dihalogeno diaryl ketones. The results
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presented here should be of interest for both medicinal and
materials science.
S. Lai, S. Lopez and V. Snieckus, J. Org. Chem., 2007, 72,
1588–1594.
Extended synthetic studies as well as evaluation of the bio-
logical properties of the new azafluorenones synthesized are in
progress. Preliminary tests performed on the functionalized
azafluorenone 17 showed a high antifungal activity against
Candida albicans (higher than nystin) and a high antibacterial
activity against Staphylococcus aureus (higher than
ciprofloxacin).
F. M. gratefully acknowledges the Institut Universitaire
de France and Rennes Métropole for financial support. N. M.,
F. C. and F. M. thank Thermo Fisher for generous gift of
2,2,6,6-tetramethylpiperidine. All the authors thank Thierry
Roisnel (Centre de DIFfractométrie X, UMR 6226) for fruitful
discussion.
7 (a) S. Tu, B. Jiang, R. Jia, J. Zhang and Y. Zhang, Tetrahe-
dron Lett., 2007, 48, 1369–1374; (b) Y. Li, W. Fan, H.-W. Xu,
B. Jiang, S.-L. Wang and S.-J. Tu, Org. Biomol. Chem., 2013,
11, 2417–2420.
8 S. Dhara, A. Ahmed, S. Nandi, S. Baitalik and J. K. Ray,
Tetrahedron Lett., 2013, 54, 63–65.
9 (a) N. Marquise, P. J. Harford, F. Chevallier, T. Roisnel,
A. E. H. Wheatley, P. C. Gros and F. Mongin, Tetrahedron
Lett., 2013, 54, 3154–3157; (b) N. Marquise, P. J. Harford,
F. Chevallier, T. Roisnel, V. Dorcet, A.-L. Gagez, S. Sablé,
L. Picot, V. Thiéry, A. E. H. Wheatley, P. C. Gros and
F. Mongin, Tetrahedron, 2013, 69, 10123–10133.
10 (a) T. T. Nguyen, F. Chevallier, V. Jouikov and F. Mongin,
Tetrahedron Lett., 2009, 50, 6787–6790; (b) T. T. Nguyen,
N. Marquise, F. Chevallier and F. Mongin, Chem. – Eur. J.,
2011, 17, 10405–10416; (c) K. Snégaroff, T. T. Nguyen,
N. Marquise, Y. S. Halauko, P. J. Harford, T. Roisnel,
V. E. Matulis, O. A. Ivashkevich, F. Chevallier,
A. E. H. Wheatley, P. C. Gros and F. Mongin, Chem. – Eur.
Notes and references
1 (a) C. D. Hufford, S. Liu, A. M. Clark and B. O. Oguntimein,
J. Nat. Prod., 1987, 50, 961–964; (b) Y. C. Wu, Heterocycles,
1989, 29, 463–475.
2 (a) J. Koyama, I. Morita, N. Kobayashi, T. Osakai, Y. Usuki
and M. Taniguchi, Bioorg. Med. Chem. Lett., 2005, 15, 1079–
J., 2011, 17, 13284–13297. For
a
review, see:
(d) P. J. Harford, A. J. Peel, F. Chevallier, R. Takita,
F. Mongin, M. Uchiyama and A. E. H. Wheatley, Dalton
Trans., 2014, 43, 14181–14203.
1082; (b) S. Prachayasittikul, P. Manam, M. Chinworrung- 11 (a) L.-C. Campeau, M. Parisien, A. Jean and K. Fagnou,
see, C. Isarankura-Na-Ayudhya, S. Ruchirawat and
V. Prachayasittikul, Molecules, 2009, 14, 4414–4424;
(c) G. A. Kraus and A. Kempema, J. Nat. Prod., 2010, 73,
1967–1968; (d) D. Addla, Bhima, B. Sridhar, A. Devi and
S. Kantevari, Bioorg. Med. Chem. Lett., 2012, 22, 7475–7480.
3 D. Mueller, R. A. Davis, S. Duffy, V. M. Avery, D. Camp and
R. J. Quinn, J. Nat. Prod., 2009, 72, 1538–1540.
J. Am. Chem. Soc., 2006, 128, 581–590; (b) D. Alberico,
M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174–
238; (c) L. Ackermann, R. Vicente and A. R. Kapdi, Angew.
Chem., Int. Ed., 2009, 48, 9792–9826.
12 (a) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457–
2483; (b) S. Kotha, K. Lahiri and D. Kashinath, Tetrahedron,
2002, 58, 9633–9695.
4 (a) M. Manpadi, P. Y. Uglinskii, S. K. Rastogi, K. M. Cotter, 13 Concerning auto-tandem reactions, see for example:
Y.-S. C. Wong, L. A. Anderson, A. J. Ortega, S. Van
Slambrouck, W. F. A. Steelant, S. Rogelj, P. Tongwa,
M. Y. Antipin, I. V. Magedov and A. Kornienko, Org. Biomol.
Chem., 2007, 5, 3865–3872; (b) K. Pumsalid, H. Thaisuchat,
C. Loetchutinat, N. Nuntasaen, P. Meepowpan and
(a) A. K. Yadav, S. Verbeeck, S. Hostyn, P. Franck,
S. Sergeyev and B. U. W. Maes, Org. Lett., 2013, 15, 1060–
1063, and references cited therein. For a review, see:
(b) D. E. Fogg and E. N. dos Santos, Coord. Chem. Rev.,
2004, 248, 2365–2379.
W. Pompimon, Nat. Prod. Commun., 2010, 5, 1931–1934; 14 M. R. Netherton and G. C. Fu, Org. Lett., 2001, 3, 4295–
(c) R. Banjerdpongchai, P. Khaw-On, C. Ristee and
4298.
W. Pompimon, Asian Pacific J. Cancer Prev., 2013, 14, 2637– 15 X. Dai, Y. Chen, S. Garrell, H. Liu, L.-K. Zhang, A. Palani,
2641.
G. Hughes and R. Nargund, J. Org. Chem., 2013, 78, 7758–
5 B. C. Shook, S. Rassnick, M. C. Osborne, S. Davis,
7763.
L. Westover, J. Boulet, D. Hall, K. C. Rupert, 16 (a) E. Maerten, M. Sauthier, A. Mortreux and Y. Castanet,
G. R. Heintzelman, K. Hansen, D. Chakravarty,
J. L. Bullington, R. Russell, S. Branum, K. M. Wells,
S. Damon, S. Youells, X. Li, D. A. Beauchamp, D. Palmer,
M. Reyes, K. Demarest, Y.-T. Tang, K. Rhodes and
P. F. Jackson, J. Med. Chem., 2010, 53, 8104–8115.
Tetrahedron, 2006, 63, 682–689; (b) S. Brumfield,
J. J. Matasi, D. Tulshian, M. Czarniecki, W. Greenlee,
C. Garlisi, H. Qiu, K. Devito, S.-C. Chen, Y. Sun,
R. Bertorelli, J. Ansell, W. Geiss, V.-D. Le, G. S. Martin,
S. A. Vellekoop, J. Haber and M. L. Allard, Bioorg. Med.
Chem. Lett., 2011, 21, 7287–7290.
6 (a) F. Bracher, Synlett, 1991, 95–96; (b) A.-S. Rebstock,
F. Mongin, F. Trecourt and G. Queguiner, Tetrahedron, 17 J.-P. Leclerc, M. André and K. Fagnou, J. Org. Chem., 2006,
2003, 59, 4973–4977; (c) A.-S. Rebstock, F. Mongin,
71, 1711–1714.
F. Trecourt and G. Queguiner, Tetrahedron, 2004, 60, 2181– 18 S. Bräse and A. de Meijere, Metal-Catalyzed Cross-Coupling
2186; (d) M. Alessi, A. L. Larkin, K. A. Ogilvie, L. A. Green,
Reactions, 2nd edn, 2004, vol. 1, 217–315.
Org. Biomol. Chem.
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