A mild, one-pot synthesis of 4-quinolones via sequential Pd-catalyzed amidation and base-promoted cyclization

Article abstract of DOI:10.1021/ol800837z

(Chemical Equation Presented) A mild, one-pot synthesis of 4-quinolones is described. Under the optimal conditions, a variety of 2-substituted 4-quinolones were synthesized via sequential palladium-catalyzed amidation of 2′-bromoacetophenones followed by base-promoted intramolecular cyclization.

Full text of DOI:10.1021/ol800837z

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2609-2612
A Mild, One-Pot Synthesis of
4-Quinolones via Sequential
Pd-Catalyzed Amidation and
Base-Promoted Cyclization†
Jinkun Huang,* Ying Chen, Anthony O. King, Mina Dilmeghani, Robert D. Larsen,
and Margaret M. Faul
Chemical Process R&D, Amgen Inc., One Amgen Center DriVe,
Thousand Oaks, California 91320
jhuang@amgen.com
Received April 22, 2008
ABSTRACT
A mild, one-pot synthesis of 4-quinolones is described. Under the optimal conditions, a variety of 2-substituted 4-quinolones were synthesized
via sequential palladium-catalyzed amidation of 2′-bromoacetophenones followed by base-promoted intramolecular cyclization.
Quinoline derivatives represent a major class of nitrogen-
containing heterocycles frequently found in naturally
occurring alkaloids and synthetic biologically active
molecules.1 Compounds containing 4-substituted quinoline
scaffolds are of particular pharmaceutical value. For
example, the historically well-known quinine, isolated
from the bark of Cinchona trees, is an active ingredient
for the treatment of malaria.2 Chimanine alkaloids are
responsible for the treatment of leishmaniasis, a tropical
disease in South America.3 Chloroquine, a synthetic
quinoline, has been used for a long time to treat and
prevent malaria attacks.4 4-Quinolones5 are also versatile
synthetic intermediates due to their facile derivatization
of the 4-hydroxyl group.6 Many synthetic methods for
4-quinolone have been documented.7 One classical and
commonly used approach is the condensation of an aniline
with Meldrum’s acid (or its derivatives) and trimethyl
orthoformate to afford the corresponding enamine. The
enamine intermediate is then cyclized in high-boiling
solvents, such as diphenyl ether, at high temperature (250
°C)8 or under microwave (300 °C) conditions.9 This
method suffers not only from the harsh reaction conditions
but also the limitation of substrate scope. Alternatively,
the mild, base-promoted cyclization of N-(o-ketoaryl)
(6) 4-Quinolones have two tautomeric forms: either the hydroxy tautomer
as 4-hydroxyquinoline or the carbonyl tautomer as 4-quinolones, although
these compounds exist favorably in the keto form. For more information,
see: (a) Pfister-Guillouzo, G.; Guimon, C.; Frank, J.; Ellison, J.; Katritzky,
A. R. Justus Liebigs Ann. Chem. 1981, 366. (b) Mphahlele, M. J.; El-Nahas,
A. M. J. Mol. Struct. 2004, 688, 129.
† Dedicated with great admiration to Professor E. J. Corey, Nobel
Laureate, on the occasion of his 80th birthday.
(1) Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic Chemistry, 3rd
ed.; Chapman & Hall: Chel Tenham, 1995; Chapter 6.
(2) Wiesner, J.; Ortmann, R.; Jomaa, H.; Schlitzer, M. Angew. Chem.,
Int. Ed. 2003, 43, 5274.
(7) For a recent review, see: (a) Kouznetsov, V. V.; Me´ndez, L. Y. V.;
Go´mez, M. M. Curr. Org. Chem. 2005, 9, 141.
(3) Fournet, A.; Hocquemiller, R.; Roblot, F.; Cave´, A.; Richomme, P.;
Bruneton, J, J. Nat. Prod. 1993, 56, 1547.
(8) (a) Werner, W. Tetrahedron 1969, 25, 255. (b) Chen, B.; Huang,
X.; Wang, J. Synthesis 1987, 482.
(4) Olliaro, P. L.; Taylor, W. R. J. J. Exp. Biol. 2003, 206, 3753.
(5) There is considerable interest in quinolones as antibacterial agents:
(a) Andriole, V. T. The Quinolones; Academic Press: London, 1988.
(9) Madrid, P. B.; Sherrill, J.; Liou, A. P.; Weisman, J. L.; DeRisi, J. L.;
Guy, R. K. Bioorg. Med. Chem. Lett. 2005, 15, 1015.
10.1021/ol800837z CCC: $40.75
Published on Web 05/21/2008
2008 American Chemical Society

amides, known as the Camps cyclization,10 is more
attractive and has been widely employed to synthesize a
variety of quinolones. However, the synthetic utility of
the Camps cyclization is restricted by the limited access
to N-(o-ketoaryl)amides. Although the scope of copper-
Table 1. Evaluation of Reaction Conditionsa, b
11
and palladium-catalyzed12 amidation of aryl halides is
broad in general, aryl halides bearing a ketone functional
group have been reported to be incompatible due to the
competitive arylation of the ketone enolate.13 In this paper,
we report our preliminary results on the efficient synthesis
N-(o-ketoaryl)amides via a Pd-catalyzed amidation of
2-acetylbromoarenes and the subsequent base-promoted
cyclization to form a wide range of 4-quinolones in one
pot.14
entry solvent
base
Cs2CO3
time (h) 2 (%) 3 (%) 4 (%)
1
2
DMF
NMP
24
24
24
24
24
24
24
22
22
7
29
40
0
48
41
47
61
22
47
17
6
6
0
0
4
0
0
Cs2CO3
We envisioned that the side reaction of ketone arylation
might be suppressed by appropriate choice of a mild base,
the ligand, and the solvent. Furthermore, it is desirable
that the subsequent cyclization can be facilitated by
addition of a stronger base without isolation of the
resultant amide intermediate. To test our hypothesis, we
selected (2-bromo-4-methoxy)acetophenone (1) as the
model substrate for reaction condition screening. Our
earlier examination of Pd-catalyzed amination of 1
employing either lithium15 or zinc16 trimethylsilylamide
was unsuccessful, presumably due to the complications
associated with steric hindrance and/or the strong basicity
of the metal amide reagents. We then carried out screening
of a variety of bases and solvents using the Pd2(dba)3/
Xantphos catalyst system.12,13,17 When Cs2CO3 was used
as the base with polar solvents such as DMF and NMP, the
reaction formed a complicated mixture with three major
products identified (Table 1, entries 1 and 2): the desired
amide 2, the cyclized quinolone 3, and the hydrolysis product
aniline 4. Reaction in toluene was sluggish due to the poor
3
4
5
toluene Cs2CO3
dioxane Cs2CO3
dioxane K3PO4
6
dioxane K2CO3
7
dioxane Na2CO3
dioxane Cs2CO3/NaOH
dioxane Cs2CO3/NaOtBu
dioxane KOAc
dioxane NaOH
dioxane NaOtBu
0
8c
9c
10
11
12
24/4
24/4
24
29/85 61/2
29/89 61/0
0/0
0/0
0
0
4
24
3
0
0
24
12
22
0
a HPLC assay yield. b Reaction conditions: A mixture of Pd2(dba)3 (1
mol %) and Xantphos (2.5 mol %) in dioxane (5 mL) was stirred at room
temperature for 5-10 min followed by addition of 1, formamide (2 equiv),
and the base (3 equiv). The resultant mixture was heated to 100 °C for
24 h and analyzed by HPLC. c The second base was added to the reaction
mixture, which was then heated to 100 °C for another 4 h.
solubility of formamide in toluene (Table 1, entry 3).18 To
our surprise, the reaction in dioxane showed the highest
combined yield of the desired amide 2 and quinolone 3 (90%,
Table 1, entry 4). The undesired products related to the
potential arylation of the ketone were not detected. However,
a longer reaction time at 100 °C in dioxane yielded more
cyclized product as well as the undesired aniline 4 resulting
from the amide hydrolysis. To avoid the hydrolysis of the
amide before cyclization, we found that addition of a stronger
base, either NaOH or NaOtBu, led to full conversion of the
amide to 7-methoxyquinolone 2 in 4 h (Table 1, entries 8
and 9). Other bases examined were either less effective
(K3PO4, K2CO3, Na2CO3, and KOAc, Table 1, entries 5, 6,
7, and 10) or led to formation of complicated mixtures
(NaOH and NaOtBu, Table 1, entries 11 and 12).
(10) Camps, R. Chem. Ber. 1899, 32, 3228.
(11) (a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem.
Soc. 2005, 127, 4120. (b) Klapars, A.; Parris, S.; Anderson, K. W.;
Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 3529. (c) Huang, X.;
Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2003, 125, 6653. (d) Jiang, L.; Job, G. E.; Klapars, A.;
Buchwald, S. L. Org. Lett. 2003, 5, 3667. (e) Klapars, A.; Antilla, J. C.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421.
(12) (a) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101. (b) Huang,
X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L.
J. Am. Chem. Soc. 2003, 125, 6653. (c) Willis, M. C.; Brace, G. M.; Holmes,
I. P. Synthesis 2005, 3229. (d) Klapars, A.; Campos, K. R.; Chen, C.-y.;
Volante, R. P. Org. Lett. 2005, 7, 1185. (e) Klingensmith, L. M.; Strieter,
E. R.; Barder, T. E.; Buchwald, S. L. Organometallics 2006, 25, 82. (f)
Fujita, K.-i.; Yamashita, M.; Puschmannn, F.; Alvarez-Falcon, M. M.;
Christopher, D. I.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 9044. (g)
Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem.
Soc. 2007, 129, 13001.
With the optimal conditions in hand, we examined the
couplings of a variety of 2-bromoacetophenones with
different amides (Table 2). The scope of the one-pot
synthesis of 4-quinolones was demonstrated to be quite
general for both coupling partners. The reaction proceeded
smoothly with alkyl, aryl, and heterocyclic amides. More
specifically, alkylamides with one or no R-proton are
suitable substrates providing high yields of quinolones
(13) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043.
(14) During the process of this study, Buchwald et al. reported a mild,
two-step synthesis of 4-quinolone via Cu-catalyzed amidation followed by
the base-promoted cyclization. The substrate scope was limited to the
preparation of 2-aryl-4-quinolones: (a) Jones, A. P.; Anderson, K. W.;
Buchwald, S. L. J. Org. Chem. 2007, 72, 7968.
(15) Lee, S.; Jørgensen, M.; Hartwig, J. F. Org. Lett. 2001, 3, 2729.
(16) Lee, D.-Y.; Hartwig, J. F. Org. Lett. 2005, 7, 1169.
(17) Xantphos has been reported to be an excellent ligand for amidation:
(a) ; Kamer, P. C.; Van Leeuwen, P. W. N.; Reek, J. N. H. Acc. Chem.
Res. 2001, 34, 895. (b) Artamkina, G. A.; Sergeev, A. G.; Beletskaya, I. P.
Tetrahedron Lett. 2001, 42, 4381. (c) Sergeev, A. G.; Artamkina, G. A.;
(18) Addition of formamide to the reaction mixture in toluene led to
formation of a gel which resulted in difficult stirring.
Beletskaya, I. P. Tetrahedron Lett. 2003, 44, 4719
.
2610
Org. Lett., Vol. 10, No. 12, 2008

Table 2. Substrate Scope
a Isolated yield. b See the Supporting Information for detailed experimental procedures.
(Table 2, entries 1-4).19 Interestingly, the five-membered
while acyclic secondary amides have not been successful
lactam couples with high efficiency (Table 2, entry 5),
thus far. Arylamides were found to be excellent coupling
partners. The resultant amides were cyclized effectively
thereafter. The reaction of benzamide with different
2-bromoacetophenones was effective (Table 2, entries 6
(19) However, the use of acetamide which has more than one R-protons
led to lower yield of 4-quinolone due to formation of 2-quinolone. Also
see ref 10.
Org. Lett., Vol. 10, No. 12, 2008
2611

and 7), although a substrate with two electron-donating
groups led to significantly lower yield (Table 2, entry 9).
The reaction appears robust to the electronic and steric
properties of the arylamides as 2-chloro-, 2-trifluorometh-
yl-, and 3-methoxybenzoamide all gave excellent yields
of the desired quinolones (Table 2, entries 8, 10, and 11).
The reaction with heterocyclic amides performed smoothly
under similar conditions (Table 2, entries 12-14).
Further scope investigation is ongoing and will be reported
in due course.
Acknowledgment. We thank Drs. Xiang Wang and
Johann Chan for their insightful suggestions and discussions
during the preparation of this manuscript. We appreciate Ms.
Jenny Chen and Drs. Kevin Turney and Tiffany Correll for
their analytical assistance.
In conclusion, we have developed a mild, one-pot
synthesis of 4-quinolones. The current method has been
demonstrated to be general for the synthesis of a wide
range of 2-substitued 4-quinolones. The easily accessible
starting materials, mild reaction conditions, and simple
manipulation render this an attractive methodology.
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL800837Z
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Org. Lett., Vol. 10, No. 12, 2008