Palladium-catalyzed decarboxylative coupling of quinolinone-3-carboxylic acids and related heterocyclic carboxylic acids with (Hetero)aryl halides

Article abstract of DOI:10.1021/ol300235k

An efficient and practical decarboxylative cross-coupling reaction of quinolin-4(1H)-one 3-carboxylic acids with (hetero)aryl halides has been established. Under a bimetallic system of PdBr₂ and silver carbonate, the protocol proved to be general, and a variety of 3-(hetero)aryl 4-quinolinones and related heterocycles, such as 3-aryl-1,8-naphthyridin-4(1H)- ones, 3-arylcoumarins, 3-arylquinolin-2(1H)-ones, and 2-arylchromones, can be prepared in good to excellent yields.

Full text of DOI:10.1021/ol300235k

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1496–1499
Palladium-Catalyzed Decarboxylative
Coupling of Quinolinone-3-Carboxylic
Acids and Related Heterocyclic
Carboxylic Acids with (Hetero)aryl Halides
Samir Messaoudi,* Jean-Daniel Brion, and Mouad Alami*
ꢀ
Universite Paris-Sud, CNRS, BioCIS-UMR 8076, LabEx LERMIT, Laboratoire de
Chimie Therapeutique, Faculte de Pharmacie, 5 rue J.-B. Clement, Chatenay-Malabry,
ꢀ
ꢀ
ꢀ
^
92296 France
samir.messaoudi@u-psud.fr; mouad.alami@u-psud.fr
Received January 30, 2012
ABSTRACT
An efficient and practical decarboxylative cross-coupling reaction of quinolin-4(1H)-one 3-carboxylic acids with (hetero)aryl halides has been
established. Under a bimetallic system of PdBr2 and silver carbonate, the protocol proved to be general, and a variety of 3-(hetero)aryl
4-quinolinones and related heterocycles, such as 3-aryl-1,8-naphthyridin-4(1H)-ones, 3-arylcoumarins, 3-arylquinolin-2(1H)-ones, and
2-arylchromones, can be prepared in good to excellent yields.
The transition metal-catalyzed decarboxylative cross-
coupling1 of aryl carboxylic acids with aryl halides is a
useful alternative to traditional methods (e.g., Negishi,
Stille, SuzukiÀMiyaura) in sp2 carbonÀcarbon bond for-
mation. These decarboxylative reactions, employing easily
available carboxylic acids as nucleophilic coupling part-
ners, avoid the need for stoichiometric amounts of the
organometallic reagent, some of which are toxic or must be
prepared through multistep procedures. Typically, the
decarboxylation protocol requires the use of a bimetallic
system based on a palladium complex to activate the aryl
halide together with a copper or silver salt promoting the
decarboxylation step to generate an arylmetal species.2
In contrast to the much more developed palladium-
catalyzed decarboxylative reaction of σ electron poor
(3) (a) Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662–
664. (b) Goossen, L. J.; Rodriguez, N.; Melzer, B.; Linder, C.; Deng, G.;
Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824–4833. (c) Becht, J.;
Catala, C.; Le Drian, C.; Wagner, A. Org. Lett. 2007, 9, 1781–1783. (d)
Wang, Z.; Ding, Q.; He, X.; Wu, J. Org. Biomol. Chem. 2009, 7, 863–865.
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Chem.;Eur. J. 2009, 15, 3674–3677. (f) Miyasaka, M.; Hirano, K.;
Satoh, T.; Miura, M. Adv. Synth. Catal. 2009, 351, 2667–2674. (g) Shang,
R.; Fu, Y.; Li, J.-B.; Zhang, S.-L.; Guo, Q.-X.; Liu, L. J. Am. Chem. Soc.
2009, 131, 5738–5739. (h) Shang, R.; Fu, Y.; Wang, Y.; Xu, Q.; Yu, H.-Z.;
Liu, L. Angew. Chem., Int. Ed. 2009, 48, 9350–9354. (i) Yamashita, M.;
Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12, 592–595. (j) Park,
K.; Bae, G.; Moon, J.; Choe, J.; Song, K. H.; Lee, S. J. Org. Chem. 2010,
75, 6244–6251. (k) Feng, C.; Loh, T. Chem. Commun. 2010, 46, 4779–
4781. (l) Shang, R.; Yang, Z.-W.; Wang, Y.; Zhang, S.-L.; Liu, L. J. Am.
Chem. Soc. 2010, 132, 14391–14393. (m) Shang, R.; Ji, D.-S.; Chu,
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(n) Cornella, J.; Righi, M.; Larrosa, I. Angew. Chem., Int. Ed. 2011, 50,
9429–9432.
(1) For Review, see: (a) Rodriguez, N.; Goossen, L. J. Chem. Soc.
Rev. 2011, 40, 5030–5048. (b) Goossen, L. J.; Collet, F.; Goossen, K. Isr.
J. Chem. 2010, 50, 617–629. (c) Bonesi, S. M.; Fagnoni, M. Chem.;Eur.
J. 2010, 16, 13572–13589. (d) Goossen, L. J.; Rodriguez, N.; Goossen, K.
Angew. Chem., Int. Ed. 2008, 47, 3100–3120. (e) Baudoin, O. Angw.
Chem., Int. Ed. 2007, 46, 1373–1375. (f) Bonesi, S. M.; Fagnoni, M.
Chem.;Eur. J. 2010, 16, 13572–13589.
(2) (a) Goossen, L. J.; Thiel, W. R.; Rodriguez, N.; Linder, C.;
Melzer, B. Adv. Synth. Catal. 2007, 349, 2241–2246. (b) (a)Goossen,
L. J.; Linder, C.; Rodriguez, N.; Lange, P. P.; Fromm, A. Chemm.
Commun. 2009, 7176–7178. (c) Lu, P.; Sanchez, C.; Cornella, J.; Larrosa,
I. Org. Lett. 2009, 11, 5710–5713.
r
10.1021/ol300235k
Published on Web 03/01/2012
2012 American Chemical Society

benzoic acids with aryl halides for biaryl synthesis,3 dec-
arboxylative couplings of heterocyclic carboxylic acids
with aryl halides have received much less attention. In
these instances, very few heterocycles were studied. Ste-
glich et al.4 reported a single example of an intramolecular
reaction of a pyrrole carboxylic acid with a bromoarene
within a total synthesis of lamellarin L. Forgione and
Bilodeau5 reported intermolecular decarboxylative cou-
plings of five-membered heterocyclic carboxylic acid sub-
strates (e.g., pyrrole, furan, oxazole, and thiazole) witharyl
bromides under palladium catalysis. Subsequently, other
groups have extended this method to substituted azoles,
including 2-aryloxazoles,6 3,4-dioxypyrrole,7 and benzo-
thiophene.8 Outside of these contributions, there have been
no focused efforts on heterocyclic carboxylic acid cou-
plings. Given the stability and high availability of hetero-
cyclic carboxylic acids relative to heterocyclic organo-
metallics, the reaction has great potential for the synthesis
of multiheteroaryl bioactive compounds.
In an ongoing medicinal chemistry program directed
toward hsp90,9 an exciting new target in cancer drug
discovery,10 we required the synthesis of 3-(hetero)aryl-4-
quinolinones 3. Traditional strategies to prepare such
molecules involve the construction of the heterocycle rings
by nontrivial multistep reaction sequences.11 Alternative
routes consist of the one pot tandem condensationÀ
cyclization of anilines with 3-(2-bromophenyl)-3-oxopro-
panal derivatives,12 or palladium-catalyzed Suzuki cross-
coupling of 3-halo-4-quinolinones withboronic acids.13 As
Table 1. Optimization of the Pd-Catalyzed Decarboxylative
Coupling of Quinolinone-3-carboxylic Acid 1a with 4-Iodoa-
nisole 2aa
ratiob
yield
(%)c
entry
[Pd]
ligand
PPh3
1a/3a/3b/4a
1
PdCl2
PdBr2
PdI2
7/56/29/8
0/64/32/5
20/47/22/11
40/42/15/2
0/17/0/83
12/20/68
42
52
39
À
2
PPh3
3
PPh3
4
Pd(OAc)2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PPh3
5
P(o-tolyl)3
P(c-hexyl)3
Xantphos
Xphos
À
6
À
7
2/51/43/4
0/36/0/64
1/40/0/59
1/15/0/84
0/82/13/5
0/85/10/5
7/72/16/5
49
À
8
9
Davephos
CyJohnphos
DPEphos
DPEphos
DPEphos
À
10
11
12
13
À
77
81d,e
60
(4) Peschko, C.; Winklhofer, C.; Steglich, W. Chem.;Eur. J. 2000, 6,
1147–1152.
a 1a (1 equiv), 4-iodoanisole (2 equiv), [Pd] (5 mol %), [L] (10 mol %),
Ag2CO3 (1 equiv), toluene/DMA (3.6/0.4 mL, 0.05M), 8 h at 150 °C.
b Ratio was determined by 1H NMR in the crude reaction mixture based
on the chemical shift of the proton signal (ppm) at the 2-position
(1a: δ = 8.79, 3a: δ = 7.79, 3b: δ = 7.83). c Isolated yields of 3a. d Heating
the reaction under microwave irradiation (MWI) for 1 h at 150 °C. e No
reaction occurred in the absence of PdBr2 or ligand and in the absence of
PdBr2 and ligand.
(5) Forgione, P.; Brochu, M.-C.; St-Onge, M.; Thesen, K. H.; Bailey,
M. D.; Bilodeau, F. J. Am. Chem. Soc. 2006, 128, 11350–11351.
(6) Zhang, F.; Greaney, M. F. Org. Lett. 2010, 12, 4745–4747.
(7) Arroyave, F. A.; Reynolds, J. R. Org. Lett. 2010, 12, 1328–1331.
(8) (a) Miyasaka, M.; Hirano, K.; Satoh, T.; Miura, M. Adv. Synth.
Catal. 2009, 351, 2683–2688. (b) Kissane, M.; McNamara, O. A.;
Mitchell, D.; Coppert, D. M.; Moynihan, H. A.; Lorenz, K. T.; Maguire,
A. R. Tetrahedron Lett. 2012, 53, 403–405.
(9) (a) Le Bras, G.; Radanyi, C.; Peyrat, J.-F.; Brion, J.-D.; Alami,
M.; Marsaud, V.; Stella, B.; Renoir, J.-M. J. Med. Chem. 2007, 50, 6189–
6200. (b) Radanyi, C.; Le Bras, G.; Messaoudi, S.; Bouclier, C.; Peyrat,
J.-F.; Brion, J.-D.; Marsaud, V.; Renoir, J.-M.; Alami, M. Bioorg. Med.
Chem. Lett. 2008, 18, 2495–2498. (c) Radanyi, C.; Le Bras, G.; Marsaud,
V.; Peyrat, J.-F.; Messaoudi, S.; Catelli, M. G.; Brion, J.-D.; Alami, M.;
Renoir, J.-M Cancer Lett. 2009, 274, 88–94. (d) Radanyi, C.; Le Bras, G.;
Bouclier, C.; Messaoudi, S.; Peyrat, J.-F.; Brion, J.-D.; Alami, M.;
Renoir, J.-M. Biochem. Biophys. Res. Commun. 2009, 379, 514–518.
(e) Audisio, D.; Messaoudi, S.; Ijjaali, I.; Dubus, E.; Petitet, F.; Peyrat,
J.-F.; Brion, J.-D.; Alami, M. Eur. J. Med. Chem. 2010, 45, 2000–2009.
(f) Audisio, D.; Messaoudi, S.; Ceigeikowski, L.; Peyrat, J.-F.; Brion,
J.-D.; Methy-Gonnot, D.; Radanyi, C.; Renoir, J.-M.; Alami, M.
ChemMedChem 2011, 6, 804–815.
(10) For reviews, see: (a) Messaoudi, S.; Peyrat, J.-F.; Brion, J.-B.;
Alami, M. Anti-Cancer Agents Med. Chem. 2008, 8, 761–782. (b)
Messaoudi, S.; Peyrat, J.-F.; Brion, J.-B.; Alami, M. Expert Opin. Ther.
Pat. 2011, 21, 1501–1542.
(11) Romek, A.; Opatz, T. Eur. J. Org. Chem. 2010, 5841–5849. (b)
G., H.; Jin, Ha, S.; K. Park, H. M.; Kang, B.; Kim, S. Y.; Kim, H.-D.;
Ryu, J.-H.; Jeon, R. Bioorg. Med. Chem. Lett. 2008, 18, 4092–4094. (b)
Xiao, Z.-P.; Xu, P.-c.; Lv, S.-P.; Zhu, T.-T.; Zhu, H.-L. ChemMedChem.
2008, 3, 1516–1519.
part of our continuing effort at the functionalization of
heterocycles via transition-metal-catalyzed reactions,14 we
decided to explore the ability of the 4-quinolinone 3-
carboxylic acids 1 to participate in metal-catalyzed decarbox-
ylative cross-coupling reactions with various (hetero)-
aryl halides. From a synthetic viewpoint, this coupling
should be the shortest and most efficient route to
(14) (a) Audisio, D.; Messaoudi, S.; Peyrat, J.-F.; Brion, J.-D.;
Alami, M. Tetrahedron Lett. 2007, 48, 6928–6932. (b) Messaoudi, S.;
Audisio, D.; Brion, J.-D.; Alami, M. Tetrahedron 2007, 63, 10202–
10210. (c) Audisio, D.; Messaoudi, S.; Peyrat, J.-F.; Brion, J.-D.; Alami,
M. J. Org. Chem. 2011, 76, 4995–5005. (d) Audisio, D.; Messaoudi, S.;
Brion, J.-D.; Alami, M. Eur. J. Org. Chem. 2010, 1046–1051. (e) Soussi,
M. A.; Audisio, D.; Messaoudi, S.; Provot, O.; Brion, J.-D.; Alami, M.
Eur. J. Org. Chem. 2011, 5077–5088. (f) Sahnoun, S.; Messaoudi, S.;
Peyrat, J.-F.; Brion, J. D.; Alami, M. Tetrahedron Lett. 2008, 49, 7279–
7283. (g) Sahnoun, S.; Messaoudi, S.; Brion, J. D.; Alami, M. Org.
Biomol. Chem. 2009, 7, 4271–4278. (h) Sahnoun, S.; Messaoudi, S.;
Brion, J. D.; Alami, M. Eur. J. Org. Chem. 2010, 6097–6102. (i)
Sahnoun, S.; Messaoudi, S.; Brion, J.-D.; Alami, M. ChemCatChem
2011, 3, 893–897. (j) Messaoudi, S.; Brion, J.-D.; Alami, M. Eur. J. Org.
Chem. 2010, 6495–6516. (k) Messaoudi, S.; Brion, J.-D.; Alami, M. Adv.
Synth. Catal. 2010, 352, 1677–1687. (l) Messaoudi, S.; Brion, J. D.;
Alami, M. Tetrahedron. Lett. 2011, 52, 2687–2691.
(12) Liu, Q. L.; Li, Q. L.; Fei, X. D.; Zhu, Y. M. ACS Comb. Sci.
2011, 13, 19–23.
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2006, 8, 243–246.
Org. Lett., Vol. 14, No. 6, 2012
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Scheme 1. Pd-Catalyzed Decarboxylative Coupling of 1a with
Various (Hetero)aryl Halidesa
Scheme 2. Pd-Catalyzed Decarboxylative Coupling of Hetero-
cyclic Carboxylic Acid Derivatives with Various Aryl Iodidesa
a Reactions of heterocyclic carboxylic acid (1 equiv) with ArI
(2 equiv) were performed under MWI in a sealed Schlenk tube at 150 °C
in toluene/DMA (3.6/0.4 mL, 0.05 M) by using PdBr2 (5 mol %),
DPEPhos (10 mol %), and Ag2CO3 (1 equiv). bIsolated yields.
already been reported.15 To circumvent the formation of
byproducts 3b and 4a, an extensive screening of various
reaction parameters (palladium, ligand, solvent, base, and
temperature) was conducted (for more details, see Sup-
porting Information). As shown in Table 1, Pdl2 and
Pd(OAc)2 were less effective (entries 3 and 4), whereas
PdBr2 gave a slightly better yield as compared to that of
PdCl2 (52%, entry 2). Evaluation of other ligands revealed
that the nature of phosphine has an important influence on
the reaction selectivity (entries 2, 5À11). Thus, we were
delighted to find that the use of the bidentate phosphine
DPEphos (entry 11) in combination with PdBr2 in toluene/
DMA at 150 °C for 8 h is superior to all other choices
(compare entries 2 and 5À11). Having determined optimal
conditions for the formation of 3a using classical heating,
we attempted to use microwave activation to enhance the
reaction rate and possibly to reduce the reaction time as
well as to increase the yield. We were pleased to find that
the coupling of 1a with 2a under microwave irradiation
using similar conditions as those of entry 11 provided 3a in
an 81% isolated yield after only 1 h (entry 12). It should be
noted that carrying out the reaction using traditional oil
bath heating (150 °C, 1 h, sealed tube) induced a lowering
of the conversion rate and provided 3a in only 60% yield
(entry 13). This result clearly demonstrated the benefit
of using microwave irradiation. In summary, the best
a Reactions of 1 (1 equiv) with ArX (2 equiv) were performed under
MWI in a sealed Schlenk tube at 150 °C in toluene/DMA (3.6/0.4 mL,
0.05 M) by using PdBr2 (5 mol %), DPEPhos (10 mol %), and Ag2CO3
(1 equiv). bIsolated yields.
3-(hetero)arylquinolin-4(1H)-ones 3 for the purpose of
medicinal chemistry screening programs. To the best of
our knowledge, there is no report describing the formation
of 3 and related heterocycles using this idea. Herein we
report our success on the development of such a protocol.
In our initial study, 4-quinolinone 3-carboxylic acid 1a
and 4-iodoanisole 2a were chosen as model substrates for
the decarboxylative coupling process. The reaction was
first investigated under previously reported conditions for
decarboxylative couplings of azole carboxylic acid sub-
strates,6 using PdCl2 (5 mol %)/PPh3 (10 mol %) as the
catalyst system and Ag2CO3 (1 equiv) as the base in
toluene/DMA at 150 °C for 8 h. However, this transfor-
mation was inefficient and resulted in concomitant forma-
tion of the expected 3-arylquinolinone derivative 3a,
together with 3b, and byproduct 4a derived from proto-
decarboxylation of 1a. After a tedious separation, 3a was
isolated in a low 42% yield (Table 1, entry 1). Of note,
compound 3b arises from the aryl migration between the
metal center and coordinated phosphine in the Pd(II)
complex. This reactivity is quite rare but has nevertheless
(15) (a) Kong, K. C.; Cheng, C. H. J. Am. Chem. Soc. 1991, 113,
6313–63155. (b) Pellegatti, L.; Vedrenne, E.; Leger, J.-M.; Jarry, C.;
Routier, S. J. Comb. Chem. 2010, 12, 604–608.
1498
Org. Lett., Vol. 14, No. 6, 2012

conditions were found to require 1a (1 equiv), 2a (2 equiv),
PdBr2 (5 mol %), DPEPhos (10 mol %), and Ag2CO3
(1 mmol), in toluene/DMA (9:1) in a sealed Schlenk tube at
150 °C for 1 h under microwave irradiation. A control
experiment revealed that the Pd-catalyst and silver carbo-
nate were necessary for the coupling to occur. No product
could be formed in the absence of PdBr2, or when Ag2CO3
was replaced by other bases (for more details, see Support-
ing Information).
Prompted by these results, we subsequently investigated
the substrate scope for the Pd-catalyzed decarboxylative
coupling of 1a with various (hetero)aryl halides possessing
different steric and electronic properties. As illustrated in
Scheme 1, both aryl iodide and bromide reacted well
providing the desired compound 3b in excellent yields,
whereas no reaction occurred when aryl chloride was used
as a coupling partner. Electron-rich and -deficient, meta
and para substituted aryl iodides and bromides all effi-
ciently underwent decarboxylative coupling with 1a in
good yields (products 3aÀd and 3iÀk). In addition, the
sterically demanding ortho substitution pattern was toler-
ated toward the coupling reaction of 1a, leading to 3-
arylquinolin-4(1H)-ones 3eÀh in yields ranging from 40 to
90%, regardlessofthe electronic nature of the substituents.
Interestingly, this coupling reaction also proceeded suc-
cessfully in the case of heterocyclic halides such as
3-bromocoumarin16 and 3-bromoquinolin-2(1H)-one, leading
to 3l and 3m in 40 and 57% yields, respectively.
pleased to observe that N-alkyl- and N-arylquinolin-
4(1H)-one 3-carboxylic acids having electron-donating or
-withdrawing groups on the aromatic nucleus led to the
formation of the corresponding 3nÀr in good yields.
Interestingly, product 3n revealed excellent chemical selec-
tivity preserving the CÀCl bond, which could undergo
further metal catalyzed functionalization processes.17
Next, we used this new catalytic system in decarboxylative
coupling of other heterocyclic carboxylic acids. Overall,
we were pleased with the generality of our protocol.
The reaction proceeded in satisfactory yields with 1,8-
naphthyridin-4(1H)-one, coumarin, quinolin-2(1H)-one
3-carboxylic acids, and chromone 2-carboxylic acids to
afford the coresponding arylated heterocycles 5À8 in
moderate to good yields.
In conclusion, we developed an efficient and practical
PdBr2/DPEphos catalyzed system for decarboxylative
coupling of various quinolin-4(1H)-one 3-carboxylic acids
with (hetero)aryl halides. The protocol exhibited a broad
substrate scope with respect to both the heterocyclic
carboxylic acids and (hetero)aryl halides, thus providing
an attractive alternative to the existing methods for the
synthesis of 3-(hetero)aryl-quinolin-4(1H)-ones 3 and re-
lated heterecycles 5À8 of biological interest.
Acknowledgment. The CNRS is gratefully acknowl-
edged for financial support of this research. Our labora-
tory BioCIS-UMR 8076 is a member of the laboratory of
Excellence LERMIT supported by a grant from ANR
(ANR-10-LABX-33).
To expand the scope of our method further, a range of
quinolin-4(1H)-one 3-carboxylic acids as well as related
heterocyclic carboxylic acids were subjected to the cou-
pling protocol with aryl iodides (Scheme 2). We were
Supporting Information Available. Experimental pro-
cedures and spectroscopic data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Audisio, D.; Messaoudi, S.; Brion, J.-D.; Alami, M. Eur. J. Org.
Chem. 2010, 1046–1051.
(17) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176–
4211.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
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