Palladium-catalyzed tandem amination reaction for the synthesis of 4-quinolones

Article abstract of DOI:10.1021/ol902626d

(Figure presented) An efficient palladium-catalyzed tandem amlnatlon approach was developed In one step to afford functlonallzed 4-qulnolones In good to excellent ylelds from easlly accessible o-haloaryl acetylenlc ketones and primary amines.

Full text of DOI:10.1021/ol902626d

ORGANIC
LETTERS
2010
Vol. 12, No. 2
212-215
Palladium-Catalyzed Tandem Amination
Reaction for the Synthesis of
4-Quinolones
Tiankun Zhao and Bin Xu*
Department of Chemistry, Shanghai UniVersity, Shanghai 200444, China
xubin@shu.edu.cn
Received September 21, 2009
ABSTRACT
An efficient palladium-catalyzed tandem amination approach was developed in one step to afford functionalized 4-quinolones in good to
excellent yields from easily accessible o-haloaryl acetylenic ketones and primary amines.
Quinolone derivatives represent a major class of nitrogen-
containing heterocycles,1 which play an increasingly impor-
tant role in drug discovery. These compounds are structural
units found in a vast array of natural products,2 synthetic
materials,3 and bioactive molecules as antimitotic,4 antiviral,5
and anticancer agents6 and HIV-1 integrase inhibitors7 and
serve as a crucial category of antibacterial agents as
exemplified by marketing drugs such as Avelox, Ciprodex,
Levaquin, and Vigamox. Such characteristics have made the
molecules significant synthetic targets and, therefore, have
resulted in sustained interest in developing new methods for
the preparation of this valuable structural unit.1c,3a,8 Among
these methods, the Camps-type cyclization9 has been widely
used. Other improved synthetic methods include the reaction
of isatoic anhydrides with ketone-derived enolates,10 triph-
(1) (a) Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic Chemistry, 3rd
ed.; Chapman & Hall: Chel Tenham, 1995; Chapter 6. (b) Pazharskii, A. F.;
Soldatenkov, A. T.; Katritzky, A. R. Heterocycles in Life and Society; John
Wiley & Sons: Chichester, 1997; pp 147-148. (c) Kouznetsov, V. V.;
Me´ndez, L. Y. V.; Go´mez, M. M. Curr. Org. Chem. 2005, 9, 141.
(2) (a) Michael, J. P. Nat. Prod. Rep. 1997, 14, 605. (b) Fort, D. M.;
Litvak, J.; Chen, J. L.; Lu, Q.; Phuan, P.-W.; Cooper, R.; Bierer, D. E. J.
Nat. Prod. 1998, 61, 1528. (c) Koyama, J.; Toyokuni, I.; Tagahara, K. Chem.
Pharm. Bull. 1999, 47, 1038.
(5) (a) Llina`s-Brunet, M.; Bailey, M. D.; Ghiro, E.; Gorys, V.; Halmos,
T.; Poirier, M.; Rancourt, J.; Goudreau, N. J. Med. Chem. 2004, 47, 6584.
(b) Lucero, B. d’A.; Gomes, C. R. B.; Frugulhetti, I. C. de P. P.; Faro,
L. V.; Alvarenga, L.; Souza, M. C. B. V.; de Souza, T. M. L.; Ferreira,
V. F. Bioorg. Med. Chem. Lett. 2006, 16, 1010. (c) Frutos, R. P.; Haddad,
N.; Houpis, I. N.; Johnson, M.; Smith-Keenan, L. L.; Fuchs, V.; Yee, N. K.;
Farina, V.; Faucher, A.-M.; Brochu, C.; Hache´, B.; Duceppe, J.-S.; Beaulieu,
P. Synthesis 2006, 2563.
(3) (a) Hadjeri, M.; Mariotte, A. M.; Boumendjel, A. Chem. Pharm.
Bull. 2001, 49, 1352. (b) Mphahlele, M. J.; Fernandes, M. A.; El-Nahas,
A. M.; Ottosson, H.; Ndlovu, S. M.; Sithole, H. M.; Dladla, B. S.; Waal,
D. D. J. Chem. Soc., Perkin Trans. 2 2002, 2159. (c) Krishnamurthy, M.;
Gooch, B. D.; Beal, P. A. Org. Lett. 2004, 6, 63. (d) Haddad, N.; Tan, J.;
Farina, V. J. Org. Chem. 2006, 71, 5031. (e) Vu, A. T.; Campbell, A. N.;
Harris, H. A.; Unwalla, R. J.; Manasc, E. S.; Mewshaw, R. E. Bioorg. Med.
Chem. Lett. 2007, 17, 4053. (f) Krishnamurthy, M.; Simon, K.; Orendt,
A. M.; Beal, P. A. Angew. Chem., Int. Ed. 2007, 46, 7044.
(6) (a) Xia, Y.; Yang, Z.-Y.; Xia, P.; Bastow, K. F.; Nakanishi, Y.;
Nampoothiri, P.; Hamel, E.; Brossi, A.; Lee, K.-H. Bioorg. Med. Chem.
Lett. 2003, 13, 2891. (b) Nakamura, S.; Kozuka, M.; Bastow, K. F.; Tokuda,
H.; Nishino, H.; Suzuki, M.; Tatsuzaki, J.; Natschke, S. L. M.; Kuo, S.-C.;
Lee, K.-H. Bioorg. Med. Chem. 2005, 13, 4396.
(4) (a) Kuo, S.-C.; Lee, H.-Z.; Juang, J.-P.; Lin, Y.-T.; Wu, T.-S.; Chang,
J.-J.; Lednicer, D.; Paull, K. D.; Lin, C. M.; Hamel, E.; Lee, K.-H. J. Med.
Chem. 1993, 36, 1146. (b) Li, L.; Wang, H.-K.; Kuo, S.-C.; Wu, T.-S.;
Lednicer, D.; Lin, C. M.; Hamel, E.; Lee, K.-H. J. Med. Chem. 1994, 37,
1126. (c) Sui, Z.; Nguyen, V. N.; Altom, J.; Fernandez, J.; Hilliard, J. J.;
Bernstein, J. I.; Barrett, J. F.; Ohemeng, K. A. Eur. J. Med. Chem. 1999,
34, 381. (d) Xia, Y.; Yang, Z.-Y.; Xia, P.; Hackl, T.; Hamel, E.; Mauger,
A.; Wu, J.-H.; Lee, K.-H. J. Med. Chem. 2001, 44, 3932. (e) Hadjeri, M.;
Peiller, E. L.; Beney, C.; Deka, N.; Lawson, M. A.; Dumontet, C.;
Boumendjel, A. J. Med. Chem. 2004, 47, 4964.
(7) (a) Moyer, M. P.; Weber, F. H.; Gross, J. L. J. Med. Chem. 1992,
35, 4595. (b) Santo, R. D.; Costi, R.; Roux, A.; Artico, M.; Lavecchia, A.;
Marinelli, L.; Novellino, E.; Palmisano, L.; Andreotti, M.; Amici, R.;
Galluzzo, C. M.; Nencioni, L.; Palamara, A. T.; Pommier, Y.; Marchand,
C. J. Med. Chem. 2006, 49, 1939. (c) Sato, M.; Motomura, T.; Aramaki,
H.; Matsuda, T.; Yamashita, M.; Ito, Y.; Kawakami, H.; Matsuzaki, Y.;
Watanabe, W.; Yamataka, K.; Ikeda, S.; Kodama, E.; Matsuoka, M.; Shinkai,
H. J. Med. Chem. 2006, 49, 1506.
10.1021/ol902626d  2010 American Chemical Society
Published on Web 12/11/2009

enylphosphonium salts,11 or alkynes,12 cyclization reaction
of N-substituted phenacyl or acetonyl anthranilates in poly-
phosphoric acid,13 base, or copper-promoted intermolecular
cyclization of 1-(2-halo-phenyl)-2-en-3-amin-1-ones,14 cy-
cloacylation of aniline derivatives in the presence of Eaton’s
reagent,15 and palladium-catalyzed carbonylative Sonogashira
coupling of 2-iodo-5-methoxyaniline with thiazolyl-acetylene.3d
Recently, Huang has reported a one-pot synthesis of 4-quino-
lones using sequential palladium-catalyzed amidation of 2′-
bromoacetophenones followed by base-promoted intramolecular
cyclization.16 Although these methods are effective, the reac-
tions are incompatible with sensitive functionalities10a or need
harsh reaction conditions,9b,15 and some starting materials are
not readily available.11b To continue our program aiming at
efficient construction of nitrogen-containing heterocycles,17
we herein report a palladium-catalyzed tandem reaction
consisting of a sequential double C-N bond formation to
give 4-quinolones from readily available o-haloaryl acety-
lenic ketones and primary amines (Scheme 1).18
exploring 1a19 with aniline in the presence of Pd(PPh3)4 (5
mol %) in dioxane using K2CO3 as a base. The reaction gave
4-quinolone 3aa in 71% yield (Table 1, entry 1). A similar
Table 1. Condition Optimizations for 4-Quinolonesa
temp yieldb
entry
Pd
ligand
solvent
base
(°C)
(%)
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd-DPPF
/
/
dioxane K2CO3 reflux
dioxane K2CO3 reflux
71
71
72
75
84
63
77
17
<5
<5
59
72
35
<5
10
<5
Pd2(dba)3 Xantphos dioxane K2CO3 reflux
Pd2(dba)3 DPPP
Pd2(dba)3 PPh3
Pd2(dba)3 PPh3
Pd2(dba)3 PPh3
Pd2(dba)3 PPh3
Pd2(dba)3 PPh3
Pd2(dba)3 PPh3
Pd2(dba)3 PPh3
Pd2(dba)3 PPh3
Pd2(dba)3 PPh3
Pd2(dba)3 PPh3
dioxane K2CO3 reflux
dioxane K2CO3 reflux
dioxane Cs2CO3 reflux
dioxane K3PO4 reflux
dioxane NaOH reflux
dioxane t-BuOK reflux
9
Scheme 1
.
Tandem Amination Strategy to 4-Quinolones from
Alkynones and Amines
10
11
12
13
14
dioxane Et3N
reflux
DMF K2CO3 120
toluene K2CO3 reflux
CH3CN K2CO3 reflux
dioxane K2CO3 60
dioxane K2CO3 reflux
dioxane K2CO3 reflux
15c Pd2(dba)3
16
/
/
/
a Reaction conditions: 1a (0.21 mmol), aniline 2a (0.25 mmol),
Pd2(dba)3-CHCl3 (5 mol %), ligand (10 mol %), base (0.42 mmol), and
solvent (1.5 mL), under nitrogen. DPPP ) 1,3-bis(diphenylphosphino)-
propane, Pd-DPPF ) (1,1′-bis(diphenylphosphino)ferrocene)dichloro-pal-
ladium(II)-CH2Cl2, Xantphos ) 4,5-bis(diphenylphosphino)-9,9-dimethylxan-
thene. b Isolated yield. c 1a was recovered in 63%.
To determine the feasibility of this double C-N bond
formation process, we initially examined the reaction by
(8) (a) Reitsema, R. H. Chem. ReV. 1948, 43, 43. (b) White, L. A.; Storr,
R. C. Tetrahedron 1996, 52, 3117. (c) Mitscher, L. A. Chem. ReV. 2005,
105, 559.
(9) (a) Camps, R. Chem. Ber. 1899, 32, 3228. (b) Ding, D.; Li, X.; Wang,
X.; Du, Y.; Shen, J. Tetrahedron Lett. 2006, 47, 6997. (c) Jones, C. P.;
Anderson, K. W.; Buchwald, S. L. J. Org. Chem. 2007, 72, 7968.
(10) (a) Coppola, G. M.; Scallen, T. J.; DelPrete, A.; Montano, R.
Heterocycles 1989, 29, 1497. (b) Hradil, P.; Grepl, M.; Hlavac, J.; Soural,
M.; Malon, M.; Bertolasi, V. J. Org. Chem. 2006, 71, 819. (c) Stern, E.;
Muccioli, G. G.; Bosier, B.; Hamtiaux, L.; Millet, R.; Poupaert, J. H.;
Hn´ichart, J.-P.; Depreux, P.; Goossens, J.-F.; Lambert, D. M. J. Med. Chem.
2007, 50, 5471.
result was obtained using the Pd-DPPF complex as a
catalyst (entry 2). When Pd2(dba)3-CHCl3 was used as
catalyst and combined with Xantphos or DPPP, the yields
were improved slightly (entries 3 and 4). The use of PPh3
turned out to be the best ligand choice and resulted in 84%
yield (entry 5, Condition A). In comparison with K2CO3,
other bases such as Cs2CO3 or K3PO4 resulted in diminished
yields (entries 6 and 7) or were less effective with NaOH,
t-BuOK, or Et3N as base (entries 8-10). When the solvent
was switched to DMF, toluene, or CH3CN, the yield of 3aa
decreased (entries 11-13). Lower reaction temperature failed
to give a good result (entry 14), and little product was
detected in the absence of catalyst and ligand (entries 15
and 16).
With the optimized reaction conditions in hand, we then
extended the reaction with a range of commercially available
aryl amines. As illustrated in Table 2, 1a was readily reacted
with functionalized aryl amines bearing ortho, meta, and para
substitutions on the aryl ring to give the corresponding
products 3ab-3am in moderate to good yields (entries
2-13). The reactions performed smoothly with aryl amines
containing electron-donating (entries 2-5 and entries 11-13)
(11) (a) Kamel, A. A.; Abdou, W. M. Synlett 2007, 1269. (b) Abdou,
W. M.; Kamel, A. A. Synth. Commun. 2007, 37, 3945.
(12) Yoshino, Y.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc. 2009,
131, 7494.
(13) Hradil, P.; Hlavac, J.; Lemr, K. J. Heterocycl. Chem. 1999, 36, 141.
(14) (a) Clemencin-Le Guillou, C.; Remuzon, P.; Bouzard, D.; Quirion,
J.-C.; Giorgi-Renault, S.; Husson, H.-P. Tetrahedron 1998, 54, 83. (b) Al-
Hiari, Y. M.; Al-Mazari, I. S.; Shakya, A. K.; Darwish, R. M.; Abu-Dahab,
R. Molecules 2007, 12, 1240. (c) Bernini, R.; Cacchi, S.; Fabrizi, G.;
Sferrazza, A. Synthesis 2009, 1209.
(15) Zewge, D.; Chen, C.-Y.; Deer, C.; Dormer, P. G.; Hughes, D. L.
J. Org. Chem. 2007, 72, 4276.
(16) Huang, J.; Chen, Y.; King, A. O.; Dilmeghani, M.; Larsen, R. D.;
Faul, M. M. Org. Lett. 2008, 10, 2609.
(17) (a) Xu, B.; Stephens, A.; Kirschenheuter, G.; Greslin, A.; Cheng,
X.; Sennelo, J.; Cattaneo, M.; Zighetti, M. L.; Chen, A.; Kim, S.-A.; Kim,
H. S.; Bischofberger, N.; Cook, G.; Jacobson, K. A. J. Med. Chem. 2002,
45, 5694. (b) Song, B. R.; Wang, S. Y.; Sun, C. Y.; Deng, H. M.; Xu, B.
Tetrehedron Lett. 2007, 48, 8982. (c) Sun, C. Y.; Xu, B. J. Org. Chem.
2008, 73, 7361. (d) Ye, W. C.; Mo, J.; Zhao, T. K.; Xu, B. Chem. Commun.
2009, 3246.
(18) During the preparation of this manuscript, a single example to
prepare 4-quinolone was reported by copper-catalyzed sequential two-step
process from R,ꢀ-ynone and aniline without isolation of the intermediate.
See ref 14c.
(19) Coppola, G. M. J. Heterocycl. Chem. 1982, 19, 727.
Org. Lett., Vol. 12, No. 2, 2010
213

Table 2. Reaction of 1a with Primary Aminesa
Table 3. Reaction of Alkynones with Aryl Aminesa
a All reactions were performed under N2 on a 0.5 mmol scale, using
aryl amines (1.2 equiv), Pd2(dba)3-CHCl3 (5 mol %), PPh3 (10 mol %),
and K2CO3 (2.0 equiv) in dioxane (3 mL) under reflux. b Isolated yield.
c Toluidine was used at 140 °C. d 4-Methoxyaniline was used at 140 °C.
(entries 1 and 2). For those substrates consisting of fluoro
and chloro groups, the yields turned out to be slightly lower
(entries 3-5). Pyridine-containing substrate 1g also showed
good reactivity and gave 3ga in moderate yield (entry 6). It
is interesting to note that the dibromo-substituted ynone 1h
afforded the corresponding quinolone 3ha in good yield
without the competitive reaction on the other bromine (entry
7). Furthermore, the less reactive chloro-substituted substrates
also gave products 3ab and 3ac in moderate yields upon
raised temperature (entries 8 and 9).
The product derivatived 3-halogenated quinolones are
versatile synthetic intermediates21 and could be further
elaborated. For example, 3-bromo-substituted 4 was easily
prepared from 3aa, which gave rise to the corresponding
3-phenyl derivatived quinolone 5 in 94% yield via Suzuki
reaction (Scheme 2). Thus, the multisubstituted 4-quinolones
could be generated smoothly.
a All reactions were performed under N2 on a 0.5 mmol scale, using
aryl amines (1.2 equiv), Pd2(dba)3-CHCl3 (5 mol %), PPh3 (10 mol %),
and K2CO3 (2.0 equiv) in dioxane (3 mL) under reflux. b Isolated yield.
and electron-withdrawing groups (entries 6-9). Substrates
with active amino and hydroxy groups remained intact under
the reaction conditions (entries 4 and 5). This reaction was
not limited to simple aromatic amines, and the naphthalene-
and pyrimidine-containing substrates 2n and 2o also afforded
3an and 3ao20 in good yields, respectively (entries 14 and
15). It should also be noted that aliphatic amines such as
n-butylamine gave product 3ap successfully in moderate
yield (entry 16).
To further explore the generality and scope of this practical
approach, a variety of ynones 1b-1i19 were investigated,
and the results are summarized in Table 3. This method was
compatible with different types of ynones substituted with
aryl and pyridinyl groups (entries 1-6). Substrates containing
electron-donating groups afforded products in good yields
Scheme 2. Formation of 3-Phenyl-Substituted Quinolone
(20) Crystal data for 3ao: C19H13N3O, MW ) 299.32, Orthorhombic,
Pbca, final R indices [I > 2σ(I)], R1 ) 0.0420, wR2 ) 0.0925, a )
7.0652(11) Å, b ) 20.188(3) Å, c ) 21.214(3) Å, R ) 90°, ꢀ ) 90.921(2)°,
γ ) 90°, V ) 3025.8(8) Å3, Crystal size: 0.30 × 0.25 × 0.20 mm, T )
296(2) K, Z ) 8, reflections collected/unique: 14 591/2679 (Rint ) 0.0413),
Data: 2679, restraints: 0, parameters: 209.
Two pathways are proposed as a possible mechanism for
this reaction (Scheme 3), which may involve either oxidative
214
Org. Lett., Vol. 12, No. 2, 2010

in 31% yield from synthesized B with 39% conversion
(Scheme 4). The total yield for the two steps is far less than
Scheme 3. Plausible Mechanism for Synthesis of 3aa from 1a
Scheme 4. Formation of B and 3aa under Condition A
84%. (ii) No 3aa and intermediate C were detected from
the chloro-substituted substrates 1i under Condition A after
reaction for 24 h, and only a trace amount of conjugate
addition product was observed, which may be due to the
low oxidative addition reactivity of the C-Cl bond. (iii)
When the reaction was conducted under Condition A, at 80
°C or under reflux, no intermediate C was detected by LC-
MS. Furthermore, no product 3aa could be found from
synthesized intermediate C26 under Condition A. On the basis
of these results, we envisioned that the Path A in Scheme 3
could be the major pathway to afford the target quinolone
3aa.
In summary, we have developed an efficient palladium-
catalyzed tandem amination protocol for the straightforward
synthesis of 4-quinolones. This approach provides one of
the easiest pathways for accessing this class of valuable
compounds from easily available starting materials, and a
wide range of multisubstituted 4-quinolones could be gener-
ated accordingly for chemical library construction. The scope
of this reaction and its applications for bioactive compounds
are currently under investigation in our laboratory.
addition of Pd(0) to the C-Br bond in 1a (intermediate A
in Path A) or conjugate addition of aniline to 1a14 (inter-
mediate B in Path B) in the first step. The formed intermedi-
ate A presumably leads to C through Buchwald-Hartwig
amination,22 or the Ct C bond in A could be actived through
coordination to the palladium and attacked by aniline to form
intermediate D.14c,23 Both pathways will go through inter-
mediates D and E,14c,24 followed by reductive elimination
of Pd(0) to give product 3aa.
To define the mechanism, several experiments were
explored, including: (i) under Condition A (Table 1, entry
5), intermediate B was isolated in 13% yield in the absence
of palladium after reaction for 7 h,25 and 3aa was produced
(21) (a) Pessolano, A. A.; Witzel, B. E.; Graham, P. M.; Clark, R. L.;
Jones, H.; Dorn, C. P., Jr.; Carty, J.; Shen, T. Y. J. Heterocycl. Chem.
1985, 22, 265. (b) Zhou, C.; Dubrovsky, A. V.; Larock, R. C. J. Org. Chem.
2006, 71, 1626. (c) Hessian, K. O.; Flynn, B. L. Org. Lett. 2006, 8, 243.
(d) Venkataraman, S.; Barange, D. K.; Pal, M. Tetrahedron Lett. 2006, 47,
7317. (e) Mphahlele, M. J.; Nwamadi, M. S.; Mabeta, P. J. Heterocycl.
Chem. 2006, 43, 255.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (No. 20672071 and
20972093), Shanghai Pujiang Program (No. 07pj14043), and
Shanghai Municipal Education Commission (No. J50102 and
10YZ06) is gratefully acknowledged. We thank Prof. Hong-
mei Deng (SHU) for NMR support and the reviewers for
nice suggestions.
(22) For reviews, see: (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998,
37, 2046. (b) Muci, A. R.; Buchwald, S. L. Practical Palladium Catalysts
for C-N and C-O Bond Formation. In Topics in Current Chemistry; Miyaura,
N., Ed.; Springer-Verlag: Berlin, 2002; Vol. 219, p 133.
(23) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63,
Supporting Information Available: Characterization data
and copies of the 1H NMR, 13C NMR, and 19F NMR spectra
for all compounds, X-ray structure of 3ao, and representative
experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
7652
.
(24) For selective seven-membered palladium intermediates, see: (a) Cao,
H.; Xiao, W.-J.; Alper, H. AdV. Synth. Catal. 2006, 348, 1807. (b) Ma, L.;
Wobser, S. D.; Protasiewicz, J. D. J. Organomet. Chem. 2007, 692, 5331.
(c) Zheng, Z.; Alper, H. Org. Lett. 2008, 10, 829
(25) For the timescale needed for addition of aniline to substrate 1a in
the absence of palladium, see Supporting Information.
.
(26) For preparation of intermediate C, see Supporting Information.
OL902626D
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