Synthesis of 3,4-disubstituted quinolin-2(1H)-ones via palladium-catalyzed regioselective cross-coupling reactions of 3-bromo-4-trifloxyquinolin-2(1H)-one with arylboronic acids

Article abstract of DOI:10.1246/cl.2005.550

Palladium-catalyzed regioselective cross-coupling reactions of 3-bromo-4-trifloxyquinolin-2(1H)-one with arylboronic acids provide an efficient and practical route for the synthesis of 3,4-disubstituted quinolin-2(1H)-ones. Copyright

Full text of DOI:10.1246/cl.2005.550

550
Chemistry Letters Vol.34, No.4 (2005)
Synthesis of 3,4-Disubstituted Quinolin-2(1H)-ones via Palladium-catalyzed
Regioselective Cross-coupling Reactions of 3-Bromo-4-trifloxyquinolin-2(1H)-one
with Arylboronic Acids
Jie Wu,Ã Liang Zhang, and Xiaoyu Sun
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, P. R. China
(Received January 26, 2005; CL-050121)
Palladium-catalyzed regioselective cross-coupling reactions
utility of these reactions for the synthesis of 3,4-disubstituted
quinolin-2(1H)-ones is quite limited.10 On the other hand, sever-
al other methods including palladium-catalyzed reactions for the
synthesis of 3,4-disubstituted quinolin-2(1H)-ones usually suffer
from low yields, harsh conditions, and limitation of substrates
scope.11–17 It is of great interest to develop general protocols
for the synthesis of 3,4-disubstituted quinolin-2(1H)-ones under
mild reaction conditions.
Recently, Yang18 reported Lewis acid Mg(ClO4)2, com-
bined with NBS, in CH3CN or EtOAc provided mild and fast
bromination of 1,3-dicarbonyl compounds. In particular, this
protocol could be applied to the ꢀ-monobromination of ꢀ-un-
substituted ꢁ-keto esters. Inspired by this result, we therefore se-
lected 4-hydroxy-1-methylquinolin-2(1H)-one as a model and
treated with NBS18 and Tf2O subsequently to afford the corre-
sponding 3-bromo-4-trifloxyquinolin-2(1H)-one 3 in good yield
(Scheme 1).
of 3-bromo-4-trifloxyquinolin-2(1H)-one with arylboronic acids
provide an efficient and practical route for the synthesis of 3,4-
disubstituted quinolin-2(1H)-ones.
A goal of chemical genetics is to find small molecules that
modulate the individual functions of gene products with high po-
tency and high specificity.1,2 Natural products and natural prod-
uct–derived compounds provide many of the most striking ex-
amples, particularly in terms of their specificity. It seems unlike-
ly that natural products alone will provide the hypothetical
‘‘complete’’ set of small molecules that would allow the func-
tions of all proteins, as well as their individual domains, to be de-
termined. For chemistry to have its maximal effect on biology,
efficient methods for discovering this set of small molecules
are in great demand.
The quinolin-2(1H)-one core is widely found in various al-
kaloids, many of which possess interesting biological activity.
There has been considerable interest in developing quinolin-
2(1H)-ones as anticancer,3 antiviral,4 and antihypertensive
agents.4 Quinolin-2(1H)-ones are also valuable intermediates
in organic synthesis, since they are easily converted into 2-
chloro- and then 2-aminoquinoline derivatives.5
OH
OTf
OH
Br
O
Br
O
Tf2O
NBS
Ref. 18
91%
Et3N
86%
N
N
N
O
CH3
CH3
CH3
1
2
3
Scheme 1.
We reasoned that the 4-trifloxy group attached to the elec-
tron-withdrawing ꢀ,ꢁ-unsaturated double bond in compound 3
may increase its capability to oxidative addition to the transition
metals. Therefore, the regioselective cross-couplings of 3 for the
synthesis of 3,4-disubstituted-quinolin-2(1H)-ones are possible.
Due to their easy handling and long shelf life, arylboronic acid
derivatives would be the starting materials of choice. Thus, we
started to explore the possibility of using 3 as an electrophile
for the Suzuki–Miyaura reaction.19
Initial studies were performed by using PdCl2(PPh3)2
(5 mol %) as catalyst in the reaction of compound 3 with 4-me-
thoxyphenylboronic acid (1.5 equiv.) at 50 ꢀC (Scheme 2).
To our delight, we observed the formation of the corre-
sponding product 4c (20% yield) combined with disubstituted
product 5a (60% yield). Fortunately, changing temperature im-
R3
R4
different
substitutions
different
aromatics
R1
N
O
R2
Figure 1. Diversity based on quinolin-2(1H)-one scaffold.
Our continued interest to build up a quinolin-2(1H)-one
based combinatorial library led us to devote our efforts to devel-
op efficient methods for the synthesis of diversified quinolin-
2(1H)-one molecules. Our library model is shown in Figure 1,
which includes four centers for introduction of diversity into qui-
nolin-2(1H)-one molecule. We, therefore, initiated a program to
develop the corresponding methods for generating a quinolin-
2(1H)-one library, which includes developing a novel synthetic
method to construct 1-substituted-4-hydroxyquinolin-2(1H)-
one scaffold, and attaching diversified R3 and R4 groups to the
quinolin-2(1H)-one scaffold. Herein, we described our recent ef-
forts for the synthesis of 3,4-disubstituted quinolin-2(1H)-ones
via palladium-catalyzed regioselective cross-coupling reactions6
of 3-bromo-4-trifloxyquinolin-2(1H)-one (derived from 4-hy-
droxyquinolin-2(1H)-one) with arylboronic acids.
OMe
OMe
B(OH)2
OMe
OTf
Br
O
MeO
(1.5 eq.)
Br
O
+
N
PdCl2(PPh3)2 (5 mol%)
THF/H2O, 50° C
Na2CO3 (8.0 eq.)
N
N
O
CH3
3
CH3
CH3
4c
5a
Although there are classic methods for the synthesis of a
wide variety of 3- or 4-substituted quinolin-2(1H)-ones,7–9 the
Scheme 2.
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.4 (2005)
551
Table 1. Palladium-catalyzed cross-coupling reactions of 3-
bromo-4-trifloxyquinolin-2(1H)-one 3 with arylboronic acids
CF3
Br
CF3
R2
OTf
R1
R1
B(OH)2
PdCl2(PPh3)2 (5 mol%)
PdCl2(PPh3)2 (5 mol%)
R1B(OH)2 (3.0 eq.)
PdCl2(PPh3)2 (5 mol%)
R1B(OH)2 (1.1 eq.)
Br
O
Br
O
R1
O
+
R2
THF/H2O/Na2CO3
60°C
N
O
N
O
THF/H2O/Na2CO3
THF/H2O/Na2CO3
N
N
N
1.5 equiv.
CH3
CH3
60° C
RT
CH3
3
CH3
4
CH3
5
R2
4f
6
Product (yield)
Condition A
Condition B
H
6a (75%)
6b (83%)
5c (71%)
Entry
R1
Condition
Product
Yield/%a
4-OMe
1
2
3
Ph
A
A
A
4a
4b
4c
80
85
81
3-CF3
2-MeOC6H4
4-MeOC6H4
3,4-
Scheme 3.
ease. We believe that this method provides an excellent comple-
ment to the palladium-catalyzed 3,4-disubstituted quinolin-
2(1H)-ones synthesis. Combinatorial synthesis of these natural
product-like compounds on solid support is under investigation
in our research group.
4
Methylene-
dioxyphenyl
3-NCC6H4
3-CF3C6H4
4-FC6H4
4-MeOC6H4
3-NCC6H4
3-CF3C6H4
A
4d
71
5
6
7
8
9
10
A
A
A
B
B
B
4e
4f
4g
5a
5b
5c
72
78
69
87
73
71
Financial support from Fudan University is gratefully
acknowledged.
aIsolated yield based on 3-bromo-4-trifloxyquinolin-2(1H)-
one 3.
References
1
2
3
4
S. L. Schreiber, Science, 287, 1964 (2000).
S. L. Schreiber, Chem. Eng. News, 81, 51 (2003).
P. Ferrer, C. Avendan˜o, and M. Sollhuber, Liebigs Ann., 1995, 1895.
proved the reaction selectivity and yield. When the reaction was
carried out at room temperature, 4c was obtained as the major
product (78% yield) and only a trace amount of di-substituted
product 5a was detected. When the usage of 4-methoxyboronic
acid was reduced to 1.1 equiv., 4c was the only product (81%
yield). Furthermore, when the reaction temperature was elevated
to 60 ꢀC, in the presence of 2.5–3.0 equiv. of 4-methoxyboronic
acid, only 5a was generated (87% yield) as expected. Thus, re-
giocontrolled cross-coupling of 3-bromo-4-trifloxyquinolin-
2(1H)-one 3 could be fulfilled by tuning the reaction temperature
and amount of arylboronic acids.
To demonstrate the generality of this method, the scope of
this reaction was investigated and the results are summarized
in Table 1. These conditions (condition A and condition B) have
proved to be useful for coupling a range of arylboronic acids.
Both electron-rich and electron-poor arylboronic acids which
are suitable partners in this process give similar yields. The reac-
tions were very clean and the desired products were afforded in
good yields. For example, when 3-trifluoromethylphenylboronic
acid was employed in the reaction, 78% yield of the correspond-
ing product 4f was obtained under condition A (Entry 6) and
71% yield of desired product 5c was generated under condition
B (Entry 10).
¨
a) A. L. Hopkins, J. Ren, J. Milton, R. J. Hazen, J. H. Chan, D. I.
Stuart, and D. K. Stammers, J. Med. Chem., 47, 5912 (2004). b)
G. A. Freeman, C. W. Andrews, III, A. L. Hopkins, G. S. Lowell,
L. T. Schaller, J. R. Cowan, S. S. Gonzales, G. W. Koszalka,
R. J. Hazen, L. R. Boone, R. G. Ferris, K. L. Creech, G. B. Roberts,
S. A. Short, K. Weaver, D. J. Reynolds, J. Milton, J. Ren, D. I.
Stuart, D. K. Stammers, and J. H. Chan, J. Med. Chem., 47, 5923
(2004).
5
6
a) M. Anzini, A. Cappelli, and S. Vomero, J. Heterocycl. Chem., 28,
1809 (1991). b) A. Godard, J. M. Fourquez, R. Tamion, F. Marsais,
and G. Queguiner, Synlett, 1994, 235.
For some recent examples of regioselective cross-coupling reac-
tions, see: a) M. Hocek, D. Hockova, and H. Dvorakova, Synthesis,
2004, 889. b) M. Hocek, I. Votruba, and H. Dvorakova, Tetrahe-
dron, 59, 607 (2003). c) T. Bach and S. Heuser, J. Org. Chem.,
67, 5789 (2002). d) T. Bach and S. Heuser, Angew. Chem., Int.
Ed., 40, 3184 (2001). e) F. Bellina, C. Anselmi, and R. Rossi,
Tetrahedron Lett., 42, 3851 (2001).
´
7
8
9
‘‘Quinolines,’’ ed. by G. Jones, John Wiley & Sons, London, New
York, Sydney, Toronto (1977), pp 181–187.
‘‘Quinolines,’’ ed. by G. Jones, John Wiley & Sons, London, New
York, Sydney, Toronto (1977), pp 191–194.
‘‘Quinolines,’’ ed. by G. Jones, John Wiley & Sons, London, New
York, Sydney, Toronto (1977), pp 151–158.
10 a) A. L. Searles and D. Ressler, J. Am. Chem. Soc., 80, 3656 (1958).
b) K. K. Park and J. J. Lee, Tetrahedron, 60, 2993 (2004).
Compound 4 could be further elaborated under the condi-
tions below (Scheme 3). For example, when compound 4f was
employed as substrate in the Suzuki–Miyaura reaction, good
yields of the corresponding products were obtained. We were al-
so pleased to find that electron-withdrawing as well as electron-
donating substituents attached on arylboronic acid are tolerated
under these conditions, although boronic acids with electron-
donating group gave better result.
In summary, the palladium-catalyzed regioselective cross-
coupling reactions of 3-bromo-4-trifloxyquinolin-2(1H)-one
with arylboronic acids disclosed herein represent a simple, effi-
cient, and practical synthesis of 3,4-disubstituted quinolin-
2(1H)-ones. The advantages of this method include good sub-
strate generality, mild reaction conditions, and experimental
11 A. Furstner, D. N. Jumbam, and N. Shi, Z. Naturforsch., B: Chem.
¨
Sci., 50, 326 (1995).
12 G. Merault, P. Bougeois, and N. Duffaut, Bull. Soc. Chim. Fr., 1974,
1949.
13 K. Kobayashi, T. Kitamura, K. Yoneda, O. Morikawa, and H.
Konishi, Chem. Lett., 2000, 798.
14 N. A. Cortese, C. B. Ziegler, Jr., B. J. Hrnjez, and R. F. Heck, J. Org.
Chem., 43, 2952 (1978).
15 C. W. Holzapfel and C. Dwyer, Heterocycles, 48, 215 (1998).
16 M. Mori, K. Chiba, N. Ohta, and Y. Ban, Heterocycles, 13, 329
(1979).
17 D. V. Kadnikov and R. C. Larock, J. Org. Chem., 69, 6772 (2004).
18 D. Yang, Y.-L. Yan, and B. Lui, J. Org. Chem., 67, 7429 (2002).
19 For recent reviews: a) N. Miyaura, Top. Curr. Chem., 219, 11
(2002). b) A. Suzuki, J. Organomet. Chem., 576, 147 (1999). c)
A. F. Littke and G. C. Fu, Angew. Chem., Int. Ed., 41, 4176 (2002).
Published on the web (Advance View) March 12, 2005; DOI 10.1246/cl.2005.550