A general solid phase synthesis of 4-substituted quinolinones via Pd-catalyzed cross coupling

Article abstract of DOI:10.1016/j.tetlet.2006.05.032

A general method for the solid phase synthesis of 4-hydroxy quinolinones and subsequent Pd-catalyzed cross coupling to afford 4-substituted quinolinones has been developed. Conversion of support-bound 4-hydroxy quinolinones to 4-tosyl quinolinones and sub

Full text of DOI:10.1016/j.tetlet.2006.05.032

Tetrahedron Letters 47 (2006) 4885–4888
A general solid phase synthesis of 4-substituted quinolinones via
Pd-catalyzed cross coupling
Caiding Xu,* Lydie Yang, Ashok Bhandari and Christopher P. Holmes
Affymax, Inc., 4001 Miranda Avenue, Palo Alto, CA 94304, USA
Received 23 November 2005; accepted 8 May 2006
Available online 30 May 2006
Abstract—A general method for the solid phase synthesis of 4-hydroxy quinolinones and subsequent Pd-catalyzed cross coupling to
afford 4-substituted quinolinones has been developed. Conversion of support-bound 4-hydroxy quinolinones to 4-tosyl quinolinones
and subsequent treatment with alkyl, aryl, benzylzinc halides, or arylboronic acids in the presence of catalytic amount of Pd(PPh3)4
provides 4-alkyl, aryl, or benzyl quinolinones. This method allows for the introduction of alkyl, aryl, and benzyl groups at the
4-position of the quinolinone ring, and is ideal for parallel and combinatorial chemistry library synthesis.
Ó 2006 Elsevier Ltd. All rights reserved.
Quinolinones are an important class of heteroaromatic
R3
R3
R3
compounds. As isosters of coumarin, quinolinones have
been found to have a broad range of biological activities
such as antiviral,1 antineoplastic,2 antiischemic,3 anti-
allergic,4 antihypertensive,5 and antiulcerative.6 We
were particularly interested in introducing carbon-based
substituents onto the quinolinone ring at the 4-position
in compounds designed for random diversity screening.
R2
O
O
O
R1
R1
R1
NH2
N
H
NH
(1)
(2)
(3)
R2
O
Scheme 1.
R3
OTs
N
O
Although quinolinones exhibit a wide range of biologi-
cal activities, there is a lack of methods for the synthesis
of quinolinones with 4-carbon-based substituents. In the
literature, 4-substituted quinolinones 1 are mostly made
from cyclization of 2, which can be derived from amino-
ketone 3 (Scheme 1).7 Aminoketones 3 are not readily
available starting materials, which has thus far limited
SAR studies in medicinal chemistry research. In the
course of our drug discovery study, we have successfully
developed a solid phase synthesis of 4-hydroxy quinol-
inones from methyl anthranilates.8 We envisioned that
transforming the 4-hydroxy group to the corresponding
sulfonate 4 would allow us to employ the Pd-catalyzed
cross coupling strategy to incorporate 4-carbon-based
substituents (Scheme 2). The Pd-catalyzed cross cou-
pling has emerged over the past three decades as one
of the most general and selective method for carbon–
carbon bond formation.9 Even though the triflate group
is often the leaving entity of choice in Pd-catalyzed cou-
R2
R2
Pd-Catalyzed
OMe
NH2
R1
R1
R1
Cross Coupling
N
H
O
O
(4)
(5)
R3 = Alkyl, Aryl, Benzyl
Scheme 2.
pling reactions,10 the corresponding quinolinone triflate
is not stable under the reaction conditions. Therefore,
we focused on the more stable tosylate11 as cross cou-
pling partner. The electron-deficient character of the
quinolinone moiety should facilitate palladium oxida-
tive insertion.
The solid phase synthesis of 4-hydroxy quinolinone and
resin-bound quinolinone tosylate is shown in Scheme 3.
HypoGel Br resin (from RAPP Polymere) was first cou-
pled with acid-labile linker 2,6-dimethoxy-4-hydroxy-
benzaldehyde, then followed by reductive amination
with methyl anthranilate to give the resin-bound methyl
anthranilate 6. For compounds designed for protein
phosphatases catalytic domain binding, we need a
*
Corresponding author. Tel.: +1 650 812 8700; fax: +1 650 424
0832; e-mail: Caiding_Xu@affymax.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.032

4886
C. Xu et al. / Tetrahedron Letters 47 (2006) 4885–4888
Table 1. Pd-catalyzed cross coupling of arylboronic acids with 4-tosyl
quinolinone 4
OMe
CHO
COOMe
NH
Br
O
b, c
a
Cpds
Arylboronic acid
Conversiona (%)
Yieldb (%)
(6)
OMe
9a
80
68
B(OH)2
OH
N
COOMe
O
N
COOMe
9b
9c
72
85
50
76
d
MeO
O
B(OH)2
e
O (8)
COOMe
(7)
B(OH)2
F
OTs
N
OH
9d
B(OH)2
85
70
COOMe
COOMe
O
f
g
(8)
F
O
N
H
(4)
Cl
Cl
B(OH)2
9e
9f
83
95
80
75
80
65
Scheme 3. Synthesis of resin-bound 4-tosyl quinolinone 4. Reagents
and conditions: (a) 2,6-dimethoxy-4-hydroxy-benzaldhyde, K2CO3,
DMF, 70 °C, 5 h; (b) methyl anthranilate, TMOF/DMF (1:1), 50 °C,
1 h; (c) HOAc, NaBH3CN, THF, 50 °C, overnight; (d) methyl 3-
chloro-3-oxopropionate, DIEA, DMF, 2 h; (e) satd K2CO3/MeOH, rt
5 h; (f) TsCl, pyridine, DCM, rt 4 h; (g) TFA/CH2Cl2 (50/50), 1 h.
F3CO
MeO
B(OH)2
9g
B(OH)2
a Conversion determined by HPLC.
b Isolated yield based on 4-tosyl quinolinone (4).
methyl ester group at the 3-position in quinolinone ring.
Thus, we treated the resin-bound methyl anthranilate
with methyl 3-chloro-3-oxopropionate and diisopropyl-
ethylamine (DIEA) to incorporate a methyl ester func-
tional group. Cyclization of intermediate 7 was then
carried out in saturated K2CO3/MeOH solution to form
the resin-bound 3-methoxycarbonyl-4-hydroxy quinol-
inone 8, which could be cleaved from the resin with
TFA/CH2Cl2 and fully characterized. Treatment of
resin-bound 4-hydroxy quinolinone with p-toluenesulfo-
nyl chloride and pyridine in dichloromethane gave the
resin-bound 3-methoxycarbonyl 4-tosyl quinolinone 4.
The successful Suzuki–Miyaura cross coupling reaction
demonstrated that the palladium oxidative insertion to
the C–OTs bond can take place in 4-tosyl quinolinone
4. If there were a more reactive organometal reagent,
the corresponding transmetallation and further reduc-
tive elimination could favorably compete with hydro-
lysis and lead to a higher yield of the desired cross
coupling product. We therefore shifted our attention
to the Pd-catalyzed organozinc coupling (Scheme 4).
In general, the Pd-catalyzed coupling of organozincs,
also known as Negishi coupling, offers a very desirable
combination of high reactivity and favorable chemo-
selectivity profile.9a
With 4-tosyl quinolinone 4 in hand, we first explored the
Pd-catalyzed Suzuki–Miyaura cross coupling reaction.9c
When 4-tosyl quinolinone 4 was treated with 5 equiv of
phenylboronic acid, 10 equiv of aqueous Na2CO3, 10%
Pd(PPh3)4 in DMF at 60 °C for 14 h, 3-methoxycarb-
onyl-4-phenyl quinolinone 9a was obtained in 35% yield,
along with 60% hydrolysis product, 3-methoxycarb-
onyl-4-hydroxy quinolinone, after TFA/CH2Cl2 (50/
50) cleavage. When the reaction temperature was
increased to 80 °C, we observed 80% conversion of 9a
on HPLC, along with 20% hydrolysis product. Higher
temperature or the use of anhydrous base such as
K3PO4 did not further improve the yield (Scheme 4).
Examples of the arylboronic acid coupling approach
are shown in Table 1.
Indeed, when the resin-bound 4-tosyl quinolinone 4 was
treated with organozinc halides (5 equiv) in the presence
of 10% Pd(PPh3)4 in THF at 65 °C for 14 h, the corre-
sponding cross coupling products were obtained in good
to excellent yields after TFA/CH2Cl2 cleavage (Table 2).
4-Hydroxy quinolinone starting material was observed
in less than 5%. Interestingly, arylzinc halides (entries
1–5), substituted benzylzinc halides (entries 6–9), and
alkylzinc halides (entries 10–12) all reacted smoothly
with 4-tosyl quinolinone 4 and afforded 4-aryl, benzyl,
and alkyl quinolinones. Organozinc halides with elec-
tron-donating and electron-withdrawing groups were
found to work well. Particularly, ethyl ester (entry 4)
and cyano (entry 12) functional groups survived the cou-
pling condition, and heteroaromatic zinc halide, such as
5-chloro-2-thienylzinc bromide, can also couple with 4-
tosyl quinolinone to give thiophene-substituted quinol-
inone (entry 5).
ArB(OH) (5 eq.)
2
Pd(PPh ) , 10%
3 4
TFA/CH Cl
2
2
aq. Na CO (10 eq.)
2
3
o
OTs
N
DMF, 80 C, 14h
R
COOMe
O
COOMe
O
N
H
RZnX (5 eq.)
Pd(PPh ) , 10%
3 4
In conclusion, a general method for the solid phase
synthesis of 4-hydroxy quinolinones and subsequent
Pd-catalyzed cross coupling to afford 4-substituted
quinolinones has been investigated. In this respect, we
(4)
(9)
TFA/CH Cl
2
2
o
THF, 65 C, 14h
Scheme 4. Pd-catalyzed cross coupling of 4-tosyl quinolinone.

C. Xu et al. / Tetrahedron Letters 47 (2006) 4885–4888
Table 2. Pd-catalyzed cross coupling of organozincs with 4-tosyl quinolinone 4
4887
Entry
Substitution type
Organozinca
Product
Yieldb (%)
1
Aryl
81
ZnBr
COOMe
O
N
H
F
2
Aryl
67
F
ZnBr
COOMe
O
N
H
Cl
Cl
Cl
ZnI
3
Aryl
90
COOMe
O
Cl
N
H
COOEt
4
Aryl
79
EtOOC
ZnI
COOMe
O
N
H
Cl
S
5
6
7
Aryl
74
87
75
ZnBr
COOMe
O
Cl
S
N
H
F
F
Benzyl
Benzyl
COOMe
O
ZnCl
N
H
F
F
F
F
COOMe
ZnBr
N
H
O
OMe
OMe
MeO
MeO
8
9
Benzyl
Benzyl
71
COOMe
O
ZnCl
N
H
COOMe
O
67
ZnBr
N
H
(continued on next page)

4888
C. Xu et al. / Tetrahedron Letters 47 (2006) 4885–4888
Table 2 (continued)
Entry
Substitution type
Alkyl
Organozinca
Product
Yieldb (%)
COOMe
O
10
78
ZnBr
N
H
COOMe
11
12
Alkyl
Alkyl
85
63
ZnBr
N
H
O
CN
ZnBr
NC
COOMe
O
N
H
a All organozinc reagents were purchased from Aldrich.
b Isolated yields based on 4-tosyl quinolinone 4.
8. A systematic study of solid phase synthesis of 4-hydroxy
quinolinones will be published separately.
have shown 4-hydroxy quinolinones can be readily
obtained from commercially available methyl anthrani-
lates. The Pd-catalyzed cross coupling of 4-tosyl quinoli-
nones with arylboronic acids and organozinc halides
gave 4-substituted quinolinones in high yields. It is note-
worthy that all the reactions involving arylzinc halides,
benzylzinc halides, and alkylzinc halides proceeded
under the same reaction conditions, which is ideal for
parallel and combinatorial chemistry library synthesis.
Since many organozinc reagents are commercially avail-
able or synthetically accessible, this general solid phase
synthesis can be applicable for the rapid synthesis of
4-substituted quinolinone analogs with diverse carbon-
based substituents.12
9. For comprehensive recent reviews of Pd-catalyzed cross
coupling reactions, see: (a) Negishi, E.; Hu, Q.; Huang, Z.;
Qian, M.; Wang, G. Aldrichimica Acta 2005, 38, 71; (b)
Handbook of Organopalladium Chemistry for Organic
Synthesis, Part III; Negishi, E., Ed.; Wiley-Interscience:
New York, 2002; Vol. 1, (c) Kotha, S.; Lahiri, K.;
Kashinath, D. Tetrahedron 2002, 58, 9633; (d) Metal-
Catalyzed Cross-Coupling Reactions; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004.
10. (a) Fu, J.-M.; Chen, Y.; Castelhano, A. L. Synlett 1998,
12, 1408; (b) Fu, J.-M.; Castelhano, A. L. Bioorg. Med.
Chem. Lett. 1998, 8, 2813; (c) Lipshutz, B. H.; Vivian, R.
W. Tetrahedron Lett. 1999, 40, 2871.
11. (a) Badone, D.; Cecchi, R.; Guzzi, U. J. Org. Chem. 1992,
57, 6321; (b) Schio, L.; Chatreaux, F.; Klich, M. Tetra-
hedron Lett. 2000, 41, 1543; (c) Wu, J.; Liao, Y.; Yang, Z.
J. Org. Chem. 2001, 66, 3642.
References and notes
12. General procedure for the solid phase synthesis of 4-
substituted quinolinones: The resin-bound 4-tosyl quinol-
inone (4) (250 mg, loading 0.5–0.9 mequiv/g) was sus-
pended in THF (3 mL) in an 8 mL vial, and 5 equiv 4-
(ethoxycarbonyl)phenylzinc bromide solution and 10%
Pd(PPh3)4 were added under nitrogen atmosphere. After
shaking for 14 h at 65 °C, the resin was cooled down to
room temperature, washed with DMF, 1 N HCl, THF,
and CH2Cl2. The resin was then treated with 5 mL TFA/
DCM (50/50) for 1 h to cleave the product. The resin was
removed by filtration and washed with MeOH/CH2Cl2.
The filtrates were combined and concentrated in vacuo to
give >90% pure crude product, 3-methoxycarbonyl-4-[4-
(ethoxycarbonyl)phenyl]-quinolinone. The crude product
was purified by short flush chromatography or preparative
HPLC. Sample analysis: 1H NMR (400 MHz, CDCl3,
ppm) d 1.44 (t, J = 7.2 Hz, 3H), 3.65 (s, 3H), 4.44 (q,
J = 7.2 Hz, 2H), 7.1–7.3 (m, 2H), 7.47 (d, J = 8.0 Hz, 2H),
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C
NMR (100 MHz, CDCl3, ppm) d 14.47, 52.50, 61.42,
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131.38, 132.06, 138.62, 139.29, 150.05, 160.72, 165.84,
166.16; HRMS: C20H17NO5, (m/z) calcd 352.1185 found
352.1190 (M+1).