Solution-phase combinatorial synthesis of 4-hydroxyquinolin-2(1H)-ones

Article abstract of DOI:10.1039/a709125g

Ion-exchange resins catalyse an intramolecular Claisen-type condensation leading to the title compounds, and also serve to purify the products.

Full text of DOI:10.1039/a709125g

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Solution-phase combinatorial synthesis of 4-hydroxyquinolin-2(1H)-ones
Bheemashankar A. Kulkarni and A. Ganesan*†
Institute of Molecular and Cell Biology, National University of Singapore, 30 Medical Drive, Singapore 117609
Ion-exchange resins catalyse an intramolecular Claisen-type
condensation leading to the title compounds, and also serve
to purify the products.
product in high yield and purity (Table 1). These cyclizations
proceed more readily than with the tetramic acids, as shown by
the ability of R2 = Ph and SPh to be sufficiently activating.
We have further extended this procedure to substituted
anthranilic acids (for examples, see Table 2, entries 1k–p).
Finally, the selectivity of product sequestration by the resin after
the Claisen-type condensation enables the use of crude
precursors 1 (Table 2, entries 1q–t). These were obtained
without purification after the reductive alkylation or acylation
steps, the workup consisting of only aqueous washing. The
ability to carry forward intermediates without full purification
facilitates the overall sequence for high-throughput synthesis.
In summary, this protocol is suitable for the preparation of
diverse 4-hydroxyquinolin-2(1H)-ones from commercially
available building blocks, while permitting wide variations in
the substitution pattern.
In recent years, much effort has been devoted to the synthesis of
chemical libraries, particularly for the generation and optimisa-
tion of biologically active compounds.1 High-throughput syn-
thesis by traditional solution-phase chemistry (as opposed to
solid-phase techniques) is gaining in popularity with the advent
of efficient methods for compound purification. One approach
employs polymer-supported reagents2 that can be readily
removed by filtration. Recent examples include immobilized
ScIII,3 hydroxybenzotriazole,4 carbodiimides5 and guanidines.6
Another application5,7 of polymer-supported functional groups
is to scavenge unreacted or excess starting materials in solution.
Conventional ion exchange resins have been used both as a
reagent8 as well as a purification aid,9 and we have recently
reported10 a synthesis of tetramic acids in which the resin
performs both functions. Here, we demonstrate the application
of this technique to the preparation of a pharmacologically
important heterocyclic ring system.
4-Hydroxyquinolin-2(1H)-ones have attracted considerable
attention for various therapeutic areas including antimicrobial
and antitumour activity,11 local anaesthetics12 and antiin-
flammatory agents,13 as well as being antagonists of thyroid
hormone,14 N-methyl-d-aspartate15 and serotonin.16 A common
route to these compounds is the intramolecular Claisen-type
condensation of N-acylated anthranilate esters. Various bases
were used17 for the cyclization (e.g. NaOH, alkoxides, lithium
amides, TBAF), but removing these and other impurities is
relatively tedious in the context of parallel synthesis. We
envisioned that an insoluble quaternary ammonium resin would
be more suitable, as in our tetramic acid synthesis.
OH
R2
CO2Me
NH2
CO2Me
O
ii, iii
i
R2
N
N
O
R1
R1
1a–d (R1 = H)
2a–d (R1 = H)
CO2Me
CO2Me
NH2
iv
NH
OH
R1
i
R2
O
CO2Me
We prepared a set of Claisen-type condensation precursors
from methyl anthranilate by Schotten–Baumann two-phase
acylation to give primary amides 1a–d (Scheme 1). For
increased diversity, additional examples were first reductively
alkylated18 before acylation to afford secondary amides 1e–j.
Treatment of compounds 1 with Amberlyst A-26 resin (OH2
form) uniformly resulted in cyclization. As expected, the
4-hydroxyquinolin-2(1H)-ones 2 remain tightly bound to the
quaternary ammonium resin, enabling impurities to be removed
by simple filtration. Subsequent acidification then releases the
ii, iii
O
R2
N
N
R1
R1
1e–j
2e–j
Scheme 1 Reagents and conditions: i, R2CH2COCl, 10% aq. Na2CO3–
CH2Cl2, room temp., 30 min; ii, Amberlyst A-26 (OH2 form), MeOH,
room temp., 16 h; iii, TFA, MeOH, room temp., 30 min; iv, R1CHO,
NaBH(OAc)3, CH2Cl2, room temp., 18 h
Table 1 Yield and purity of 4-hydroxyquinolin-2(1H)-ones prepared by the intramolecular Claisen-type condensation
Precursor
R1
R2
Product
Yield (%)
Puritya (%)
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
H
H
H
CN
3-pyridyl–S
SPh
Ph
SPh
2-NO2C6H4
CO2Me
2-NO2C6H4
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
82
78
80
86
94
96
89
96
89
91
98
97
99
85
94
95
95
94
95
99
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
CH2CHMe2
4-MeOC6H4
Ph
1j
SPh
2l
a Assessed by HPLC analysis with UV detection (254 nm). All compounds were characterised spectroscopically (NMR, MS).
Chem. Commun., 1998
785

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Table 2 Yield and purity of additional 4-hydroxyquinolin-2(1H)-ones prepared
OH
(i) Amberlyst A-26
CO2Me
O
R1
R2
R4
O
R1
R2
(OH– form)
R4
(ii) TFA, MeOH
N
N
R3
R3
2k–t
1k–t
Precursor
R1
R2
R3
R4
Product
Yield (%)
Puritya (%)
1k
1l
1m
1n
1o
1p
1qb
1rb
1sb
1tb
H
H
H
F
H
OMe
H
H
H
H
H
Cl
F
CO2Me
OMe
H
H
H
H
Me
Ph
Bn
Bn
Bn
Ph
SPh
2k
2l
86
91
89
90
88a
72
84
97
83
92
98
97
79
95
97
91
90
97
91
95
CO2Me
CO2Me
Ph
CO2Me
CO2Me
CO2Me
SPh
2m
2n
2o
2p
2q
2r
2s
4-MeOC6H4CH2
H
Me
4-MeOC6H4CH2
Bn
H
SPh
2t
a
Two products were isolated (ca. 1 :1 ratio), due to the partial hydrolysis of the ester (R2 = CO2Me to CO2H). b Crude material used without
chromatographic purification after either the reductive alkylation or acylation.
1997, 553; M. G. Siegel, P. J. Hahn, B. A. Dressman, J. E. Fritz, J. R.
Grunwell and S. W. Kaldor, Tetrahedron Lett., 1997, 38, 3357; A. J.
Shuker, M. G. Siegel, D. P. Matthews and L. O. Weigel, Tetrahedron
Lett., 1997, 38, 6149.
This work was supported by funds from the National Science
and Technology Board of Singapore. Dedicated to Professor M.
Vandewalle on the occasion of his 65th Birthday.
10 B. A. Kulkarni and A. Ganesan, Angew. Chem., Int. Ed. Engl., 1997, 36,
2454.
Notes and References
11 M. Rideau, C. Verchere, P. Hibon, J.-C. Chenie´ux, P. Maupas and C.
Veil, Phytochemistry, 1979, 18, 155.
12 I. V. Ukrainets, S. V. Slobodzyan, V. I. Krivobok, P. A. Bezuglyi, V. I.
Treskach, A. V. Turov, S. V. Gladchenko and G. V. Obolenteseva,
Farm. Zh. (Kiev), 1991, 2, 78.
† E-mail: mcbgane@imcb.nus.edu.sg
1 For recent journal issues devoted to combinatorial chemistry, see:
Chem. Rev., 1997, 97, Issue 2; Curr. Opin. Chem. Biol., 1997, 1, Issue
1.
2 For a review on functionalised polymers including combinatorial
chemistry applications, see S. J. Shuttleworth, S. M. Allin and P. K.
Sharma, Synthesis, 1997, 1217.
3 S. Kobayashi and S. Nagayama, J. Am. Chem. Soc., 1996, 118, 8977; S.
Kobayashi, S. Nagayama and T. Busujima, Tetrahedron Lett., 1996, 37,
9221.
4 I. E. Pop, B. P. De´prez and A. L. Tartar, J. Org. Chem., 1997, 62,
2594.
5 D. L. Flynn, J. Z. Crich, R. V. Devraj, S. L. Hockerman, J. J. Parlow,
M. S. South and S. Woodard, J. Am. Chem. Soc., 1997, 119, 4874; J. J.
Parlow, D. A. Mischke and S. S. Woodard, J. Org. Chem., 1997, 62,
5908.
13 I. V. Ukrainets, O. V. Gorokhava, S. G. Taran and A. V. Turov, Khim.
Geterotsikl. Soedin., 1994, 1397.
14 I. V. Ukrainets, P. A. Bezugly, O. V. Borokhova, V. I. Treskach and
A. V. Turov, Khim. Geterotsikl. Soedin., 1993, 105.
15 P. D. Leeson, R. Baker, R. W. Carling, J. J. Kulagowski, I. M. Mawer,
M. P. Ridgill, M. Rowley, J. D. Smith, I. Stansfield, G. I. Stevenson,
A. C. Foster and J. A. Kemp, Bioorg. Med. Chem. Lett., 1993, 3, 299; M.
Rowley, P. D. Leeson, G. I. Stevenson, A. M. Moseley, I. Stansfield, I.
Sanderson, L. Robinson, R. Baker, J. A. Kemp, G. R. Marshall, A. C.
Foster, S. Grimwood, M. D. Tricklebank and K. L. Saywell, J. Med.
Chem., 1993, 36, 3386; J. J. Kulagowski, R. Baker, N. R. Curtis, P. D.
Leeson, I. M. Mawer, A. M. Moseley, M. P. Ridgill, M. Rowley, I.
Stansfield, A. C. Foster, S. Grimwood, R. G. Hill, J. A. Kemp, G. R.
Marshall, K. L. Saywell and M. D. Tricklebank, J. Med. Chem., 1994,
37, 1402.
16 H. Hayashi, Y. Miwa, S. Ichikawa, N. Yoda, I. Miki, A. Ishii, M. Kono,
T. Yasuzawa and F. Suzuki, J. Med. Chem., 1993, 36, 617.
17 A. Detsi, V. Bardakos, J. Markopoulos and O. Igglessi- Markapoulou,
J. Chem. Soc., Perkin Trans. 1, 1996, 2909 and references cited
therein.
6 W. Xu, R. Mohan and M. M. Morrissey, Tetrahedron Lett., 1997, 38,
7337.
7 S. W. Kaldor, M. G. Siegel, J. E. Fritz, B. A. Dressman and P. J. Hahn,
Tetrahedron Lett., 1996, 37, 7193; S. W. Kaldor, J. E. Fritz, J. Tang and
E. R. McKinney, Bioorg. Med. Chem. Lett., 1996, 6, 3041; R. J. Booth
and J. C. Hodges, J. Am. Chem. Soc., 1997, 119, 4882;J. J. Parlow, W.
Naing, M. S. South and D. L. Flynn, Tetrahedron Lett., 1997, 38, 7959;
M. M. Sim, C. L. Lee and A. Ganesan, J. Org. Chem., 1997, 62,
9358.
8 J. J. Parlow, Tetrahedron Lett., 1996, 37, 5257.
9 L. M. Gayo and M. J. Suto, Tetrahedron Lett., 1997, 38, 513; R. M.
Lawrence, S. A. Biller, O. M. Fryszman and M. A. Poss, Synthesis,
18 A. K. Szardenings, T. S. Burkoth, G. C. Look and D. A. Campbell,
J. Org. Chem., 1996, 61, 6720.
Received in Cambridge, UK, 22nd December 1997; 7/09125G
786
Chem. Commun., 1998