Novel solid-phase synthetic method for combinatorial generation of a 4-hydroxyquinolin-2(1H)-one-based library

Article abstract of DOI:10.1055/s-2007-980368

Utilizing polymer-bound anthranilic acid derivatives, we were able to obtain 4-hydroxyquinolin-2(1H)-ones in 50-99% five-or six-step overall yields and 65-95% purities through the adaptation of a Dieckmann-type condensation reaction to a C-C bond-forming

Full text of DOI:10.1055/s-2007-980368

LETTER
1431
Novel Solid-Phase Synthetic Method for Combinatorial Generation of a
4-Hydroxyquinolin-2(1H)-one-Based Library
C
ombinatorial Generat
o
ion of 4-Hyd
o
roxyquinoli
n
H
)-one-
-
Based L
K
a
Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, South Korea
Fax +82(42)8607698; E-mail: ydgong@krict.re.kr
b
Department of Chemistry, Korea University, Seoul 151-742, South Korea
Received 19 March 2007
O
X
O
O
Ph
Abstract: Utilizing polymer-bound anthranilic acid derivatives, we
were able to obtain 4-hydroxyquinolin-2(1H)-ones in 50–99% five-
or six-step overall yields and 65–95% purities through the adapta-
tion of a Dieckmann-type condensation reaction to a C–C bond-
forming cyclative cleavage step. The reactions on solid phase were
monitored by on-bead ATR-FTIR spectroscopic methods, colori-
metric tests, and/or cleavage experiments.
O
NH2
N
OMe
NH2
2
1
O
O
H
Key words: combinatorial chemistry, solid-phase synthesis, quino-
linone, Dieckmann condensation, cyclative cleavage
R
Ph
N
R
N
N
X
O
N
CN
N
CN
3
3'
Solid-phase synthesis of combinatorial libraries has
emerged as a powerful tool for an efficient drug discovery
process.1 In particular, derivation of various core struc-
tures with the same or different substituents from a versa-
tile intermediate resin has been an interesting strategy for
the construction of small molecule libraries on solid
O
R1
N
X
R2
O
N
4
phase, in that varying the scaffold as well as the substitu- Figure 1
ents might further increase the diversity of the libraries
compared to relying on a single scaffold.2 The strategy has
been called skeletal diversity generation in diversity-
oriented synthesis (DOS),2d combinatorial scaffold ap-
proach,2c and multiple core structure library approach,2b
with subtle differences among them in their capacities. In
this context, we have recently been exploring the potential
of resin-bound anthranilic acid derivatives 1 and 2 as
versatile intermediates for combinatorial generation of
drug-like heterocyclic compound libraries.3 Previously,
we reported the preparation of the intermediate resins 1
and 2 and the solid-phase synthesis of 2-cyanoquinazolin-
4(3H)-ones 3 and 3¢, and 2,3-dihydrooxazolo[2,3-
b]quinazolin-5-ones 4 from the resins3a (Figure 1). Herein
we would like to present the novel solid-phase synthetic
method for combinatorial generation of 4-hydroxyquino-
lin-2(1H)-one-based library from resin-bound anthranilic
acid derivatives 1 together with monitoring of the solid-
phase reactions by ATR (attenuated total reflection)-FTIR
spectroscopy, colorimetric tests, and/or cleavage experi-
ments.
tic,4b GnRH receptor antagonistic,4c antiangiogenic,4d and
antinephritic4e activities. The solution-phase synthetic
methods for 4-hydroxyquinolin-2(1H)-one derivatives
may be primarily divided into three categories from the
viewpoint of the skeleton construction: (i) condensation
of anilines with malonates,5 (ii) Dieckmann-type conden-
sation of N-acylated anthranilate esters,6 (iii) condensa-
tion of isatoic anhydrides4d,e,7a,b or 4H-3,1-benzoxazin-4-
ones7c with acetic esters. Some other methods have also
been reported involving such intermediates as furan-2,3-
dione,8a 4-hydroxycoumarin,8b 2¢-aminoacetophenone,8c
and 2-nitrobenzoic acid.8d On the other hand, there has
been only one report regarding the solid-phase methods
for combinatorial synthesis of 4-hydroxyquinolin-2(1H)-
one derivatives:9 condensation of Wang resin-bound cy-
anoacetic acid with isatoic anhydrides or their N-alkylated
derivatives.9a As a novel approach to solid-phase synthe-
sis of 4-hydroxyquinolin-2(1H)-one derivatives, we envi-
sioned that the resin-bound anthranilic acid derivatives 1
could be adapted to the second solution-phase protocol
mentioned above, Dieckmann-type condensation of N-
acylated anthranilate esters, encompassing more diverse
substituents at 3-position of 4-oxyquinolin-2(1H)-one
skeleton and introducing the alkyl substituents at its 1-po-
sition on solid phase (Scheme 1).
During the past decade 4-hydroxyquinolin-2(1H)-ones
and their derivatives have attracted much attention for
their interesting biological activities including glycine/
NMDA receptor antagonistic,4a 5HT3 receptor antagonis-
SYNLETT 2007, No. 9, pp 1431–1435
Advanced online publication: 23.05.2007
DOI: 10.1055/s-2007-980368; Art ID: U02207ST
© Georg Thieme Verlag Stuttgart · New York
0
1.
0
6.
2
0
0
7
The resin-bound anthranilic acid derivatives 1 were pre-
pared from coupling of Wang resin 5 with 2-nitrobenzoic
acids10 (2 equiv) in the presence of DIC (3 equiv) and

1432
M.-K. Jeon et al.
LETTER
O
X
O
O
X
O
SnCl2·2H2O
2-nitrobenzoic acid
NO2
NH2
OH
DMF
DIC, DMAP
CH2Cl2, DMF
r.t.
80 °C
5
1
6
R2
O
O
O
O
X
O
H
R2CH2CO2H
R1CHO
R1
N
R1
N
POCl3, py
CH2Cl2
r.t.
NaBH(OAc)3
DCE
r.t.
X
7
8
OH
N
i) KHMDS
THF, r.t.
R2
O
X
ii) H+
Me2NH·HCl
N
KI, DIPEA
R1
O
O
9
DMF, 60 °C
O
N
for 8 (X = H, R1 = Ph, R2 = Cl)
8 (X = H, R1 = Ph, R2 = NMe2)
Scheme 1
DMAP (3 equiv) in CH2Cl2–DMF (4:1) at room tempera- DMAP; 3 equiv/cat.) combinations for the reaction of the
ture and subsequent reduction of the resultant resins 6 resin 7 (X = H, R1 = Ph) with 4-methoxyphenylacetic acid
with SnCl2·2H2O (10 equiv) in DMF at 80 °C (Scheme 1 in CH2Cl2 at room temperature or elevated temperature.12
and Table 1) according to the previously reported proce- The POCl3/pyride (3 equiv/6 equiv) or NCS/PPh3/pyri-
dure.3a Treatment of the resins 1 with aldehyde building dine (3 equiv/3 equiv/6 equiv) conditions at room temper-
blocks (3 equiv) under typical reductive alkylation condi- ature gave the desired intermediate resin 8 (X = H,
tions [in the presence of NaBH(OAc)3 (3 equiv) in DCE] R1 = Ph, R2 = 4-MeOC6H4), for which the on-bead ATR-
at room temperature gave the N-alkylated anthranilate FTIR spectrum showed two carbonyl bands at 1722 (O–
resins 7. The progress of the reductive alkylation step was C=O, shift from 1680 cm–1 to a higher frequency due to
monitored
utilizing
both
on-bead
ATR-FTIR loss of intramolecular hydrogen bonding with N–H) and
spectroscopy11 and cleavage experiment. As exemplified 1660 (N–C=O) cm–1 with the disappearance of a NH band
in Figure 2, a NH2 band (3485–3490 cm–1) observed on confirming the complete transformation as shown in
the IR spectra of the resins 1 disappeared as the reactions Figure 2. Meanwhile, the other conditions did not bring
proceeded. However, the IR data were insufficient to con- any change on the IR spectrum of the resin 7 (X = H,
firm the completion of the reactions due to the weakness R1 = Ph) at room temperature or reflux. The POCl3/pyri-
of the N–H bands. In order to confirm the reaction com- dine (3 equiv/6 equiv) system in CH2Cl2 at room temper-
pleteness, we performed a cleavage experiment involving ature was selected as a standard taking into account of its
methanolysis of resins 7 by the use of NaOMe/MeOH (3 handling simplicity and could successfully be applied to
equiv) in THF at room temperature. For example, the the coupling of resins 7 with variously substituted acetic
methanolysis of resin 7 (X = H, R1 = Ph) gave methyl 2- acids (Table 1, R2) except dimethylaminoacetic acid
benzylaminobenzoate in 80% yield, with a satisfactory (R2 = NMe2), which resulted in no reaction based on the
purity when judged on the basis of its 1H NMR spectrum. inspection of IR spectrum of the resin. So, the dimeth-
ylaminoacetyl derivative resin 8 (X = H, R1 = Ph,
For the next acylation step, we selected monosubstituted
acetic acid building blocks as acetyl group source instead
of the corresponding acetyl chlorides considering the
former broader commercial availability compared with
R2 = NMe2) was prepared from the reaction of the chloro-
acetyl resin 8 (X = H, R1 = Ph, R2 = Cl) with dimethylam-
monium chloride (3 equiv) in the presence of DIPEA (6
equiv) and a catalytic amount of KI in DMF at 80 °C as
that of the latter. We examined a variety of reaction con-
shown in Scheme 1. The progress of the reaction was
ditions such as POCl3/pyridine (3 equiv/6 equiv), NCS/
checked by a fluorescein test13 combined with ATR-FTIR
PPh3/pyridine (3 equiv /3 equiv/6 equiv), NBS/PPh3/pyri-
spectroscopy. The resin 8 (X = H, R1 = Ph, R2 = NMe2)
dine (3 equiv/3 equiv/6 equiv), NIS/PPh3/pyridine (3
equiv/3 equiv/6 equiv), Br2PPh3/pyridine (3 equiv/6
equiv), CDI (3 equiv), CMPI/pyridine (3 equiv/3 equiv),
showed a negative response for the test and exhibited the
same IR spectrum before and after the test.
DPPA (3 equiv), and DIC (DCC or EDC)/HOBT (or
Synlett 2007, No. 9, 1431–1435 © Thieme Stuttgart · New York

LETTER
Combinatorial Generation of a 4-Hydroxyquinolin-2(1H)-one-Based Library
Table 1 Yields and Purities of Compounds 9
1433
Com-
pound
X
R1
R2
Yield
Purity
(%/%)a (%/%)b
9a
9b
9c
9d
9e
9f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
4-MeOC6H4 68/53
91/99
91/99
93/96
75/97
92/98
87/93
80/95
84/92
93/99
83/94
88/99
89/94
79/97
94/98
90/95
65/98
–
Ph
Ph
65/44
66/50
73/51
66/44
63/55
68/45
59/46
61/52
95/59
99/52
58/36
76/43
Ph
4-FC6H4
4-O2NC6H4
4-MeOBn
Bn
Ph
Ph
Ph
9g
9h
9i
Ph
4-F-Bn
Et
Ph
Ph
Me2N
MeO
MeS
9j
Ph
9k
9l
Ph
Ph
Cl
9m
9n
9o
9p
9q
9r
9s
Ph
CN
4-FC6H4
4-FC6H4
4-MeOC6H4 66/55
4-MeOBn 60/43
4-O2NC6H4 4-MeOC6H4 66/31
4-O2NC6H4 4-MeOBn
4-MeOC6H4 4-MeOC6H4 61/50
4-MeOC6H4 4-MeOBn 70/35
4-MeOC6H4 65/49
4-MeOBn 71/47
4-MeOC6H4 61/34
4-MeOBn 50/22
4-MeOC6H4 78/60
4-MeOBn 76/55
–
94/98
88/92
92/95
84/94
76/94
70/96
95/97
89/96
9t
i-Pr
i-Pr
9u
9v
9w
9x
9y
6-MeO Ph
6-MeO Ph
6-Cl
6-Cl
Ph
Ph
a Five- or six-step overall crude/isolated yields from Wang resin
(loading capacity 1.00 or 0.92 mmol/g).
Figure 2
b Determined on the basis of LC-UV(200–400 nm)-MS spectrum of
crude/isolated products.
For utilization of Dieckmann-type condensation
reaction14 as C–C bond-forming cyclative cleavage15 step,
several bases (3 equiv) were screened at room temperature
for the two resins 8 (X = H, R1 = Ph, R2 = 4-MeOC6H4
and 4-MeOBn) under the conditions such as NaOMe/
MeOH in THF, KOt-Bu/t-BuOH in THF, aq NaOH in
THF, LHMDS in THF, KHMDS in THF, LDA in THF,
and NaH in DMF or DMSO. Among the examined condi-
tions, KHMDS (3 equiv) in THF at room temperature was
concluded to give the best results for both resins in terms
of yield and purity of product and reaction time.16 The sys-
tem was selected as a standard cleavage condition and
gave satisfactory results for the various acetyl derivative
resins 8 having alkyl, dialkylamino, alkoxy, alkylthio,
chloro, and cyano substituents as well as aryl and benzyl
groups to afford 4-hydroxyquinolin-2(1H)-one deriva-
tives 9 in 50–99% five- or six-step overall yields and 65–
95% purities. Exceptionally, the resin 8q gave a complex
mixture, from which any identifiable product could not be
isolated. The progress of the cleavage step was checked
by ATR-FTIR spectroscopy as exemplified in Figure 2,
where the resins showed nearly the same fingerprints as
the Wang resin 5 after the cleavage reactions. The yields
Synlett 2007, No. 9, 1431–1435 © Thieme Stuttgart · New York

1434
M.-K. Jeon et al.
LETTER
(5) For examples, see: (a) Laschober, R.; Stadlbauer, W.
and purities of the crude and purified products 9 are
summarized in Table 1.17 The compounds 9 are unknown
except 9b,18a 9f,18b 9i,18c 9l,18d and 9m,9a and all final
Liebigs Ann. Chem. 1990, 1083. (b) Lange, J. H. M.;
Verveer, P. C.; Osnabrug, S. J. M.; Visser, G. M.
Tetrahedron Lett. 2001, 42, 1367. (c) Xiao, Z.; Waters, N.
C.; Woodard, C. L.; Li, Z.; Li, P.-K. Bioorg. Med. Chem.
Lett. 2001, 11, 2875.
1
products 9a–y were characterized on the basis of H
NMR, (13C NMR) and LC-UV-MS spectral data.
(6) For examples, see: (a) Ukrainets, I. V.; Taran, S. G.;
Gorokhova, O. V.; Kodolova, O. L.; Turov, A. V. Khim.
Geterotsikl. Soedin 1997, 33, 928. (b) Kulkarni, B. A.;
Ganesan, A. Chem. Commun. 1998, 785. (c) DeVita, R. J.;
Goulet, M. T.; Wyvratt, M. J.; Fisher, M. H.; Lo, J.-L.; Yang,
Y. T.; Cheng, K.; Smith, R. G. Bioorg. Med. Chem. Lett.
1999, 9, 2621. (d) Walsh, T. F.; Toupence, R. B.; Young, J.
R.; Huang, S. X.; Ujjainwalla, F.; DeVita, R. J.; Goulet, M.
T.; Wyvratt, M. J. Jr.; Fisher, M. H.; Lo, J.-L.; Ren, N.;
Yudkovitz, J. B.; Yang, Y. T.; Cheng, K.; Smith, R. G.
Bioorg. Med. Chem. Lett. 2000, 10, 443. (e) Spears, G. W.;
Tsuji, K.; Tojo, T.; Nishimura, H.; Ogino, T. J. Heterocycl.
Chem. 2002, 39, 799.
(7) For examples, see: (a) Ismaili, L.; Refouvelet, B.; Robert, J.
F. J. Heterocycl. Chem. 1999, 36, 719. (b) Tojo, T.; Spears,
G. W.; Tsuji, K.; Nishimura, H.; Ogino, T.; Seki, N.;
Sugiyama, A.; Matsuo, M. Bioorg. Med. Chem. Lett. 2002,
12, 2427. (c) Mitsos, C. A.; Zografos, A. L.; Igglessi-
Markopoulou, O. J. Org. Chem. 2003, 68, 4567.
In brief, we were able to establish a novel solid-phase
synthetic method for 4-hydroxyquinolin-2(1H)-one
derivatives 9 utilizing polymer-bound anthranilic acid
derivatives 1, securing sufficient functional group com-
patibility at 3-position of the skeleton, and introducing
alkyl substituents at its 1-position on solid phase, suitable
for library generation without amendment or with some
modifications. The reactions on solid phase were checked
by single-bead ATR-FTIR spectroscopic methods, colori-
metric tests, and/or cleavage experiments. Now we are
pursuing modified forms of the protocol, useful for con-
struction of target-directed 4-hydroxyquinolin-2(1H)-
one-based libraries. In addition, the investigation into ef-
ficient methods for other heterocyclic compounds utiliz-
ing the resin-bound anthranilic acid derivatives 1 and 2 is
in progress.
(8) (a) Borowiec, H.; Grochowski, J.; Serda, P. J. Chem. Res.,
Synop. 1996, 248. (b) El Kihel, A.; Benchidmi, M.; Essassi,
E. M.; Bauchat, P.; Danion-Bougot, R. Synth. Commun.
1999, 29, 2435. (c) Jung, J.-C.; Jung, Y.-J.; Park, O.-S.
Synth. Commun. 2001, 31, 1195. (d) Jung, J.-C.;Jung, Y.-J.;
Park, O.-S. J. Heterocycl. Chem. 2001, 38, 61.
(9) (a) Sim, M. M.; Lee, C. L.; Ganesan, A. Tetrahedron Lett.
1998, 39, 6399. (b) Xu, C.; Yang, L.; Bhandari, A.; Holmes,
C. P. Tetrahedron Lett. 2006, 47, 4885: The recent report
described the solid-phase synthesis of 3-carbomethoxy-4-
hydoxyquinolin-2(1H)-one bound to a resin through the
bonding to nitrogen at 1-position as an intermediate resin for
introduction of carbon-based substituents at 4-position of
quinolin-2(1H)-one skeleton.
Acknowledgment
We are grateful to Seoul Research and Business Development Pro-
gram (grant number 10574), the Center for Biological Modulators,
and Korea Research Institute of Chemical Technology for financial
support of this research.
References and Notes
(1) Dolle, R. E.; Le Bourdonnec, B.; Morales, G. A.; Moriarty,
K. J.; Salvino, J. M. J. Comb. Chem. 2006, 8, 597.
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(3) (a) Jeon, M.-K.; Kim, D.-S.; La, H. J.; Ha, D.-C.; Gong, Y.-
D. Tetrahedron Lett. 2005, 46, 7477. (b) Jeon, M.-K.; Kim,
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4979.
(4) (a) Rowley, M.; Kulagowski, J. J.; Watt, A. P.; Rathbone,
D.; Stevenson, G. I.; Carling, R. W.; Baker, R.; Marshall, G.
R.; Kemp, J. A.; Foster, A. C.; Grimwood, S.; Hargreaves,
R.; Hurley, C.; Saywell, K. L.; Tricklebank, M. D.; Leeson,
P. D. J. Med. Chem. 1997, 40, 4053. (b)Hayashi, H.; Miwa,
Y.; Ichikawa, S.; Yoda, N.; Miki, I.; Ishii, A.; Kono, M.;
Yasuzawa, T.; Suzuki, F. J. Med. Chem. 1993, 36, 617.
(c) DeVita, R. J.; Walsh, T. F.; Young, J. R.; Jiang, J.;
Ujjainwalla, F.; Toupence, R. B.; Parikh, M.; Huang, S. X.;
Fair, J. A.; Goulet, M. T.; Wyvratt, M. J.; Lo, J.-L.; Ren, N.;
Yudkovitz, J. B.; Yang, Y. T.; Cheng, K.; Cui, J.; Mount, G.;
Rohrer, S. P.; Schaeffer, J. M.; Rhodes, L.; Drisko, J. E.;
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(d) Khan, S. R.; Mhaka, A.; Pili, R.; Isaacs, J. T. Bioorg.
Med. Chem. Lett. 2001, 11, 451. (e) Tsuji, K.; Spears, G.
W.; Nakamura, K.; Tojo, T.; Seki, N.; Sugiyama, A.;
Matsuo, M. Bioorg. Med. Chem. Lett. 2002, 12, 85.
(10) In addition to commercially available 2-nitrobenzoic acids,
they can be prepared from the regioselective nitration of
benzoic acids, the oxidation of o-nitrotoluenes, 2-
nitrobenzyl alcohols, 2-nitrobenzaldehydes, and 2¢-
nitroacetophenones, and the substitutions of halogenated 2-
nitrobenzoic acids. On the other hand, variation of the X
group would be possible for the resin-bound 2-nitrobenzoic
acid derivatives 6 and will be reported elsewhere. For
examples of the nitration, see ref. 8d and: (a) Coppola, G.
M.; Schuster, H. F. J. Heterocycl. Chem. 1989, 26, 957.
(b) Cotelle, P.; Catteau, J. P. Synth. Commun. 1996, 26,
4105. (c) Thurston, D. E.; Bose, D. S.; Thompson, A. S.;
Howard, P. W.; Leoni, A.; Croker, S. J.; Jenkins, T. C.;
Neidle, S.; Hartley, J. A.; Hurley, L. H. J. Org. Chem. 1996,
61, 8141. (d) Gregson, S. J.; Howard, P. W.; Thurston, D. E.
Bioorg. Med. Chem. Lett. 2003, 13, 2277. For examples of
the oxidation, see: (e) Yamazaki, S. Synth. Commun. 1999,
29, 2211. (f) Sawatari, N.; Sakaguchi, S.; Ishii, Y.
Tetrahedron Lett. 2003, 44, 2053. (g) Venturello, C.;
Cambaro, M. J. Org. Chem. 1991, 56, 5924. (h) Singh, M.;
Singh, K. N.; Dwivedi, S.; Misra, R. A. Synthesis 1991, 291.
(i) Das, S.; Punniyamurthy, T. Tetrahedron Lett. 2003, 44,
6033. (j) De Luca, L.; Giacomelli, G.; Masala, S.;
Porcheddu, A. J. Org. Chem. 2003, 68, 4999. (k) Madler,
M. M.; Klucik, J.; Soell, P. S.; Brown, C. W.; Liu, S.; Berlin,
K. D.; Benbrook, D. M.; Birckbichler, P. J.; Nelson, E. C.
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K. R.; Mohanta, P. K.; Ila, H.; Junjappa, H. Synth. Commun.
Synlett 2007, No. 9, 1431–1435 © Thieme Stuttgart · New York

LETTER
Combinatorial Generation of a 4-Hydroxyquinolin-2(1H)-one-Based Library
1435
1999, 29, 3781. (m) Anjum, A.; Srinivas, P. Chem. Lett.
2001, 900. (n) Balicki, R. Synth. Commun. 2001, 31, 2195.
(17) Representative Procedure for Preparation of
Compounds 9
(o) For an example of the substitution, see ref. 4e.
(11) Yan, B. Acc. Chem. Res. 1998, 31, 621.
Preparation of 2-Benzylaminobenzoate Resin (7a;
X = H, R1 = Ph)
(12) With respect to acylation of N-alkylanthranilates with acetic
acids, the conditions used in solution phase were pivaloyl
chloride, pyridine, and MS in CH2Cl2 at r.t. for coupling of
2-methylaminobenzoates with thiocarbamoylacetic acids,6e
EDC in THF at r.t. for reaction of 2-methylaminobenzoates
with mono-tert-butyl malonate and cyanoacetic acid, and in
POCl3 at 80 °C for the reaction of benzyl 2-benzylamino-
benzoate and (3-methylisoxazol-5-yl)acetic acid. See:
(a) Blackburn, C.; LaMarche, M. J.; Brown, J.; Che, J. L.;
Cullis, C. A.; Lai, S.; Maguire, M.; Marsilje, T.; Geddes, B.;
Govek, E.; Kadambi, V.; Doherty, C.; Brian, D.; Brodjian,
S.; Marsh, K. C.; Collins, C. A.; Kym, P. R. Bioorg. Med.
Chem. Lett. 2006, 16, 2621. (b) Wall, M. J.; Player, M. R.;
Patch, R. J.; Meegalla, S.; Liu, J.; Illig, C. R.; Cheung, W.;
Chen, J.; Asgari, D. WO 2005009967, 2005; Chem. Abstr.
2005, 142, 197893.
To a mixture of the resin 1a (X = H; 4.00 g, theoretically
3.59 mmol), prepared from Wang resin (1.00 mmol/g), and
benzaldehyde (1.14 g, 10.8 mmol) in DCE (60 mL) at r.t.
was added NaBH(OAc)3 (2.28 g, 10.8 mmol). The mixture
was stirred at r.t. for 12 h and the resin was filtered, washed
several times with CH2Cl2, DMF, MeOH, H2O, and MeOH,
and dried in a vacuum oven to give 7a (4.30 g, 99%): on-
bead ATR-FTIR: 3365 (NH), 3025, 2922, 1680 (C=O),
1602, 1581, 1512, 1492, 1451, 1221, 1172, 1097, 822, 750,
697 cm–1.
Preparation of 2-{Benzyl[3-(4-methoxyphenyl)acet-
yl]amino}benzoate Resin (8a; X = H, R1 = Ph, R2 = 4-
MeOC6H4)
To a mixture of the resin 7a (X = H, R1 = Ph; 1.00 g,
theoretically 0.830 mmol) and 4-methoxyphenylacetic acid
(413 mg, 2.49 mmol) in CH2Cl2 (30 mL) at r.t. was added
pyridine (391 mg, 4.98 mmol) and phosphorus oxychloride
(385 mg, 2.49 mmol). The mixture was stirred at r.t. for 2 h
and the resin was filtered, washed several times with
CH2Cl2, DMF, MeOH, H2O, and MeOH, and dried in a
vacuum oven to give 8a (1.09 g, 97%): on-bead ATR-FTIR:
3026, 2921, 1719 (O–C=O), 1662 (N–C=O), 1605, 1510,
1492, 1448, 1380, 1243, 1176, 1078, 1025, 822, 755, 697
cm–1.
(13) Gaggini, F.; Porcheddu, A.; Reginato, G.; Rodriquez, M.;
Taddei, M. J. Comb. Chem. 2004, 6, 805.
(14) Since the seminal contributions of Rapoport to the solid-
phase unidirectional Dieckmann reaction, Dieckmann-type
condensation reaction has been utilized for the solid-phase
synthesis of tetramic acid derivatives. See: (a) Crowley, J.
I.; Rapoport, H. J. Am. Chem. Soc. 1970, 92, 6363.
(b) Crowley, J. I.; Rapoport, H. J. Org. Chem. 1980, 45,
3215. (c) Matthews, J.; Rivero, R. A. J. Org. Chem. 1998,
63, 4808. (d) Weber, L.; Iaiza, P.; Biringer, G.; Barbier, P.
Synlett 1998, 1156. (e) Romoff, T. T.; Ma, L.; Wang, Y.;
Campbell, D. A. Synlett 1998, 1341. (f) Kulkarni, B. A.;
Ganesan, A. Tetrahedron Lett. 1998, 39, 4369. (g) Fitch, D.
M.; Evans, K. A.; Chai, D.; Duffy, K. J. Org. Lett. 2005, 7,
5521. (h) Evans, K. A.; Chai, D.; Graybill, T. L.; Burton, G.;
Sarisky, R. T.; Lin-Goerke, J.; Johnston, V. K.; Rivero, R. A.
Bioorg. Med. Chem. Lett. 2006, 16, 2205.
(15) For a recent review on cyclative cleavage strategy, see:
Pernerstorfer, J. In Combinatorial Chemistry; Bannwarth,
W.; Hinzen, B., Eds.; Wiley-VCH: Weinheim, 2006, 111–
142.
(16) Another reason for selection of KHMDS as a standard base
was the known favorable character of potassium enolates for
O-alkylation, which is needed to obtain the 4-alkoxy
derivatives in high purities through a subsequent in situ
alkylation of the cleaved products. The study on the efficient
alkylation is in progress using polymer-supported alkylating
agents and will be reported elsewhere.
Preparation of 1-Benzyl-4-hydroxy-3-(4-methoxy-
phenyl)-1H-quinolin-2-one (9a; X = H, R1 = Ph, R2 = 4-
MeOC6H4)
To a suspension of the resin 8a (X = H, R1 = Ph, R2 = 4-
MeOC6H4; 100 mg, theoretically 0.0739 mmol) in THF (3
mL) at r.t. was added 0.5 M KHMDS in toluene (0.440 mL,
0.227 mmol) and the mixture was stirred at r.t. for 6 h. The
mixture was filtered and washed with MeOH (about 10 mL).
The filtrate was evaporated in vacuo, acidified to pH 4–5
with 3 N HCl, and extracted with EtOAc (2 × 3 mL). The
organic layer was dried over MgSO4. The solvent was
evaporated in vacuo and the residue (18 mg, 68%; 91%
purity on the basis of LC-UV-MS spectrum) was purified by
a silica gel column chromatography (n-hexane–EtOAc, 2:1)
to afford 9a (14 mg, 53%; 99% purity on the basis of LC-
UV-MS spectrum): 1H NMR (500 MHz, CDCl3): d = 3.86 (s,
3 H), 5.56 (br s, 2 H), 7.05 (d, J = 8.7 Hz, 2 H), 7.20–7.23
(m, 2 H), 7.25–7.31 (m, 5 H), 7.43–7.47 (m, 3 H), 8.04 (dd,
J = 8.0, 1.3 Hz, 1 H). 13C NMR (125 MHz, CDCl3): d = 46.2,
55.4 111.2, 114.8, 115.0, 115.7, 121.9, 123.4, 124.1, 126.8,
127.2, 128.7, 131.1, 132.0, 137.0, 138.8, 156.0, 159.8,
162.8. ESI-MS: m/z = 358 [M + H]+.
(18) (a) Kafka, S.; Klkgek, A.; Polis, J.; Komrlj, J. Heterocycles
2002, 57, 1659. (b) Stadlbauer, W.; Laschober, R.;
Lutschounig, H.; Schindler, G.; Kappe, T. Monatsh. Chem.
1992, 123, 617. (c) Bowman, R. E.; Grey, T. F.; Huckle, D.;
Lockhart, I. M.; Wright, M. J. Chem. Soc. 1964, 3350.
(d) Ziegler, E.; Kappe, T. Monatsh. Chem. 1963, 94, 736.
Synlett 2007, No. 9, 1431–1435 © Thieme Stuttgart · New York