Preparation of a resin-bound cyclic malonic ester and a facile solid-phase synthesis of 4(1H)quinolones

Article abstract of DOI:10.1016/S0040-4039(01)01622-7

A resin-bound cyclic malonic ester has been prepared on Merrifield resin. Reaction of the cyclic malonic ester with triethyl orthoformate and subsequent substitution by an arylamine afforded arylaminomethylene cyclic malonic ester preloaded resin. A serie

Full text of DOI:10.1016/S0040-4039(01)01622-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7655–7657
Preparation of a resin-bound cyclic malonic ester and a facile
solid-phase synthesis of 4(1H)quinolones
Xian Huang* and Zhanxiang Liu
Department of Chemistry, Zhejiang University (Campus Xixi ), Hangzhou 310028, People’s Republic of China
Received 21 June 2001; revised 16 August 2001; accepted 30 August 2001
Abstract—A resin-bound cyclic malonic ester has been prepared on Merrifield resin. Reaction of the cyclic malonic ester with
triethyl orthoformate and subsequent substitution by an arylamine afforded arylaminomethylene cyclic malonic ester preloaded
resin. A series of 4(1H)quinolones were prepared by thermal cyclization in moderate yields and high purity. © 2001 Elsevier
Science Ltd. All rights reserved.
The solid-phase synthesis of small molecules has been
under intensive study recently.1 Due to the ease of
workup and isolation, solid-phase organic synthesis
(SPOS) allows rapid synthesis of a large number of
structurally diverse molecules in a short period of time
which can accelerate the lead generation and lead opti-
mization processes in the pharmaceutical industry.
4(1H)Quinolone and its derivatives are found in many
naturally occurring alkaloids2 which exhibit broad bio-
logical activities. This ring system has been successfully
prepared by the reaction of arylamines with Meldrum’s
acid derivatives via solution-phase synthesis.3
synthesis of quinolones,3b pyrazolones5a and pyrim-
idine.5b However, for the construction of libraries of
these heterocyclic compounds, solution-phase strategies
are time-consuming and cannot be easily isolated. To
the best of our knowledge, the use of this chemistry to
prepare combinatorial libraries of small molecules on
solid supports has not been explored. In continuation
of our work on Meldrum’s acid derivatives, we
attempted to develop resin-bound cyclic malonic esters
and to prepare heterocyclic compounds by solid-phase
synthesis. Herein, we describe solid-phase synthesis of
4(1H)quinolones from a resin-bound, cyclic, malonic
ester. We have also prepared a novel scaffold—a resin-
bound cyclic malonic ester.
Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione) is
a remarkable reagent of varied reactivities.4 The suscep-
tibility to electrophilic attack (via its anion) at C-5 and
nucleophilic attack at C-4 and C-6 along with the ring
opening reactions makes this reagent useful in organic
synthesis. 5-Ethoxymethylene or 5-methylthiomethylene
derivatives of Meldrum’s acid (Scheme 1, i, X=H,
Y=OEt; or X=R, SMe, Y=SMe) are new synthetic
intermediates of considerable utility. As shown in
Scheme 1, compound (i) can easily be attacked by
doubly nucleophilic reagents (Nu1-A-Nu2), followed by
loss of the ketone and CO2 to afford the heterocyclic
compound (iv).
Our solid-phase synthetic route (Scheme 2) begins with
commercially available Merrifield resin. It was reacted
O
O
O
R1
R2
R1
R2
X
O
O
O
X
+
Nu1-A-Nu2
-HY
Nu1
A
Y
O
(i)
O
(ii)
Nu2
R1
O
O
X
-
Our group has reported work on 5-(bismethylthio-
methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione in novel
R1
R2
R2
O
X
O
Nu1
Nu2
(iv)
A
O
O
Nu1
A
- CO2
Nu2
(iii)
Keywords: 4(1H)quinolone; solid-phase synthesis; Meldrum’s acid;
cyclic malonic ester.
* Corresponding author. Fax: +86-571-88807077; e-mail: huangx@
mail.hz.zj.cn
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01622-7

7656
X. Huang, Z. Liu / Tetrahedron Letters 42 (2001) 7655–7657
O
O
ii
i
CH3
CH2CH2
CH2Cl
O
2
1
EtO
O
O
O
O
O
iv
iii
O
NH
R2
O
3
O
O
4
R1
O
R2
v
CH3
+
CH2CH2
N
H
2
R1
5
Scheme 2. Reagents and conditions: (i) sodium ethyl acetoacetate, DMF, 80°C, 16 h; (ii) DMSO, NaCl, 140°C, 48 h; (iii) malonic
R1
acid, acetic anhydride, conc. H2SO4; (iv) a. HC(OEt)3, reflux, 6 h, b.
, reflux, 20 h; (v) thermolysis, N2, 240°C, 30
min.
R2
NH2
with resin 3. Resin 4 was cleaved by thermal cycliza-
tion. This is a novel traceless cleavage strategy based on
the electrocyclization of an intermediate amino
ketene.3c The recovered resin can be recycled (converted
to resin 27) at the end of the reaction.
with sodium ethyl acetoacetate in DMF to give the
b-keto ester resin 1. Decarboxylation of resin 1 in
DMSO yielded the ketone resin 2. The ketone resin 2
was reacted with malonic acid and acetic anhydride
under concentrated H2SO4 conditions according to
Ott’s method6 to give the resin-bound cyclic malonic
ester 3. Resin 3 was treated with triethyl orthoformate
and various arylamines to give the resin-bound aryl-
aminomethylene, cyclic malonic ester 4.3a Excess
reagents were removed by filtering before the resin was
heated for thermal cyclization. The resin was washed
with solvents after thermal cleavage to give the prod-
ucts. The products generally do not require purification
and show good purity (>90%) by 1H NMR analysis
(400 MHz).
Procedure for the preparation of the resin bound cyclic
malonic ester
To a solution of sodium ethyl acetoacetate (39.2 mmol,
5.96 g) in 30 ml DMF, Merrifield resin (2 g, 1%
cross-linked, 200–400 mesh, loading=1.96 meq Cl/g)
was added and the mixture was stirred at 80°C for 16 h.
After being washed with DMF, EtOH and CH2Cl2, the
b-keto ester resin 1 was obtained. The b-keto ester resin
1 (2 g) was suspended in a mixture of DMSO (30 ml),
NaCl (40 mmol) and H2O (120 mmol) and the mixture
refluxed for 48 h. After washing with water, DMF,
EtOH and CH2Cl2, the ketone resin 2 (loading=1.88
mmol/g, based on CꢀO) was obtained. A solution of
malonic acid (38 mmol), concentrated sulfuric acid (0.1
Table 1 summarizes the yields and purities of a number
of 4(1H)quinolones that were prepared using this
methodology.
The successful formation of resin 1 was supported by a
comparative FTIR study of Merrifield resin and a
sample of resin 1 (KBr pellets). In the IR spectrum of
resin 1, several characteristic signals were present which
confirmed the attachment of the ethyl acetoacetate moi-
ety to the resin. There were two strong bands at 1740
Table 1. Yields and purities of 4(1H)quinolonesa
4(1H)Quinolone R1
R2
Yield (%)b
Purity (%)
5a
H
CH3
H
H
NO2
H
H
H
Cl
H
H
62
59
95
90
92
90
94
91
90
93
93
and 1716 cm−1, typical for CꢀOs of b-keto esters. Also,
the peak at 1260 cm−1 (CH2-Cl) had disappeared. The
formation of resin 2 was shown by the existence of a
single strong carbonyl peak at 1716 cm−1. The cyclic
malonic ester was monitored by IR spectroscopy which
showed carbonyl peaks at 1767 and 1794 cm−1. There
was also a weak peak at 1710 cm−1 because the resin 2
was not completely converted into 3. When the cyclic
malonic ester resin was converted to the resin 4, the IR
carbonyl peak shifted to 1738 and 1684 cm−1 (4a). Also,
a new peak appeared at 1625 cm−1 (CꢀC) compared
5b
5c
5d
5e
5f
5g
5h
5i
COCH3 59
NO2
H
OCH3
CH3
Br
62
47
57
49
58
61
Cl
a All compounds are determined by 1H NMR, MS, IR.
b The yields are based on the loading of the cyclic malonic ester resin
3.

X. Huang, Z. Liu / Tetrahedron Letters 42 (2001) 7655–7657
7657
Acknowledgements
ml) and acetic anhydride (117 mmol) was allowed to
stand for 24 h at rt and was then concentrated in
vacuum below 40°C. The resin 2 (2 g, pre-swelled in
dry CH2Cl2) was added to the residue after cooling to
0°C. Then 2 ml dry CH2Cl2 was added to the mix-
ture. The mixture was stirred below 20°C for 24 h.
The resin was then washed with water, EtOH and
CH2Cl2. The cyclic malonic ester resin 3 (loading=
1.20 mmol/g) was obtained. The loading of resin 3
was determined by reversed titration with hydrochlo-
ride acid after saponification with excess NaOH in
EtOH.
Project 20072032 was supported by the National
Nature Science Foundation of China.
References
1. Recent reviews on SPOS, see: (a) Brown, R. C. D. J.
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rahedron 1999, 55, 4855–4946; (d) Corbett, J. W. Org.
Prep. Proc. Int. 1998, 30, 491–550; (e) Lorsbach, B. A.;
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General procedure for the solid-phase synthesis of
4(1H)quinolones: Resin 3 (500 mg, 1.20 mmol/g) was
added to triethyl orthoformate (50 equiv., 5 ml) and
then refluxed for 6 h. The arylamine (10 equiv.) was
added and the mixture was heated under reflux for 20
h. The resin was filtered and washed with EtOH and
CH2Cl2. Then the resin was heated in an oil bath at
240°C for 30 min under a N2 atmosphere. The resin
was then washed with EtOH/acetone thoroughly in a
sintered glass funnel. The filtrates were combined and
the solvents removed in vacuo to afford the product.
4. (a) McNab, H. Chem. Soc. Rev. 1978, 7, 345–358; (b)
Chen, B. C. Heterocycles 1991, 32, 529–597.
5. (a) Chen, B. C.; Huang, X.; Ma, S. M. Synth. Commun.
1987, 17, 1519–1522; (b) Ye, F. C.; Chen, B. C.; Huang, X.
Synthesis 1989, 4, 317–320.
6. (a) Ott, E. Annals 1913, 401, 159–177; (b) Michael, A.;
Weiner, N. J. Am. Chem. Soc. 1936, 58, 680–685.
7. The IR spectroscopy of the recovered resin showed a
single strong carbonyl peak at 1716 cm−1. (identical to
resin 2). The loading of this resin is 1.80 mmol/g (based on
CꢀO group). The cyclic malonic resin 3 (loading=1.06
mmol/g) can be prepared from the recovered resin.
In conclusion, we have developed a method for the
preparation of polymer-bound cyclic malonic ester. A
series of 4(1H)quinolones were synthesized by thermal
cyclization based cleavage providing a SPOS route.
The resin-bound cyclic malonic ester can be consid-
ered to be an appropriate scaffold for solid-phase
synthesis. Further work is in progress on the solid-
phase synthesis of heterocyclic compounds via the
resin-bound cyclic malonic ester.