Solid-supported synthetic equivalents of 3-formylchromone and chromone

Article abstract of DOI:10.1016/S0040-4039(01)00999-6

Treatment of bound o-hydroxyacetophenone 10 under Vilsmeier-Haack reaction conditions yields 11a or 12b, synthetic equivalents of 3-formylchromone (1) and chromone (13) respectively, depending on the resin used as solid support (Merrifield or Wang chloro

Full text of DOI:10.1016/S0040-4039(01)00999-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5331–5334
Solid-supported synthetic equivalents of 3-formylchromone
and chromone
a,
a
a
b
Jos e´ I. Borrell, * Jordi Teixid o´ , Elisabeth Schuler and Enrique Michelotti
a
Grup d’Enginyeria Molecular, Institut Qu ´ı mic de Sarri a` , Universitat Ramon Llull, Via Augusta, 390, E-08017 Barcelona, Spain
b
Rohm and Haas Company, 727 Norristown Road, Spring House, PA 19477-0904, USA
Received 30 March 2001; accepted 11 June 2001
Abstract—Treatment of bound o-hydroxyacetophenone 10 under Vilsmeier–Haack reaction conditions yields 11a or 12b, synthetic
equivalents of 3-formylchromone (1) and chromone (13) respectively, depending on the resin used as solid support (Merrifield or
Wang chloro resin respectively). © 2001 Elsevier Science Ltd. All rights reserved.
3
-Formylchromone derivatives (1) have been exten-
Several solution phase methods are reported in the
literature for the preparation of substituted 3-
sively used as versatile solution phase building blocks
for the synthesis of a large number of hetero-
cyclic systems (Scheme 1). In contrast, despite
their versatility in solution phase chemistry, resin
bound chromone derivatives have received no atten-
tion.
2–4
formylchromones.
The most convenient method to
1
synthesize 1 uses substituted o-hydroxyacetophenones
as starting materials which are treated using Vilsmeier–
Haack reaction conditions (POCl in DMF) to afford
3
4
the desired 3-formylchromones in good yields.
Scheme 1.
Keywords: solid-phase synthesis; Vilsmeier–Haack reaction; 3-formylchromones; chromones; Merrifield resin; Wang resin.
*
Corresponding author. Tel.: +34 932 038 900; fax: +34 932 056 266; e-mail: jibor@iqs.url.es
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00999-6

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J. I. Borrell et al. / Tetrahedron Letters 42 (2001) 5331–5334
As a part of our ongoing research in the area of
combinatorial chemistry focused on the preparation of
random libraries for high throughput screening (HTS),
we considered preparing two types of solid-supported
NaOMe at 80°C for 24 h quantitatively afforded 10a
(R1=H, Merrifield resin) as established by MAS-
NMR. Compound 10a was then treated under
Vilsmeier–Haack reaction conditions varying the
5
3-formylchromone derivatives (Scheme 2). The first
amount of POCl , the temperature and the reaction
3
attaches the resin through an ester or ether linkage to a
second hydroxy group present in the phenyl ring of an
o-hydroxyacetophenone 6, converting the resulting
compound 7 to a solid-supported 3-formylchromone 8.
The second, more appealing method, attaches the poly-
mer support directly to the C-2 hydroxy group of a
o-hydroxyacetophenone 9 leading to 10, which can be
converted to compound 11, a synthetic equivalent of
time (Table 1). Upon cleavage from the polymer with
1
:1 TFA/CH Cl2 for 3 h at rt, the resulting crude
2
1
6
materials were analyzed by HPLC–MS and H NMR.
The first chromatograms obtained (entries 1–4) showed
a main peak that was assigned to 3-formylchromone 1
1
on the basis of the MS. However, the H NMR spectra
showed the presence of both 3-formylchromone (1) and
chromone (13). The ratio between both species was
established by using the formyl group signal of 1 (10.40
ppm, s) and the H-C3 signal of 13 (6.53 ppm, d). The
latter presumably is formed from the monoformyl
derivative 12a during the Vilsmeier–Haack reaction. It
was necessary to increase the temperature to 50°C
3
-formylchromone. A search carried out in the Sigma–
Aldrich Chemical Directory on CD-ROM (1999 ver-
sion) showed that the number of dihydroxy substituted
acetophenones was rather low but, differently substi-
tuted o-hydroxyacetophenones were numerous. Conse-
quently, in order to ensure the maximum diversity of a
possible combinatorial library to be constructed, we
decided to investigate the synthesis of the solid-sup-
ported a,a-diformyl-o-hydroxyacetophenones 11. The
present paper presents the results obtained in such a
study.
(
Entry 8) to achieve both a total conversion of 10a and
the sole formation of 11a. However, when the resulting
resin was cleaved with 1:1 TFA/CH Cl for 3 h at rt,
2
2
3
-formylchromone (1) was obtained in high purity but
7
only in modest yield (25%).
This result prompted us to change Merrifield resin to
the Wang chloro resin in order to facilitate the cleavage
step. Thus, Wang resin (1% cross linked, 1.13 mmol/g)
was converted to the Wang chloro resin by using SOCl2
in CH Cl . Treatment of this resin in DMA with 3
The first part of the study was carried out using the
Merrifield resin as the solid support and o-hydroxyace-
tophenone 9 (R1=H) (Scheme 3). Treatment of the
resin (1% cross linked, 3.9 mmol/g) in DMA with 3
equiv. of o-hydroxyacetophenone (9) and 3 equiv. of
2
2
Scheme 2.
Table 1. Vilsmeier–Haack reaction of 10a
Conversiona (%)
1:13 ratio (%)
b
Entry
POCl3 (equiv.)
T (°C)
t (h)
1
2
3
4
5
6
7
8
9
4.0
4.0
4.0
4.0
8.0
30.0
30.0
4.0
25
25
25
25
25
25
25
50
100
24
48
72
96
96
48
96
24
48
44
84
90
92
97
100
100
100
Decomp.
–
–
42:58
52:48
–
77:23
87:13
100:0
–
4.0
a
Determined by HPLC–MS.
b
Determined by 1H NMR.

J. I. Borrell et al. / Tetrahedron Letters 42 (2001) 5331–5334
5333
Scheme 3. (a) POCl , DMF; (b) 1:1 TFA:CH Cl ; (c) HCOOEt, HNa, 1:1 DMA:THF then (b).
3
2
2
Y. Tetrahedron 1974, 30, 3553–3561; (c) Klutchko, S.;
Kminsky, D.; von Strandtmann, M. US Patent 4,098,799,
equiv. of o-hydroxyacetophenone and 3 equiv. of
NaOMe at 80°C overnight quantitatively afforded 10b
1978; Chem. Abstr. 1979, 90, 22813c.
(R1=H, Wang resin) as established by MAS-NMR.
5
6
. See, for instance: Obrecht, D.; Villalgordo, J. M. Solid-
Supported Combinatorial and Parallel Synthesis of Small-
Molecular-Weight Compound Libraries; Pergamon, 1998.
. The isolated yields were calculated based on Merrifield
and Wang resin substitution levels. The purity was deter-
mined based on area of peak corresponding to the correct
molecular weight by a C18 reverse phase HPLC column
Compound 10b was then treated under Vilsmeier–
Haack reaction conditions varying the amount of
POCl , the temperature and the reaction time as above.
3
Surprisingly, in all the experiments carried out, after the
cleavage step with 1:1 TFA/CH Cl for 1 h at rt,
2
2
chromone 13 was formed as the major product even
though large excesses of POCl (2–20 equiv.) were used,
3
(
Monochrom, 5 m, 5–95% CH CN/H O containing 0.1%
3
2
even in the optimal conditions found (10 equiv, of
acetic acid), monitored by UV detection at 220 and 254
nm.
POCl , 50°C, 3 h) a mixture of 13 and 1 in a 94:6 ratio
3
8
was obtained. The monoformylated intermediate 12b
7
. Merrifield resin (100 mg, 0.39 mmol) was suspended in
DMA (1 ml) and treated with NaOMe (3 equiv) and
O-hydroxyacetophenone (3 equiv.). The mixture was
heated at 70–80°C overnight. Resin 10a thus obtained was
filtered, washed extensively with DMA, MeOH:HAcO 1:1,
MeOH and CH Cl and dried under vacuum. Resin 10a
appears to be selectively formed. Consequently, we
decided to obtain the monoformyl derivative 12b by
using a different strategy. Thus, the treatment of 10b
with ethyl formate (15 equiv.) and NaH (20 equiv.) in
9
1
:1 DMA/THF afforded 12b in high yield. No further
2
2
work was carried out to explain the different behavior
of 10 in the Vilsmeier–Haack reaction between the use
of the Merrifield and the Wang chloro resin as solid
support.
(
138 mg, 0.39 mmol) was suspended in DMF (1 ml),
cooled in a salt ice bath and POCl (0.13 ml, 1.56 mmol, 4
3
equiv) was added. The bath was removed and the reaction
was stirred at 50°C for 48 h. Ice–water (1 ml) was carefully
added to the reaction mixture. Resin 11a was filtered,
washed with H O:MeOH 1:1, MeOH and CH Cl and
In conclusion, we have developed procedures for the
synthesis of the solid-supported synthetic equivalents of
substitued 3-formylchromones and chromones. An
application of such methodology to the production of
heterocyclic libraries will be reported in due course.
2
2
2
dried under vacuum to a constant weight (157 mg). The
resin 11a (100 mg) was treated with TFA:CH Cl (1 ml) at
2
2
room temperature with stirring for 3 h. The resulting
solution was concentrated in vacuo to yield 20 mg of a
crude material, which was purified by preparative HPLC
to yield 13 mg (0.07 mmol, 25%) of 3-formylchromone 1.
. Wang resin (100 mg, 0.17 mmol) was converted in Wang
chloro resin by two sequential treatments with thionyl
chloride (5 equiv) in CH Cl (1 ml) with stirring at 0–5°C
8
References
2
2
1
2
3
4
. Sabitha, G. Aldrichim. Acta 1996, 29, 15–25 and references
cited therein.
. Becket, G. J. P.; Ellis, G. P. Tetrahedron Lett. 1976,
for 45 min followed by overnight stirring at rt. This resin
(103 mg, 0.17 mmol) was treated as above [DMA (1 ml),
NaOMe (3 equiv), 9 (3 equiv), 70–80°C overnight] to yield
resin 10b. Resin 10b (117 mg, 0.17 mmol) was converted to
resin 12b [DMF (1 ml), POCl3 (0.14 ml, 1.56 mmol, 10
equiv), 48 h rt]. Resin 12b [100 mg (0.087 mmol)] was
treated with TFA:CH Cl (1 ml) at room temperature with
719–720.
. Klutchko, S.; Cohen, M. P.; Shavel, Jr., J.; von Strandt-
mann, M. J. Heterocyclic Chem. 1974, 11, 183–188.
. (a) Nohara, A.; Umetani, T.; Sanno, Y. Tetrahedron Lett.
2
2
1973, 1995–1998; (b) Nohara, A.; Umetani, T.; Sanno,
stirring for 1 h to yield 12 mg of a crude material, which

5
334
J. I. Borrell et al. / Tetrahedron Letters 42 (2001) 5331–5334
was purified by SPE (Alltech Silica, part. no. 209362, 1:3
AcOEt:hexane) to yield 6 mg (0.06 mmol, 50%) of
chromone 13.
. Resin 10b (100 mg, 0.15 mmol) was suspended in
DMA:THF 1:1 (1 ml) and NaH (132 mg, 3 mmol, 20
equiv., 60% dispersion in mineral oil) was added followed
by ethyl formate (0.2 ml, 2.25 mmol, 15 equiv.). The
mixture was stirred at room temperature for 3 h. Resin 12b
was filtered, washed with HAcO:MeOH 1:1, MeOH and
9
CH Cl and dried under vacuum (92% purity by HPLC).
2 2
.