Solid phase synthesis of 3-(5-arylpyridin-2-yl)-4-hydroxycoumarins

Article abstract of DOI:10.1016/j.tetlet.2006.01.069

A solid phase strategy has been developed for the synthesis of 3-(5-arylpyridin-2-yl)-4-hydroxycoumarins. The key transformation is an intramolecular ipso substitution reaction which forms the coumarin heterocycle and culminates with cleavage of product f

Full text of DOI:10.1016/j.tetlet.2006.01.069

Tetrahedron Letters 47 (2006) 1985–1988
Solid phase synthesis of 3-(5-arylpyridin-2-yl)-4-hydroxycoumarins
Yannan Liu, Aaron D. Mills and Mark J. Kurth*
Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616-5295, USA
Received 13 December 2005; revised 6 January 2006; accepted 13 January 2006
Abstract—A solid phase strategy has been developed for the synthesis of 3-(5-arylpyridin-2-yl)-4-hydroxycoumarins. The key trans-
formation is an intramolecular ipso substitution reaction which forms the coumarin heterocycle and culminates with cleavage of
product from the polymer support. The pyridine moiety at C3 can be further modified with Suzuki coupling. A sample library with
two diversity elements has been synthesized to demonstrate this ipso substation-based cyclo-elimination strategy.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
synthetic step, including Pechmann,10 Perkin,11 Knoeve-
nagel,12 Reformatsky,13 ring closing metathesis (C3–C4
bond formation),14 and Wittig15 reactions. Coumarins
have been synthesized by the Kostanecki–Robinson
reaction of o-hydroxyarylalkyl ketones with acid anhy-
drides, which proceeds through an ester enolate inter-
mediate.16 Disadvantages of this method include the
formation of chromone byproducts and variable yields.
One of the most widely used methods is the Pechmann
reaction, which involves the condensation of a phenol
with a b-ketoester. The major drawback of this protocol
stems from its requirement for strong acid (e.g., concen-
trated sulfuric acid) in large excess and at high temper-
ature with obvious limitations on the scope of this
reaction. In contrast, a mild, room temperature method
for the synthesis of coumarins has been developed which
involves the Pd-catalyzed addition of an arene to an
alkyne in the presence of a carboxylic acid.17,18 Couma-
rins have also been synthesized by the Pd-catalyzed cou-
pling of o-iodophenols with internal alkynes and carbon
monoxide.19 For the synthesis of 3-(5-arylpyridin-2-yl)-
4-hydroxycoumarins, direct arylation at C3 of the pre-
formed 4-hydroxycoumarin skeleton is an obvious
route.20,21 An alternative strategy is to form the couma-
rin ring at the final stage.22
The 1-benzopyran-2-one moiety—the structural core of
coumarins—is often found in more complex natural
products1 and is frequently associated with biological
activity, such as anti-cancer,2 antifungal,3 anti-HIV,4
and anti-clotting.5 For example, carbochromen is a
potent specific coronary vasodilator used for many years
in the treatment of angina pectoris.6 Anti-HIV activity
has been reported for seseline,7 a pyranocoumarin, while
novobiocin8 has antibiotic properties and wedelolac-
tone9 is used as a venomous snakebite antidote (Fig. 1).
The biological importance and considerable therapeutic
potential of coumarins has stimulated interest in the
design of efficient methodology for their synthesis. Sev-
eral transformations have been employed as the key
HO
HO
HO
O
O
O
O
O
N
OMe
O
O
O
Carbochromen
Wedelolactone
OH
OH
O
H
N
O
O
O
2. Results and discussion
O
RO
O
Seselin
Novobiocin
As part of our search for small molecule activators
of the cystic fibrosis transmembrane conductance regu-
lator protein, we discovered an unexpected intramole-
cular ipso substitution by a carboxy group as a route
to 4-hydroxy-3-(20-pyridyl)coumarins.23 Expanding on
Figure 1. Representative biological active coumarins.
*
Corresponding author. Tel.: +1 530 752 8192; fax: +1 530 752
8995; e-mail: mjkurth@ucdavis.edu
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.069

1986
Y. Liu et al. / Tetrahedron Letters 47 (2006) 1985–1988
this interesting and, to our knowledge, unprecedented
reaction, we have now applied it to the solid phase syn-
thesis of other 4-hydroxycoumarins with N-containing
heterocyclic substituents at C3, a class of coumarins dif-
ficult to prepare by other means.
Ph
Br
PhB(OH)2, Pd(PPh3)4
2M Na2CO3, benzene
BnO2C
BnO2C
N
N
4 (80%)
80 C, 12 h
˚
Ph
Ph
O
BnO2C
1) LDA/THF, -78
C
˚
xylenes
140 C
N
O
N
The key transformation anticipated intramolecular ipso
substitution of polymer bound 3-oxo-2-(20-pyridyl)-3-
(20-halophenyl)propanoate with concomitant release of
the coumarin product (Fig. 2). We believed this cyclo-
elimination strategy24 would afford the advantage of
releasing only the cyclized product from the support
and thus deliver the targeted coumarin in high purity.
Furthermore, realization of this cyclo-elimination step
would amount to a traceless linker strategy.25
2)
C(O)Cl
˚
OH
OH
Br
5 (78%)
Br
6 (93%)
Scheme 2. Suzuki coupling in solution phase coumarin synthesis.
Suzuki coupling reaction to allow for diversification of
the pyridyl ring of 3. This reaction sequence was first
studied in solution phase (Scheme 2). Suzuki coupling
of benzyl 20-(5-bromo)pyridylacetate with phenyl boro-
nic acid delivered benzyl 20-(5-phenyl)pyridylacetate (4)
which was then treated with LDA followed by 2-bro-
mobenzoyl chloride to give 5. This C-acylated product
is highly enolized since the enolic proton forms an intra-
molecular H-bond with the pyridine nitrogen. Enolic 5
was then heated in xylenes at 140 ꢁC, which delivered
coumarin 6 as a yellow precipitate in 93% yield as a high
melting (mp > 200 ꢁC) solid.
Our first tasks were to select both the polymeric support
(Merrifield resin) and linker (benzyl ester) as well as to
determine the optimal solid phase reaction conditions
for the ensuing polymeric reactions (Scheme 1). Target-
ing the simple 4-hydroxy-3-(20-pyridyl)coumarin (3) sys-
tem, we began by attaching 2-pyridylacetic acid to
Merrifield resin (!1) through an ester bond.26 This sub-
strate was then treated with LDA in THF at ꢀ78 ꢁC and
the resulting lithium enolate was reacted with various 2-
halobenzoyl chlorides to give C-acylated 2. The key
intramolecular ipso substitution step was carried out in
xylenes at 140 ꢁC. Following this protocol, coumarin
products (3) were isolated in 37–50% yield based on an
initial resin loading of 1.0 mequiv/g (Scheme 1). In each
case, HPLC analysis27 established the crude product
purity to be >90%. Completion of the chemistry out-
lined in Scheme 1 established that chloromethyl-func-
tionalized polystyrene resin is compatible with all the
synthetic steps, yet the ester linkage is labile in the key
ipso substitution-cleavage reaction.
We next explored the preparation of a small coumarin
library on polymer support. The reaction sequence
Br
O
A, Cs2CO3, DMF
KI (cat), 80
ArB(OH)2, Pd(PPh3)4
O
N
C
2M Na2CO3, benzene
˚
Cl
80 C, 12 h
˚
Ar
O
Ar
O
1) LDA, THF, -78 C
O
N
H
˚
2) B
O
N
O
With the success of this solid phase coumarin synthesis
in hand, we turned our attention to incorporating a
X
Z
Ar
Br
O
HOOC
A =
O
N
H
xylenes, 140
C
˚
N
O
O
C(O)Cl
O
B =
N
O
N
O
Z
X
4-14
Z
HO
HO
Ph
X
O
O
Cl
O
NO2
Figure 2. An ipso substitution-based traceless linker.
O
N
O
N
O
N
H
H
H
O
8
O
O
5
Z
Z
Z
O
A, Cs2CO3, DMF
KI (cat), 80
1) LDA, THF, -78 C
˚
7
8
F
Z = 8-NO2 (38%)
Z = 6-NO2 (40%)
9
Z = 6-NO2 (39%)
4
5
6
Z = H (25%)
Z = 8-NO2 (37%)
C
˚
2) B
Cl
O
O
N
Z = 6-CF3 (34%)
1
SMe
O
S
O
A = HOOC
N
O
F
O
O
N
H
O
N
H
xylenes
140
C(O)Cl
Br
O
N
O
N
H
O
N
H
C
˚
O
O
B =
H
O
O
O
Br
Z
Z
Z
2
3a: Z = H (37%)
3b: Z = 3-NO2 (50%)
3c: Z = 5-NO2 (46%)
Z
Z
Z
10 Z = H (26%)
11 Z = 8-NO2 (37%)
12 Z = 6-NO2 (40%)
13 Z = 8-NO2 (34%)
14 Z = 6-NO2 (38%)
Scheme 1. Solid phase synthesis of 4-hydroxy-3-(20-pyridyl)coumarins.
Scheme 3. 4-Hydroxy-3-(20-pyridyl)coumarin library.

Y. Liu et al. / Tetrahedron Letters 47 (2006) 1985–1988
1987
(Scheme 3) consists of loading the 5-bromo-20-pyridylacetic
acid on to Merrifield resin via an ester linker, Suzuki
coupling of the polymer-bound aryl bromide with vari-
ous aryl boronic acids, C-acylation with substituted 2-
halobenzoyl chlorides, and, finally, cyclo-elimination to
yield the final product.
HCl/THF (1:1), THF, methanol, CH2Cl2, methanol,
CH2Cl2, and ether. The polymer was dried under
vacuum at 40 ꢁC overnight.
Mixed xylenes (2 mL) were added to the dry polymer
and the resulting mixture was heated at 150 ꢁC in a
sealed glass tube for 16 h. After cooling to room temper-
ature, the mixture was filtered and the polymer was
washed with THF, warm DMSO, and methanol. The
combined organic phase was concentrated in vacuum,
and the solid was recrystallized from a mixture of
DMSO and methanol.28
A total of 11 coumarins (4–14) have been synthesized.
The overall yield for the four-step solid phase reaction
sequence is between 25% and 40% based on the initial
loading (1.0 mequiv/g) of Merrifield resin. We have
found that the sequence works best when a strong elec-
tron-withdrawing nitro group is present in the 2-halo-
benzoyl chloride (‘Z’ in Scheme 3) as this activates the
aryl ring for ipso substitution. With two chlorine substit-
uents on the benzoyl chloride, the reaction is slow and
the yield of coumarin is low.
In summary, a solid phase strategy has been developed
for the synthesis of 3-(5-aryl-pyridin-2-yl)-4-hydroxy-
coumarins. The key transformation is an intramolecular
ipso substitution to form the coumarin ring with simul-
taneous cleavage of product from the polymer support.
The pyridine group at C3 can be further modified with
Suzuki coupling. A sample library with two diversity
elements has been synthesized to demonstrate the effi-
cacy of this cyclo-elimination strategy.
3. General procedures for the solid phase synthesis of 4-
hydroxy-3-(5-arylpyridin-20-yl)coumarins (4–14)
Chloro-methylated polystyrene–2% divinylbenzene copoly-
mer beads (3 g, 1 mequiv/g, 3 mmol) were swollen in
DMF (100 mL). 5-Bromo-2-pyridylacetic acid hydrochlo-
ride (0.781 g, 4.5 mmol), cesium carbonate (2.932 g,
9 mmol), and potassium iodide (0.249 g, 1.5 mmol) were
added at room temperature and the mixture was agi-
tated at 80 ꢁC for 48 h. During this time, the polymer
beads changed color from white to dark reddish orange.
For the work-up, a solution of 0.1 N HCl (100 mL) was
added and, after shaking for 20 min, the polymer was
collected by filtration, washed with 1:1 THF/0.1 N
HCl (10 mL · 3), 1:1 THF/H2O (10 mL · 3), THF
(10 mL · 3), CH2Cl2 (10 mL), methanol (10 mL),
CH2Cl2 (10 mL), methanol (10 mL), CH2Cl2 (10 mL),
and ether (10 mL · 3). The polymer was dried under
Acknowledgements
We thank the National Science Foundation, for finan-
cial support of this research. The 400 and 300 MHz
NMR spectrometers used in this study were funded in
part by a Grant from NSF (CHE-9808183).
References and notes
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To a benzene suspension of the polymer-bound benzyl
5-bromo-20-pyridylacetate in a two-neck round bottom
flask equipped with an upright condenser and N2 inlet
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1:1 THF/0.1 N HCl (10 mL · 3), 1:1 THF/H2O
(10 mL · 3), THF (10 mL · 3), CH2Cl2 (10 mL), metha-
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of LDA (1 mmol) in dry THF was added at ꢀ78 ꢁC.
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was continued at ꢀ78 ꢁC for 1 h. The mixture was
allowed to warm to room temperature and the polymer
was collected by filtration and washed with THF, 0.1 N

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equipped with a Nova-Pak C18 column (3.9 · 50 mm).
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99.9% water with 0.1% TFA. The separation gradient was
0–100% organic over 15 min, 100% organic for 10 min,
and 100–0% organic over 1 min. Samples were run over at
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28. Representative spectral data: 4-Hydroxy-3-(5-phenyl-pyri-
1
14. (a) Nicolaou, K. C.; Pfeffer-korn, J. A.; Roecker, A. J.;
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din-2-yl)-coumarin (4). H NMR (DMSO-d6): d 17.03 (br
s, 1H), 9.82 (d, J = 9.5 Hz, 1H), 9.51 (s, 1H), 8.90 (d,
J = 8.8 Hz, 1H), 8.53 (d, J = 8.1 Hz, 1H), 8.33 (d,
J = 9.5 Hz, 1H), 7.99 (t, J = 8.8 Hz, 1H), 7.91–7.81 (m,
3H), 7.56–7.45 (m, 3H); 13C NMR (DMSO-d6, 100 ꢁC): d
173.7, 166.8, 146.1, 135.90, 135.78, 134.07, 133.0, 128.67,
128.57, 128.42, 128.32, 128.31, 126.64, 125.68, 125.17,
123.07, 118.19, 99.48; IR (neat) 1728, 1511, 1492, 1170,
698 cmꢀ1; MS (ESI) m/z 316 [(M+H)+]. 3-[5-(3-Chloro-
phenyl)-pyridin-2-yl]-4-hydroxy-6-nitro-coumarin (8). 1H
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NMR (DMSO-d6, 400 MHz, 100 ꢁC):
d
9.77 (d,
J = 9.5 Hz, 1H), 9.58 (s, 1H), 9.23 (d, J = 9.5 Hz, 1H),
9.17 (s, 1H), 8.66 (dd, J = 9.5, 1.8 Hz, 1H), 8.42 (d,
J = 9.9 Hz, 1H), 8.02 (d, J = 1.5 Hz, 1H), 7.86 (d,
J = 7.3 Hz, 1H), 7.60–7.52 (m, 2H); 13C NMR (DMSO-
d6, 100 ꢁC): d 173.0, 166.0, 147.3, 146.4, 139.2, 136.9,
133.7, 130.3, 129.8, 128.4, 127.7, 126.6, 126.1, 126.0, 125.5,
123.1, 121.4, 121.0, 100.7; MS (ESI) m/z 396 [(M+H)+]. 4-
Hydroxy-8-nitro-3-(5-thiophen-3-yl-pyridin-2-yl)-coumarin
(13). 1H NMR (DMSO-d6, 400 MHz):
d 9.54 (d,
J = 9.5 Hz, 1H), 8.77–8.69 (m, 3H), 8.51 (d, J = 9.9 Hz,
1H), 8.06–8.01 (m, 2H), 7.76 (dd, J = 5.1, 2.6 Hz, 1H),
7.48 (d, J = 4.0 Hz, 1H); 13C NMR (DMSO-d6, 100 ꢁC): d
172.9, 165.4, 146.8, 142.4, 136.4, 134.4, 133.0, 130.4, 130.3,
129.3, 128.8, 128.5, 127.9, 124.7, 123.1, 122.5, 122.4, 101.5;
MS (ESI) m/z 407 [(M+H)+].
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