A convenient synthesis of 3-pyridinyl- and 3-pyrimidinylcoumarins

Article abstract of DOI:10.1055/s-2006-942461

A mild and efficient synthesis of 3-pyridinyl- and 3-pyrimidinylcoumarins through one-pot tandem condensation-cyclization of various 2′- hydroxyacetophenones and pyridinyl- or pyrimidinylacetic acids is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942461

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2568
PAPER
A Convenient Synthesis of 3-Pyridinyl- and 3-Pyrimidinylcoumarins
S
ynthesisof 3-Pyr
u
idinyl- and
P
q
yrimidinylco
i
umarin
n
s
g Zhang,* Zhihua Sui
Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, LLC, 665 Stockton Drive, Exton, PA 19341, USA
Fax +1(610)4588249; E-mail: xzhang5@prdus.jnj.com
Received 13 March 2006; revised 6 April 2006
O
O
Abstract: A mild and efficient synthesis of 3-pyridinyl- and 3-py-
rimidinylcoumarins through one-pot tandem condensation–cycliza-
tion of various 2¢-hydroxyacetophenones and pyridinyl- or
pyrimidinylacetic acids is described.
R2
N
N
R2
R1
R1
R3
O
O
O
Key words: coumarin, benzopyran, Perkin reaction, DCC cou-
pling, SERM
I
II
Figure 1 3-Pyridinyl- and 3-pyrimidinylcoumarins I and benzo-
pyrans II
In our recent medicinal chemistry efforts toward the dis-
covery of selective estrogen receptor modulators
(SERMs) for the prevention and treatment of osteoporosis
and breast cancer, we developed an efficient and practical
synthesis of a novel series of bis-benzopyrans.1 As an ex-
tension of our continued interest in the benzopyran struc-
tures as SERMs, we were attracted to pursue the synthesis
of 3-pyridinyl- and 3-pyrimidinylcoumarins I as the key
intermediates to the benzopyran lead structures II
(Figure 1). A significant number of synthetic methods to
3-phenylcoumarins have been documented in the litera-
ture, including the Perkin reaction,2 the Knoevenagel re-
action,3 and the Pechmann reaction.4 Recently, these
efforts have been aided by progress in the transition met-
al-catalyzed annulation protocol.5 However, very few
synthetic methods to 3-heteroaryl group substituted cou-
marins are available, especially for 3-aromatic substitu-
tions bearing basic functional groups.6 This might be due
to the major disadvantages of these classic methods: the
use of stoichiometric amounts of strong acids and high
temperature. Herein, we wish to report a convenient syn-
thesis of 3-pyridinyl- and pyrimidinylcoumarins I through
a one-pot tandem condensation–cyclization of the corre-
sponding 2¢-hydroxyacetophenones and pyridinyl- or py-
rimidinylacetic acids under mild conditions and in good
yields.
We first applied the standard coumarin synthesis proce-
dures on the pyridinyl or pyrimidinyl substrates. The re-
quired precursors 2 and 3 were prepared by the method
shown in Scheme 1. Nucleophilic aromatic substitutions7
of halopyridines or halopyrimidines 1 by ethyl acetoace-
tate or diethyl malonate sodium salt catalyzed by CuBr af-
forded 2a–c. Decarboxylations of 2b,c were carried out
through alkaline hydrolysis followed by acidic work-up to
afford the phenyl acetic acids 3a,b. However, Pechmann
condensation between resorsinol or 3-methoxyphenol and
b-keto ester 2a in the presence of strong acids such as PPA
or methanesulfonic acid failed to give any desired prod-
ucts. Perkin reaction of a mixture of 2-hydroxyacetophe-
nones and pyridinyl- or pyrimidinylacetic acids 3 in the
presence of triethylamine in refluxing acetic anhydride
delivered only trace amounts of the desired coumarins.8
This might be due to the basicity of the pyridinyl or pyri-
midinyl substrates. In general, the substrates or the inter-
mediates could not tolerate the harsh reaction conditions.
It is well known that the Perkin reaction, for the synthesis
of 3-arylcoumarins, involves the condensation of 2-hy-
droxyphenylcarbonyl substrate with arylacetic acid in the
presence of a coupling agent followed by a Dieckmann
cyclization under catalysis by a base. Many attempts on
improving the Perkin method have been described in the
O
N
R2
N
R2
b
c
a
N
R2
Y
X
CO2Et
COOH
42–65%
50–72%
1
2a, Y = Me, 2-methoxypyridinyl
2b, Y = OEt, 2-methoxypyridinyl
2c, Y = OEt, 2,4-dimethoxypyrimidinyl
3a, 2-methoxypyridinyl
3b, 2,4-dimethoxypyrimidinyl
X = Br or I
Scheme 1 Reagents and conditions: a) Ethyl acetoacetate or diethyl malonate, NaH, CuBr, 100 °C in dioxane overnight; b) aq 2 N NaOH,
2 h; c) 1 N HCl.
SYNTHESIS 2006, No. 15, pp 2568–2572
x
x.
x
x
.
2
0
0
6
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-942461; Art ID: M01406SS
© Georg Thieme Verlag Stuttgart · New York

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PAPER
Synthesis of 3-Pyridinyl- and Pyrimidinylcoumarins
2569
literature.9 We envisaged that condensation of 2-hydroxy- be achieved in one-pot tandem fashion by using DCC as
acetophenones 4 and pyridinyl- or pyrimidinylacetic acids coupling agent and Et3N as base. The reaction was also
3 required a mild coupling agent. N,N-Dicyclohexylcar- successfully executed with various 3 and 4 to afford the
bodiimide (DCC) is considered as powerful coupling corresponding coumarins 5 in moderate to good yields, as
agent that fits the criteria here. For this reason, we exam- illustrated in Table 1. Unlike other Perkin modifications,
ined DCC coupling (DCC ~ 1.0 equiv, DMAP 0.1 equiv) the present method obviates the need to prepare unstable
process between 3 and 4. To our satisfaction, we observed phenylacetic chloride or anhydride, eliminates strong
the coupling product in good yields with some Dieckmann acid/acid derivative as the condensing agent and avoids
cyclization adducts – the desired coumarins 5. After pre- high reaction temperature. Thus, it appears to be an attrac-
liminary investigation, we found that condensation– tive approach toward 3-aryl substituted coumarins bear-
cyclization of various 2¢-hydroxyacetophenones 4 and py- ing basic groups.
ridinyl- or pyrimidinylacetic acids 3 to coumarins 5 could
Table 1 One-Pot Synthesis of Coumarins 5 via Condensation–Cyclization Process
O
Me
R2
R2
N
Me
DCC, DMAP
Et3N
N
+
HOOC
R1
OH
R1
O
O
4
3
5
R2
Entry
R1
Product 5a
Yield (%)b
N
Me
N
N
1
2
3
4
5
6
H
75
58
71
68
65
82
O
O
5a
Me
N
N
N
OMe
OMe
OMe
OMe
Me
MeO
O
O
5b
Me
N
N
N
MeO
O
O
O
O
5c
OMe
OMe
Me
OMe
N
MeO
O
5d
MeO
Me
N
MeO
N
OMe
N
MeO
O
5e
Me
N
N
Me
O
O
5f
Synthesis 2006, No. 15, 2568–2572 © Thieme Stuttgart · New York

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2570
X. Zhang, Z. Sui
PAPER
Table 1 One-Pot Synthesis of Coumarins 5 via Condensation–Cyclization Process (continued)
O
Me
R2
R2
N
Me
DCC, DMAP
Et3N
N
+
HOOC
R1
OH
R1
O
O
4
3
5
R2
Entry
R1
Product 5a
Yield (%)b
N
OMe
OMe
Me
OMe
N
N
N
7
8
9
OSEM
OSEM
OTBS
66
65
60
SEMO
O
O
5g
MeO
Me
N
MeO
N
OMe
N
SEMO
O
O
5h
Me
N
N
TBSO
O
O
5i
a Reagents and conditions: 3 (1.0–1.5 equiv), 4 (1.0 equiv), Et3N (2.0–2.5 equiv), DCC (1.0 equiv), DMAP (0.1 equiv) in CH2Cl2, r.t. to reflux,
10 –20 h.
b Yield of isolated product.
Melting points were taken using a Thomas-Hoover MelTemp appa-
ratus and are uncorrected. H NMR spectra were recorded at 300
Synthetic utility of this reaction has been shown by the
synthesis of a key intermediate – tetracyclic coumarin 7
for SERM targets (Scheme 2). Anionic bromination of 5e
with LiHMDS and NBS in THF at –78 °C provided
monobromide 6 in 81% yield. Demethylation of 6 was
carried out by treatment with BBr3 in 1,2-dichloroethane.
In situ treatment of the corresponding tris-phenol interme-
diate with 10% K2CO3 in 1:1 methanol and acetone solu-
tion afforded the tetracyclic coumarin 7 in 51% yield.
1
MHz with CDCl3 or DMSO-d6 as solvent on a Bruker AVANCE
300 spectrometer. Chemical shifts are reported in ppm downfield
from TMS as an internal standard. TLC was carried out using silica
gel 60 (250 mM layer) plates with UV detection. Anhydrous Na2SO4
was employed to dry organic extracts prior to concentration by ro-
tary evaporation. Flash chromatography was done using EM Sci-
ence silica gel 60 (230–400 mesh). Solvents from J. T. Baker or
Aldrich and all other commercially available reagents were used
without further purification. Microanalysis was done by Quantita-
tive Technologies Inc., Whitehouse, NJ. Mass spectra were ob-
tained on a Hewlett-Packard 5989A quadrupole mass spectrometer.
HPLC analysis was carried on Agilent 1100 Series LC/MSD equip-
ment. 3-Pyridylacetic acid, 4-pyridylacetic acid, 2¢-hydroxy-
4¢methoxyacetophenone, 2¢-hydroxy-4¢-methylacetophenone and
2¢,4¢-dihydroxyacetophenone are available from Aldrich. 1-[4-(tert-
In summary, we have developed an efficient one-pot syn-
thesis of 3-pyridinyl and 3-pyrimidinyl coumarins 5 under
mild conditions and in moderate to good yields. Further
investigation on converting the coumarins 5 and 7 into
typical SERMs structures II are under way in our labora-
tory and the biological data will be reported in due course.
MeO
N
OMe
MeO
N
OMe
b
O
N
O
Br
N
N
NH
a
MeO
O
O
MeO
O
O
HO
O
O
5e
6
7
Scheme 2 Reagents and conditions: a) LiHMDA for 20 min, NBS for 2 h, –78 °C, 81%; b) 1. BBr3, ClCH2CH2Cl, r.t. to reflux for overnight,
2. 10% K2CO3, MeOH–acetone (1:1), 0 °C for 2 h, 51%.
Synthesis 2006, No. 15, 2568–2572 © Thieme Stuttgart · New York

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PAPER
Synthesis of 3-Pyridinyl- and Pyrimidinylcoumarins
2571
Butyldimethylsilyloxy)-2-hydroxyphenyl]ethanone and 1-[2-hy-
4-Methyl-3-pyridin-4-yl-2H-chromen-2-one (5a)
droxy-4-(2-trimethylsilylethoxymethoxy)phenyl]ethanone
were
Yield: 75%; white solid; mp 123–125 °C.
prepared according to the literature.10
1H NMR (CDCl3): d = 8.81 (d, J = 7.5 Hz, 2 H), 7.65 (m, 1 H), 7.55
(d, J = 7.5 Hz, 2 H), 7.50 (d, J = 8.0 Hz, 1 H), 7.26 (m, J = 6.5 Hz,
1 H), 7.22 (d, J = 8.0 Hz, 1 H), 2.32 (s, 3 H).
2-(6-Methoxypyridin-3-yl)malonic Acid Diethyl Ester (2b)
NaH (60%, 36.2 mmol, 1.45 g) was added to a solution of 5-bromo-
2-methoxypyridine (16.5 mmol, 2.13 mL), CuBr (32.9 mmol, 4.72
g) and diethyl malonate (32.9 mmol, 5.0 mL) in 1,4-dioxane (20
mL) slowly at r.t. After the addition, the resulting mixture was heat-
ed to 100 °C and stirred overnight. The mixture was then passed
through a pad of Celite to remove the brown solid. The filtrate was
then concentrated in vacuo to afford a brown oil, which was then
purified by silica gel column chromatography using hexanes–
EtOAc (4:1–2:1 ratio) as eluent to afford the title compound 2b as
a light-yellow oil; yield: 2.87 g (65%).
LC-CIMS: m/z (%) = 238 ([M + 1]+, 16), 260 ([M + Na]+, 100).
Anal. Calcd for C15H11NO2: C, 75.94; H, 4.67; N, 5.90. Found: C,
76.88; H, 4.65; N, 5.85.
7-Methoxy-4-methyl-3-pyridin-4-yl-2H-chromen-2-one (5b)
Yield: 58%; white solid; mp 150–153 °C.
1H NMR (CDCl3): d = 8.75 (s, 1 H), 7.58 (d, J = 6.8 Hz, 1 H), 7.25
(d, J = 4.3 Hz, 2 H), 6.90 (d, J = 6.8 Hz, 1 H), 6.82 (s, 1 H), 3.91 (s,
3 H), 2.30 (s, 3 H).
1H NMR (CDCl3): d = 8.10 (s, 1 H), 7.74 (d, J = 8.5 Hz, 1 H), 6.75
(d, J = 8.5 Hz, 1 H), 4.55 (s, 1 H), 4.25 (m, 4 H), 3.95 (s, 3 H), 1.25
(m 6 H).
LC-CIMS: m/z (%) = 268 ([M + 1]+, 100).
Anal. Calcd for C16H13NO3: C, 71.90; H, 4.90; N, 5.24. Found: C,
71.79; H, 4.86; N, 5.18.
LC-CIMS (LC purity: 98%): m/z (%) = 268 ([M + 1]+, 100).
7-Methoxy-4-methyl-3-pyridin-3-yl-2H-chromen-2-one (5c)
Yield: 71%; white solid; mp 133–135 °C.
1H NMR (CDCl3): d = 8.65 (s, 1 H), 8.60 (d, J = 6.5 Hz, 1 H), 7.62–
7.49 (m, 3 H), 7.02 (d, J = 7.5 Hz, 1 H), 6.15 (s, 1 H), 3.88 (s, 3 H),
2.48 (s, 3 H).
2-(2,4-Dimethoxypyrimidin-5-yl)malonic Acid Diethyl Ester
(2c)
Prepared following the procedure for 2b using 5-iodo-2,4-
dimethoxypyrimidine as the starting material.
Yield: 42%; light-yellow oil.
1H NMR (CDCl3): d = 8.28 (s, 1 H), 4.32 (m, 4 H), 4.05 (s, 3 H),
4.01 (s, 3 H), 1.35 (m, 6 H).
LC-CIMS: m/z (%) = 268 ([M + 1]+, 100).
Anal. Calcd for C16H13NO3: C, 71.90; H, 4.90; N, 5.24. Found: C,
71.86; H, 4.77; N, 5.23.
LC-CIMS (LC purity: 98%): m/z (%) = 298 ([M + 1]+, 100).
7-Methoxy-3-(6-methoxypyridin-3-yl)-4-methyl-2H-chromen-
2-one (5d)
Yield: 68%; off-white solid; mp 155–157 °C.
1H NMR (CDCl3): d = 8.10 (s, 1 H), 7.62 (d, J = 7.5 Hz, 1 H), 7.60
(d, J = 7.5 Hz, 1 H), 6.92 (d, J = 9.2 Hz, 1 H), 6.85 (d, J = 9.2 Hz, 1
H), 6.82 (s, 1 H), 4.01 (s, 3 H), 3.95 (s, 3 H), 2.32 (s, 3 H).
(6-Methoxypyridin-3-yl)acetic Acid (3a)
2-(6-Methoxypyridin-3-yl)malonic acid diethyl ester (2b; 5.6 g,
21.0 mmol) was dissolved in a solution of 2 N NaOH in THF–H2O
(1:1, 20 mL). The resulting mixture was refluxed for 2 h. The mix-
ture was then adjusted to pH 1 with conc. HCl and stirred for anoth-
er 1 h at r.t.. The solution was then adjusted to pH 13 with aq 1 N
NaOH and extracted with Et2O. The aqueous phase was acidified to
pH 5 with 1 N HCl and extracted with EtOAc (3 ×). The combined
organic phases were then washed with brine, dried (Na2SO4), fil-
tered and concentrated to give the title compound as an off-white
solid; yield: 2.45 g (72%); mp 110–113 °C.
LC-CIMS: m/z (%) = 298 ([M + 1]+, 100).
Anal. Calcd for C17H15NO4·0.5EtOAc: C, 66.85; H, 5.61; N, 4.10.
Found: C, 66.97; H, 5.55; N, 4.23.
3-(2,4-Dimethoxypyrimidin-5-yl)-7-methoxy-4-methyl-2H-
chromen-2-one (5e)
Yield: 65%; white solid; mp 161–163 °C.
1H NMR (CDCl3): d = 8.15 (s, 1 H), 7.62 (d, J = 7.5 Hz, 1 H), 6.91
(d, J = 7.5 Hz, 1 H), 6.88 (s, 1 H), 4.05 (s, 3 H), 4.00 (s, 3 H), 3.91
(s, 3 H), 2.25 (s, 3 H).
1H NMR (CDCl3): d = 12.5 (br, 1 H), 7.91 (s, 1 H), 7.46 (d, J = 8.1
Hz, 1 H), 6.62 (d, J = 8.1 Hz, 1 H), 3.83 (s, 3 H), 3.42 (s, 2 H).
LC-CIMS (LC purity: 98%): m/z (%) = 168 ([M + 1]+, 100), 190
([M + Na]+, 26).
(2,4-Dimethoxypyrimidin-5-yl)acetic Acid (3b)
LC-CIMS: m/z (%) = 329 ([M + 1]+, 25), 351 ([M + Na]+, 100), 679
Prepared following the procedure for 3b using 2-(2,4-dimethoxypy-
rimidin-5-yl)malonic acid diethyl ester (2c) as the starting material;
yield: 50%; off-white solid; mp 101–103 °C.
1H NMR (CDCl3): d = 10.3 (br s, 1 H), 8.15 (s, 1 H), 4.05 (s, 6 H),
3.48 (s, 2 H).
([2 M + Na]+, 16).
Anal. Calcd for C17H16N2O5: C, 62.19; H, 4.91; N, 8.53. Found: C,
62.10; H, 4.85; N, 8.46.
4,7-Dimethyl-3-pyridin-4-yl-2H-chromen-2-one (5f)
Yield: 82%; white solid; mp 120–122 °C.
1H NMR (CDCl3): d = 8.72 (d, J = 6.1 Hz, 2 H), 7.52 (s, 1 H), 7.42
(d, J = 8.5 Hz, 1 H), 7.23 (d, J = 8.5 Hz, 1 H), 7.20 (d, J = 6.1 Hz, 2
H), 2.55 (s, 3 H), 2.34 (s, 3 H).
LC-CIMS (LC purity: 98%): m/z (%) = 199 ([M + 1]+, 100), 221
([M + Na]+, 31).
One-Pot Synthesis of Coumarins 5; General Procedure
To a solution of acetophenone 4 (27 mmol) and AcOH (27 mmol)
in CH2Cl2 (40 mL), was added Et3N (68.0 mmol), DMAP (2.72
mmol) and CH2Cl2 (27 mmol) at r.t. The mixture was stirred over-
night and then refluxed for 2 h. The resulting solution was concen-
trated in vacuo and dissolved in Et2O (~ 200 mL). The solid was
removed by filtration. The filtrate was then concentrated to give the
crude material, which was then purified by silica gel chromatogra-
phy using hexanes–EtOAc (3:1 to 1:1) as eluent to give 5 as white
solids (Table 1).
LC-CIMS: m/z (%) = 252, ([M + 1]+, 100), 274 ([M + Na]+, 35).
Anal. Calcd for C16H13NO2·0.5EtOAc: C, 73.20; H, 5.80; N, 4.74.
Found: C, 73.08; H, 5.65; N, 4.62.
3-(6-Methoxypyridin-3-yl)-4-methyl-7-(2-trimethylsilyl-
ethoxymethoxy)-2H-chromen-2-one (5g)
Yield: 66%; off-white solid; mp 175–177 °C.
Synthesis 2006, No. 15, 2568–2572 © Thieme Stuttgart · New York