Preparation and optical properties of novel 3-alkoxycarbonyl aza- and diazacoumarins

Article abstract of DOI:10.1080/00397910903353747

A series of 14 new 3-alkoxycarbonyl 6-aza-, 7-aza-, and 6,8-diaza-coumarins was prepared using various strategies involving either a Knoevenagel or a Pechmann condensation reaction. The coumarin nucleus displays different reactive functional groups allowing straightforward derivatization. The optical properties of the new azacoumarins were measured in methanol. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903353747

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Preparation and Optical Properties
of Novel 3-Alkoxycarbonyl Aza- and
Diazacoumarins
Clémentine Féau a , Emmanuel Klein a , Paul Kerth b & Luc Lebeau a
a Laboratoire de Chimie Organique Appliquée, CAMB, CNRS–UdS,
Faculté de Pharmacie , Illkirch, France
b Preventor µTBC GmbH , Pfungstadt, Germany
Published online: 13 Sep 2010.
To cite this article: Clémentine Féau , Emmanuel Klein , Paul Kerth & Luc Lebeau (2010)
Preparation and Optical Properties of Novel 3-Alkoxycarbonyl Aza- and Diazacoumarins, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:20, 3033-3045, DOI: 10.1080/00397910903353747
To link to this article: http://dx.doi.org/10.1080/00397910903353747
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Synthetic Communications1, 40: 3033–3045, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903353747
PREPARATION AND OPTICAL PROPERTIES OF NOVEL
3-ALKOXYCARBONYL AZA- AND DIAZACOUMARINS
1
Clementine Feau, Emmanuel Klein, Paul Kerth,
1
2
´
´
and Luc Lebeau1
1
´
Laboratoire de Chimie Organique Appliquee, CAMB, CNRS–UdS,
´
Faculte de Pharmacie, Illkirch, France
2Preventor lTBC GmbH, Pfungstadt, Germany
A series of 14 new 3-alkoxycarbonyl 6-aza-, 7-aza-, and 6,8-diaza-coumarins was prepared
using various strategies involving either a Knoevenagel or a Pechmann condensation reaction.
The coumarin nucleus displays different reactive functional groups allowing straightforward
derivatization. The optical properties of the new azacoumarins were measured in methanol.
Keywords: Azacoumarin; chromophore; coumarin; Knoevenagel condensation; Pechmann condensation
Coumarins are structurally simple compounds belonging to the class of
benzopyrones.[1,2] Because of their widespread occurrence in nature (more than
1,300 coumarins have been identified from natural source) and their biological
and pharmacological activities, they have long been the focus of attention by syn-
thetic chemists. Many natural and synthetic coumarins have shown interesting
properties as anticoagulant, antithrombotic, antilipemic, antioxidant, antibiotic,
antineoplastic, antiviral, and anti-inflammatory drugs.[3–7] For several decades, the
optical properties of coumarins have gained much attention because of applications
as optical brighteners, triplet sensitizers, or laser dyes.[8–12] Thus, the synthesis of new
members in the coumarin family still is of much interest. With this in mind, we
recently focused on the synthesis and spectroscopic study of new 3-alkoxycarbonyl
azacoumarins. They are close to the family of coumarin dyes, one of the most
famous classes of fluorescent compounds, but 3-alkoxycarbonyl azacoumarins have
not attracted much attention until now and no data are available on their coloring
and fluorescent properties.
To the best of our knowledge, there are only a few reports in the literature
on the synthesis of 3-carboxy azacoumarins and related esters.[13–19] Herein, we
describe the preparation and characterization of a series of new 3-alkoxycarbonyl
6-aza-, 7-aza-, and 6,8-diaza-coumarins.
Received July 17, 2009.
Address correspondence to Luc Lebeau, Laboratoire de Chimie Organique Appliquee, C.A.M.B.,
´
UMR 7199 CNRS–UdS, Faculte de Pharmacie, 74 route du Rhin, BP 60024, 67401 Illkirch Cedex,
´
France. E-mail: llebeau@unistra.fr
3033

´
C. FEAU ET AL.
3034
Scheme 1. Syntheses of 3-carboxy azacoumarins via Knoevenagel condensation reported in the
literature.[13,21]
The Knoevenagel and Pechmann reactions are the most common synthetic
methods to produce coumarins. The first one involves condensation of salicylic alde-
hydes with malonic acids or derivatives giving the 3-carboxylic acids (or derivatives)
that may successively undergo decarboxylation.[20] The reaction is catalyzed by weak
bases. The Knoevenagel condensation was used by Bredereck et al.[13] to prepare
3-ethoxycarbonyl-5-hydroxy-7-methyl-6,8-diazacoumarin 1 and later by Moffett[21]
to produce 3-carboxy-5-azacoumarin 2 (Scheme 1). The Pechmann synthesis
involves condensation of phenols with b-ketonic esters under acidic conditions.[22]
Schmidt and Junek prepared 3-ethoxycarbonyl-5-hydroxy-7-methyl-6-azacoumarin
3 by reacting 2,4-dihydroxy-6-methyl pyridine with ethyl (ethoxymethylene)cyanoa-
cetate (Scheme 2).[17] More recently, Stanovnik et al. reported on the synthesis of
3-ethoxycarbonyl-5-hydroxy-6-azacoumarin 4 and 3-ethoxycarbonyl-5-hydroxy-
6,8-diazacoumarin 5 using diethyl N,N-dimethylaminomethylene malonate.[19]
Our route to 6-aza- and 6,8-diazacoumarins involved the Pechmann reaction
and coumarins 3–6, which constitute starting material for further modifications.
These were prepared according to Kusar et al.[19] However, the reported procedure
was slightly modified, and the corresponding dihydroxypyridines or pyrimidines
were treated with diethyl N,N-diethylaminomethylene malonate (more readily
available than diethyl N,N-dimethylaminomethylene malonate)[23] in refluxing acetic
acid (Table 1). The coumarins were obtained in good yield, except for compound 6,
which was difficult to purify.
Scheme 2. Syntheses of 3-carboxy azacoumarins via Pechmann condensation reported in the
literature.[17,19]

SYNTHESIS OF 3-ALKOXYCARBONYL AZACOUMARINS
3035
Table 1. 6-Aza- and 6,8-diazacoumarins synthesized via a Pechmann condensation in this work
Entry
R
X
Time (h)
Product
Yield (%)
1
2
3
4
CH3
H
CH
CH
N
6
8
4
4
3
4
5
6
79
75
55
13
H
CH2OH
N
Coumarin 3 was subjected to a series of transformations (Scheme 3). Chlori-
nation at the C5 position afforded compound 7 together with some decarboxylated
coumarin 8. Coumarin 7 was further brominated at the benzylic position with
N-bromosuccinimide (NBS) under radical-promoting conditions. The resulting
7-bromomethyl-5-chlorocoumarin
9
was selectively transformed into 7-
bromomethyl-5-hydroxycoumarin 10 by reaction in refluxing acetic acid. On the
other side, bromine was easily subjected to nucleophilic displacement by reaction with
a secondary amine to yield coumarin 11. Other reaction sequences were applied to
azacoumarin 3. Treatment of the compound with bromine yielded 4-bromocoumarin
12 in 85% yield, and alkylation at O5 was achieved by reacting 3 with methyl iodide at
room temperature in the presence of silver carbonate to furnish 13 in moderate yield.
Azacoumarin 4 has been as well modified through various functional transfor-
mations (Scheme 4). Chlorination with phosphorus oxychloride in the presence of
N,N-dimethylaniline provided 5-chlorocoumarin 14, which was quantitatively
transformed into substituted pyridine 15 by catalytic hydrogenation. Whatever the
catalyst used, reduction of C4-C5 double bond could not be avoided. Bromination
Scheme 3. Preparation of 6-azacoumarins substituted at position 7.

´
C. FEAU ET AL.
3036
Scheme 4. Preparation of 6-azacoumarins unsubstituted at position 7.
of 4 was realized under the conditions described by Mase et al.,[24] and the resulting
bromide 16 offered an access to specifically reduced azacoumarin 17 in 45% yield.
Finally, treatment of coumarin 4 with dimethylsulfate resulted in N6 alkylation,
and coumarin 18 was obtained in 89% yield.
The two previous series of transformations were not satisfactorily extended to
6,8-diazacoumarin 5. As an example, coumarin 5 was converted into the correspond-
ing chloride 19 upon reaction with phosphorus oxychloride (Scheme 5). However,
the chlorination compound proved to be unstable and was isolated only in poor yield
because of massive back hydrolysis into precursor 5 during purification by silica-gel
chromatography.
Until now, no synthesis of 5-hydroxy-7-azacoumarins has been reported in the
literature. Indeed, classical routes to coumarins are not effective for that isomer series,
and specific access had to be developed. Thus, we propose a synthetic route for the
preparation of 3-ethoxycarbonyl-5-hydroxy-7-azacoumarin 24 (Scheme 6). That com-
pound was elaborated starting from 2,5-dichloropyridine, which was converted into
dibenzyl ether 20. Formylation of compound 20 led to 4-pyridinecarboxaldehyde 21 in
61% yield, together with the formation of [5-(benzyloxy)pyridin-3-yl](phenyl)methanol
Scheme 5. Preparation of 5-chloro-6,8-diazacoumarin 19.

SYNTHESIS OF 3-ALKOXYCARBONYL AZACOUMARINS
3037
Scheme 6. Preparation of 7-azacoumarin 24.
22 as a major side product (33%). Knoevenagel condensation of 21 with dimethyl
malonate produced compound 23 in good yield, and debenzylation by catalytic hydro-
genolysis induced direct cyclization with quantitative formation of 5-hydroxy-7-
azacoumarin 24. Following that strategy, 5-alkoxy derivatives of coumarin 24 may
be easily obtained from 3-alkoxy-5-benzyloxypyridine, which is readily available from
3,5-dichloropyridin.
In conclusion, we described the synthesis of a series of original coumarins
obtained either by functional transformation of coumarins prepared by known
methods (Pechmann or Knoevenagel condensation) or by a new procedure starting
from 3,5-dichloropyridine.
EXPERIMENTAL
Silica gel for flash chromatography (silica gel 60, 0.040–0.063 mm, 230–400
mesh ASTM) and thin-layer chromatographic (TLC) plates (0.25-mm silica-gel 60
precoated plates, F254) were from E. Merck. Melting points were determined using
a Stuart SMP3 apparatus. 1H NMR and 13C NMR spectra were recorded on Bruker
WP-200-Sy, Avance DPX-300, and Avance III-400 instruments, and chemical shifts d
are reported in parts per million (ppm) relative to their standard reference (1H: CHCl3
at 7.27 ppm, HDO at 4.63 ppm, CD2HOD at 3.31 ppm; 13C: CDCl3 at 77.0 ppm,
CD3OD at 49.0 ppm). Infrared (IR) spectra were recorded on a Perkin-Elmer 1600
Fourier transform (FT)–IR spectrometer in the attenuated total reflection (ATR)
mode, and absorptions values n are in wave numbers (cmꢀ1). Ultraviolet–visible
(UV-vis) absorption spectra were recorded in MeOH on a Kontron Uvikon 930
instrument. Absorption maxima kabs and molar extinction coefficients e are in
M
ꢀ1 cmꢀ1. Fluorescence spectroscopy was performed with a Jobin Yvon Fluoromax
P spectrophotometer equipped with a xenon lamp. Emission maxima kem are given in
nm. Mass spectra (MS) were recorded on a Waters Micromass ZQ instrument, using
electrospray ionization (ESI) mode. Mass data are reported in mass units (m=z).
High-resolution mass spectra (HRMS) were recorded on a Bruker Daltonics
MicrOTOF-Q spectrometer in ESI mode.

´
C. FEAU ET AL.
3038
Starting Materials
Starting materials were purchased from Sigma-Aldrich (Saint-Quentin Falla-
vier, France) and Alfa Aesar (Bischeim, France) and used without purification.
All reactions were carried out with reagent-grade solvents. When required, solvents
were dried according to standard procedures as described elsewhere.[25]
3-Ethoxycarbonyl-5-hydroxy-7-methyl-6-azacoumarin (3)
Diethyl N,N-diethylaminomethylene malonate (1.80 g, 7.4 mmol) and
2,4-dihydroxy-6-methylpyridine (0.40 g, 3.2 mmol) were stirred in refluxing AcOH
(4 mL) for 6 h. The yellow precipitate was collected by centrifugation and washed
with Et2O to yield analytically pure compound 3 (0.63 g, 79%) as a light orange pow-
1
der. TLC Rf 0.6 (AcOEt=EtOH 4:1). Mp 291 ꢁC (lit.[17] 295 ꢁC). H NMR (DMSO-
D6, 300 MHz) d 8.51 (s, 1H); 6.27 (s, 1H); 4.25 (q, J ¼ 7.2 Hz, 2H); 2.29 (s, 3H); 1.28
(t, J ¼ 7.2, 3H). 13C NMR (DMSO-D6, 50 MHz) d 166.2; 162.1; 160.0; 155.4; 154.3;
145.6; 111.2; 104.7; 96.6; 60.8; 19.3; 14.0. IR (film) n 2913; 1615; 1553. UV-vis kabs
368 (e 6,500), kem 442. HRMS (ESI) (C12H11NO5) calcd. 250.0710 [M þ H]þ; found
250.0706.
3-Ethoxycarbonyl-5-hydroxy-6-azacoumarin (4)
Diethyl N,N-diethylaminomethylene malonate (4.38 g, 18.0 mmol) and
2,4-dihydroxypyridine (1.00 g, 9.0 mmol) were stirred in refluxing AcOH (8 mL)
for 8 h and for 10 h more at rt. The orange precipitate was collected by filtration
and washed with Et2O to yield analytically pure compound 4 (0.84 g, 40%) as a yel-
low powder. The filtrate was reduced under vacuum, and the residue was purified by
silica-gel chromatography to yield another portion of pure compound 4 (0.73 g,
35%). TLC Rf 0.5 (AcOEt=EtOH 4:1). Mp 265 ꢁC (lit.[19] 245–265 ꢁC, dec.). 1H
NMR (CD3OD, 300 MHz) d 8.78 (s, 1H); 7.71 (d, J ¼ 7.2 Hz, 1H); 6.40 (2,
J ¼ 7.2 Hz, 1H); 4.34 (q, J ¼ 7.1 Hz, 2H); 1.37 (t, J ¼ 7.1, 3H). 13C NMR (DMSO-
D6, 50 MHz) d 167.0; 163.2; 160.9; 156.9; 146.6; 142.9; 113.7; 108.1; 98.1; 62.2;
15.1. IR (film) n 3192; 3094; 1754; 1682. UV-vis kabs 372 (e 11,600), kem 445. HRMS
(ESI) (C11H9NO5) calcd. 236.0553 [M þ H]þ; found 236.0548.
3-Ethoxycarbonyl-5-hydroxy-6,8-diazacoumarin (5)
Compound 5 (0.15 g, 55%) was obtained as a light yellow powder after
silica-gel chromatography, starting from 2,4-dihydroxypyrimidine and following
the same procedure as described for 3. TLC Rf 0.45 (AcOEt=EtOH 4:1). Mp
213 ꢁC (lit.[19] 213–215 ꢁC). 1H NMR (CDCl3=CD3OD 1:1, 300 MHz) d 8.78 (s,
1H); 8.24 (s, 1H); 4.35 (q, J ¼ 6.9 Hz, 2H); 1.36 (t, J ¼ 6.9, 3H). 13C NMR
(CDCl3=CD3OD 1:1, 100 MHz) d 168.3; 160.1; 156.5; 154.3; 152.3; 146.0; 121.2;
115.9; 62.6; 14.4. IR (film) n 3209; 1766; 1681. UV-vis kabs 354 (e 14,200), kem
417. HRMS (ESI) (C10H8N2O5) calcd. 237.0506 [M þ H]þ; found 237.0497.

SYNTHESIS OF 3-ALKOXYCARBONYL AZACOUMARINS
3039
3-Ethoxycarbonyl-5-hydroxy-7-hydroxymethyl-6,8-diazacoumarin (6)
Compound 6 (51 mg, 13%) is obtained as colorless glassy solid after silica-gel
chromatography, starting from 2,4-dihydroxy-6-hydroxymethylpyrimidine and
following the same procedure as described for 3. TLC Rf 0.3 (CH2Cl2=MeOH
1
1:1). Mp 212–220 ꢁC. H NMR (CD3OD, 300 MHz) d 7.86 (s, 1H); 4.46 (s, 2H);
4.18 (q, J ¼ 7.2 Hz, 2H); 1.29 (t, J ¼ 7.2, 3H). IR (film) n 2924; 1733; 1608. UV-vis
kabs 351 (e 7,000), kem 435. HRMS (ESI) (C11H10N2O6) calcd. 267.0612 [M þ H]þ;
found 267.0606.
3-Ethoxycarbonyl-5-chloro-7-methyl-6-azacoumarin (7)
Coumarin 3 (55 mg, 0.22 mmol) was stirred in refluxing freshly distilled phos-
phorus oxychloride (2 mL) for 2 h. Toluene (5 mL) was added, and volatile was
removed under reduced pressure. The crude residue was dissolved in CH2Cl2 and
washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4
and purified over silica gel to yield coumarin 7 (50 mg, 85%) as a white powder. TLC
Rf 0.3 (Et2O=n-hexane 1:1). Mp 153 ꢁC. 1H NMR (CDCl3, 300 MHz) d 8.70 (s, 1H);
7.03 (s, 1H); 4.40 (q, J ¼ 7.2 Hz, 2H); 2.61 (s, 3H); 1.39 (t, J ¼ 7.2, 3H). 13C NMR
(CDCl3, 75 MHz) d 163.8; 161.9; 151.8; 154.6; 150.5; 144.4; 119.0; 111.2; 110.1;
62.3; 24.8; 14.1. IR (film) n 3067; 2985; 1770; 1606. UV-vis kabs 309 (e 6,700), kem
440. HRMS (ESI) (C12H10ClNO4) calcd. 268.0371 [M þ H]þ; found 268.0360.
5-Chloro-7-methyl-6-azacoumarin (8)
This compound (6 mg, 14%) was obtained as a white powder and was a side
1
product in the preparation of 7. TLC Rf 0.2 (Et2O=n-hexane 1:1). Mp 136 ꢁC. H
NMR (CDCl3, 300 MHz) d 7.98 (d, J ¼ 9.9 Hz, 1H); 7.01 (s, 1H); 6.45 (d, J ¼ 9.9 Hz,
1H); 2.59 (s, 3H). 13C NMR (CDCl3, 50 MHz) d 161.5; 161.1; 158.4; 149.0; 139.5;
117.5; 111.8; 110.4; 24.5. IR (film) n 3084; 1752; 1599. UV-vis kabs 288 (e 4,400),
kem 438. HRMS (ESI) (C9H6ClNO2) calcd. 196.0165 [M þ H]þ; found 196.0145.
3-Ethoxycarbonyl-5-chloro-7-bromomethyl-6-azacoumarin (9)
A mixture of coumarin 8 (1.20 g, 4.5 mmol), NBS (1.00 g, 5.6 mmol), and
benzoyl peroxide (0.05 g, 0.2 mmol) in H2O=CH2Cl2 2:1 (30 mL) was stirred under
irradiation for 5 h using a 150-W spotlight. Ether was added, and the organic layer
was washed with saturated aqueous NaHCO3 and dried over MgSO4, and the
residue was purified by chromatography to yield 9 (0.65 g, 42%) as a yellow solid.
A fraction of starting material (0.46 g, 38%) was recovered during purification.
1
TLC Rf 0.35 (CH2Cl2). Mp 123 ꢁC. H NMR (CDCl3, 300 MHz) d 8.73 (s, 1H);
7.34 (s, 1H); 4.52 (s, 2H); 4.44 (q, J ¼ 7.2 Hz, 2H); 1.42 (t, J ¼ 7.2 Hz, 3H). 13C
NMR (CDCl3, 75 MHz) d 162.1; 161.8; 160.9; 154.1; 151.1; 143.7; 120.4; 112.8;
110.7; 62.6; 31.5; 14.1. IR (film) n 3075; 1765; 1589. UV-vis kabs 378 (e 11,600)
[306 (e 2,600)], kem 453. HRMS (ESI) (C12H9BrClNO4) calcd. 345.9476 [M þ H]þ;
found 345.9461.

´
C. FEAU ET AL.
3040
3-Ethoxycarbonyl-5-hydroxy-7-bromomethyl-6-azacoumarin (10)
Compound 9 (0.31 g, 0.90 mmol) was refluxed for 16 h in acetic acid (5 mL).
The yellow precipitate was collected by centrifugation and washed with Et2O to
furnish analytically pure coumarin 10 (0.24 g, 81%) as a yellow powder. TLC Rf
1
0.4 (AcOEt). Mp 276–279 ꢁC. H NMR (DMSO-d6, 300 MHz) d 8.49 (s, 1H); 6.61
(s, 1H); 4.48 (s, 2H); 4.26 (q, J ¼ 7.0 Hz, 2H); 1.29 (t, J ¼ 7.0 Hz, 3H). 13C NMR
(DMSO-d6, 50 MHz) d 166.6; 163.0; 160.9; 156.1; 152.1; 146.0; 114.2; 108.0; 99.0;
62.0; 28.4; 15.0. IR (film) n 3045; 2795; 1770; 1667. UV-vis kabs 379 (e 5,200), kem
457. HRMS (ESI) (C12H10BrNO5) calcd. 327.9815 [M þ H]þ; found 327.9791.
3-Ethoxycarbonyl-5-hydroxy-7-[(N-methyl-N-benzyl)aminomethyl]-
6-azacoumarin (11)
A mixture of coumarin 10 (36 mg, 0.10 mmol) and methylbenzylamine (26 mL,
0.20 mmol) in CH2Cl2 (2 mL) was refluxed for 2 h. Volatile was removed under
reduced pressure, and the residue was dissolved in Et2O and washed with water
and brine. The organic layer was dried over MgSO4, evaporated, and purified by
chromatography to yield tertiary amine 11 (31 mg, 77%) as a yellow glassy solid.
1
TLC Rf 0.2 (CH2Cl2=AcOEt 9:1). H NMR (CDCl3, 200 MHz) d 8.74 (s, 1H); 7.53
(s, 1H); 7.36–7.17 (m, 5H); 4.44 (q, J ¼ 7.2 Hz, 2H); 3.73 (s, 2H); 3.65 (s, 2H); 2.32
(s, 3H); 1.42 (t, J ¼ 7.2 Hz, 3H). 13C NMR (CDCl3, 50 MHz) d 166.2; 162.3; 162.1;
154.7; 150.5; 144.4; 138.3; 128.8; 128.4; 127.3; 119.4; 112.0; 109.4; 62.4; 62.3; 62.2;
42.8; 14.1. IR (film) n. 2924; 1767; 1594. UV-vis kabs 379 (e 4,500) [319 (e 4,200)],
kem 478. HRMS (ESI) (C20H20ClN2O4) calcd. 387.1106 [M þ H]þ; found 387.1072.
3-Ethoxycarbonyl-4-bromo-5-hydroxy-7-methyl-6-azacoumarin (12)
Bromine (22 mL, 0.44 mmol) in CH2Cl2 (0.3 mL) was added dropwise to
coumarin 3 (33 mg, 0.14 mmol) in CH2Cl2=H2O 1:1 (8 mL). The resulting mixture
was refluxed for 3 h, cooled down to rt, treated with saturated aqueous Na2S2O3
(10 mL), and extracted with AcOEt. The organic layer was dried over MgSO4,
reduced under vacuum, and purified by silica-gel chromatography to yield 12
1
(39 mg, 85%) as a yellow glassy solid. TLC Rf 0.6 (Et2O=EtOH 9:1). H NMR
(DMSO-d6, 300 MHz) d 6.28 (s, 1H); 4.39 (q, J ¼ 7.2 Hz, 2H); 2.44 (s, 3H); 1.40 (t,
J ¼ 7.2 Hz, 3H). MS (ESI) 328 [M þ H]þ, 350 [M þNa]þ.
3-Ethoxycarbonyl-5-methoxy-7-methyl-6-azacoumarin (13)
Methyl iodide (0.2 mL, 3.2 mmol) and Ag2CO3 (0.32 g, 1.1 mmol) were added
to coumarin 3 (0.22 g, 0.9 mmol) in CHCl3 (10 mL). The mixture was stirred at rt
for 36 h, and a second portion of methyl iodide (0.2 mL, 3.2 mmol) and Ag2CO3
(0.16 g, 0.6 mmol) was added before another 24-h stirring period. Volatile was
removed, and the residue was purified by chromatography to yield coumarin 13
(95 mg, 41%) as a white powder. TLC Rf 0.15 (Et2O=n-hexane 3:7). Mp 136 ꢁC.
1H NMR (CDCl3, 300 MHz) d 8.74 (s, 1H); 6.68 (s, 1H); 4.39 (q, J ¼ 7.2 Hz, 2H);
4.07 (s, 3H); 2.51 (s, 3H); 1.40 (t, J ¼ 7.2 Hz, 3H). 13C NMR (CDCl3, 100 MHz) d

SYNTHESIS OF 3-ALKOXYCARBONYL AZACOUMARINS
3041
163.0; 162.9; 162.8; 161.0; 156.1; 144.3; 115.6; 104.7; 100.9; 61.8; 54.5; 25.2; 14.3. IR
(film) n 2958; 1765; 1703; 1614. UV-vis kabs 334 (e 13,200) [354 (e 7,800)], kem 424.
HRMS (ESI) (C13H13NO5) calcd. 264.0866 [M þ H]þ; found 264.0842.
3-Ethoxycarbonyl-5-chloro-6-azacoumarin (14)
Coumarin 4 (0.10 g, 0.42 mmol) was added to freshly distilled POCl3 (1.3 mL)
and N,N-dimethylaniline (54 mL, 0.42 mmol), and the resulting mixture was refluxed
for 3 h. Volatile was removed under vacuum, and saturated aqueous NaHCO3 was
added to the residue to reach pH 7–8. The aqueous solution was extracted with
CH2Cl2, and the organic layer was dried over MgSO4, reduced under vacuum,
and purified by silica-gel chromatography to yield 7 (0.10 g, 93%) as a yellow
powder. TLC Rf 0.5 (AcOEt=n-hexane 1:1). Mp 99 ꢁC. 1H NMR (CDCl3,
200 MHz) d 8.63 (s, 1H); 8.39 (d, J ¼ 5.8 Hz, 1H); 7.16 (d, J ¼ 5.8 Hz, 1H); 4.31 (q,
J ¼ 7.2 Hz, 2H); 1.30 (t, J ¼ 7.2, 3H). 13C NMR (CDCl3, 50 MHz) d 162.0; 154.6;
152.8; 150.0; 144.9; 144.4; 120.8; 114.0; 111.8; 62.8; 14.5. IR (film) n 1776; 1695.
UV-vis kabs 295 (e 8,600) [358 (e 1,200)], kem 445. HRMS (ESI) (C11H8ClNO4) calcd.
254.0220 [M þ H]þ; found 358.0209.
Ethyl 3,4-Dihydro-2-oxo-2H-pyrano[3,2-c]pyridine-3-carboxylate (15)
Coumarin 14 (50 mg, 0.23 mmol) and Pd=C 10% (5 mg) in MeOH = tetrahydro-
furan (THF) (4:5, 6 mL) were vigorously stirred under a hydrogen atmosphere for
2 h. The catalyst was filtered off and rinsed with MeOH, and the filtrate was evapo-
rated to dryness to yield analytically pure reduced compound 15 (43 mg, 99%) as a
colorless glassy solid. TLC Rf 0.3 (AcOEt=EtOH 4:1). 1H NMR (CD3OD,
300 MHz) d 8.39 (s, 1H); 8.35 (d, J ¼ 6.6 Hz, 1H); 7.16 (d, J ¼ 6.6 Hz, 1H); 4.15
(q, J ¼ 6.9 Hz, 2H); 3.28 (m, 2H); 1.21 (t, J ¼ 7.2, 3H). MS (ESI) 222 [M þ H]þ.
3-Ethoxycarbonyl-5-bromo-6-azacoumarin (16)
Phosphorus pentoxide (0.66 g, 4.7 mmol) was added to coumarin 4 (0.50 g,
2.1 mmol) and n-Bu4NBr (0.83 g, 2.5 mmol) in toluene (6 mL), and the resulting mix-
ture was refluxed for 16 h. Water was added, and the aqueous layer was extracted
with CH2Cl2. The organic layer was dried over MgSO4 and reduced under vacuum,
and the residue was purified by silica-gel chromatography to yield coumarin 16
1
(0.56 g, 88%) as a brown solid. TLC Rf 0.6 (AcOEt=n-hexane 1:1). Mp 111 ꢁC. H
NMR (CDCl3, 300 MHz) d 8.70 (s, 1H); 8.45 (d, J ¼ 5.6 Hz, 1H); 7.23 (d, J ¼ 5.6 Hz,
1H); 4.42 (q, J ¼ 7.2 Hz, 2H); 1.41 (t, J ¼ 7.2, 3H). 13C NMR (CDCl3, 50 MHz)
d 162.5; 161.8; 154.6; 153.2; 146.7; 144.8; 121.1; 116.2; 112.2; 63.0; 14.6. IR (film)
n 1768; 1715. UV-vis kabs 302 (e 9,600) [360 (e 2,000)], kem 444. HRMS (ESI)
(C11H8BrNO4) calcd. 297.9709 [M þ H]þ; found 297.9690.
3-Ethoxycarbonyl-6-azacoumarin (17)
Coumarin 16 (24 mg, 0.08 mmol) and Pd=BaSO4 5% (1.2 mg) in CH2Cl2
(2.5 mL) were vigorously stirred under a hydrogen atmosphere for 16 h. The catalyst

´
C. FEAU ET AL.
3042
was filtered off and rinsed with CH2Cl2, and the filtrate was evaporated to dryness.
The crude residue was purified by silica-gel chromatography to yield compound 17
1
(8 mg, 45%) as a brown solid. TLC Rf 0.4 (AcOEt). Mp 109 ꢁC. H NMR (CDCl3,
400 MHz) d 8.89 (s, 1H); 8.75 (d, J ¼ 5.6 Hz, 1H); 8.57 (s, 1H); 7.28 (d, J ¼ 5.6 Hz,
1H); 4.44 (q, J ¼ 7.2 Hz, 2H); 1.43 (t, J ¼ 7.2 Hz, 3H). 13C NMR (CDCl3,
100 MHz) d 162.2; 160.2; 155.0; 153.9; 151.3; 145.7; 120.1; 114.8; 111.4; 62.4; 14.2.
IR (film) n 1763; 1693. UV-vis kabs 285 (e 17,000) [321 (e 7,700)], kem 434. HRMS
(ESI) (C11H9NO4) calcd. 220.0604 [M þ H]þ; found 220.0594.
Ethyl 5,6-Dihydro-6-methyl-2,5-dioxo-2H-pyrano[3,2-c]-
pyridine-3-carboxylate (18)
A mixture of coumarin 4 (140 mg, 0.60 mmol), dimethylsulfate (100 mL,
0.9 mmol), and K2CO3 (84 mg, 0.60 mmol) in acetone (15 mL) was refluxed for 1 h.
Volatile was removed under reduced pressure, and the residue was purified by chro-
matography to yield 18 (143 mg, 97%) as a yellow powder. TLC Rf 0.5 (EtOAc=
EtOH 4:1). Mp 150 ꢁC. 1H NMR (CDCl3, 400 MHz) d 8.89 (s, 1H); 7.53 (d,
J ¼ 7.6 Hz, 1H); 6.27 (d, J ¼ 7.6 Hz, 1H); 4.38 (q, J ¼ 7.2 Hz, 2H); 3.60 (s, 3H);
1.39 (t, J ¼ 7.2 Hz, 3H). 13C NMR (CDCl3, 100 MHz) d 165.1; 162.3; 159.8; 155.6;
146.3; 143.3; 114.7; 107.8; 98.2; 61.8; 37.7; 14.2. IR (film) n 1760; 1662. UV-vis kabs
7 (e 12,700) [264 (e 4,100)], kem 447. HRMS (ESI) (C12H11NO5) calcd. 250.0710
[M þ H]þ; found 250.0693.
3-Ethoxycarbonyl-5-chloro-6,8-diazacoumarin (19)
Compound 19 (22 mg, 9%) was obtained as a brown glassy solid from cou-
marin 5, following the same procedure as described for 7 unless N,N-dimethylaniline
(1 eq.) was introduced in the reaction mixture before refluxing. Rf 0.5 (CH2Cl2=
1
EtOH 95:5). H NMR (CDCl3, 300 MHz) d 8.93 (s, 1H); 8.70 (s, 1H); 4.46 (t,
J ¼ 6.9 Hz, 2H); 1.43 (t, J ¼ 6.9, 3H). MS (ESI) 255 [M þ H]þ.
3,5-Bis(benzyloxy)pyridine (20)
Benzyl alcohol (12.9 mL, 125.0 mmol) was slowly added to a mixture of
3,5-dichloropyridine (7.38 g, 49.8 mmol) and NaH (60% in oil; 5.00 g, 125.0 mmol)
in anhydrous DMF (40 mL) at 0 ꢁC. When hydrogen evolution had ceased, the sus-
pension was heated at 80 ꢁC and stirred for 20 h. Then it was cooled down to rt,
water was added, and the dark reaction mixture was extracted with CH2Cl2. The
organic layer was washed with water and brine and then dried over MgSO4. Solvent
was removed under vacuum, and the residue was recrystallized from Et2O to yield
compound 20 (6.52 g, 45%) as a white powder. Rf 0.2 (Et2O=cyclo-hexane 1:1).
1
Mp 111–112 ꢁC. H NMR (CDCl3, 200 MHz) d 8.07 (d, J ¼ 2.2 Hz, 2H); 7.44–7.33
(m, 10H); 6.90 (t, J ¼ 2.2 Hz, 1H); 5.09 (s, 4H). 13C NMR (CDCl3, 50 MHz) d
155.5; 136.0; 130.5; 128.6; 128.2; 127.4; 108.5; 70.4. IR (film) n 1576. HRMS (ESI)
(C19H17NO2) calcd. 292.3512 [M þ H]þ; found 292.3505.

SYNTHESIS OF 3-ALKOXYCARBONYL AZACOUMARINS
3043
3,5-Bis(benzyloxy)pyridine-4-carbaldehyde (21)
Pyridine 20 (4.0 g, 13.7 mmol) in anhydrous THF (65 mL) was treated dropwise
with 1.6 M n-BuLi (9.4 mL, 15.0 mmol) at ꢀ78 ꢁC. At the end of the addition, anhy-
drous DMF (2.1 mL, 27.4 mmol) was introduced in the flask, and the reaction mix-
ture was stirred for 35 min before H2O (40 mL) was added. Then the mixture was
allowed to warm at rt and was extracted with AcOEt. The organic layer was washed
with brine, dried over MgSO4, and reduced under vacuum. The residue was purified
by silica-gel chromatography to yield compound 21 (2.68 g, 61%) as a white solid. Rf
1
0.4 (Et2O). Mp 103 ꢁC. H NMR (CDCl3, 200 MHz) d 10.61 (s, 1H); 8.21 (s, 2H);
7.45–7.37 (m, 10H); 5.29 (s, 4H). 13C NMR (CDCl3, 75 MHz) d 188.4; 154.0;
135.5; 129.6; 128.3; 127.7; 127.1; 118.5; 71.4. IR (film) n 1692; 1559. HRMS (ESI)
(C20H17NO3) calcd. 320.1281 [M þ H]þ; found 320.1266.
[5-(Benzyloxy)pyridin-3-yl](phenyl)methanol (22)
Compound 22 (1.31 g, 33%) is a side product in the preparation of 21 and was
obtained as an orange powder. Rf 0.2 (Et2O). Mp 71 ꢁC. 1H NMR (CDCl3, 200 MHz)
d 8.24–8.20 (m, 2H); 7.41–7.33 (m, 11H); 5.86 (s, 1H); 5.07 (s, 2H). 13C NMR (CDCl3,
75 MHz) d 154.9; 140.0; 143.3; 141.1; 136.0; 135.7; 128.5; 128.1; 127.6; 127.4; 126.4;
120.0; 73.1; 70.1. IR (film) n 3030; 1582. MS (ESI) 292 [M þ H]þ; 314 [M þNa]þ.
HRMS (ESI) (C19H17NO2) calcd. 292.1332 [M þ H]þ; found 292.1322.
Dimethyl 2-{[3,5-bis(Benzyloxy)pyridin-4-yl]methylene}malonate (23)
Dimethyl malonate (0.42 mL, 3.7 mmol) and piperidine (0.32 mL, 3.3 mmol)
were added to pyridine carbaldehyde 21 (1.05 g, 3.3 mmol) in anhydrous THF
(20 mL). The reaction mixture was refluxed for 8 h. Volatile was removed under
reduced pressure, and the residue was dissolved in AcOEt and washed with saturated
aqueous NH4Cl. The organic layer was dried and purified by chromatography to
1
yield 23 (1.32 g, 92%) as a white solid. Rf 0.4 (Et2O). Mp 74 ꢁC. H NMR (CDCl3,
200 MHz) d 8.05 (s, 2H); 7.84 (s, 1H); 7.40–7.36 (m, 10H); 5.19 (s, 4H); 3.86 (s,
3H); 3.51 (s, 3H). 13C NMR (CDCl3, 75 MHz) d 165.0; 164.7; 152.0; 135.6; 135.1;
130.4; 130.3; 128.5; 128.1; 127.1; 119.8; 71.5; 52.6; 51.8. IR (film) n 1730; 1713;
1454; 1433. HRMS (ESI) (C25H23NO6) calcd. 434.1598 [M þ H]þ; found 434.1591.
3-Methoxycarbonyl-5-hydroxy-7-azacoumarin (24)
Compound 23 (91 mg, 0.21 mmol) and Pd=C 10% (6 mg) in THF (5 mL) were
vigorously stirred under a hydrogen atmosphere for 4 h. Catalyst was removed by
filtration over a celite pad and rinsed with MeOH. The filtrate was reduced under
vacuum to yield analytically pure coumarin 24 (48 mg, 99%) as an orange powder.
1
Rf 0.05 (Et2O). Mp 198 ꢁC. H NMR (CDCl3=CD3OD 1:1, 300 MHz) d 8.83 (s,
1H); 8.12 (s, 1H); 8.05 (s, 1H); 3.91 (s, 3H). 13C NMR (CDCl3=CD3OD 1:1,
50 MHz) d 162.6; 155.6; 151.3; 150.0; 142.5; 131.8; 128.0; 119.5; 112.5; 52.4. IR (film)
n 3258; 1732; 1585. MS (ESI) 244 [M þNa]þ, 465 [2 M þNa]þ. UV-vis kabs 340 (e
8,500), kem 555. HRMS (ESI) (C10H7NO5) calcd. 222.0397 [M þ H]þ; found 222.0377.

´
C. FEAU ET AL.
3044
ACKNOWLEDGMENT
The authors thank Mr. Stephane Nehlig for the analytical work.
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