Synthesis of potentially photoactivatable coumarin derivatives via a 1,3-dipolar cycloaddition

Article abstract of DOI:10.1002/jhet.5570450528

(Chemical Equation Presented) A copper (I)-catalyzed 1,3-dipolar cycloaddition reaction was used to prepare a series of mono and disubstituted 1,2,3-triazolyl-coumarins using a 1,3-cycloaddition ("Click Chemistry"). Starting coumarins were synthesized using classical or modified Pechmann's reaction. The propargyl group was introduced as either propargylether or as a propargylamide. Azides were prepared in a three steps procedure. Cycloaddition products, containing a coumarin and a photoactivatable moiety, were obtained in good yields.

Full text of DOI:10.1002/jhet.5570450528

Sep-Oct 2008
1429
Synthesis of Potentially Photoactivatable Coumarin Derivatives via
a 1,3-Dipolar Cycloaddition
Elodie-Denise Chenot,a Juan Carlos Rodríguez-Domínguez, a Paul Hannewald,b
Alain Comel, a Gilbert Kirsch,*a
a Laboratoire d’Ingénierie Moléculaire et Biochimie Pharmacologique (LIMBP)
b Laboratoire de Spectroscopie de Masse et Chimie Laser
Université Paul Verlaine-Metz, Institut Jean Barriol, 1 Boulevard Arago, 57078 Metz, France
Received March 19, 2008
O
O
+
Coumarin
X2
X1
X2
X1
Coumarin
N3
N
N
N
A copper (I)-catalyzed 1,3-dipolar cycloaddition reaction was used to prepare a series of mono and
disubstituted 1,2,3-triazolyl-coumarins using a 1,3-cycloaddition ("Click Chemistry"). Starting coumarins
were synthesized using classical or modified Pechmann’s reaction. The propargyl group was introduced as
either propargylether or as a propargylamide. Azides were prepared in a three steps procedure.
Cycloaddition products, containing a coumarin and a photoactivatable moiety, were obtained in good
yields.
J. Heterocyclic Chem., 45, 1429 (2008).
INTRODUCTION
Benzophenones are often used for photoaffinity
labeling (PAL) [19,20]. The photolabeling principle is to
form, by UV-irradiation, a covalent bond between the tag
which contains the photoactivatable group and enzymes
or proteins. This technique allows the access to a large
amount of structural information and it is a good tool to
identify molecular interaction sites. Detection of the
labeled proteins through fluorescence can be achieved
using the photophysical properties of coumarins.
Introducing propargyl chains as coumarin side chains and
azides on the benzophenones gave the starting material
for the click chemistry.
1,3-Dipolar cycloaddition reactions are very useful in
synthetic organic chemistry. One of them is the Huisgen
reaction [1], which was recently improved and named
"Click Chemistry" by Sharpless et al. [2] This consists in
a cycloaddition reaction between an azide and a terminal
alkyne. The regioselectivity of this reaction, controlled by
the introduction of catalytic quantities of copper (I),
allows the exclusive formation of a 1,4-disubstituted
1,2,3-triazole [3]. Moreover, utilization of the catalyst
increases the reaction rate and allows the reaction to
proceed at room temperature. The range of application of
this reaction has been constantly increasing. Its tolerance
to a large variety of functional groups, ease to carry out
and good yields, make this method a very useful synthetic
tool. This reaction has been applied in order to selectively
modify biomolecules and living cells [4], synthesize
pseudopeptide conjugates [5] and recently, coumarin-
nucleoside conjugates [6].
In this paper, the 1,3-dipolar cycloaddition between
terminal alkynes (coumarin derivatives, compound a) and
azides (benzophenone or analogues, compound b) was
performed using CuSO4.5H2O and sodium ascorbate as
catalytic system in DMF (Scheme I).
Scheme I
On the other hand, coumarins have a wide spectrum of
biological activities and uses [7-14]. Moreover, coumarins
constitute an important class of organic fluorescent dyes.
These fluorescent properties have been used to study
proteins and nucleic acids [15,16].
R'
Copper (I)
+
+
R'
N
N
N
N
R"
N
R"
N
a
b
Recent articles exposed the use via click chemistry of
some of coumarin derivatives [17]. As a continuation of
our research about photolabeling of proteins [18], we
choose to combine, via a triazole formed by click
chemistry, benzophenone and thiophene analogues to
coumarins in order to prepare new photoactivatable agents
for proteins labeling.
RESULTS AND DISCUSSION
We have developed in our laboratory an environmental
friendly procedure to synthesize some hydroxy substituted
coumarins, (see compounds 1-3) [21], in good yields.
Only, coumarin-4-acetic acid 4 was obtained by a
classical Pechmann reaction (Table 1).

1430
E.-D. Chenot, J. C. Rodríguez-Domínguez, P. Hannewald, A. Comel, G. Kirsch
Vol 45
Table 1
Scheme II
Prepared hydroxy coumarins and coumarinyl-4-acetic acid.
O
i, ii
R3
R3
R4
COOH
X1
X2
X1
Pechmann's
reaction
CH3
a X1=X2 : CH=CH
9a-d
b X1: CH=CH and X2 : S
c X1: S and X2: CH=CH
d X1=X2 : S
R2
OH
R2
O
O
iii
R1
R1
O
O
1-4
iv
X1
X2
X1
X2
Compd
R1
R2
OH
R3
R4
Yields (%)
CH2Br
CH2N3
1
2
3
4
H
OH
H
H
H
CH3
CH3
CH3
91i or ii
52i/64ii
92i/48ii
36iii
11a-d
10a-d
OH
OH
Reaction conditions: i. SOCl2; ii. toluene or 2-methylthiophene,
AlCl3, DCM; iii. NBS, AIBN, DCM; iv. NaN3, DMF, 50 °C.
OH
H
CH=CH-CH=CH
CH2COOH
Reaction conditions : i. SZr, b-ketoester, 80 °C, 24h or 60-65 °C,
24h; ii. ZrOCl2.8H2O, beta-ketoester, 80 °C, 24h or 60-65 °C, 24h;
iii. 1,3-acetone dicarboxylic acid, sulfuric acid
reaction (Scheme II). Acyl chlorides were prepared from
benzoic acid or 2-thiophenecarboxylic acid and thionyl
chloride, and reacted with toluene or 2-methylthiophene
in presence of aluminium chloride. The residual methyl
chain in those di-(het) aryl-ketones was then transformed
by radical substitution using NBS to obtain bromo-
derivatives 10a-d as mixtures with unreacted 9. The
mixture was reacted with sodium azide without further
purification and expected azides 11a-d were obtained in
good yields (56-85 %) after final column chromatography
purification.
The terminal alkyne group was introduced as either a
propargylether for 1-3 or a propargylamide for 4.
Propargylethers 5-7 were prepared by reacting coumarins 1-
3 with propargylbromide in dry acetone in presence of dry
potassium carbonate. Amidification of compound 4 to yield
propargyl amide 8 was done by activating the acid (NHS,
DCC) and reacting the ester with propargylamine. The "one
pot" reaction gave amide 8 in 57% yield (Table 2).
Table 2
Prepared terminal alkyne coumarins
Starting
coumarins
Yields
(%)
Starting
coumarins
Yields
(%)
Compd
Product
Compd
Product
CH3
O
CH3
90i
7
3
80i
O
O
5
1
2
O
O
O
O
O
O
CH3
N
H
6
91i
8
4
57ii
O
O
O
O
O
Reaction conditions: i. K2CO3, propargylbromide, dry acetone; ii. NHS, DCC, propargylamine, DMF".
On the other hand, the azido function was introduced on
benzophenone analogues. For this purpose a three-step
procedure was developed to synthesize 4-azidomethyl-
benzophenone and thiophene analogues (Scheme II).
The synthesis of 4-methylbenzophenone 9a is well
documented in the literature [22] contrary to thiophene
analogues 9b-d. Only several examples of them have been
reported [23], being 9d the less described [24].
Compounds 9a-d were prepared by a Friedel-Crafts
Classical conditions were used (CuSO4.5H2O and
sodium ascorbate) for the Cu (I)-catalyzed Huisgen 1,3-
dipolar cycloaddition. Reactions were performed in DMF
in order to increase the starting material solubility and to
simplify the work up. After 36 h at room temperature
reactions were quenched with water. The formed
precipitate was collected by filtration, washed with water
and dried at room temperature until constant weight.
Recrystallization from diethyl ether gave compounds 12a-

Sep-Oct 2008 Synthesis of Potentially Photoactivatable Coumarins derivatives via a 1,3-Dipolar Cycloaddition
1431
Table 3
Coumarin derivatives obtained by a copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition.
Alkynes Azides
Click Chemistry Product
Compd Yields (%)
CH3
O
11a
12a
12b
12c
12d
98
97
56
94
11b
5
O
O
N
11c
11d
X1
N
X2
N
O
N
N
N
O
CH3
O
X1
X2
11a
13a
13b
13c
13d
74
74
89
86
11b
6
11c
O
O
O
N
11d
X1
N
X2
N
O
N
N
CH3
X2
X1
N
O
11a
14a
14b
14c
14d
92
53
89
95
O
O
O
11b
7
11c
O
N
X1
X2
11d
O
N
N
O
N
H
11a
N
15a
15b
15c
15d
92
96
97
65
N
N
11b
8
11c
X2
O
O
11d
X1
O
EXPERIMENTAL
d, 13a-d, 14a-d and 15a-d in good yields. Results are
listed in Table 3.
Reagents and solvents used in this work were obtained from
Acros Organics. Melting points were measured on a Stuart
Scientific SMP3 apparatus and are uncorrected. MALDI-
FTICRMS (Matrix Assisted Laser Desorption/Ionization
coupled to Fourier Transform Ion Cyclotron Resonance Mass
Spectrometry) measurements were carried out on an IonSpec
Explorer Fourier Transform Mass Spectrometer 9.4 T equipped
with a ProMALDI module (IonSpec, Lake Forest, USA)
provided with an Orion air cooled Nd:YAG System (355 nm,
New wave research, Fremont, USA). The matrix used was a
saturated 2,5-dihydroxybenzoic acid (2,5-DHB) solution in 50%
methanol, 0.1% trifluoro acetic acid (TFA). All the depositions
were made using the dried-droplet method. All the spectrum
were internally calibrated using a methotrexate solution (1.10-6
CONCLUSION
Some alkyne substituted coumarins and thiophene
benzophenone analogues have been synthesized and
coupled using the Cu(I)-catalyzed Huisgen 1,3-dipolar
cycloaddition in order to obtain new potentially
photoactivatable compounds. The latter have been
described for the first time and fully characterized. The
ability of some of them to perform photoaffinity labeling
of proteins is actually under investigation and results will
be published when due.

1432
E.-D. Chenot, J. C. Rodríguez-Domínguez, P. Hannewald, A. Comel, G. Kirsch
Vol 45
M) and the peak used to create
a calibration list was
2-(2-Oxo-2H-benzo[h]chromen-4-yl)-N-(2-propyn-yl)-
acetamide (8). To solution of (2-oxo-2H-benzo[h]-
methotrexate’s [M+H]+ pseudomolecular ion at m/z = 455.17859
Da. Gc/ms spectra measurements were performed on a Hewlett-
Packard 5971A electron impact (70eV) mass spectrometer,
a
chromen-4-yl)acetic acid (1 g, 3.93 mmol) in dry dimethyl-
formamide (5 mL) were added N-hydroxysuccinimide
(0.476 g, 4.13 mmol) and N,N'-dicyclohexylcarbodiimide
(1.7 g, 8.28 mmol) in dimethylformamide (5 mL). The
mixture was stirred at room temperature for 24 h, then
propargylamine (0.276 mL, 4.02 mmol) was added and left
to stir overnight at the same temperature. The formed
precipitate was filtered. The obtained filtrate was poured
into water, filtrated, washed with water and dried at room
temperature until constant weight. Pure product was
obtained by cristallisation from diethyl ether. (0.65 g), 57
equipped with
a Hewlett Packard 5890 series II gas
chromatograph. 1H and 13C nmr spectra were recorded on a
Bruker-AC 250-M Hz spectrometer with CDCl3 or DMSO-d6 as
both solvent and internal reference. The chemical shifts (ꢀ) are
expressed in ppm and coupling constants (J) in Hz. Compounds
1-3 were prepared as described in the literature [21].
(2-Oxo-2H-benzo[h]chromen-4-yl)-acetic acid (4).
1-Naphthol (4.9 g, 34.22 mmol) and 1,3-acetone dicarboxylic
acid (5 g, 34.22 mmol) were added to sulfuric acid (25 mL). The
mixture was stirred overnight at room temperature and poured
onto water. The obtained precipitate was washed with water and
dried in vacuo until constant weight yielding 3.13 g, 36 %, as a
pink solid, mp 207-208 °C (mplit 212-213 °C [25]). 1H nmr
(DMSO-d6): ꢀ 8.38-8.34 (m, 1H), 8.04-8.00 (m, 1H), 7.84 (d,
1H, J= 7.5 Hz), 7.74-7.69 (m, 2H), 6.61 (s, 1H), 4.00 (s, 2H,
CH2). 13C nmr (DMSO-d6): ꢀ 170.6, 159.5, 150.8, 149.9, 134.2,
128.7, 127.9, 127.4, 123.9, 122.2, 121.5, 121.3, 115.8, 114.6,
37.5.
1
%, dark beige solid, mp 245-246 °C. H nmr (DMSO-d6):
ꢀ 8.71 (t, 1H, NH, J=5.3 Hz), 8.38-8.34 (m, 1H), 8.05-8.00
(m, 1H), 7.84 (d, 1H, J=8.7 Hz), 7.74-7.69 (m, 3H), 6.55 (s,
1H), 3.93-3.88 (m, 4H), 3.17 (t, 1H, J=2.5 Hz). 13C nmr
(DMSO-d6): ꢀ 167.5, 159.5, 151.4, 149.9, 134.2, 128.7,
127.9, 127.4, 123.9: 122.2, 121.5, 121.2, 115.6, 114.6, 80.7,
73.2, 39.7, 28.2. hrms-maldi: m/z [M+H]+ calcd for
C18H13NO3 : 292.09682, found : 292.09687.
General procedure for the preparation of compounds 9 (a-
d). To benzoic acid (1.22 g, 10 mmol) or 2-thiophenecarboxylic
acid (1.28 g, 10 mmol) was added thionyl chloride (10 mL). The
mixture was refluxed for 4 h. Thionyl chloride excess was
evaporated in vacuo. To the obtained acid chloride was added
toluene (2.13 mL, 20 mmol) or 2-methylthiophene (1.94 mL, 20
mmol) in dichloromethane (20 mL), and aluminium chloride (2
g, 15 mmol) by portions. The mixture was stirred for 4 h at room
temperature and hydrolyzed with concentrated hydrochloric acid
(4 mL) in iced-water (50 mL). The product was extracted with
ethyl acetate. The organic layer was washed twice with water,
dried and solvent was removed until dryness. Pure products
were obtained after purification by column chromatography
using dichloromethane as eluent.
Methyl-7-(2-propynyloxy)-2H-chromen-2-one (5). To
solution of 7-hydroxy-4-methylcoumarin (4-methylum-
a
belliferone) (2.64 g, 15 mmol) in 40 mL of dry acetone was
added anhydrous potassium carbonate (2.07 g, 15 mmol) and
propargyl bromide (1.67 mL, 15 mmol). The mixture was stirred
at 50 °C for 18 h. After that time, the solvent was removed under
reduced pressure. The residue was treated with 20 mL of water
and extracted with ethyl acetate. Organic phases were combined
and washed with a 0.1 N sodium hydroxide solution and twice
with water. The organic layer was dried, filtered and solvent was
removed in vacuo. Crystallization from diethyl ether gave (2.89
1
g), 90 %, beige solid, mp 135-136 °C (mplit 134 °C 26). H nmr
(CDCl3): ꢀ 7.55-7.51 (m, 1H), 6.95-6.91 (m, 2H), 6.17 (s, 1H),
4.74 (d, 2H, J=2.3 Hz), 2.57 (t, 1H, J=2.3 Hz), 2.41 (d, 3H, CH3,
J=1.2 Hz). nmr (CDCl3): ꢀ 161.1, 160.3, 155.0, 152.4, 125.6,
114.2, 112.7, 112.4, 102.1, 77.4, 56.2, 18.7. hrms-maldi : m/z
[M+H]+ calcd for C13H10O3 : 215.07027, found : 215.07023.
General procedure for the preparation of compounds 6
and 7. Compounds 6 and 7 were obtained from 5,7-dihydroxy-
4-methyl-2H-chromen-2-one and 7,8-dihydroxy-4-methyl-2H-
chromen-2-one respectively, using the same procedure as for 5.
In this case twice of molar quantities of anhydrous potassium
carbonate and propargyl bromide was employed.
4-Methyl-5,7-bis (2-propynyloxy)-2H-chromen-2-one (6).
(3.64 g), 91 %, beige solid, mp 186-188 °C. 1H nmr (CDCl3):
ꢀ 6.59 (d, 1H, J=2.5 Hz), 6.47 (d, 1H, J=2.5 Hz), 6.00 (d, 1H,
J=1.2 Hz), 4.75 (d, 2H, J=2.5 Hz), 4.74 (d, 2H, J=2.5 Hz), 2.60-
2.49 (m, 5H). 13C nmr (CDCl3): ꢀ 160.7, 160.2, 156.9, 156.7,
154.0, 112.3, 105.8, 97.3, 95.4, 77.2, 56.5, 56.2, 24.3. hrms-
maldi: m/z [M+H]+ calcd for C16H12O4 : 269.08084, found :
269.08083.
4-Methyl-7,8-bis(2-propynyloxy)-2H-chromen-2-one (7).
(3.22 g), 80 %, yellow solid, mp 135-137 °C. 1H nmr (CDCl3):
ꢀ 7.35 (d, 1H, J=9.0 Hz), 7.05 (d, 1H, J=9.0 Hz), 6.18 (d, 1H,
J=1.2 Hz), 4.90 (d, 2H, J=2.4 Hz), 4.87 (d, 2H, J=2.4 Hz), 2.55
(t, 1H, J=2.4 Hz), 2.44 (t, 1H, J=2.4 Hz), 2.41 (d, 3H, CH3, J=1.2
Hz). 13C nmr (CDCl3): ꢀ 160.2, 153.5, 152.4, 148.2, 134.2,
120.0, 115.5, 112.9, 110.2, 78.5, 77.7, 77.2, 75.9, 60.6, 57.0,
18.8. hrms-maldi: m/z [M+H]+ calcd for C16H12O4 : 269.08084,
found : 269.08087.
(4-Methylphenyl)(phenyl)methanone (9a). (1.41 g), 72 %,
1
yellow solid, mplit 56.5-57 °C [22]. H nmr (CDCl3): 7.83-7.77
(m, 2H), 7.75 (d, 2H, J=7.9Hz), 7.62-7.56 (m, 1H), 7.51-7.44
(m, 2H), 7.29 (d, 2H, J=7.9 Hz), 2.45 (s, 3H, CH3). 13C nmr
(CDCl3): 196.5, 143.2, 138.0, 134.9, 132.1, 130.3, 129.9, 129.0,
128.2, 21.6. gc/ms: m/z (%): 196 (71, M+), 181 (21), 119 (100),
105 (27), 91 (39).
(5-Methyl-2-thienyl)(phenyl)methanone (9b). (1.80 g), 89
1
%, brown oil. H nmr (CDCl3): ꢀ 7.83 (d, 2H, J=7.5 Hz), 7.60-
7.53 (m, 1H), 7.51-7.45 (m, 3H), 6.83 (d, 1H, J=3.6 Hz), 2.58 (s,
3H, CH3). 13C nmr (CDCl3): ꢀ 188.1, 150.4, 141.6, 138.3, 135.7,
132.0, 129.0, 128.3, 126.7, 16.1. gc/ms: m/z (%): 202 (98, M+),
187 (11), 125 (100), 105 (16), 97 (10).
(4-Methylphenyl)(2-thienyl)methanone (9c). (0.97 g), 48 %,
brown-pink solid, mp 72-75 °C. 1H nmr (CDCl3): ꢀ 7.79 (d, 2H,
J=8.1 Hz), 7.70 (d, 1H, J=4.7 Hz), 7.65 (d, 1H, J=3.6 Hz), 7.30
(d, 2H, J=8.1 Hz), 7.16 (dd, 1H, J=3.6, 4.7 Hz), 2.45 (s, 3H,
CH3). 13C nmr (CDCl3): ꢀ 187.7, 143.9, 143.0, 135.4, 134.4,
133.8, 129.4, 129.1, 127.8, 21.6. gc/ms: m/z ( %): 202 (100,
M+), 187 (43), 119 (87), 111 (67), 91 (43).
(5-Methyl-2-thienyl)(2-thienyl)methanone (9d). (1.00 g), 48
%, brown solid, mp 50-52 °C. 1H nmr (CDCl3): ꢀ 7.84 (d, 1H,
J=3.6 Hz), 7.72 (d, 1H, J=3.6 Hz), 7.66 (d, 1H, J=4.9 Hz), 7.17
(dd, 1H, J=3.6, 4.9 Hz), 6.85 (d, 1H, J=3.6 Hz), 2.57 (s, 3H,
CH3). 13C nmr (CDCl3): ꢀ 178.4, 149.7, 143.0, 140.7, 133.9,
133.0, 132.7, 127.8, 126.7, 15.9. gc/ms: m/z ( %): 208 (M+,100),
125 (69), 11 (31), 97 (8).

Sep-Oct 2008 Synthesis of Potentially Photoactivatable Coumarins derivatives via a 1,3-Dipolar Cycloaddition
1433
General procedure for the preparation of compounds 10
(a-d). To solution of compounds 9a-d (5 mmol) in
128.4, 127.8, 125.7, 123.0, 114.1, 112.4, 112.3, 102.1, 77.2,
62.3, 53.9, 18.7. hrms-maldi: m/z [M+H]+ calcd for C27H21N3O4
: 452.16048, found : 452.16049.
a
dichloromethane (15 mL) was added a catalytic amount of ꢀ,ꢀ'-
azodiisobutyronitrile. The mixture was refluxed for 30 min with
a 500 W-halogen lamp and N-bromosuccinimide (1.07 g, 6
mmol) was added in three portions and left to stir at reflux for 2
h. The reaction was quenched with water. The organic layer was
washed with water, dried and evaporated until dryness. The
crude product was directly used in the next step without further
purification.
General procedure for the preparation of compounds 11
(a-d). The above obtained mixture (compounds 9 and 10) was
dissolved in dimethylformamide (20 mL) and sodium azide
(0.326 g, 5 mmol) was added. The resultant mixture was heated
at 50 °C for 3 h, then water (50 mL) was added at room
temperature and left to stir overnight. The mixture was dissolved
with diethyl ether (25 mL) and washed with water, dried and
concentrated until dryness. Pure product was obtained after
purification by column chromatography using dichloromethane
as eluent.
7-({1-[(5-Benzoyl-2-thienyl)methyl]-1H-1,2,3-triazol-4-yl}-
methoxy)-4-methyl-2H-chromen-2-one (12b). (0.44 g), 97 %,
pale yellow solid, mp 108-111 °C. 1H nmr (CDCl3): ꢁ 7.78 (d,
2H, J=7.2 Hz), 7.73 (s, 1H), 7.59 (m, 1H), 7.54-7.47 (m, 4H),
7.14 (d, 1H, J=4.0 Hz), 6.97-6.92 (m, 2H), 6.15 (s. 1H), 5.78 (s,
2H, NCH2), 5.27 (s, 2H, OCH2), 2.40 (s, 3H, CH3). 13C nmr
(CDCl3): ꢁ 187.7, 161.2, 161.0, 155.1, 152.5, 144.7, 144.5,
137.3, 134.8, 132.7, 129.1, 128.6, 125.7, 122.9, 114.1, 112.4,
112.3, 102.1, 77.2, 62.2, 48.8, 18.6. hrms-maldi: m/z [M+H]+
calcd for C25H19N3O4S : 458.11690, found : 458.11697.
4-Methyl-7-({1-[4-(2-thienylcarbonyl)benzyl]-1H-1,2,3-
triazol-4-yl}methoxy)-2H-chromen-2-one (12c). (0.26 g), 56
%, light yellow solid, mp 144-146 °C. 1H nmr (CDCl3): ꢁ 7.87
(d, 2H, J=8.0 Hz), 7.75 (dd, 1H, J=4.9, 1.1 Hz), 7.65 (s, 1H),
7.62 (dd, 1H, J=3.8, 1.1 Hz), 7.51 (d, 1H, J=8.7 Hz), 7.40 (d,
2H, J=7.8 Hz), 7.17 (dd, 1H, J=4.5, 3.8 Hz), 6.97-6.93 (m, 2H),
6.16 (s, 1H), 5.65 (s, 2H, NCH2), 5.27 (s, 2H, OCH2), 2.40 (s,
3H, CH3). 13C nmr (CDCl3): ꢁ 187.3, 164.8, 161.1, 161.0, 155.1,
152.4, 138.6, 138.4, 135.0, 134.7, 130.0, 128.1, 128.0, 125.7,
114.1, 112.4, 112.3, 102.1, 77.2, 62.2, 53.8, 18.7. hrms-maldi:
m/z [M+H]+ calcd for C25H19N3O4S : 458.11690, found :
458.11679.
[4-(Azidomethyl)phenyl](phenyl)methanone (11a). (098 g),
83 % (2steps), yellow oil. 1H nmr (CDCl3): ꢁ 7.85-7.79 (m, 4H),
7.64-7.58 (m, 1H), 7.53-7.43 (m, 4H), 4.46 (s, 2H, CH2N3). 13C
nmr (CDCl3): ꢁ 196.1, 140.0, 137.4, 132.6, 130.6, 130.0, 128.4,
127.9, 54.3.
[5-(Azidomethyl)-2-thienyl](phenyl)methanone (11b).
(0.68 g), 56 % (2 steps), orange solid, mp 33 °C. H nmr
4-Methyl-7-[(1-{[5-(2-thienylcarbonyl)-2-thienyl]methyl}-
1H-1,2,3-triazol-4-yl) methoxy]-2H-chromen-2-one (12d).
(0.44 g), 94 %, yellow solid, mp 173-175 °C. 1H nmr (CDCl3):
ꢁ 7.86 (dd, 1H, J=3.8, 1.1 Hz), 7.77 (d, 1H, J=3.8 Hz), 7.73-7.70
(m, 2H), 7.51 (d, 1H, J=8.7 Hz), 7.21-7.15 (m, 2H), 6.96-6.91
(m, 2H), 6.14 (s, 1H), 5.78 (s, 2H, NCH2), 5.26 (s, 2H, OCH2),
2.39 (s, 3H, CH3). 13C nmr (CDCl3): ꢁ 178.2, 161.1, 161.0,
155.1, 152.4, 144.1, 143.7, 142.2, 134.0, 133.4, 133.0, 128.6,
128.1, 125.7, 114.1, 112.4, 112.3, 102.1, 77.2, 62.2, 48.7, 29.7.
hrms-maldi: m/z [M+H]+ calcd for C23H17N3O4S2 : 464.07332,
found : 464.07331.
1
(CDCl3): ꢁ 7.85 (d, 2H, J=7.3 Hz), 7.64-7.48 (m, 4H), 7.09 (d,
1H, J=3.7 Hz), 4.56 (s, 2H, CH2N3). 13C nmr (CDCl3): ꢁ 187.9,
146.6, 143.9, 137.7, 134.8, 132.4, 129.1, 128.6, 127.4, 49.3.
[4-(Azidomethyl)phenyl](2-thienyl)methanone (11c). (1.03
1
g), 85 % (2steps), yellow solid, mp 42 °C. H nmr (CDCl3):
ꢁ 7.88 (d, 2H, J=7.9 Hz), 7.73 (d, 1H, J=4.9 Hz), 7.64 (d, 1H,
J=3.7 Hz), 7.45 (d, 2H, J=7.9 Hz), 7.17 (dd, 1H, J=3.7, 4.9 Hz),
4.45 (s, 2H, CH2N3). 13C nmr (CDCl3): ꢁ 187.5, 143.4, 139.8,
138.0, 134.8, 134.4, 129.7, 128.0, 54.3.
[5-(Azidomethyl)-2-thienyl](2-thienyl)methanone (11d).
(0.97 g), 78 % (2steps), yellow oil. H nmr (CDCl3): ꢁ 7.90 (d,
General procedure for the preparation of compounds 13
(a-d) and 14 (a-d). Compounds 13a-d and 14a-d were obtained
1
1H, J=3.6 Hz), 7.80 (d, 1H, J=3.6 Hz), 7.72 (d, 1H, J=4.9 Hz),
7.20 (dd, 1H, J=4.9, 3.8 Hz), 7.12 (d, 1H, J=3.8 Hz), 4.57 (s, 2H,
CH2N3). 13C nmr (CDCl3): ꢁ 178.4, 145.9, 143.2, 142.5, 133.7,
133.2, 128 .4, 128.0, 127.4, 49.3.
from 4-Methyl-5,7-bis(2-propynyloxy)-2H-chromen-2-one
and 4-Methyl-7,8-bis(2-propynyloxy)-2H-chromen-2-one
respectively, using the same procedure as for 12a-d and twice of
molar quantities of compounds 11a-d.
6
7
General procedure for the preparation of compounds 12
(a-d). A suspention of CuSO4•5H2O (0.025 g, 0.1 mmol) and
sodium ascorbate (0.04 g, 0.2 mmol) in dimethylformamide (0.5
mL) was stirred at room temperature for 15 min, then compound
5 (0.22 g, 1 mmol) in dimethylformamide (0.5 mL) was added.
After the mixture changed color, a suspension of compounds
11a-d (1.01 mmol) in dimethylformamide (0.5 mL) was added
dropwise. The mixture was stirred for 36 h at room temperature
in the absence of light. The reaction was stopped by the addition
of water (10 mL). The obtained precipitate was collected by
filtration, washed with water and dried at room temperature until
constant weight. Crystallization from diethyl ether yields the
pure product.
7-{[1-(4-Benzoylbenzyl)-1H-1,2,3-triazol-4-yl]methoxy}-4-
methyl-2H-chromen-2-one (12a). (0.44 g), 98 %, pale yellow
solid, mp 139-140 °C. 1H nmr (CDCl3): ꢁ 7.80 (t, 4H, J=8.0 Hz),
7.64-7.59 (m, 2H), 7.52-7.46 (m, 3H), 7.38 (d, 2H, J=8.0 Hz),
6.96-6.92 (m, 2H), 6.15 (s, 1H), 5.65 (s, 2H, NCH2), 5.27 (s, 2H,
OCH2), 2.40 (s, 3H, CH3). 13C nmr (CDCl3): ꢁ 195.8, 161.1,
161.0, 155.1, 152.4, 138.5, 138.1, 137.1, 132.8, 130.8, 130.0,
5,7-Bis{[1-(4-benzoylbenzyl)-1H-1,2,3-triazol-4-yl]-
methoxy}-4-methyl-2H-chromen-2-one (13a). (0.55 g), 74 %,
beige solid, mp 99-100 °C. H nmr (CDCl3): ꢁ 7.82-7.75 (m,
1
8H), 7.66 (d, 2H, J=3.7 Hz), 7.64-7.58 (m, 2H), 7.48 (dd, 4H,
J=7.3, 1.0 Hz), 7.37 (t, J=7.3 Hz, 4H), 6.54 (dd, 2H, J=7.3, 2.2
Hz), 5.91 (d, 1H, J=1.2 Hz), 5.65 (d, 4H, NCH2, J=3.7 Hz), 5.21
(s, 4H, OCH2), 2.42 (s, 3H, CH3). 13C nmr (CDCl3): ꢁ 195.8,
161.2, 161.0, 157.5, 156.7, 154.4, 154.0, 143.5, 143.3, 138.6,
138.1, 137.0, 132.8, 130.8, 130.0, 128.4, 127.9, 127.7, 123.3,
111.9, 105.3, 96.8, 95.2, 77.2, 62.5, 62.1, 53.8, 24.4. hrms-
maldi: m/z [M+H]+ calcd for C44H34N6O6 : 743.26126, found :
743.26116.
5,7-Bis({1-[(5-benzoyl-2-thienyl)methyl]-1H-1,2,3-triazol-
4-yl}methoxy)-4-methyl-2H-chromen-2-one (13b). (0.56 g),
74 %, beige solid, mp 156-158 °C. 1H nmr (CDCl3): ꢁ 7.84-7.78
(m, 6H), 7.64-7.58 (m, 2H), 7.53-7.47 (m, 6H), 7.14 (t, 2H,
J=3.7 Hz), 6.54 (dd, 2H, J=9.0, 2.2 Hz), 5.92 (s, 1H), 5.80 (s,
2H, NCH2), 5.79 (s, 2H, NCH2), 5.22 (s, 4H, OCH2), 2.44 (s,
3H, CH3). 13C nmr (CDCl3): ꢁ 187.7, 161.0, 160.7, 157.5, 156.8,

1434
E.-D. Chenot, J. C. Rodríguez-Domínguez, P. Hannewald, A. Comel, G. Kirsch
Vol 45
154.0, 144.8, 144.5, 144.4, 143.4, 137.3, 134.7, 132.7, 129.1,
128.6, 128.5, 123.0, 112.0, 105.5, 96.9, 95.4, 77.2, 62.4, 62.0,
48.9, 48.8, 23.4. hrms-maldi: m/z [M+H]+ calcd for
C40H30N6O6S2 : 755.17410, found : 755.17432.
4-Methyl-7,8-bis[(1-{[5-(2-thienylcarbonyl)-2-thienyl]-
methyl}-1H-1,2,3-triazol-4-yl)methoxy]-2H-chromen-2-one
(14d). (0.73 g), 95 %, pink-brown solid, mp 190-191 °C. 1H nmr
(DMSO-d6): ꢀ 8.41 (s, 1H), 8.22 (s, 1H), 8.09 (dt, 2H, J=5.0, 2.7
Hz), 8.00 (dd, 2H, J=3.9, 1.1 Hz), 7.93-7.88 (m, 2H), 7.43 (d,
1H, J=8.9 Hz), 7.30-7.18 (m, 5H), 6.15 (d, 1H, J=1.2 Hz), 5.95
(s, 2H, NCH2), 5.87 (s, 2H, NCH2), 5.31 (s, 2H, OCH2), 5.16 (s,
2H, OCH2), 2.33 (s, 3H, CH3). 13C nmr (DMSO-d6): ꢀ 177.7,
159.6, 153.8, 153.3, 147.4, 146.4, 146.3, 142.4, 142.3, 141.6,
141.5, 135.2, 134.0, 133.8, 133.7, 133.5, 129.0, 128.9, 128.8,
124.9, 120.5, 114.4, 111.5, 110.3, 65.7, 62.1, 47.4, 47.3, 18.1.
hrms-maldi: m/z [M+H]+ calcd for C36H26N6O6S4 : 767.08694,
found : 767.08662.
4-Methyl-5,7-bis({1-[4-(2-thienylcarbonyl) benzyl]-1H-
1,2,3-triazol-4-yl}methoxy)-2H- chromen-2-one (13c). (0.67
g), 89 %, light yellow solid, mp 147-150 °C. 1H nmr (CDCl3):
ꢀ 7.86 (d, 4H, J=8.0 Hz), 7.76-7.74 (m, 2H), 7.68 (d, 2H, J=5.0
Hz), 7.62-7.60 (m, 2H), 7.38 (t, 4H, J=8.0 Hz), 7.18-7.15 (m,
2H), 6.53 (dd, 2H, J=7.8, 2.3 Hz), 5.91 (d, 1H, J=1.2 Hz), 5.66
(s, 2H, NCH2), 5.65 (s, 2H, NCH2), 5.21 (s, 4H, OCH2), 2.42 (s,
3H, CH3). 13C nmr (CDCl3): ꢀ 187.3, 161.0, 160.7, 157.6, 156.8,
154.0, 143.3, 143.2, 142.6, 138.6, 138.5, 138.4, 135.0, 134.8,
134.7, 130.0, 128.2, 128.0, 127.9, 123.2, 113.7, 112.0, 105.4,
96.9, 95.3, 77.2, 62.5, 62.1, 53.8, 24.4. hrms-maldi: m/z [M+H]+
calcd for C40H30N6O6S2 : 755.17410, found : 755.17424.
General procedure for the preparation of compounds 15
(a-d). Compounds 15a-d were obtained from 2-(2-Oxo-2H-
benzo[h]chromen-4-yl)-N-(2-propyn-yl)acetamide 8, using the
same procedure as for 12a-d.
4-Methyl-5,7-bis[(1-{[5-(2-thienylcarbonyl)-2-thienyl]methyl}-
1H-1,2,3-triazol-4-yl)methoxy]-2H-chromen-2-one (13d).
1
(0.66 g), 86 %, dark beige solid, mp 192-195 °C. H nmr
N-{[1-(4-Benzoylbenzyl)-1H-1,2,3-triazol-4-yl]methyl}-2-
(2-oxo-2H-benzo[h]chromen-4-yl) acetamide (15a). (0.49 g),
92 %, beige-brown solid, mp 165-168 °C. 1H nmr (DMSO-d6):
ꢀ 8.81 (t, 1H, NH, J=5.3 Hz), 8.36-8.32 (m, 1H), 8.01-7.97 (m,
2H), 7.80-7.66 (m, 9H), 7.57-7.51 (m, 2H), 7.40 (d, 2H, J=8.1
Hz), 6.55 (s, 1H), 5.68 (s, 2H, NCH2), 4.34 (d, 2H, NHCH2,
J=5.4 Hz), 3.86 (s, 2H, COCH2). 13C nmr (DMSO-d6): ꢀ 195.2,
167.6, 159.6, 151.6, 149.9, 140.5, 136.8, 136.6, 134.2, 132.7,
130.0, 129.6, 128.6, 128.5, 127.8, 127.4, 123.8, 122.2, 121.5,
121.2, 115.7, 114.7, 52.2, 34.6, 33.2. hrms-maldi: m/z [M+H]+
calcd for C32H24N4O4 : 529.18703, found : 529.18699.
(DMSO-d6): ꢀ 8.42 (d, 2H, J=1.2 Hz), 8.09 (d, 2H, J=4.7 Hz),
8.02 (d, 2H, J=3.7 Hz), 7.94 (d, 2H, J=3.7 Hz), 7.31-7.27 (m,
4H), 6.79 (s, 1H), 6.77 (s, 1H), 5.98-5.96 (m, 5H), 5.27 (s, 4H),
2.36 (s, 3H, CH3). 13C nmr (DMSO-d6): ꢀ 177.7, 161.1, 159.5,
157.4, 156.2, 153.9, 146.6, 146.4, 142.4, 142.3, 141.6, 135.3,
134.0, 133.8, 129.1, 128.9, 125.1, 124.9, 111.0, 104.4, 97.4,
94.9, 62.3, 61.6, 47.6, 47.5, 23.7. hrms-maldi: m/z [M+H]+ calcd
for C36H26N6O6S4 : 767.08694, found : 767.08713.
7,8-Bis{[1-(4-benzoylbenzyl)-1H-1,2,3-triazol-4-yl]-
methoxy}-4-methyl-2H-chromen-2-one (14a). (0.68 g), 92 %,
beige-brown solid, mp 117-119 °C. 1H nmr (DMSO-d6): ꢀ 8.40
(s, 1H), 8.22 (s, 1H), 7.68-7.65 (m, 12H), 7.55-7.40 (m, 6H),
7.32-7.25 (m, 2H), 6.15 (s, 1H), 5.74 (s, 2H, NCH2), 5.69 (s, 2H,
NCH2), 5.31 (s, 2H, OCH2), 5.16 (s, 2H, OCH2), 2.49 (s, 3H,
CH3). 13C nmr (DMSO-d6): ꢀ 195.2, 159.4, 153.8, 153.3, 147.3,
140.5, 140.4, 136.9, 136.8, 136.6, 136.5, 133.6, 132.7, 130.1,
130.0, 129.5, 128.5, 127.8, 127.5, 125.2, 125.1, 120.5, 114.2,
111.6, 110.2, 65.4, 62.3, 52.3, 52.2, 18.1. hrms-maldi: m/z
[M+H]+ calcd for C44H34N6O6 : 743.26126, found : 743.26120.
7,8-Bis({1-[(5-benzoyl-2-thienyl)methyl]-1H-1,2,3-triazol-
4-yl}methoxy)-4-methyl-2H-chromen-2-one (14b). (0.40 g),
53 %, beige-brown solid, mp 135-137 °C. 1H nmr (DMSO-d6):
ꢀ 8.41 (s, 1H), 8.23 (s, 1H), 7.80-7.76 (m, 4H), 7.67-7.59 (m,
2H), 7.57-7.7.45 (m, 7H), 7.30-7.25 (m, 2H), 7.20-7.16 (m, 1H),
6.16 (s, 1H), 5.95 (s, 2H, NCH2), 5.88 (s, 2H, NCH2), 5.31 (s,
2H, OCH2), 5.15 (s, 2H, OCH2), 2.34 (s, 3H, CH3). 13C nmr
(DMSO-d6): ꢀ 187.1, 159.4, 153.8, 153.3, 147.3, 147.1, 147.0,
143.1, 142.9, 142.7, 137.0, 135.4, 133.5, 132.6, 129.0, 128.8,
128.6, 124.9, 120.5, 114.4, 111.5, 110.2, 65.7, 62.5, 47.7, 47.5,
30.7, 18.1. hrms-maldi: m/z [M+H]+ calcd for C40H30N6O6S2 :
755.17410, found : 755.17410.
N-({1-[(5-Benzoyl-2-thienyl)methyl]-1H-1,2,3-triazol-4-yl}-
methyl)-2-(2-oxo-2H-benzo[h]chromen-4-yl)acetamide (15b).
(0.51 g), 96 %, pale yellow solid, mp 142-145 °C. H nmr
1
(DMSO-d6): ꢀ 8.81 (t, 1H, NH, J=5.3 Hz), 8.38-8.34 (m, 1H),
8.04-7.98 (m, 2H), 7.81-7.76 (m, 3H), 7.73-7.67 (m, 4H), 7.58-
7.53 (m, 3H), 7.21 (d, 1H, J=3.9 Hz), 6.55 (s, 1H), 5.89 (s, 2H,
NCH2), 4.33 (d, 2H, NHCH2, J=5.2 Hz), 3.86 (s, 2H, COCH2).
13C nmr (DMSO-d6): ꢀ 187.1, 167.6, 159.5, 151.6, 149.9, 147.2,
142.9, 137.0, 135.4, 134.2, 132.6, 128.9, 128.8, 128.7, 127.9,
127.4, 123.8, 122.2, 121.5, 121.2, 115.7, 114.7, 47.4, 34.4, 33.4.
hrms-maldi: m/z [M+H]+ calcd for C30H22N4O4S : 535.14345,
found : 535.14352.
2-(2-Oxo-2H-benzo[h]chromen-4-yl)-N-({1-[4-(2-thienyl-
carbonyl)benzyl]-1H-1,2,3-triazol-4-yl}methyl)acetamide
(15c). (0.52 g), 97 %, pale yellow solid, mp 196-199 °C. 1H
nmr (DMSO-d6): ꢀ 8.81 (t, 1H, NH, J=5.3 Hz), 8.37-8.33
(m, 1H), 8.12 (dd, 1H, J=4.9, 0.8 Hz) 8.02-7.98 (m, 2H),
7.81-7.67 (m, 7H), 7.41 (d, 2H, J=8.1 Hz), 7.27 (dd, 1H,
J=4.8, 3.9 Hz), 6.55 (s, 1H), 5.68 (s, 2H, NCH2), 4.34 (d,
2H, NHCH2, J=5.3 Hz), 3.86 (s, 2H, COCH2). 13C nmr
(DMSO-d6): ꢀ 186.8, 167.6, 159.6, 151.6, 149.9, 142.5,
140.4, 137.1, 135.8, 135.6, 134.2, 129.2, 128.8, 128.7,
127.9, 127.8, 127.5, 123.8, 122.2, 121.5, 121.2, 115.7,
114.7, 52.2, 34.4. hrms-maldi: m/z [M+H]+ calcd for
C30H22N4O4S : 535.14345, found : 535.14343.
4-Methyl-7,8-bis({1-[4-(2-thienylcarbonyl) benzyl]-1H-1,2,3-
triazol-4-yl}methoxy)-2H-chromen-2-one (14c). (0.67 g), 89
1
%, yellow-orange solid, mp 120-121 °C. H nmr (DMSO-d6):
ꢀ 8.40 (s, 1H), 8.23 (s, 1H), 8.11-8.09 (m, 2H), 7.82-7.76 (m,
4H), 7.67 (d, 2H, J=3.8 Hz), 7.48-7.41 (m, 3H), 7.33-7.23 (m,
6H), 6.17 (s, 1H), 5.75 (s, 2H, NCH2), 5.68 (s, 2H, NCH2), 5.32
(s, 2H, OCH2), 5.16 (s, 2H, OCH2), 2.35 (s, 3H, CH3). 13C nmr
(DMSO-d6): ꢀ 186.8, 159.5, 153,8, 153.3, 147.3, 142.5, 140.4,
140.3, 137.1, 137.0, 135.8, 135.6, 133.6, 129.3, 129.2, 128.8,
127.9, 127.7, 125.2, 120.5, 114.4, 111.6, 110.3, 65.4, 62.3, 52.4,
52.2, 18.1. hrms-maldi: m/z [M+H]+ calcd for C40H30N6O6S2 :
755.17410, found : 755.17411.
2-(2-Oxo-2H-benzo[h]chromen-4-yl)-N-[(1-{[5-(2-thienyl-
carbonyl)-2-thienyl]methyl}-1H-1,2,3-triazol-4-yl)methyl]-
acetamide (15d). (0.35 g), 65 %, pale yellow solid mp 136-139
°C. 1H nmr (DMSO-d6): ꢀ 8.81 (t, 1H, NH, J=5.3 Hz), 8.38-8.34
(m, 1H), 8.10 (d, 1Hμ, J=4.1 Hz) 8.04-8.00 (m, 3H), 7.89 (d,
1H, J=3.8 Hz), 7.80-7.67 (m, 4H), 7.31-7.28 (m, 1H), 7.24 (d,
1H, J=3.8 Hz), 6.55 (s, 1H), 5.859 (s, 2H, NCH2), 4.33 (d, 2H,
NHCH2, J=4.6 Hz), 3.86 (s, 2H, COCH2). 13C nmr (DMSO-d6):

Sep-Oct 2008 Synthesis of Potentially Photoactivatable Coumarins derivatives via a 1,3-Dipolar Cycloaddition
1435
Chem. 2008, 19, 211.
ꢀ 177.7, 167.6, 159.5, 151.6, 149.9, 149.8, 146.6, 142.3, 141.6,
135.3, 134.2, 134.0, 133.8, 128.9, 128.8, 128.7, 127.9, 127.4,
123.8, 122.2, 121.5, 121.2, 115.7, 114.7, 47.5, 34.5. hrms-maldi:
m/z [M+H]+ calcd for C28H20N4O4S2 : 541.09987, found :
541.09993.
[16] (a) Kosiova, I.; Kovackova, S.; Kois, P. Tetrahedron
2007, 63, 312. (b) Nonaka, H.; Tsukiji, S.; Ojida, A.; Hamachi, I. J.
Am. Chem. Soc. 2007, 129, 15777.
[17] (a) Beatty, K. E.; Xie, F.; Wang, Q.; Tirrell, D. A. J. Am.
Chem. Soc. 2005, 127, 14150. (b) Gierlich, J.; Burley, G. A.;
Gramlich, P. M. E.; Hammond, D. H.; Carell, T. Org. Lett. 2006, 8,
3639. (c) Jawalekar, A. M.; Cremers Meeuwenoord, N. J. (S.) G. O.;
Overkleeft, H. S. Van der Marel, G. S.; Rutjes, F. P. J. T.; Van
Delft, F. L. J. Org. Chem. 2008, 73, 287. (d) Haensch, C.;
Hoeppener, S.; Schubert, U. S. Nanotechnology 2008, 19, 035703
(7pp). (e) Sivakumar, K.; Xie, F.; Cash, B. M.; Long, S.; Barnhill,
H. N.; Wang, Q. Org. Lett. 2004, 6, 4603. (f) Zhou, Z.; Fahrni, C. J.
J. Am. Chem. Soc. 2004, 126, 8862.
Acknowledgements. We want to thank Mrs. Véronique Poddig
for recording the NMR spectra.
REFERENCES
ꢁ
Corresponding author. Tel.: +33 3 87 31 52 95; fax: +33 3 87
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