Efficient C-3 reductive alkylation of 4-hydroxycoumarin by dehydrogenative oxidation of benzylic alcohols through ruthenium catalysis

Article abstract of DOI:10.1039/c3nj01517c

A practical route to prepare 4-hydroxycoumarin derivatives functionalized at the C-3 position is described through a catalytic coupling reaction between 4-hydroxycoumarin and a series of substituted benzylic alcohols. The reaction is conducted in the pres

Full text of DOI:10.1039/c3nj01517c

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Efficient C-3 reductive alkylation of 4-hydroxy-
coumarin by dehydrogenative oxidation of
benzylic alcohols through ruthenium catalysis†
Cite this: New J. Chem., 2014,
38, 1794
A. Montagut-Romans,ab M. Boulven,c M. Lemaire*a and F . Popowycz*ac
Received (in Montpellier, France)
2nd December 2013,
Accepted 11th February 2014
A practical route to prepare 4-hydroxycoumarin derivatives functionalized at the C-3 position is described
through a catalytic coupling reaction between 4-hydroxycoumarin and a series of substituted benzylic
alcohols. The reaction is conducted in the presence of tris(triphenylphosphine)ruthenium(II) dichloride
(5 mol%), KOH (0.2 eq.) in tertamyl alcohol under microwave irradiation at 140 1C for 2 hours.
DOI: 10.1039/c3nj01517c
www.rsc.org/njc
reduction of the carbonyl.17 The nucleophilic character of
4-hydroxycoumarin was highlighted by the reaction of Baylis–
Introduction
The family of 3-substituted 4-hydroxycoumarins has been reported Hillman acetate adducts.18 Condensation with aldehydes in the
to exhibit potent efficiency in a wide range of therapeutic axes:1 presence of a reducing agent (such as Hantzsch ester19 or a
anti-coagulants (such as Warfarin developed in the 1950s),2 anti- combination of HCOOH–Et3N20) was also an efficient strategy.
viral agents potentially against HIV3 or anti-bacterial molecules.4
The metal-catalyzed auto-transfer hydrogen (or borrowing
The synthesis of 3-substituted 4-hydroxycoumarins has been hydrogen) reaction has been recently reported for the generation
largely described by condensation of 4-hydroxycoumarin on of C–C and C–N bonds in replacement of traditional couplings
benzylic alcohols by Brønsted or Lewis acidic catalysis: HClg at and reductive amination.21 Activation of the substrate by cata-
160 1C,5 para-toluene sulfonic acid (free6 or supported7), iron8 lytic dehydrogenative oxidation is followed by a Knoevenagel
or multimetallic catalysis.9 Specific allylic alcohols also react condensation–reduction sequence. These steps proceed under
with 4-hydroxycoumarin via C-allylation catalyzed by palladium ‘one-pot’ conditions with a single catalyst. In a general strategy,
directly in water.10 Another palladium-catalyzed coupling reac- a less reactive species (such as an alcohol) is converted to a
tion involved aryl/vinyl iodides in the presence of an allene11 or more reactive one (an organic carbonyl compound) then react-
prefunctionalisation of the 4-hydroxycoumarin into the corre- ing in a tandem ‘one-pot’ procedure.
sponding phenyliodonium intermediate followed by condensa-
We report here our efforts to develop a selective C-3 alkylation
tion with alkylborane.12 The coumarinic substrate should be of 4-hydroxycoumarin with benzyl alcohol by optimization of the
envisioned as a b-dicarbonyl compound reacting as a nucleo- reaction parameters (catalyst, solvent, activation method, reac-
phile through direct synthesis of halogenated compounds by tion time, temperature, base) (Scheme 1). With respect to some
C-3 alkylation (in competition with O-alkylation),13 via Mannich aspects of the economy principle, the need for pre-activation
base,14 by Michael addition on a,b-unsaturated ketones15 and through corresponding bromide, tosylate or other leaving groups
b-nitroalkenes,16 or reaction with acyl chlorides followed by was avoided.
a
´
´
Institut de Chimie et Biochimie Moleculaires et Supramoleculaires,
`
´
UMR-CNRS 5246, Equipe Catalyse Synthese Environnement, Universite de Lyon,
´
ˆ
Universite Claude Bernard-Lyon 1, Batiment Curien, 43 Bd du 11 novembre 1918,
F-69622 Villeurbanne, France. E-mail: florence.popowycz@insa-lyon.fr;
Fax: +33(4) 72 43 88 96
b
c
´
USC 1233 INRA/Vetagro Sup, Mycotoxines et Toxicologie Comparee des
´
Xenobiotiques, Veterinary School of Lyon, 1 av. Bourgelat, 69280 Marcy l’Etoile,
France
´
´
Institut de Chimie et Biochimie Moleculaires et Supramoleculaires,
UMR-CNRS 5246, Equipe Chimie Organique et Bioorganique,
´
ˆ
Institut National des Sciences Appliquees, Batiment Jules Verne,
20 Avenue Albert Einstein, F-69621 Villeurbanne, France
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3nj01517c
Scheme 1 General scheme.
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Table 1 Screening of catalystsa
Entry Catalyst (2.5 mol%)
Results and discussion
Ratio 4OH-C/DIM/1c
Pioneering results on heterocyclic systems were reported in
2009 by Grigg and co-workers, describing an iridium-catalyzed 1b
[IrCp*Cl2]2
0/0/100
0/63/37
0/67/33
34/58/8
48/51/1
0/0/100
2
Pd/alumina
Ru/alumina
RhCl[PPh3]3
RuCl2(DMSO)4
RuCl2[PPh3]3
alkylation of 4-hydroxy-2-quinolones and quinolin-4(1H)-one with a
range of substituted benzylic and aliphatic alcohols under solvent-
3
4
5
6
free thermal conditions.22 A unique example of 4-hydroxycoumarin
was reported with a large excess of benzyl alcohol (10 eq.) in the
presence of [IrCp*Cl2]2 (2.5 mol%) and KOH (20 mol%) at 110 1C
for 48 h. To our knowledge, this is the sole example reported in the
literature on 4-hydroxycoumarin.
a
Reaction conditions: 10 eq. of benzyl alcohol, 2.5 mol% of catalyst,
b
c
KOH (0.2 eq.), 110 1C, 48 h. Conditions, ref. 22. 4OH-C/DIM/1 ratio
was determined by 1H NMR analysis.
The serious limitation of this methodology arises from the
cost of the metal catalyst, a long reaction time (up to 2 days) of 2.5 mol%: conversions with Pd or Ru on alumina were
and the necessity of using 10 equivalents of benzyl alcohol. In complete with DIM detected as the major product (Table 1,
the framework of this project we decided to explore the metal- entries 2 and 3). In the case of Wilkinson’s catalyst RhCl[PPh3]3
catalyzed transfer hydrogen reaction as two pivotal parameters or dichlorotetrakis(methylsulfoxide)ruthenium, the conversion
have been clearly identified as serious limitations to a large was moderate (66% and 52% respectively) with a selectivity in
exploitation of this methodology: the cost of the catalyst as well favour of dimeric compound DIM (Table 1, entries 4 and 5).
as the large excess of the equivalents of the alcohol partner In both cases, traces of the expected product were detected.
introduced.
To our delight, the use of less expensive tris(triphenylphosphine)-
The reaction parameters shown in Scheme 1 were screened ruthenium(II) dichloride provided similar results in terms of
through the specific reaction of 4-hydroxycoumarin with benzyl conversion and selectivity than the [IrCp*Cl2]2 catalyst (Table 1,
alcohol. As previously described by Grigg,22 the main side entry 6) and thus was selected for the further experiments.
product of the reaction is the dimeric form DIM (Scheme 2).
Under the solvent-free conditions (entry 6), we were exposed to
We decided to study the impact of each factor (nature of recurrent difficulty in the isolation of compound 1 (due to the
catalyst, solvent, time, activation method, concentration, tem- large excess of benzyl alcohol), leading to a significant drop in
perature, catalyst and base loadings) on the ratio between the the isolated yield.
starting material (4OH-C), dimer-product DIM and expected
product 1 (ratio determined by H NMR experiments).
As the second critical limitation of this methodology was the
use of a large excess of benzyl alcohol used both as a reagent and
1
The dicoumarol family (amongst them DIM compound) has a solvent, we decided to come to the stoichiometric quantities
been already synthesized under direct conditions as the desired between both coupling partners, and to evaluate the influence
product (without catalyst or with piperidine, iodine).23
of a newly added solvent (Table 2). In an apolar solvent such
Ir- and Ru-catalyzed hydrogen transfer reactions have been as toluene (Table 2, entry 1) or aprotic but moderately polar
described with very elegant examples in the literature.24 Even if THF (Table 2, entry 2), the formation of compound 1 was not
the majority of case studies involve the use of Ir-pre catalyst, observed.
ruthenium catalysis has been less explored. The high cost of the
One of the reasons for the low conversion was the lack of
[IrCp*Cl2]2 catalyst25 has impeded, for the moment, industrial solubility of 4-hydroxycoumarin in these solvents. To overcome
developments and applications. As a consequence, preliminary the problems of solubility, the choice of a protic solvent inert to
efforts were devoted to find a cheaper catalyst in comparison the first step of oxidation by the ruthenium-catalyst became
to the pentamethylcyclopentadienyliridium(III) chloride dimer. obvious. The tertamyl alcohol, previously used for this reason,26
We started our range of experiments repeating the method was selected and provided 15% of expected compound 1 at
described by Grigg to afford an internal reference: the reaction 110 1C in 48 hours (Table 2, entry 3). A longer reaction time
was conducted neat, with 10 equivalents of benzyl alcohol, (60 hours instead of 48 hours) and an increased temperature
2.5 mol% of catalyst and KOH (0.2 eq.) upon thermal activation (140 1C instead of 110 1C) afforded a 5.9 : 1 selectivity in favour
(110 1C) over 48 hours (Table 1, entry 1). Under these condi- of 3-benzyl-4-hydroxycoumarin but the conversion was not
tions, the full conversion was detected by performing a 1H NMR
experiment without any trace of residual starting material
or the dimeric form. Other metals were tested at a loading
Table 2 Screening of solvents and activation methodsa
Entry Solvent
Time (h) Temp. (1C) Ratio 4OH-C/DIM/1c
1
2
3
4
5
Toluene
THF
48
48
110
110
110
140
140b
79/21/0
93/7/0
69/15/16
22/11/67
71/14/15
tertAmyl alcohol 48
tertAmyl alcohol 60
tertAmyl alcohol
1
a
Reaction conditions: 1 eq. of benzyl alcohol, solvent (substrate concen-
b
Scheme 2 Expected products resulting from the condensation of
4-hydroxycoumarin and benzyl alcohol.
tration [0.5 M]), RuCl2[PPh3]3 (2.5 mol%), KOH (0.2 eq.). Microwave
irradiation. 4OH-C/DIM/1 ratio was determined by 1H NMR analysis.
c
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Table 3 Influence of the reaction timea
Table 5 Influence of the temperaturea
Entrya
Time (h)
Ratio 4OH-C/DIM/1b Entry
Temperature (1C)
Ratio 4OH-C/DIM/1c
1
2
3
4
0.5
1
2
81/12/7
1
2
3
4
120
130
140
160b
76/14/10
49/16/35
1/10/89
0/2/98
71/14/15
56/17/27
39/17/44
3
a
a
Reaction conditions: 1 eq. of benzyl alcohol, tertamyl alcohol (sub-
Reaction conditions: 1
eq. of benzyl alcohol, tertamyl alcohol
strate concentration [0.5 M]), RuCl2[PPh3]3 (2.5 mol%), KOH (0.2 eq.), (substrate concentration [2.5 M]), RuCl2[PPh3]3 (2.5 mol%), KOH
b
b
microwave irradiation. 4OH-C/DIM/1 ratio was determined by (0.2 eq.), 140 1C, 2 h, microwave irradiation. Other secondary product
1H NMR analysis.
observed. 4OH-C/DIM/1 ratio was determined by 1H NMR analysis.
c
Table 6 Catalyst loadinga
complete (Table 2, entry 4). Finally, the use of microwave
irradiation for 1 hour at 140 1C (Table 2, entry 5) gave similar
results in terms of conversion and selectivity than the thermic
conditions (48 h, 110 1C). Even if the results obtained with
microwaves were not for the moment satisfying, we decided to
investigate this method of activation, in order to gain on the
parameters of the reaction time (48 fold less time to obtain the
same results) and optimize the residual factors. We follow
the monitoring of the reaction by evaluation of the impact of
the reaction time (Table 3).
Entry
Catalyst loading (mol%)
Ratio 4OH-C/DIM/1b
1
2
3
1
2.5
5
29/30/41
1/10/89
1/1/98
a
Reaction conditions: 1 eq. of benzyl alcohol, tertamyl alcohol (sub-
strate concentration [2.5 M]), RuCl2[PPh3]3 (x mol%), KOH (0.2 eq.),
b
140 1C, 2 h, microwave irradiation. 4OH-C/DIM/1 ratio was deter-
mined by 1H NMR analysis.
As intended, the rate of conversion into compound 1 was
linear with a regular increase of the time and conversion (Table 3,
entries 1–4). Nevertheless, even after 3 hours of irradiation by
microwaves, 39% of 4-hydroxycoumarin was recovered as the
unreacted starting material. For a convenient experimental pro-
cedure, a reasonable time of experience was settled at 2 hours for
the further series of experiments.
One factor that should be detrimental or pivotal to the
smooth progress of the conversion is the concentration of
the reaction medium (Table 4). In the previous experiment,
when the substrate concentration was fixed at 0.5 M, the ratio
between 4-hydroxycoumarin/dimer/compound 1 was assessed
as 56/17/27 (Table 4, entry 1). When the concentration was
multiplied by a factor of 2.5 (Table 4, entry 2) in comparison
with the standard value, conversion and selectivity were both
enhanced.
side product (ratio not evaluated). The secondary product that
could not be ruled out under these conditions could originate
from the lactone ring opening followed by decarboxylation,
described earlier by West et al. in 1968.27
The influence of the catalyst loading was then probed (Table 6).
The use of only 1 mol% decreased in an impressive manner
both selectivity and conversion (Table 6, entry 1). Performing
the reaction with 5 mol% (Table 6, entry 3) afforded a satisfying
selectivity/conversion.
The final parameter to evaluate was the impact of base amount
(Table 7) starting from a preliminary value of 0.2 eq. of potassium
hydroxide. When only 0.1 eq. was used, a slight decrease in
selectivity was noticed (Table 7, entry 1). In contrast, when
0.4 eq. of KOH was introduced, the formation of the by-product
resulting from the ring-opening–decarboxylation reaction
sequence was observed (Table 7, entry 3).
Finally at a concentration of 2.5 M, the major improvement
was the almost quantitative conversion of the starting material
with a selectivity much more important in favour of compound
1 (Table 4, entry 3).
Then, the impact of temperature was explored (Table 5).
A lower reaction temperature led to a decreased conversion and
selectivity (Table 5, entries 1 and 2). When the reaction was
run at 160 1C (Table 5, entry 4), the conversion was improved,
but degradation began with the formation of another reaction
The supposed mechanism of the reaction is proposed in
Scheme 3. The reduction of ortho-quinone methide type inter-
mediate o-QM (path A) is in competition with Michael addi-
tion of 4-hydroxycoumarin (path B) remaining in the reaction
medium.
The substrate scope was next examined under optimized
conditions: 1 eq. of benzyl alcohol, tertamyl alcohol (substrate
concentration [2.5 M]), RuCl2[PPh3]3 (5 mol%), KOH (20 mol%)
Table 7 Quantities of basea
Table 4 Impact of the substrate concentrationa
Entry
Quantities of base (eq.)
Ratio 4OH-C/DIM/1c
Entry
Concentration (M)
Ratio 4OH-C/DIM/1b
1
2
3
0.1
0.2
0.4b
1/2/97
1/1/98
0/9/91
1
2
3
0.5
1.25
2.5
56/17/27
16/14/70
1/10/89
a
Reaction conditions: 1 eq. of benzyl alcohol, tertamyl alcohol (sub-
a
Reaction conditions:
1
eq. of benzyl alcohol, tertamyl alcohol, strate concentration [2.5 M]), RuCl2[PPh3]3 (5 mol%), KOH (x eq.),
b
RuCl2[PPh3]3 (2.5 mol%), KOH (0.2 eq.), 140 1C, 2 h, microwave 140 1C,
2
h, microwave irradiation. Other secondary product
irradiation. 4OH-C/DIM/1 ratio was determined by 1H NMR analysis. observed. 4OH-C/DIM/1 ratio was determined by 1H NMR analysis.
b
c
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Scheme 3 Suggested mechanism.
Table 8 Condensation with para-substituted benzyl alcoholsa
at 140 1C for 2 h under microwave irradiation. With these
optimized reaction conditions, a variety of substrates were
considered to explore the scope and limitations of the reaction
(Table 8). Compound 1 used for the exploration of the method-
ology of C-3 alkylation of 4-hydroxycoumarin was isolated in
78% yield (Table 8, entry 1). All the substrates exhibiting an
electron-donating character provided the expected compound
with moderate to good yield. The para-substitution of benzyl
alcohols was a significant factor as the first step of the reaction
was the oxidation into the corresponding aldehyde. It has been
largely discussed in the literature that the electronic factors,
due to the environment, influenced the average relative rate of
the kinetics of oxidation.28
Entrya
Code
Product
Isolated yield (%)
1
1
78
2
3
2
3
84
75
4
4
80
Electron-donating groups such as the methoxy group in
p-anisyl alcohol increase the rate of oxidation, whereas electron-
withdrawing groups such as the nitro group (in p-nitrobenzyl
alcohol) decrease the rate of oxidation. It is in accordance with
the result observed in the laboratory with no reaction with para-
nitrobenzyl alcohol or methyl 4-(hydroxymethyl)benzoate (only
starting materials recovered). Thus when a methyl (Table 8,
entry 2) or a methoxy (Table 8, entry 3) were present in the para
position, products 2 and 3 were obtained, respectively, in 84
and 75% yields. Though electrodonation of the phenyl group
was less than that of the methyl group, the biphenyl derivative 4
was obtained with a satisfying yield of 80%. Replacement of the
methoxy ether (Table 8, entry 3) by a thiomethyl ether (Table 8,
entry 5) provided similar results in terms of yields of isolated
compounds (respectively 75% for 3 versus 80% for 5). In the
case of halogenated benzyl alcohol (Table 8, entries 6–8), the
rate constant of p-F benzyl alcohol oxidation is similar to that of
benzyl alcohol providing thus the same orientation for the
progress of the reaction (Table 8, entry 8). For Cl and Br
5
6
7
8
5
6
7
8
9
80
31
74
83
47
9
a
Reaction conditions: 1 eq. of benzyl alcohol, tertamyl alcohol (sub-
strate concentration [2.5 M]), RuCl2[PPh3]3 (5 mol%), KOH (0.2 eq.),
140 1C, 2 h, microwave irradiation.
displaying similar behavior facing oxidation, the bromine is really poor yield. The case of the trifluoromethyl substituent
more sensitive to dehalogenation conditions leading to a poor (Table 8, entry 9) was the sole example of an electron-
yield of 31% (Table 8, entry 6) and can also be due to the withdrawing substrate affording a moderate yield of 47%.
opposite effects of electronic factors (+M, ꢀI). For compound 6,
The scope was extended to other substituent positions and
degradation of the reaction mixture was observed, probably due aromatic systems (Fig. 1). When the methoxy substituent was
to the liberation of HBr during the dehalogenation, leading to a introduced in the ortho-position, compound 10 was obtained
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(d ppm) and coupling constants (Hz) are reported in the
standard fashion. The following abbreviations are used to
explain the multiplicities: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, br = broad. Electrospray ionization
(ESI) mass spectrometry (MS) experiments were performed on a
Thermo Finnigan LCQ Advantage mass spectrometer. High-
resolution mass spectra (HRMS) were recorded on a Finnigan
Mat 95xL mass spectrometer using electrospray. Analytical thin-
layer chromatography was carried out on silica gel Merck 60
D254 (0.25 mm). Flash chromatographies were performed on
Merck Si 60 silica gel (40–63 mm) or Merck aluminum oxide 90
active neutral (63–200 mm).
General procedure for metallo-auto transfer hydrogen reaction
of 4-hydroxycoumarin
Fig. 1 Scope of the molecules prepared by the ‘‘borrowing hydrogen’’
methodology.
A solution of 4-hydroxycoumarin (324 mg, 2 mmol, 1 eq.),
commercial alcohol (2 mmol, 1 eq.), RuCl2[PPh3]3 (96 mg,
0.1 mmol, 5 mol%), and KOH (22 mg, 0.4 mmol, 20 mol%) in
tertamyl alcohol (0.8 ml) was irradiated at 140 1C in a sealed
Pyrexs vessel for 2 hours in a Biotages microwave synthesizer
(Initiatort 2.0). The mixture was cooled rapidly to room tem-
perature, by passing compressed air through the microwave
cavity for 5 min and then filtered through Celites (rinsing by
MeOH). The filtrate was concentrated and purified, if necessary,
by flash chromatography on silica gel affording C-3 function-
alized 4-hydroxycoumarins.
with similar yield to compound 3, a logical consequence of the
similar influence of electronic factors. In the meta-position
(preparation of compound 11), the yield was slightly affected
(in comparison with the obtention of compound 3). Thus, the
combination of meta and para positions with electron-donating
groups such as the piperonyl substituent allowed the obtention
of derivative 12 with a very good yield of 83%. Other aromatic
systems such as naphthyl substituents either in a- or b-positions
could be introduced efficiently (compounds 13 and 14). The
biphenyl-2-methanol coupled in an identical result (compound 15)
to biphenyl-4-methanol (80%). For compound 16, the behaviour
of the starting material alcohol 9-fluorenemethanol was similar
to an aliphatic alcohol and probably displayed less efficiency for
the oxidation step, in comparison with a benzylic alcohol. For
the moment, the reaction with allylic and cinnamic alcohols
resulted in failure. The first investigation on aliphatic alcohols
such as phenylethanol type substrates produced an impressive
decrease of the yield, as confirmed by compound 16 (Fig. 1).
Physical data of compounds isolated
3,30-(Phenylmethylene)bis 4-hydroxycoumarin (DIM). For
NMR reference, a solution of benzaldehyde (106 mg, 1 mmol,
1 eq.) and 4-hydroxycoumarin (324 mg, 2 mmol, 2 eq.) in
methanol (20 ml) was refluxed for 24 hours. At the end of the
reaction, the product precipitated and was collected by simple
filtration affording DIM as a white solid (m = 340 mg, yield =
83%); mp 231–232 1C; IR 3068, 1652, 1602, 725 cmꢀ1; 1H NMR
(400 MHz, DMSO-d6) d = 6.36 (s, 1H, CH), 7.12–7.16 (m, 3H,
H
arom), 7.20–7.24 (m, 2H, Harom), 7.30–7.37 (m, 4H, Harom), 7.59
(td, 2H, J = 1.5, J = 7.8, Harom), 7.90 (dd, 2H, J = 1.5, J = 8.0,
arom) 9.62 (s, 2H, HOH). 13C NMR (100 MHz, DMSO-d6) d = 35.9
Conclusion
An effective procedure for C-3 reductive alkylation of 4-hydroxy-
coumarin was developed based on a borrowing hydrogen concept.
In this methodology, alcohols could be considered as electro-
philes towards carbon nucleophiles. The major improvement of
the reaction developed in our hands was the use of stoichiometric
quantity of each partner involved in the coupling reaction. For the
moment, the reaction could be extended to a large range of
benzylic alcohols. Further studies are actually under investigation
to extend the scope to any primary alcohol.
H
(CH), 104.1 (2 Cq), 115.9 (2 CH), 118.1 (2 Cq), 123.7 (2 CH), 123.9
(2 CH), 125.5 (CH), 126.7 (2 CH), 128.0 (2 CH), 131.8 (2 CH),
140.1 (Cq), 152.2 (2 Cq), 164.8 (2 Cq), 165.5 (2 Cq). MS (ESI,
CH3CN): m/z calcd 412; [M + Na]+ found 435; HRMS-ESI: calcd
for C25H16NaO6: 435.0839; found: 435.0820.
3-Benzyl-4-hydroxycoumarin (1). Alcohol: benzyl alcohol;
white solid; yield = 78%; mp 203–204 1C (MeOH); IR 3035,
1650, 1627, 1604, 1494, 1396, 1260, 1178, 1081, 949 cmꢀ1
;
1H NMR (300 MHz, DMSO-d6) d = 3.88 (s, 2H, CH2), 7.12–7.18
(m, 1H, Harom), 7.24 (m, 4H, Harom), 7.36 (m, 2H, Harom), 7.61
(td, 1H, J = 1.5, J = 7.9, Harom), 7.97 (dd, 1H, J = 1.5, J = 8.3,
Harom). 13C NMR (75 MHz, DMSO-d6) d = 29.2 (CH2), 104.1 (Cq),
Experimental section
General information
Reagents and solvents were supplied by Aldrich, Acros, Lancaster, 116.2 (CH), 116.4 (Cq), 123.4 (CH), 123.9 (CH), 125.9 (CH), 128.1
Alfa Aesar, Fluka or TCI and purchased at the highest commercial (2 CH), 128.2 (2 CH), 131.9 (CH), 139.9 (Cq), 152.0 (Cq), 160.7
quality to be used without further purification. NMR spectra were (Cq), 162.9 (Cq). MS (ESI, CH3CN): m/z calcd 252; [M + H]+
recorded on a Bruker DPX-300 (1H: 300 or 400 MHz; 13C: 75 or found 253; HRMS-ESI: calcd for C16H12NaO3: 275.0679; found:
100 MHz) spectrometer using DMSO-d6. The chemical shifts 275.0684.
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4-Hydroxy-3-(4-methylbenzyl)-coumarin (2). Alcohol: 4-methyl- 7.62 (dd, 1H, J = 7.3, J = 7.6, Harom), 7.98 (d, 1H, J = 7.5, Harom).
benzyl alcohol; white solid; yield = 84%; mp 180–181 1C (MeOH); 13C NMR (100 MHz, DMSO-d6) d = 28.6 (CH2), 103.7 (Cq), 116.1
IR 3198, 3051, 2925, 1661, 1628, 1587, 1565, 1460, 1384, 119, (Cq), 116.2 (CH), 118.9 (Cq), 123.4 (CH), 123.9 (CH), 130.4
1109, 948, 755 cmꢀ1 1H NMR (400 MHz, DMSO-d6) d = 2.23 (2 CH), 131.0 (2 CH), 132.0 (CH), 139.3 (Cq), 152.0 (Cq),
;
(s, 3H, CH3), 3.83 (s, 2H, CH2), 7.04 (d, 2H, J = 7.9, Harom), 7.13 160.7 (Cq), 162.8 (Cq). MS (ESI, CH3CN): m/z calcd 330;
(d, 2H, J = 7.9, Harom), 7.36 (m, 2H, Harom), 7.60 (td, 1H, J = 1.3, [M + H]+ found 331; HRMS-ESI: m/z [M + H]+ calcd for
J = 7.9, Harom), 7.98 (dd, 1H, J = 1.1, J = 8.4, Harom). 13C NMR
(100 MHz, DMSO-d6) d = 20.6 (CH3), 28.7 (CH2), 104.4 (Cq),
C
16H12BrO3: 330.9964; found: 330.9955.
3-(4-Chlorobenzyl)-4-hydroxycoumarin (7). Alcohol: 4-chloro-
116.2 (CH), 116.3 (Cq), 123.3 (CH), 123.9 (CH), 128.0 (2 CH), benzyl alcohol; white solid; yield = 74%; mp 226–227 1C
128.7 (2 CH), 131.8 (CH), 134.8 (Cq), 136.7 (Cq), 152.0 (Cq), 160.4 (MeOH); IR 3190, 1663, 1629, 1496, 1395, 1194, 1162, 1147,
(Cq), 162.8 (Cq). MS (ESI, CH3CN): m/z calcd 266; [M + H]+ found 1070, 961, 756 cmꢀ1 1H NMR (400 MHz, DMSO-d6) d = 3.86
;
267; HRMS-ESI: m/z [M + Na]+ calcd for C17H14NaO3: 289.0835; (s, 2H, CH2), 7.27–7.34 (m, 4H, Harom), 7.37 (d, 2H, J = 7.4,
found: 289.0826. arom), 7.62 (td, 1H, J = 1.5, J = 7.7, Harom), 7.98 (dd, 1H, J = 1.7,
H
4-Hydroxy-3-(4-methoxybenzyl)-coumarin (3). Alcohol: 4-methoxy- J = 8.2, Harom). 13C NMR (100 MHz, DMSO-d6) d = 28.5 (CH2),
benzyl alcohol; white solid; yield = 75%; mp 184–185 1C 103.7 (Cq), 116.2 (Cq + CH), 123.4 (CH), 123.9 (CH), 128.1
(MeOH); IR 3070, 2989, 2955, 1677, 1651, 1621, 1608, 1508, (2 CH), 129.9 (2 CH), 130.4 (Cq), 132.0 (CH), 138.9 (Cq), 152.0
1430, 1393, 1244, 1220, 1164, 1075, 962, 791, 760 cmꢀ1; 1H NMR (Cq), 160.8 (Cq), 162.8 (Cq). MS (ESI, CH3CN): m/z calcd 286;
(400 MHz, DMSO-d6) d = 3.69 (s, 3H, OCH3), 3.81 (s, 2H, CH2), [M + H]+ found 287; HRMS-ESI: m/z [M + H]+ calcd for
6.80 (d, 2H, J = 8.6, Harom), 7.16 (d, 2H, J = 8.6, Harom), 7.36
(m, 2H, Harom), 7.61 (td, 1H, J = 1.5, J = 7.8, Harom), 7.97 (dd, 1H,
C
16H12ClO3: 287.0469; found: 287.4072.
3-(4-Fluorobenzyl)-4-hydroxycoumarin (8). Alcohol: 4-fluoro-
J = 1.5, J = 8.0, Harom). 13C NMR (100 MHz, DMSO-d6) d = 28.2 benzyl alcohol; white solid; yield = 83%; mp 220–221 1C
(CH2), 55.0 (CH3), 104.7 (Cq), 113.6 (2 CH), 116.2 (CH), 116.3 (MeOH); IR 3187, 1678, 1608, 1567, 1508, 1494, 1192, 1154,
1
(Cq), 123.3 (CH), 123.9 (CH), 129.1 (2 CH), 131.7 (Cq), 131.8 1062, 909, 764, 753, 659 cmꢀ1; H NMR (400 MHz, DMSO-d6)
(CH), 151.9 (Cq), 157.5 (Cq), 160.2 (Cq), 162.8 (Cq). MS (ESI, d = 3.86 (s, 2H, CH2), 7.07 (m, 2H, Harom), 7.24–7.30 (m, 2H,
CH3CN): m/z calcd 282; [M + H]+ found 283; HRMS-ESI: m/z
H
H
arom), 7.31–7.39 (m, 2H, Harom), 7.61 (td, 1H, J = 1.5, J = 7.8,
arom), 7.97 (dd, 1H, J = 1.3, J = 8.3, Harom). 13C NMR (100 MHz,
[M + Na]+ calcd for C17H14NaO4: 305.0784; found: 305.0779.
3-([1,10-Biphenyl]-4-ylmethyl)-4-hydroxycoumarin (4). Alcohol: DMSO-d6) d = 28.3 (CH2), 104.1 (Cq), 114.8 (2 CH, J2C-F = 21.1),
biphenyl-4-methanol alcohol; white solid; yield
= 80%; 116.2 (CH), 116.3 (Cq), 123.4 (CH), 123.9 (CH), 129.8 (2 CH,
mp 221–222 1C (MeOH); IR 3235, 3042, 1666, 1629, 1497, J3C-F = 8), 131.9 (CH), 135.9 (Cq, J4C-F = 3), 152.0 (Cq), 160.6
1392, 1195, 1163, 1109, 1063, 962, 940, 751, 695 cmꢀ1
;
(Cq, J1C-F = 239.2), 160.7 (Cq), 162.8 (Cq). 19F NMR (282 MHz,
1H NMR (400 MHz, DMSO-d6) d = 3.93 (s, 2H, CH2), 7.32–7.46 DMSO-d6) d = ꢀ117.9. MS (ESI, CH3CN): m/z calcd 270; [M + H]+
(m, 7H, Harom), 7.53–7.62 (m, 5H, Harom), 7.99 (dd, 1H, J = 1.3, found 271; HRMS-ESI: m/z [M + Na]+ calcd for C16H11FNaO3:
J = 7.7, Harom). 13C NMR (100 MHz, DMSO-d6) d = 28.8 (CH2), 293.0584; found: 293.0577.
104.1 (Cq), 116.2 (CH), 116.3 (Cq), 123.4 (CH), 123.9 (CH), 126.5
3-(4-Trifluoromethylbenzyl)-4-hydroxy-coumarin (9). Alcohol:
(2 CH), 126.6 (2 CH), 127.2 (CH), 128.7 (2 CH), 128.9 (2 CH), 4-trifluoromethylbenzyl alcohol; white solid; yield = 47%; mp
131.9 (CH), 137.9 (Cq), 139.1 (Cq), 140.1 (Cq), 152.0 (Cq), 160.6 260–262 1C (MeOH); IR 3193, 1660, 1630, 1498, 1419, 1396, 1329,
(Cq), 162.9 (Cq). MS (ESI, CH3CN): m/z calcd 328; [M + H]+ found 1159, 1150, 1102, 1065, 943, 757 cmꢀ1 1H NMR (400 MHz,
;
329; HRMS-ESI: m/z [M + Na]+ calcd for C22H16NaO3: 351.0992; DMSO-d6) d = 3.97 (s, 2H, CH2), 7.34–7.40 (m, 2H, Harom), 7.46
found: 351.0984.
(m, 2H, Harom), 7.60–7.66 (m, 3H, Harom), 7.99 (dd, 1H, J = 1.3,
4-Hydroxy-3-(4-methylthiobenzyl)-coumarin (5). Alcohol: J = 8.4, Harom). 13C NMR (100 MHz, DMSO-d6) d = 29.1 (CH2),
4-(methylthio)-benzyl alcohol; white solid; yield = 80%; mp 103.3 (Cq), 116.2 (Cq), 116.3 (CH), 123.4 (CH), 123.9 (CH), 124.4
202–204 1C (MeOH); IR 3194, 1663, 1629, 1493, 1394, 1196, (Cq, J1C-F3 = 270.5), 125.0 (2 CH, J3C-F3 = 4), 126.7 (Cq, J2C-F3 = 31),
1164, 1068, 962, 752 cmꢀ1; H NMR (300 MHz, DMSO-d6) d = 128.9 (2 CH), 132.0 (CH), 144.8 (Cq), 152.1 (Cq), 161.0 (Cq), 162.8
1
2.41 (s, 3H, CH3), 3.84 (s, 2H, CH2), 7.14–7.21 (m, 4H, Harom), (Cq). 19F NMR (282 MHz, DMSO-d6) d = ꢀ61.2. MS (ESI, CH3CN):
7.33–7.36 (m, 2H, Harom), 7.60 (td, 1H, J = 1.6, J = 7.9, Harom), m/z calcd 320; [M + H]+ found 321; HRMS-ESI: m/z [M + Na]+ calcd
7.97 (dd, 1H, J = 1.5, J = 8.2, Harom). 13C NMR (75 MHz, DMSO-d6) for C17H11F3NaO3: 343.0552; found: 343.0554.
d = 15.1 (CH3), 28.6 (CH2), 104.2 (Cq), 116.1 (CH), 116.2 (Cq),
4-Hydroxy-3-(2-methoxybenzyl)-coumarin (10). Alcohol:
123.3 (CH), 123.9 (CH), 126.3 (2 CH), 128.8 (2 CH), 131.8 (CH), 2-methoxybenzyl alcohol; white solid; yield = 72%; mp 123–124 1C
135.1 (Cq), 136.7 (Cq), 151.9 (Cq), 160.5 (Cq), 162.8 (Cq). MS (ESI, (MeOH); IR 3184, 1690, 1626, 1610, 1573, 1491, 1453, 1303, 1290,
CH3CN): m/z calcd 298; [M + H]+ found 299; HRMS-ESI: m/z 1149, 1109, 1021, 906, 750 cmꢀ1; 1H NMR (400 MHz, DMSO-d6)
[M + Na]+ calcd for C17H14NaO3S: 321.0556; found: 321.0550.
3-(4-Bromobenzyl)-4-hydroxycoumarin (6). Alcohol: 4-bromo-
benzyl alcohol; white solid; yield = 31%; mp 240–242 1C (MeOH);
d = 3.81 (s, 2H, CH2), 3.83 (s, 3H, OCH3), 6.77–6.87 (m, 2H,
H
H
arom), 6.97 (d, 1H, J = 7.8, Harom), 7.17 (td, 1H, J = 1.7, J = 7.7,
arom), 7.35 (m, 2H, Harom), 7.63 (td, 1H, J = 1.5, J = 7.8, Harom),
IR 3187, 1663, 1628, 1497, 1422, 1406, 1288, 1161, 1065, 1010, 7.96 (dd, 1H, J = 1.3, J = 7.9, Harom). 13C NMR (100 MHz, DMSO-d6)
1
777, 755 cmꢀ1; H NMR (400 MHz, DMSO-d6) d = 3.84 (s, 2H, d = 23.7 (CH2), 55.3 (CH3), 102.2 (Cq), 110.3 (CH), 116.2 (CH), 116.3
CH2), 7.19–7.24 (m, 2H, Harom), 7.34–7.44 (m, 4H, Harom), (Cq), 120.1 (CH), 123.3 (CH), 123.9 (CH), 126.8 (Cq), 127.0 (CH),
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127.3 (CH), 131.8 (CH), 152.1 (Cq), 157.1 (Cq), 161.1 (Cq), 131.9 (CH), 133.1 (Cq), 137.4 (Cq), 152.1 (Cq), 160.7 (Cq),
162.7 (Cq). MS (ESI, CH3CN): m/z calcd 282; [M + H]+ found 162.9 (Cq). MS (ESI, CH3CN): m/z calcd 302; [M + H]+ found
283; HRMS-ESI: m/z [M + H]+ calcd for C17H15O4: 283.0965; 303 [M + Na]+ found 325; HRMS-ESI: m/z [M + H]+ calcd for
found: 283.0965; m/z [M + Na]+ calcd for C17H14NaO4: 305.0784;
found: 305.0785.
C
20H15O3: 303.1016; found: 303.1016.
3-([1,10-Biphenyl]-2-ylmethyl)-4-hydroxycoumarin (15). Alcohol:
4-Hydroxy-3-(3-methoxybenzyl)-coumarin (11). Alcohol: biphenyl-2-methanol alcohol; white solid; yield
= 80%;
3-methoxybenzyl alcohol; white solid; yield = 61%; mp 200–201 1C mp 190–191 1C (MeOH); IR 3235, 3042, 1666, 1629, 1497, 1392,
(MeOH); IR 3178, 1663, 1629, 1608, 1576, 1495, 1397, 1292, 1195, 1163, 1109, 1063, 962, 940, 751, 695 cmꢀ1 1H NMR
;
1175, 1149, 1045, 951, 758 cmꢀ1; 1H NMR (400 MHz, DMSO-d6) (400 MHz, DMSO-d6) d = 3.82 (s, 2H, CH2), 7.00 (dd, 1H, J =
d = 3.70 (s, 3H, OCH3), 3.86 (s, 2H, CH2), 6.73 (dd, 1H, J = 1.5, 2.0, J = 6.3, Harom), 7.19–7.26 (m, 3H, Harom), 7.38 (d, 3H, J = 7.8,
J = 8.5, Harom), 6.82 (m, 2H, Harom), 7.16 (dd, 1H, J = 7.8, J = 8.3,
arom), 7.35 (m, 2H, Harom), 7.61 (td, 1H, J = 1.5, J = 7.8, Harom),
H
H
arom), 7.47–7.48 (m, 4H, Harom), 7.62 (td, 1H, J = 1.5, J = 8.5,
arom), 7.97 (dd, 1H, J = 1.2, J = 8.0, Harom). 13C NMR (100 MHz,
H
7.98 (dd, 1H, J = 1.0, J = 8.2, Harom). 13C NMR (100 MHz, DMSO-d6) DMSO-d6) d = 27.4 (CH2), 103.3 (Cq), 116.2 (CH), 116.2 (Cq), 123.3
d = 29.1 (CH2), 54.9 (CH3), 104.1 (Cq), 111.0 (CH), 114.1 (CH), 116.2 (CH), 123.9 (CH), 125.9 (CH), 126.6 (CH), 127.0 (CH), 127.4 (CH),
(CH + Cq), 120.3 (CH), 123.3 (CH), 123.9 (CH), 129.2 (CH), 131.9 128.2 (2 CH), 129.1 (2 CH), 129.7 (CH), 131.9 (CH), 136.4 (Cq),
(CH), 141.4 (Cq), 152.0 (Cq), 159.2 (Cq), 160.6 (Cq), 162.9 (Cq). 141.2 (Cq), 141.5 (Cq), 152.1 (Cq), 161.3 (Cq), 162.7 (Cq). MS (ESI,
MS (ESI, CH3CN): m/z calcd 282; [M + H]+ found 283; HRMS-ESI: CH3CN): m/z calcd 328; [M + H]+ found 329; HRMS-ESI: m/z
m/z [M + H]+ calcd for C17H15O4: 283.0965; found: 283.0966; [M + Na]+ calcd for C22H16NaO3: 351.0992; found: 351.0983; m/z
m/z [M + Na]+ calcd for C17H14NaO4: 305.0784; found: 305.0785. [M + H]+ calcd for C22H17O3: 329.1172; found: 329.1165.
4-Hydroxy-3-(3,4-methylenedioxybenzyl)-coumarin (12). Alcohol:
3-(9-Fluorenylmethyl)-4-hydroxycoumarin (16). Alcohol:
piperonyl alcohol; white solid; yield = 83%; mp 217–218 1C (MeOH); 9-fluorenemethanol; yellow solid; yield = 31%; mp 229–230 1C
IR 3176, 1663, 1633, 1485, 1395, 1243, 1169, 1039, 934, 752 cmꢀ1
;
(MeOH); IR 3235, 1663, 1604, 1564, 1495, 1182, 1153, 1067, 912,
1H NMR (300 MHz, DMSO-d6) d = 3.79 (s, 2H, CH2), 5.93 (s, 2H, 734 cmꢀ1; 1H NMR (400 MHz, DMSO-d6) d = 2.99 (d, 2H, J = 7.8,
CH2), 6.69–6.81 (m, 3H, Harom), 7.32–7.38 (m, 2H, Harom), 7.60 CH2), 4.33 (t, 1H, J = 7.8, CH), 7.23–7.26 (m, 2H, Harom), 7.35–7.42
(td, 1H, J = 1.6, J = 7.9, Harom), 7.97 (dd, 1H, J = 1.5, J = 8.1, (m, 5H, Harom), 7.47 (d, 1H, J = 7.6, Harom), 7.67 (td, 1H, J = 1.5,
H
arom). 13C NMR (75 MHz, DMSO-d6) d = 28.7 (CH2), 100.6 J = 7.8, Harom), 7.88 (m, 2H, Harom), 7.98 (dd, 1H, J = 1.5, J = 8.1,
(O–CH2–O), 104.5 (Cq), 108.0 (CH), 108.7 (CH), 116.2 (CH),
H
arom). 13C NMR (100 MHz, DMSO-d6) d = 28.6 (CH2), 44.4 (CH),
116.3 (Cq), 120.8 (CH), 123.3 (CH), 123.8 (CH), 131.8 (CH), 103.0 (Cq), 116.2 (Cq), 116.4 (CH), 120.0 (2 CH), 123.5 (CH), 124.0
133.6 (Cq), 145.3 (Cq), 147.0 (Cq), 152.0 (Cq), 160.3 (Cq), 162.8 (CH), 124.4 (2 CH), 127.0 (2 CH), 127.1 (2 CH), 132.0 (CH), 140.3
(Cq). MS (ESI, CH3CN): m/z calcd 296; [M + H]+ found 297; (2 Cq), 147.0 (2 Cq), 152.2 (Cq), 161.1 (Cq), 163.0 (Cq). MS (ESI,
HRMS-ESI: m/z [M + Na]+ calcd for C17H12NaO5: 319.0577; CH3CN): m/z calcd 340; [M + H]+ found 341; HRMS-ESI: m/z
found: 319.0581.
[M + H]+ calcd for C23H17O3: 341.1172; found: 341.1170;
4-Hydroxy-3-(1-naphthalenylmethyl)-coumarin (13). Alcohol: HRMS-ESI: m/z [M + Na]+ calcd for C23H16NaO3: 363.0992;
1-naphthalenemethanol alcohol; white solid; yield = 70%; mp found: 363.0987.
237–239 1C (MeOH); IR 3062, 3050, 2955, 1650, 1625, 1494,
1392, 1197, 1167, 1090, 787, 758 cmꢀ1 1H NMR (400 MHz,
;
Acknowledgements
DMSO-d6) d = 4.33 (s, 2H, CH2), 7.12 (d, 1H, J = 7.0, Harom),
7.34–7.43 (m, 3H, Harom), 7.52–7.68 (m, 3H, Harom), 7.77 (d, 1H,
J = 8.1, Harom), 7.94 (d, 1H, J = 7.6, Harom), 8.00 (d, 1H, J = 1.3,
J = 7.9, Harom), 8.28 (d, 1H, J = 8.1, Harom). 13C NMR (100 MHz,
DMSO-d6) d = 26.5 (CH2), 102.4 (Cq), 116.3 (CH + Cq), 123.4
(2 CH), 123.7 (CH), 123.9 (CH), 125.5 (CH), 125.6 (CH), 125.9
(CH), 126.4 (CH), 128.5 (CH), 131.8 (Cq), 132.0 (CH), 133.3 (Cq),
134.8 (Cq), 152.2 (Cq), 161.6 (Cq), 162.9 (Cq). MS (ESI, CH3CN):
m/z calcd 302; [M + H]+ found 303; HRMS-ESI: m/z [M + H]+
calcd for C20H15O3: 303.1016; found: 303.1014.
The authors are grateful for the access to the MS analysis at the
Centre Commun de Spectroscopie de Masse and NMR facilities
´
at the Universite Lyon 1.
Notes and references
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4-Hydroxy-3-(2-naphthalenylmethyl)-coumarin (14). Alcohol:
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200–202 1C (MeOH); IR 3054, 1652, 1625, 1602, 1566, 1496,
1390, 1256, 1199, 1164, 1081, 953, 805, 755 cmꢀ1 1H NMR
;
(400 MHz, DMSO-d6) d = 4.06 (s, 2H, CH2), 7.35–7.47 (m, 5H, Harom),
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123.4 (CH), 123.9 (CH), 125.2 (CH), 125.7 (CH), 126.0 (CH),
127.2 (CH), 127.3 (CH), 127.4 (CH), 127.7 (CH), 131.6 (Cq),
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