Synthesis of coumarins and neoflavones through zinc chloride catalyzed hydroarylation of acetylenic esters with phenols

Article abstract of DOI:10.1055/s-0031-1289576

Acetylenic esters react with oxygenated phenols under solvent-free conditions in the presence of only 5 mol% of zinc chloride as a catalyst to give coumarins and neoflavones in reasonable-to-good yields. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0031-1289576

3692
PAPER
Synthesis of Coumarins and Neoflavones through Zinc Chloride Catalyzed
Hydroarylation of Acetylenic Esters with Phenols
S
ynthesis of Coum
a
arins and
q
N
eoflavones
u
Catalyzed b
e
y Zinc Chlo
l
ride A. C. Leão, Paula de F. de Moraes, Marcella C. B. C. Pedro, Paulo R. R. Costa*
Laboratório de Química Bioorgânica (LQB), Núcleo de Pesquisas de Produtos Naturais, Universidade Federal do Rio de Janeiro,
Centro de Ciências da Saúde, Bloco H, Ilha da Cidade Universitária, 21941-590, Rio de Janeiro, RJ, Brazil
Fax +55(21)25626793; E-mail: prrcosta2011@gmail.com
Received 25 July 2011; revised 26 August 2011
Lewis acid catalysts,10 immobilized11 or recyclable cata-
Abstract: Acetylenic esters react with oxygenated phenols under
lysts,12 microwave irradiation,13 or ionic liquids.14,15 The
development of milder methods for the synthesis of cou-
solvent-free conditions in the presence of only 5 mol% of zinc chlo-
ride as a catalyst to give coumarins and neoflavones in reasonable-
marins has received considerable attention. A method in-
volving Wittig reaction of ortho-hydroxy aromatic
aldehydes followed by one-pot isomerization of the re-
sulting cinnamate derivatives and cyclization has been
used as a replacement for the classical method.16 Efforts
have also been made to synthesize coumarins from ortho-
halophenols by using transition metal catalysts.17 Trost et
al.18 developed the first palladium-catalyzed synthesis of
coumarins from propiolic acid derivatives. This atom-
economic synthesis does not use any halogenated phenols.
Shi and He19 synthesized coumarins directly by hydro-
arylation of aryl propiolates with phenols using gold(III)
chloride and silver triflate as a catalyst system, whereas
Oyamada and Kitamura20 performed a similar reaction us-
ing potassium tetrachloroplatinate and silver triflate as the
catalyst system. More recently, Yamamoto and Kirai re-
ported a copper-catalyzed synthesis of 4-arylcoumarins,
but in this case am arylboronic acid were used as the
source of the in situ-generated arylpalladium intermedi-
ate.21 In 1965, Kaufman and Kelly22a reported the hy-
droarylation of ethyl propiolate by benzene-1,3,5-triol
(phloroglucinol) in the presence of a stoichiometric
amount of zinc chloride under solvent-free conditions to
give 5,7-dihydroxy-2H-chromen-2-one in a good yield.
Surprisingly, this protocol has not been widely ex-
plored,22b and no attempts to use substoichiometric
amounts of zinc chloride have been reported. This situa-
tion prompted us to study the Lewis acid promoted hy-
droarylation of ethyl propiolate with oxygenated phenols.
to-good yields.
Key words: phenols, catalysis, arylations, heterocycles, alkynes,
esters
Coumarins and 4-arylcoumarins (neoflavones) are a
group of naturally occurring benzopyrone (2H-1-
chromen-2-one) derivatives and, although they are widely
distributed in the plant kingdom, their specific roles are
not well understood.1,2 Since coumarin was first isolated
in 1820, many of its derivatives have been isolated and the
interest in this family of compounds has focused on their
biological activity.1 Naturally occurring coumarins have
been used in traditional medicine for thousands of years
and their pharmacological and biochemical properties, as
well as their therapeutic applications, depend on their pat-
terns of substitution. For example, coumarin associated
with troxerutin has been used in the treatment of varicose
veins, hemorrhoids, and leg ulcers.3 Natural furocou-
marins such as psoralen and methoxsalen are used in the
treatment of psoriasis, eczema, vitiligo, and cutaneous T-
cell lymphoma.4 Synthetic aminopsoralen has been used
at European blood centers in the inactivation of infectious
pathogens (bacteria, viruses, and protozoa) in platelets
and plasma blood components prepared for transfusion
support of patients.5 Warfarin (Marevan®/Coumadin®),
another synthetic coumarin, is an anticoagulant that is
used clinically to prevent heart attacks, strokes, and blood
clots.6 Some natural and synthetic coumarins have also
been reported to display antiviral7 and antineoplastic ac-
tivity in cell culture.8
First, we examined the reaction of benzene-1,3,5-triol
(1a) or resorcinol (1c) with 1.5 equivalents of ethyl propi-
olate (2a) under solvent-free conditions in the presence of
stoichiometric amounts of zinc chloride or boron trifluo-
ride etherate at 100 °C (Scheme 1) for comparison with
the previously reported results.22a Both reactions were
complete after 10 minutes, but whereas the expected cou-
marins 3a and 3g, respectively, were formed in good
yields in the presence of zinc chloride, the cinnamates 4a
and 4c were obtained as mixtures of isomers in the pres-
ence of boron trifluoride etherate, suggesting that the elec-
trophilic substitution at the aromatic ring is the first step
in the formation of the coumarin. The ability of zinc chlo-
ride to coordinate to both ethyl propiolate (lowering its
LUMO energy) and to the phenol appears to be responsi-
The most common method for the synthesis of coumarins
is the Peckmann condensation of phenols with b-keto es-
ters promoted by acids, which was first described more
than one hundred years ago,9 and its variants. However,
the need to use harsh conditions and a stoichiometric
amount of the condensing agents limit the scope of this re-
action. Several improved versions of the reaction have
been reported, including the use of a set of new protic and
SYNTHESIS 2011, No. 22, pp 3692–3696
Advanced online publication: 27.10.2011
DOI: 10.1055/s-0031-1289576; Art ID: M70011SS
© Georg Thieme Verlag Stuttgart · New York
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1
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PAPER
Synthesis of Coumarins and Neoflavones Catalyzed by Zinc Chloride
3693
HO
OH
HO
O
O
R1
R2
OH
R1
R2
O
O
H
CO2Et
R4
2a (1.5 equiv)
CO2Et
2a (1.5 equiv)
100 °C
ZnCl2 (5 mol%)
100 °C
R3
R3
for 1, 3 and 4
R3
R3
R4
a, R3 = OH; b, R3 = H
1a and 1c
3a and 3g
1a–f
3a–n
for 1, 2 and 3 see Table 1
+
Scheme 2 Hydroarylation of propiolates 2a–c with phenols 1a–f in
the presence of 5 mol% of zinc chloride
ZnCl2 (1 equiv), 3a (88%); 3g (85%)
HO
OH
BF3⋅OEt2 (1 equiv), 3a (17%) + 4a (40%,
E/Z = 63:37)
CO2Et
4a and 4b
Table 1. Initially, we gradually reduced the amount of cat-
alyst in the reaction of benzene-1,3,5-triol (1a) with ethyl
propiolate (2a), and in the presence of 5 mol% of zinc
chloride, the coumarin 3a was obtained in 88% yield
(Table 1, entry 1) after only five minutes. It is noteworthy
that Kaufman and Kelly reported an 85% yield after 12
hours of reaction when a stoichiometric amount of zinc
chloride was used.22a With the catalytic amount of zinc
chloride under solvent-free conditions, the propiolates 2b
and 2c also reacted with 1a within five minutes to give the
coumarin 3b (entry 2) and the isoflavone 3c (entry 3), re-
spectively, in excellent yields.
BF3⋅OEt2 (1 equiv), 3g (15%) + 4b (66%,
E/Z = 50:50)
R3
Scheme 1 Hydroarylation of ethyl propiolate (2a) with benzene-
1,3,5-triol (1a) or resorcinol (1c) in the presence of zinc chloride or
boron trifluoride etherate
ble for the regio- and stereoselectivity of the electrophilic
aromatic substitution step, in which a cis-cinnamic ester
intermediate must be formed, and for the good yields of
coumarins that are obtained. We then selected zinc chlo-
ride for further studies.
The hydroarylation of acetylenic esters 2a–c with phenols
1a–f (Scheme 2) gave the known products shown in
Table 1 Yields of the Reactions Shown in Scheme 2
Entry Phenol
RC≡CCO2Et Coumarin
Time
Yield (%) N/Se
Mp (°C)
HO
OH
O
R
O
HO
1
2
3
2a: R = H
2b: R = Me
2c: R = Ph
3a: R = H
3b: R = Me
3c: R = Ph
5 min
5 min
5 min
88a
84b
95b
N15,23,24 261–262
N18,24,25 280–282
N26
239–239.5
OH
OH
1a
MeO
OH
O
O
2a: R = H
2b: R = Me
2c: R = Ph
MeO
HO
4
5
6
3d: R = H
3e: R = Me
3f: R = Ph
30 min
30 min
12 h
73c
77b
71b
N15,24
N18,24
N20,27
138–140
168–169
150–152
OMe
R
OMe
1b
2a: R = H
2b: R = Me
2c: R = Ph
O
R
O
OH
OH
HO
7
8
9
3g: R = H
3h: R = Me
3i: R = Ph
30 min
3 h
12 h
85a
88b
54b
N2,23,24 230–231
N18,24
N26,28
155–156
210–211
1c
O
O
O
O
O
10
11
12
2a: R = H
2b: R = Me
2c: R = Ph
3j: R = H
3k: R = Me
3l: R = Ph
1 h
1 h
12 h
70c
31c
nrd
N15,29
N27,29
S20
223–226
149–150
–
O
1d
R
O
O
MeO
OH
MeO
13
2a: R = H
2a: R = H
3m: R = Hf
3n: R = Hg
12 h
12 h
15c
N15,25
116–119
154–157
1e
R
O
O
BnO
OH
BnO
14
7c
S17,23
1f
R
a Yields of purified compounds after crystallization (H2O).
b Yields of purified compounds after crystallization (hexane).
c Yields of purified compounds after chromatography (neutral alumina).
d No reaction.
e N = natural; S = synthetic.
f Mixture of isomers (60:40).
g Mixture of isomers (52:48).
Synthesis 2011, No. 22, 3692–3696 © Thieme Stuttgart · New York

3694
R. A. C. Leão et al.
PAPER
IR (KBr): 3192, 1700, 1640, 1610, 1570, 1475, 1361, 1303, 1244,
1153, 1130, 1070, 817 cm–1.
3,5-Dimethoxyphenol (1b) was much less reactive than
the triol 1a, and its reaction with 2a and 2b took 30 min-
utes to complete, giving the coumarins 3d and 3e, respec- 1H NMR (400 MHz, CD3OD): d = 6.03 (d, J = 9.6 Hz, 1 H, H-3),
6.18 (d, J = 1.7 Hz, 1 H, H-8), 6.26 (d, J = 1.7 Hz, 1 H, H-6), 7.96
tively, in slight lower yields (entries 4 and 5,
respectively). For the less reactive propiolate 2c, the reac-
tion was incomplete after five hours, but when left over-
(d, J = 9.6 Hz, 1 H, H-4), 10.36 and 10.64 (br s, 2 H).
UV (MeOH): lmax = 334, 260 nm.
night it gave 3f in a reasonable yield (entry 6).
5,7-Dihydroxy-4-methyl-2H-chromen-2-one (3b)
Resorcinol (1c) showed a similar reactivity to the 3,5-
dimethoxyphenol (1b), and its reactions with 2a–c gave
the coumarins 3g and 3h and the isoflavone 3i, respective-
ly, in the same reaction times and with slightly better
yields (entries 7–9).
Mp 280–282 °C.
1H NMR (400 MHz, DMSO-d6): d = 2.49 (d, J4,3 = 1.0 Hz, 3 H,
CH3), 5.85 (d, J3,4 = 1.0 Hz, 1 H, H-3), 6.17 (d, J6,8 = 2.3 Hz, 1 H,
H-6), 6.26 (d, J8,6 = 2.3 Hz, 1 H, H-8), 10.28 and 10.50 (br s, 2 H,
OH).
Surprisingly, 1,3-benzodioxol-5-ol (1d; sesamol) was less
reactive than 1b. Whereas its reaction with the more-
reactive ethyl propiolate (2a) took one hour leading regio-
selectively to coumarin 3j in good yield (entry 10), its re-
action with 2b gave coumarin 3k in only a moderate yield
(entry 11), and it did not react with 2c, even after 12 hours
(entry 12).
5,7-Dihydroxy-4-phenyl-2H-chromen-2-one (3c)
Mp 239–239.5 °C.
1H NMR (400 MHz, DMSO-d6): d = 5.74 (s, 1 H, H-3), 6.16 (d,
J6,8 = 2.1 Hz, 1 H, H-6), 6.26 (d, J8,6 = 2.1 Hz, 1 H, H-8), 7.31–7.38
(m, 5 H, H-Ar).
5,7-Dimethoxy-2H-chromen-2-one (3d)
Mp 138–140 °C.
IR (KBr): 2945, 1712, 1616, 1222, 1205, 1153, 1116, 817 cm–1.
When the less-activated phenols 1e and 1f were allowed
to react with 2a, the corresponding coumarins 3m and 3n
were obtained in poor yields in mixture with the corre- 1H NMR (400 MHz, CDCl3): d = 3.86 (s, 3 H, OCH3), 3.89 (s, 3 H,
OCH3), 6.15 (d, J = 9.6 Hz, 1 H, H-3), 6.28 (d, J6,8 = 2.1 Hz, 1 H,
H-6), 6.42 (d, J8,6 = 2.1 Hz, 1 H, H-8), 7.96 (d, J = 9.6 Hz, 1 H, H-
4).
sponding regioisomeric coumarins in ratios of 60:40 and
58:42, respectively (entries 13 and 14). However, these
products can be obtained in high yield by methylation or
benzylation, respectively, of coumarin 3g.23
UV (CH2Cl2): lmax = 324, 255, 246, 228 nm.
In conclusion, the scope of the hydroarylation of propi-
olates with phenols in the presence of 5 mol% of zinc
chloride was studied for the first time. Activated phenols
gave coumarins or neoflavones in reasonable-to-good
yields. The method provides an atom-economic synthesis
of coumarins and neoflavones using an inexpensive Lewis
acid catalyst, and permits the synthesis of twelve naturally
occurring coumarins and neoflavones.
5,7-Dimethoxy-4-methyl-2H-chromen-2-one (3e)
Mp 168–169 °C.
1H NMR (400 MHz, CDCl3): d = 2.52 (s, 3 H, CH3), 3.85 (s, 3 H,
OCH3), 3.86 (s, 3 H, OCH3), 5.94 (s, 1 H, H-3), 6.20 (d, J6,8 = 2.3
Hz, 1 H, H-6), 6.42 (d, J8,6 = 2.3 Hz, 1 H, H-8).
5,7-Dimethoxy-4-phenyl-2H-chromen-2-one (3f)
Mp 150–152 °C.
1H NMR (400 MHz, CDCl3): d = 3.42 (s, 3 H, OCH3), 3.82 (s, 3 H,
OCH3), 6.00 (s, 1 H, H-3), 6.23 (d, J6,8 = 2.3 Hz, 1 H, H-6), 6.53 (d,
J8,6 = 2.3 Hz, 1 H, H-8), 7.25–7.27 (m, 3 H, H-Ar), 7.36–7.38 (m, 2
H, H-Ar).
All the reagents and solvents were purchased from the Aldrich
Chemical Co. and used without purification. Melting points were
determined with a Thomas–Hoover apparatus. Column chromatog-
raphy was performed on neutral alumina (Neutra-90) 70–290 mesh
(Vetec). IR spectra were recorded on an IR Prestige-21 spectrome-
ter (Shimadzu). UV spectra were recorded on a Shimadzu UV-
Visible Spectrophotometer UV-1601. NMR spectra were recorded
on a Varian 400 (400 MHz) spectrometer.
7-Hydroxy-2H-chromen-2-one (Umbelliferone) (3g)
Mp 230–231 °C.
IR (KBr): 3134, 1650, 1620, 1560, 1455, 1406, 1321, 1234, 1128,
835 cm–1.
1H NMR (400 MHz, CD3OD): d = 6.18 (d, J3,4 = 9.4 Hz, 1 H, H-3),
6.71 (d, J8,6 = 2.2 Hz, 1 H, H-8), 6.79 (dd, J6,5 = 8.5 Hz and
Hydroarylation of Propiolates by Phenols in the Presence of
Zinc Chloride; General Procedure
J6,8 = 2.3 Hz, 1 H, H-6), 7.45 (d, J = 8.5 Hz, 1 H, H-5), 7.74 (d,
ZnCl2 (0.049 g; 5 mol%) was added to a soln of the appropriate phe-
nol 1a–k (7.24 mmol) in an adequate amount of the propiolate 2a–
c (10.66 mmol) heated to 100 °C. The resulting mixture was stirred
at 100 °C for the time shown in Table 1 and then cooled to r.t. 5%
aq HCl (10 mL) was then added. In the reactions of 1a and 1c, the
resulting solid was filtered off and crystallized (H2O) to give 3a–c
and 3e–i as crystalline solids. In the reactions of 1b and 1d–k, the
mixture was extracted with EtOAc (3 × 10 mL), and the extracts
were dried (Na2SO4) and concentrated to give a residue that was pu-
rified by column chromatography (basic alumina, 30% EtOAc–hex-
ane) to give the coumarins as pale yellow solids (Table 1).
J4,3 = 9.6 Hz, 1 H, H-4).
UV (MeOH): lmax = 324, 204 nm.
7-Hydroxy-4-methyl-2H-chromen-2-one (3h)
Mp 155–156 °C.
1H NMR (400 MHz, DMSO-d6): d = 2.37 (s, 3 H, CH3), 6.13 (s, 1
H, H-3), 6.70 (d, J8,6 = 2.3 Hz, 1 H, H-8), 6.81 (dd, J6,5 = 8.7 Hz and
J6,8 = 2.3 Hz, 1 H, H-6), 7.59 (d, J5,6 = 8.7 Hz, 1 H, H-5), 10.5 (br s,
1 H, OH).
7-Hydroxy-4-phenyl-2H-chromen-2-one (3i)
Mp 110–111 °C.
5,7-Dihydroxy-2H-chromen-2-one (3a)
Mp 261–262 °C.
Synthesis 2011, No. 22, 3692–3696 © Thieme Stuttgart · New York

PAPER
Synthesis of Coumarins and Neoflavones Catalyzed by Zinc Chloride
3695
1H NMR (400 MHz, DMSO-d6): d = 6.15 (s, 1 H, H-3), 6.79 (dd,
6,5 = 8.7 and J6,8 = 2.3 Hz, 1 H, H-6), 6.81 (d, J8,6 = 2.2 Hz, 1 H, H-
8), 7.28 (d, J5,6 = 8.7 Hz, 1 H, H-5), 7.49–7.57 (m, 5 H, H-Ar),
6.87–6.91 (m, 2 H, H-5 and H-3), 7.50 (d, J6,5 = 8.4 Hz, 1 H, H-6 of
E-isomer), 7.51 (d, J6,5 = 8.4, 1 H, H-6 of Z-isomer), 8.21 (d,
J3,2 = 9.7 Hz, 1 H, H-3).
J
10.64 (br s, 1 H, OH).
UV (CH2Cl2): lmax = 299, 239, 206 cm–1.
6H-[1,3]Dioxolo[4,5-g]chromen-6-one (Ayapin) (3j)
Mp 223–226 °C.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
IR (KBr): 2916, 1720, 1629, 1579, 1489, 1452, 1269, 1257, 1122,
1041, 941, 883 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.07 (s, 2 H, OCH2O), 6.27 (d,
J = 9.5 Hz, 1 H, H-3), 6.81 (s, 1 H, H-5), 6.82 (s, 1 H, H-8), 7.57 (d,
J = 9.5 Hz, 1 H, H-4).
Acknowledgment
We are indebted to FAPERJ, CNPq, and CAPES for financial sup-
port. R.A.C.L. acknowledges an individual fellowship from
FAPERJ, and P.F.M. and P.R.R.C. acknowledge individual fel-
lowships from CNPq.
UV (CH2Cl2): lmax = 346, 294, 233 nm.
8-Methyl-6H-[1,3]dioxolo[4,5-g]chromen-6-one (3k)
Mp 149–150 °C.
1H NMR (400 MHz, CDCl3): d = 2.37 (d, 4J4,3 = 1.2 Hz, 3 H, CH3)
6.07 (s, 2 H, OCH2O), 6.16 (d, 4J3,4 = 1.2 Hz, 1 H, H-3), 6.82 (s, 1
H, H-8), 6.96 (s, 1 H, H-6).
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J = 8.5 and J = 2.4 Hz, 1 H, H-Ar), 7.35–7.44 (m, 6 H, H-Ar), 7.64
(d, J = 9.5 Hz, 1 H, H-4).
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Ethyl (2E/2Z)-3-(2,4,6-Trihydroxyphenyl)acrylate [Mixture of
(E)-4a and (Z)-4a]
1H NMR (400 MHz, CD3OD): d = 1.39 (t, J = 7.0 Hz, 3 H, CH3 of
Z-isomer), 1.46 (t, J = 7.0 Hz, 3 H, CH3 of E-isomer), 4.06 (q,
J = 7.0 Hz, 2 H, CH2 of Z-isomer), 4.12 (q, J = 7.0 Hz, 2 H, CH2 of
E-isomer), 6.07 (d, J2,3 = 9.6 Hz, 1 H, H-2 of E-isomer), 6.09 (d,
J2,3 = 9.6 Hz, 1 H, H-2of Z-isomer), 6.28–6.30 (m, 2 H, H-Ar), 6.35
(d, J = 2.0 Hz, 1 H, H-Ar of E-isomer), 6.37 (d, J = 2.0 Hz, 1 H, H-
Ar of Z-isomer), 8.06 (dd, J = 9.6 and J = 0.8 Hz, 1 H, H-3 of E-iso-
mer), 8.08 (dd, J = 9.6 and J = 0.8 Hz, 1 H, H-3 of Z-isomer).
Ethyl (2E)-3-(2,4-Dihydroxyphenyl)acrylate [(E)-4b]
1H NMR (400 MHz, CD3OD): d = 1.42 (t, J = 7.0 Hz, 3 H, CH3),
4.12 (q, J = 7.0 Hz, 2 H, CH2), 6.23 (d, J2,3 = 9.5 Hz, 1 H, H-2), 6.87
(d, J3,5 = 2.3 Hz, 1 H, H-3), 6.90 (dd, J5,6 = 8.6 and J5,3 = 2.4 Hz, 1
H, H-5), 7.51 (d, J6,5 = 8.6, 1 H, H-6), 7.87 (d, J3,2 = 9.6 Hz, 1 H, H-
3).
UV (CH2Cl2): lmax = 322, 316, 205 cm–1.
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Ethyl (2Z)-3-(2,4-Dihydroxyphenyl)acrylate [(Z)-4b]
1H NMR (400 MHz, CD3OD): d = 1.48 (t, J = 7.0 Hz, 3 H, CH3),
4.21 (q, J = 7.0 Hz, 2 H, CH2), 6.34 (d, J2,3 = 9.7 Hz, 1 H, H-2),
Synthesis 2011, No. 22, 3692–3696 © Thieme Stuttgart · New York

3696
R. A. C. Leão et al.
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