Microwave-promoted, one-pot, solvent-free synthesis of 4-arylcoumarins from 2-hydroxybenzophenones

Article abstract of DOI:10.1002/ejoc.201000051

4-Arylcoumarins are synthesized in very good yields through solvent-free microwave irradiation of 2-hydroxybenzophenones and alkyl malonate in the presence of DBU. The onepot synthesis is carried out with Knoevenagel condensation, intramolecular lactonization, and decarboxylation reactions. The method can be applied to a broad scope of neoflavonoids.

Full text of DOI:10.1002/ejoc.201000051

FULL PAPER
DOI: 10.1002/ejoc.201000051
Microwave-Promoted, One-Pot, Solvent-Free Synthesis of 4-Arylcoumarins
from 2-Hydroxybenzophenones
José Crecente-Campo,[a] M. Pilar Vázquez-Tato,*[a] and Julio A. Seijas*[a]
Keywords: Microwave chemistry / Natural products / Neoflavonoids / Lactones / Synthetic methods
4-Arylcoumarins are synthesized in very good yields through
solvent-free microwave irradiation of 2-hydroxybenzophen-
ones and alkyl malonate in the presence of DBU. The one-
pot synthesis is carried out with Knoevenagel condensation,
intramolecular lactonization, and decarboxylation reac-
tions. The method can be applied to a broad scope of neo-
flavonoids.
hydroxybenzophenones for the synthesis of 4-arylcoumar-
ins are known. There are also some papers on Knoevenagel
condensation of benzophenones with different activated
methylene compounds, but the reactions proceed to give
products in moderate yields.[19–21] These precedents, as well
as prior work by Charles[22–28] and Bihlmayer[29] on the re-
activity of benzophenones towards active methylene com-
pounds, and which reported higher reactivity for diarylket-
imines in Knoevenagel condensation, led us to design a ret-
rosynthetic approach to neoflavonoids on the basis of the
imine of 2-hydroxybenzophenone 2 instead of ketone 1
(Scheme 1).
Introduction
The coumarin nucleus is widely distributed in natural
products, such as neoflavonoids (4-arylcoumarins) and 3-
arylcoumarins. In particular, 4-aryl derivatives constitute a
subgroup of flavonoids that have received considerable at-
tention, as they exhibit important biological activities such
as anti-HIV,[1] antimalarial,[2,3] antibacterial,[4] and cyto-
toxic properties.[5] Several natural and synthetic polyoxy-
genated 4-arylcoumarins have been evaluated as the noniso-
merizable analogues of combretastatin A-4, which is an im-
portant antitubulin agent that interacts with the binding
site of colchicine.[6,7]
The use of microwave irradiation in the synthesis of cou-
marins has been extensively studied.[8,9] Microwave-assisted
organic synthesis (MAOS) has shown to be a valuable tool
for reducing reaction times, getting cleaner reactions, im-
proving yields, simplifying workup, and designing energy-
saving protocols. The increasing demand for clean and ef-
ficient “ecofriendly” chemical syntheses has focused general
interest on solvent-free reactions, which when combined
with microwave irradiation, have advantages from economi-
cal and environmental standpoints.[10–13] One of the pre-
dominantly employed strategies for the synthesis of couma-
rins is based on the Knoevenagel condensation of salicyl
aldehydes and active methylene compounds. Besides the use
of aldehydes,[14,15] there are some reports on the use of 2-
hydroxyacetophenones[16] for the synthesis of 4-methylcou-
marins[17] and on the use of 2-hydroxybenzophenones for
the synthesis of 3,4-diphenylcoumarins by condensation
with phenylacetic acids,[18] but no reports on the use of 2-
Scheme 1. Retrosynthetic analysis of 4-arylcoumarins.
The key step in the retrosynthesis outlined in Scheme 1
is a microwave Knoevenagel condensation. Subsequent lac-
tonization of intermediate 4 followed by decarboxylation
should lead to the formation of the neoflavonoid skeleton
(i.e., 6).
[a] Departamento de Química Orgánica, Facultad de Ciencias,
Universidad de Santiago de Compostela,
Alfonso X, el sabio. 27002 Lugo, Spain
Fax: +34-982285872
Results and Discussion
As a model, the synthesis of the basic 4-phenylcoumarin
skeleton was studied. So, benzophenone 1a was trans-
E-mail: pilar.vazquez.tato@usc.es;
julioa.seijas@usc.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000051.
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Eur. J. Org. Chem. 2010, 4130–4135

4-Arylcoumarins from 2-Hydroxybenzophenones by Microwave Irradiation
formed into corresponding imine 2 following the method
described by Perlmutter et al.[30] for benzophenones with a
hydroxy group at the 2-position. The procedure is very sim-
ple and is carried out in the absence of solvent,[31] providing
50% yield of the product. The study of the Knoevenagel
condensation with compounds containing an active methyl-
ene group was limited to symmetric compounds, as unsym-
metric substrates will give mixtures of E/Z isomers and only
one of them can lactonize to the neoflavonoid skeleton.
Thus, Meldrum’s acid was treated with 2 under microwave
irradiation under different conditions, in the absence or in
the presence of bases such as tBuOK or piperidine, but in
no case was the product obtained in significant quantities.
Meldrum’s acid was replaced by malononitrile because
there were precedent in the literature that it condensed with
the imine of benzophenone.[26,32] As in the previous case,
numerous tests were conducted in the absence and presence
of a base (piperidine or tBuOK) and under different condi-
tions, but unfortunately none of them provided the desired
compound.
Despite the drawbacks discussed earlier about the use of
unsymmetrical active methylene groups, we decided to test
the condensation of ethyl cyanoacetate, which has an inter-
mediate pKa value of 13.1, which is between those of ma-
Scheme 3.
Hydrolysis of the ester group in the 3-position of the cou-
lononitrile (pKa = 11.1) and diethyl malonate (pKa = 16.4). marin with aqueous NaOH gave 2-oxo-4-phenyl-2H-
Thus, ethyl cyanoacetate and imine 2 were irradiated with chromene-3-carboxylic acid (9) in quantitative yield. This
microwaves (10 min, 180 °C) in the presence of tBuOK acid was decarboxylated by using copper salts, as this
(10 mol-%). tBuOK was the base chosen, as it has proven method was described as being compatible with microwave
to be particularly useful in MAOS and has been applied irradiation to decarboxylate aromatic carboxylic acids[36] or
successfully to obtain various skeletons (4-aminoquinazol- indoles.[37] Several tests were conducted with copper metal
ines,[33] indolines,[34] and pyrazole [3,4-d] pyrimidine[35]). or copper(II) salts (carbonate and chloride) under solvent-
This allowed us to isolate a compound whose characteriza- free conditions or in the presence of the ionic liquid 1-butyl-
tion confirmed that the condensation had taken place, and 3-methyl imidazolium chloride. In all cases, the decarboxyl-
as expected, the cyclization occurred spontaneously to form ated compound was obtained, but the best performance
the neoflavonoid skeleton, obtaining compound 8 in 47% (91%) was obtained with copper metal (100 mol-%). The
yield (Scheme 2).
optimized conditions were irradiation in a single-mode mi-
crowave oven for 15 min at 190 °C at a power of 300 W
(Scheme 3).
Therefore, the 4-phenylcoumarin (6a) neoflavonoid skel-
eton was successfully synthesized. The route consists of four
steps with an overall yield of 30%. Two stages are carried
out in a microwave oven and two with conventional heating.
The starting materials, 2-hydroxybenzophenone and diethyl
malonate, are easily affordable.
In an effort to improve the process, the condensation,
cyclization, hydrolysis, and decarboxylation sequence was
attempted in one pot by raising the temperature (180 °C) to
Scheme 2.
Although the yield achieved was moderate, one must re- favor the decarboxylation step. In this way, 6a was obtained
call that the Knoevenagel reaction leads to both the E and from imine 2 in 57% yield (Scheme 3). Although the overall
Z isomers, yet only the Z isomer can cyclize. This result yield of the reaction from 2-hydroxybenzophenone is sim-
raised the possibility of using diethyl malonate (3a), whose ilar (29%), the process was carried out in two stages, with
symmetry would avoid the existence of geometric isomers the consequent savings in effort, energy, and reagents.
and both ester functions are able to build the coumarin nu-
These results caused us to think about bypassing the
cleus. When imine 2 was treated with diethyl malonate (3a) imine formation stage, because it occurs in moderate yield.
in the presence of tBuOK (10 mol-%) under microwave irra- However, because it was already reported that the direct
diation for 15 min at 100 °C the reaction was successful, condensation of 2-hydroxybenzophenone with diethyl
and the condensation–cyclization took place to give neofla- malonate was low yielding, we decided to check its en-
vonoid 5 in 65% yield (Scheme 3).
hancement by microwave irradiation and performed the
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FULL PAPER
Table 1. Synthesis of 4-arylcoumarins 6 from 2-hydroxybenzophenones 1.
Entry
2-Hydroxybenzophenone
Alkyl malonate
4-Arylcoumarin
Yield [%][a]
R1
R2
R3
1
2
3
4
5
6
7
8
1a
1a
1b
1c
1d
1e
1f
1g
1g
1h
1h
1i
H
H
H
H
H
OMe
OMe
H
OMe
H
H
H
H
H
H
H
H
H
Me
H
H
tBu
H
H
tBu
tBu
H
3a
3b
3b
3b
3b
3b
3b
3b
3a
3b
3a
3b
6a
71
77
75
76
75
75
62
75
6a
6b
H
6c
OMe
OMe
OMe
OH
OH
OH
OH
Cl
6d
6e
6f
6d
9
6g (R1 = OEt)
62 (23, R1 = OH)[b]
79
73 (14, R1 = OH)[b]
55
10
11
12
6f
6h (R1 = OEt)
6i
[a] Reactions were heated at 180 °C for 7 min. All yields are for isolated products with previous purification by flash chromatography
with 2-hydroxybenzophenone/alkyl malonate/DBU (1:1.5:0.5). [b] Yield of nonalkylated neoflavonoid is given in parentheses.
whole process in one pot. Hence, the use of tBuOK as a
This result was surprising, and one might suppose that
base under different conditions (temperature, irradiation the exchange of the methoxy group by the ethoxy group
power, time, and molar ratio of tBuOK) showed that at was due to the presence of diethyl malonate. The demethyl-
moderate temperatures (90 °C) the neoflavonoid skeleton in ation should be helped by DBU. To provide evidence for
coumarin 5 was obtained directly, but in moderate yield this path, 4,4Ј-dimethoxybenzophenone was irradiated for
(44%), and in no case could the formation of decarboxyl- 7 min at 180 °C in the presence of DBU (50 mol-%), as this
ated product 6a be detected (Scheme 3). In this way, the compound – lacking a hydroxy group in the 2-position –
synthesis of neoflavonoid 6a was conducted in three stages: would not be able to cyclize to the coumarin skeleton. DBU
two steps were performed in a microwave oven, and the is not an overly strong base, and it is not described as a
product was obtained in a slightly improved overall yield of demethylating agent. Nonetheless, in the presence of DBU
40% from benzophenone 1a. This reduced the reaction time (in the absence of diethyl malonate) and under microwave
and avoided the imine formation step. Presumably, the irradiation 4,4Ј-dimethoxybenzophenone underwent de-
decarboxylation should require higher temperatures methylation to give 4-hydroxy-4Ј-methoxybenzophenone in
(≈180 °C), as for the decarboxylation of 9 or in the direct low yield (16%). To detect the way in which the ethyl group
synthesis of 6a from imine 2. However, irradiation of benzo- was transferred, the molar ratio of diethyl malonate (3a)
phenone 1a with diethyl malonate (3a) and tBuOK at high with respect to 2-hydroxy-4-methoxybenzophenone (1b)
temperatures led to carbonization. Therefore, other bases was increased; this should encourage the formation of eth-
were tested and DBU was found to yield better results. With oxylated coumarin 6j. However, when a mixture of 1b/3a/
this base and in only one step, the synthesis of neoflavonoid DBU (1:3:1) was irradiated, the percentage of 6j did not
6a was achieved from 2-hydroxybenzophenone and diethyl increase. Therefore, the ethyl group must come from an-
malonate. To optimize the conditions, the influences of tem- other species in the reaction, and the only remaining com-
perature, reaction time, and molar ratio between reagents pound bearing an ethyl group is coumarin 5. To test this
were analyzed. The optimum conditions were thus irradia- alternative, a mixture of 5/6b/DBU (1:1:1) was irradiated
tion of a mixture of 1a/3a/DBU (molar ratio 1:1.5:0.5) for under the described conditions and afforded products 6a,
7 min at 180 °C, leading to neoflavonoid 6a in good yield 6j, and 6k (Scheme 5). These results are consistent with the
(71%; Scheme 3; Table 1, Entry 1).
possibility that the transferred ethyl group, at least in part,
The synthetic routes to 4-phenylcoumarin are summa- comes from intermediate 5.
rized in Scheme 3. The drastic reduction in the reaction
To prevent the formation of mixtures of products and
time, reagents, and energy requirements achieved with the the production of only coumarins with methoxy groups, we
use of DBU, as well as the substantial increase in the overall decided to exchange ethyl malonate (3a) for methyl malon-
performance, are quite remarkable.
ate (3b). Under these conditions, only product 6b was ob-
With the optimized conditions in hand, a series of substi- tained in a similar yield (75%) to the model 4-phenylcou-
tuted 2-hydroxybenzophenones were subjected to explore marin (Table 1, Entries 2 and 3).
the generality and scope of the process. Thus, 2-hydroxy-4-
To extend the study of this one-step synthesis for neo-
methoxybenzophenone (1b) was treated with diethyl malon- flavonoids, other 2-hydroxybenzophenones with different
ate and DBU under the optimized conditions (7 min at positions and natures of the substituents were tested
180 °C in a single-mode microwave oven). As might be ex- (Scheme 6). Thus, when a methyl group is present in the 4Ј-
pected, neoflavonoid 6b was the result of the Knoevenagel position, neoflavonoid 6c was obtained also in good yield
condensation, cyclization, and subsequent decarboxylation (Table 1, Entry 4). The presence of a methoxy group in the
sequence. However, it was only obtained in 24% yield, and para position to the hydroxy group, or two methoxy groups,
additionally, 6j was obtained in 42% yield (Scheme 4).
resulted in the same yield (75%; Table 1, Entries 5 and 6).
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4-Arylcoumarins from 2-Hydroxybenzophenones by Microwave Irradiation
Scheme 4.
Scheme 5.
A slightly lower yield was obtained when a tBu group was was worked up and purified by column chromatography on
present in ring C of the coumarin (Table 1, Entry 7). As silica gel, yielding only 14% of neoflavonoid 6a (Scheme 7).
expected, the presence of a second hydroxy group in the Whereas microwave irradiation leads to neoflavonoids in
aromatic ring resulted in alkylation of the phenol. The reac- just 7 min with high yield, conventional heating is less ef-
tion occurs in good yield with or without substituents in ficient, and the time required is much longer and the decar-
ring C (Table 1, Entries 8–11). The alkylation step is more boxylation process of 5 is much less favored. Because this
effective when it is done with dimethyl malonate instead reaction was found to be thermally driven, the use of micro-
of diethyl malonate, as evidenced by the presence of some wave irradiation resulted in a considerably reduced reaction
nonalkylated coumarins (Table 1, Entries 9 and 11). The time and the yield was significantly increased. The benefi-
presence of a halogen leads to 6i, also in good yield cial effect of microwave irradiation may be associated with
(Table 1, Entry 12).
the quicker formation of dipolar intermediates.
Scheme 6.
To study the influence of microwaves on the formation
of neoflavonoids, a mixture of 2-hydroxybenzophenone, di-
ethyl malonate, and DBU was conventionally heated at
180 °C (the same temperature as that reached in the micro-
wave method). After 7 min, the reaction time necessary for
the reaction in the microwave method, a considerable
amount of 1a remained unchanged together with the for-
mation of 5. Compounds 1a and 5 were in a molar ratio of
approximately 2:3, as determined by 1H NMR spec-
troscopy. The reaction was followed by thin-layer
Scheme 7. Microwave versus conventional procedure.
Conclusions
In summary, we have developed a highly efficient and
chromatography up to the total consumption of the starting direct solvent-free microwave-assisted synthesis of neo-
material, which required 20 h. After this time, the mixture flavonoids from alkyl malonates and 2-hydroxybenzophen-
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J. Crecente-Campo, M. Pilar Vázquez-Tato, J. A. Seijas
FULL PAPER
(30), 195 (11), 165 (27), 152 (16). C17H14O3 (266.09): calcd. C 76.68,
H 5.30; found C 76.39, H 5.27.
6e: M.p. 143–145 °C (EtOH/CH2Cl2; ref.[43] 145–146). UV
ones in the presence of DBU, applicable to a broad sub-
strate scope on substituted 2-hydroxybenzophenones. The
key step is a Knoevenagel-type condensation followed by
lactonization and decarboxylation all in a one-pot reaction.
The presence of an additional methoxy group allowed us to
detect the existence of a secondary reaction consisting of
demethylation and alkylation, where the alkylating agent
might be intermediate carboxyalkylcoumarin 5 produced in
the reaction. The use of methyl instead of ethyl malonate
avoided the formation of mixtures of ethoxylated and meth-
ylated compounds. When the reaction is heated by conven-
tional methods the yield is very low, which establishes the
importance of the microwave irradiation for the good per-
formance of the reaction. Synthesized neoflavonoids
6b[38,39] and 6e[40] show interesting pharmacological proper-
ties.
(MeOH): λ = 207, 238, 259, 299, 351 nm. IR (Golden-Gate): ν
˜
= 1715 (C=O), 1512, 1273, 1229, 1149, 999, 852 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 3.74 (s, 3 H, OCH3), 3.95 (s, 3 H, OCH3),
6.23 (s, 1 H, COCH), 6.85 (s, 1 H, ArH), 6.90 (s, 1 H, ArH), 7.43–
7.53 (m, 5 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 56.6
(q, 2 OCH3), 100.6 (C-8), 107.6 (d, C-5), 111.6 (s, C-4a), 112.5 (C-
3), 128.5 (d, C-2Ј, 6Ј), 129.1 (d, C-3Ј, 5Ј), 129.8 (d, C-4Ј), 136.1 (s,
C-1Ј), 146.4 (s, C-8a), 150.4 (s, C-6), 153.2 (s, C-7), 155.8 (s, C-4),
161.4 (s, C=O) ppm. MS: m/z (%) = 283 (29) [M + 1]+, 282 (100)
[M]+, 254 (24), 239 (15), 235 (22), 168 (6), 152 (6), 127 (15).
C17H14O4 (282.09): calcd. C 72.33, H 5.00; found C 71.93, H 5.47.
6f: M.p. 158–160 °C (AcOEt/hexane). UV (MeOH): λ = 206, 224,
283, 345 nm. IR (Golden-Gate): ν = 2963, 1714 (C=O), 1567, 1462,
˜
1273, 1237, 1030, 934, 845, 821 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 1.39 [s, 9 H, C(CH3)3], 3.75 (s, 3 H, OCH3), 6.35 (s, 1 H,
COCH), 7.01 (d, J = 2.8 Hz, 1 H, ArH), 7.11 (dd, J = 9.0, 2.9 Hz,
1 H, ArH), 7.32 (d, J = 9.0 Hz, 1 H, ArH), 7.39 (d, J = 8.3 Hz, 2
H, ArH), 7.53 (d, J = 8.3 Hz, 2 H, ArH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 31.5 [q, C(CH3)3], 35.1 [s, C(CH3)3], 56.1 (q, OCH3),
110.7 (d, C-3), 115.6 (d, C-5), 118.3 (d, C-7), 118.9 (d, C-8), 119.8
(s, C-4a), 126.1 (d, C-3Ј, 5Ј), 128.4 (d, C-2Ј, 6Ј), 132.6 (s, C-1Ј),
148.9 (s, C-8a), 153.3 (s, C-4Ј), 155.5 (s, C-4), 156.0 (s, C-6), 161.2
(s, C=O) ppm. MS: m/z (%) = 309 (23) [M + 1]+, 308 (100) [M]+,
294 (20), 293 (81), 265 (22), 251 (13), 152 (7), 133 (12). C20H20O3
(308.14): calcd. C 77.90, H 6.54; found C 78.15, H 6.65.
Experimental Section
General: Melting points were measured in open capillaries with a
1
Gallenkamp MPD350.BM.2.5. H NMR spectra were recorded at
300 MHz (1H) and 75 MHz (13C) in CDCl3 with a Varian Mercury
300. Low-resolution mass spectra were recorded with a Thermo
Finnigan Trace-DSQ spectrometer. Infrared spectra were measured
with an FTIR ABB Bomen MB102 instrument with a SPECAC
Golden GateTM accessory. Reaction mixtures were irradiated in an
open vessel with a single-mode Discover CEM microwave.
6g: M.p. 157–160 °C (hexane). UV (MeOH): λ = 203, 227, 251,
Representative Procedure for the Synthesis of Coumarins 6: A mix-
ture of 2-hydroxy-4-methoxybenzophenone (1d; 228 mg, 1 mmol),
methyl malonate (3b; 240 mg, 1.5 mmol), and DBU (76 mg,
0.5 mmol) was treated with microwave irradiation in an open vessel
(100 W, temperature control set at 180 °C measured with an IR
sensor) for 7 min. The crude product was dissolved in dichloro-
methane and purified by flash chromatography (AcOEt/hexane,
1:9) to give 6d (189 mg, 75%), as a solid.
282, 349 nm. IR (Golden-Gate): ν = 1714 (C=O), 1565, 1488, 1232,
˜
1043, 822 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.35 (t, J =
7.0 Hz, 3 H, CH3), 3.92 (q, J = 7.0 Hz, 2 H, CH2), 6.34 (s, 1 H,
COCH), 6.90 (d, J = 2.9 Hz, 1 H, ArH), 7.10 (dd, J = 9.0, 2.9 Hz,
1 H, ArH), 7.30 (d, J = 9.0 Hz, 1 H, ArH), 7.41–7.46 (m, 2 H,
ArH), 7.47–7.56 (m, 3 H, ArH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 14.9 (q, OCH2CH3), 64.4 (t, OCH2CH3), 111.1 (d, C-3), 115.8
(d, C-5), 118.3 (d, C-7), 119.6 (d, C-8), 119.7 (s, C-4a), 128.5 (d,
C-2Ј,6Ј), 129.1 (d, C-3Ј, 5Ј), 129.9 (d, C-4Ј), 135.6 (s, C-1Ј), 148.8
(s, C-8a), 155.48 and 155.54 (2s, C-4 and C-6), 161.0 (s, C=O) ppm.
MS: m/z (%) = 267 (22) [M + 1]+, 266 (100) [M]+, 252 (10), 238
(34), 237 (34), 210 (78), 181 (30), 153 (19), 152 (32), 127 (15).
C17H14O3 (266.09): calcd. C 76.68, H 5.30; found C 77.06, H 5.52.
6d: M.p. 154–155 °C (hexane; ref.[41] 109–110 °C). UV (MeOH): λ
= 206, 226, 252, 282, 347 nm. IR (Golden-Gate): ν = 1714 (C=O),
˜
1564, 1420, 1235, 1178, 1031, 942, 875, 821 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 3.72 (s, 3 H, OCH3), 6.35 (s, 1 H, COCH),
6.92 (d, J = 3.0 Hz, 1 H, ArH), 7.11 (dd, J = 9.0, 3.0 Hz, 1 H,
ArH), 7.32 (d, J = 9.0 Hz, 1 H, ArH), 7.42–7.48 (m, 2 H, ArH),
7.48–7.57 (m, 3 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ =
56.0 (q, OCH3), 110.3 (d, C-3), 115.9 (d, C-5), 118.4 (d, C-7), 119.2
(d, C-8), 119.7 (s, C-4a), 128.5 (d, C-2Ј,6Ј), 129.1 (d, C-3Ј,5Ј), 129.9
(d, C-4Ј), 135.5 (s, C-1Ј), 148.8 (s, C-8a), 155.5 (s, C-4), 156.1 (s,
C-6), 161.0 (s, C=O) ppm. MS: m/z (%) = 253 (18) [M + 1]+, 252
(100) [M]+, 224 (57), 209 (25), 181 (33), 165 (26), 153 (42), 152 (74),
127 (26), 77 (32), 58 (33), 51 (32). C16H12O3 (252.08): calcd. C
76.18, H 4.79; found C 75.72, H 4.81.
6h: M.p. 131–132 °C (hexane). UV (MeOH): λ = 206, 225, 283,
350 nm. IR (Golden-Gate): ν = 2966, 1716 (C=O), 1571, 1429,
˜
1235, 1179, 1048, 938, 819 cm–1. 1H NMR (300 MHz, CDCl3): δ =
1.36–1.38 (m, 12 H, CH3), 3.95 (q, J = 6.9 Hz, 2 H, CH2), 6.33 (s,
1 H, COCH), 6.99 (d, J = 2.7 Hz, 1 H, ArH), 7.09 (dd, J = 9.0,
2.7 Hz, 1 H, ArH), 7.29 (d, J = 9.0 Hz, 1 H, ArH), 7.38 (d, J =
8.2 Hz, 2 H, ArH), 7.52 (d, J = 8.2 Hz, 2 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.9 (q, OCH2CH3), 31.5 [q, C(CH3)3], 35.0
[s, C(CH3)3], 64.4 (t, OCH2CH3), 111.5 (d, C-3), 115.6 (d, C-5),
118.2 (C-7), 119.3 (d, C-8), 119.8 (s, C-4a), 126.0 (d, C-3Ј, 5Ј), 128.4
(d, C-2Ј, 6Ј), 132.6 (s, C-1Ј), 148.7 (s, C-8a), 153.3 (s, C-4Ј), 155.4
and 155.5 (2s, C-4 and C-6), 161.2 (s, C=O) ppm. MS: m/z (%) =
323 (23) [M + 1]+, 322 (100) [M]+, 307 (35), 279 (32), 237 (9), 152
(6), 57 (10). C21H22O3 (322.15): calcd. C 78.23, H 6.88; found C
78.28, H 7.14.
6c: M.p. 152–153 °C (AcOEt/hexane; ref.[42] 152 °C). IR (Golden-
Gate): ν = 1718 (C=O), 1602, 1373, 1280, 1145, 1118, 1022,
˜
814 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.45 (s, 3 H, CH3),
3.88 (s, 3 H, OCH3), 6.20 (s, 1 H, COCH), 6.78 (dd, J = 8.9, 2.4 Hz,
1 H, ArH), 6.89 (d, J = 2.4 Hz, 1 H, ArH), 7.32 (m, 4 H, ArH),
7.41 (d, J = 8.9 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 21.5 (q, CH3), 56.0 (q, OCH3), 101.3 (d, C-8), 111.9 (d, C-3),
112.4 (d, C-6), 112.9 (s, C-4a), 128.2 (d, C-5), 128.5 (d, C-2Ј, 6Ј),
129.7 (d, C-3Ј, 5Ј), 133.0 (s, C-1Ј), 140.0 (s, C-4Ј), 156.0 (s, C-4),
156.3 (s, C-8a), 161.4 (s, C-2), 163.0 (s, C-7) ppm. MS: m/z (%) =
267 (20) [M + 1]+, 266 (100) [M]+, 239 (23), 238 (91), 223 (19), 222
6j: M.p. 101–103 °C (hexane). UV (MeOH): λ = 204, 237, 256,
327 nm. IR (Golden-Gate): ν = 1730 (C=O), 1604, 1376, 1281,
˜
1
1153, 1106, 1039, 1003, 814 cm–1. H NMR (300 MHz, CDCl3): δ
= 1.44 (t, J = 7.0 Hz, 3 H, CH3), 4.09 (q, J = 7.0 Hz, 2 H, CH2),
6.18 (s, 1 H, COCH), 6.76 (dd, J = 8.9, 2.5 Hz, 1 H, ArH), 6.85
4134
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4130–4135

4-Arylcoumarins from 2-Hydroxybenzophenones by Microwave Irradiation
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(d, J = 2.5 Hz, 1 H, ArH), 7.34 (d, J = 8.9 Hz, 1 H, ArH), 7.40–
7.44 (m, 2 H, ArH), 7.47–7.51 (m, 3 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.7 (q, OCH2CH3), 64.4 (t, OCH2CH3),
101.9 (d, C-8), 112.0 (d, C-3), 112.6 (s, C-4a), 112.9 (d, C-6), 128.1
(d, C-5), 128.6 (d, C-2Ј, 6Ј), 129.0 (d, C-3Ј, 5Ј), 129.7 (d, C-4Ј),
135.9 (s, C-1Ј), 156.0 (s, C-4), 156.3 (s, C-8a), 161.4 (s, C=O), 162.4
(s, C-7) ppm. MS: m/z (%) = 267 (20) [M + 1]+, 266 (100) [M]+,
252 (63), 238 (36), 224 (32), 210 (31), 210 (57), 209 (23), 181 (35),
165 (35), 153 (29), 152 (47). C17H14O3 (266.09): calcd. C 76.68, H
5.30; found C 76.27, H 5.03.
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Acknowledgments
This work was supported financially by the Xunta de Galicia (IN-
CITE09 262346PR). The Universidad de Santiago de Compostela
(USC) is thanked for a predoctoral fellowship to J.C.C., and Dr.
JoDee Anderson (Project PGIDIT07-PXID263100PR and English
Language, Literature & Identity Network: 2007/145, Xunta de Gal-
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Received: January 14, 2010
Published Online: May 31, 2010
Eur. J. Org. Chem. 2010, 4130–4135
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4135