NbCl5-Promoted Synthesis of 4-Aryl-3,4-dihydrocoumarins by Multicomponent Reaction

Article abstract of DOI:10.1055/s-0032-1317340

Substituted 4-aryl-3,4-dihydrocoumarins are synthesized from multicomponent reactions between phenols, dimethyl malonate, and aryl aldehydes catalyzed by niobium pentachloride. This new method is simple, cost-effective, and high-yielding, and can be condu

Full text of DOI:10.1055/s-0032-1317340

PAPER
▌3361
paper
NbCl -Promoted Synthesis of 4-Aryl-3,4-dihydrocoumarins by
5
Multicomponent Reaction
Synthesis of 4-Aryl-3,4-dihydrocoumarins
Willian Henrique dos Santos, Luiz Carlos da Silva-Filho*
Department of Chemistry, São Paulo State University (UNESP), 17033-360 Bauru, São Paulo, Brazil
Fax +55(14)31036099; E-mail: lcsilva@fc.unesp.br
Received: 02.08.2012; Accepted after revision: 10.09.2012
OH
Abstract: Substituted 4-aryl-3,4-dihydrocoumarins are synthe-
MeO
sized from multicomponent reactions between phenols, dimethyl
malonate, and aryl aldehydes catalyzed by niobium pentachloride.
This new method is simple, cost-effective, and high-yielding, and
can be conducted in acceptable reaction times.
OH
OH
OMe
O
O
Key words: niobium pentachloride, multicomponent reaction, cou-
marin derivatives, Lewis acid, phenols
MeO
HO
O
O
HO
O
O
1
2
Coumarins are an important class of natural products that
can be found in many plants and fruits. They were first
isolated by Vogel in 1820 from the plant species Couma-
rona odorata and, currently, more than 1400 types of nat-
ural coumarins have been described. They are found in
several families of the plant kingdom, as in Papilonaceae
OH
HO
OH
OH
1
HO
O
(
Fabaceae), Lamiaceae, Asteraceae, Solanaceae, Poaceae,
2
Umbelliferae, Rutaceae, and Apiaceae. Their concentra-
tion is higher in fruits, seeds, and roots. The coumarins
2
HO
O
O
show anti-inflammatory, antioxidant, anticoagulant, anti-
biotic, immunomodulatory, antimicrobial, antiviral, and
bronchodilator properties and thus, they are widely used
3
Figure 1 Examples of natural 4-aryl-3,4-dihydrocoumarins
3
in medicine. They are also used in various sectors of the
chemical industry, such as dyes, essences, perfumes,
toothpastes, synthetic rubber, plastics, insecticides, deter-
gents, paints, and sprays.4
In this work, a new method for the synthesis of derivatives
of 4-aryl-3,4-dihydrocoumarins by multicomponent reac-
tion (MCR) between 2,5-dimethoxyphenol, dimethyl
Coumarins can be synthesized through several methods, malonate, and benzaldehyde derivatives promoted by
including Knoevenagel, Perkin, Pechmann, and Wittig re- niobium pentachloride is described. Niobium pentachlo-
actions, using different acid catalysts, such as AlCl3, ride, a stronger Lewis acid that is currently gaining in-
ZrCl , TiCl , Sm(NO) , InCl , H SO , HCl, P O , and oth- creasing popularity as a reagent in organic synthesis, has
4
4
3
3
2
4
2
5
ers.5
Coumarin derivatives, which have the carbon structure of
-aryl-3,4-dihydrocoumarin, belong to the class of the
neoflavonoids and are present in several classes of plants. A multicomponent reaction is usually defined as a process
Among them, we can mention the derivatives 1, 2, and 3 in which three or more reactants are combined in order to
been used by our group and other researchers as an effec-
tive catalyst in synthetic methodologies of a variety of or-
ganic reactions.
9
,10
4
6
(
Figure 1), isolated, respectively, from Aloe vera, Gnetum form a product that has structural characteristics of each
cleistostachyum, and Vaccinum myrtillus L., showing reagent used, generating products with a good structural
anti-inflammatory and antioxidant activities.7
11
complexity in only one step. MCRs also have the addi-
tional advantages of being selective and having atom
economy, presenting a very important role in modern syn-
The most frequently used method for the synthesis of 4-
aryl-3,4-dihydrocoumarin derivatives is through the hy-
droarylation of cinnamic acid derivatives with different
1
2
thetic methodology. The application of catalysts (met-
als, acids, or enzymes) in the development of MCRs has
also been the subject of research in various research
types of phenols and catalytic hydrogenation of couma-
rins.8
1
3
groups.
The multicomponent reaction between 3,5-dimethoxy-
phenol (4; 1.0 equiv), dimethyl malonate (5; 1.1 equiv),
and benzaldehyde derivatives 6a–k (1.1 equiv) in the
presence of niobium pentachloride (1.0 equiv) was per-
SYNTHESIS 2012, 44, 3361–3365
Advanced online publication: 20.09.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1317340; Art ID: SS-2012-M0594-OP
Georg Thieme Verlag Stuttgart · New York
©

3362
W. H. dos Santos, L. C. da Silva-Filho
PAPER
formed under N atmosphere in dichloromethane at room for compound 7e (entry 6) can be explained by the high
2
temperature for 48 hours, to give the corresponding steric impediment caused by methyl groups present in po-
3
4
4
-alkyl-3,4-dihydrocoumarins 7a–k, in high yields. The sitions R and R in the mesitylaldehyde (6e).
results are summarized in Scheme 1 and Table 1.
All products were isolated and their structures confirmed due to the occurrence of Knoevenagel condensation be-
Probably, the multicomponent reaction proceeds initially
1
13
by H NMR, C NMR, and IR spectra. The trans-stereo- tween the aldehyde 6 and dimethyl malonate (5), followed
chemistry of adducts obtained are in accordance with the by the reaction of hydroarylation of the benzylidene mal-
results described by Tunge and co-workers,8b who ob- onate formed in situ with phenol, with subsequent intra-
tained similar derivatives of 4-alkyl-3,4-dihydrocouma- molecular lactonization (Scheme 2). This statement is
rins by hydroarylation of benzylidene malonates with justified, because in the reaction between benzaldehyde
phenols catalyzed by TiCl , followed by lactonization re- (6a), dimethyl malonate (5), and 3,5-dimethoxylphenol
4
action. In all reactions carried out, the formation of the (4), with a reaction duration of 24 hours (entry 1), benzyl-
cis-isomer was not observed.
idene malonate 8 was isolated as one of the products of the
reaction.
In general, the results in Table 1 show that high yields of
4-alkyl-3,4-dihydrocoumarins were obtained with 1.0 In conclusion, a concise new three-component reaction
equivalent of NbCl at room temperature in dichlorometh- was described for the synthesis of coumarin derivatives
5
ane for 48 hours. An increase of reaction yield was ob- catalyzed by niobium pentachloride. The method reported
served by conducting the reaction for a longer reaction here is simple and efficient, providing the products in high
time (48 h), but a reaction time of 24 hours gives only a yields in acceptable reaction times.
yield of 64% (Table 1, entry 1). The low yield observed
O
O
R4
O
O
OMe
OH
R4
O
O
H
NbCl5 (1.0 equiv)
CH2Cl2, r.t.
+
+
MeO
OMe
R1
R3
MeO
OMe3
R
MeO
OMe
R1
R2
R2
4
5
6a–k
7a–k
Scheme 1 NbCl -Promoted multicomponent reaction between 3,5-dimethoxyphenol (4), dimethyl malonate (5), and several aryl aldehydes 6a–
5
k
Table 1 Results Obtained from MCRs Catalyzed by NbCl5
Entry
Aldehyde
R1
R2
R3
R4
Time (h)
Product,
yield (%)a
1
2
3
4
5
6
7
8
9
9
6a
6a
6b
6c
6d
6e
6f
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
24
48
48
48
48
48
48
48
48
48
48
48
7a, 648b
7a, 888b
7b, 938b
7c, 87
H
H
H
Me
H
H
H
Me
H
H
H
Me
Me
H
7d, 98
7e, 56
Me
t-Bu
H
H
H
7f, 78
6g
6h
6i
OMe
H
H
7g, 808b
7h, 938b
7i, 92
H
OMe
H
F
H
1
1
6j
Cl
Br
H
H
7j, 80
1
2
6k
H
H
7k, 858b
a
Isolated yield.
Synthesis 2012, 44, 3361–3365
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 4-Aryl-3,4-dihydrocoumarins
3363
MeO
OH
O
O
O
O
O
MeO
OMe
NbCl5
O
O
MeO
O
OMe
5
MeO
OMe
4
+
R
R
MeO
OMe
8
H
R
7
6
Scheme 2 Proposed reaction mechanism of the multicomponent reaction for the synthesis of 4-alkyl-3,4-dihydrocoumarins catalyzed by NbCl5
All reactions were carried out under an atmosphere of N unless
4.96 (s, 1 H), 3.95 (d, J = 1.5 Hz, 1 H), 3.83 (s, 3 H), 3.75 (s, 3 H),
3.71 (s, 3 H), 2.31 (s, 3 H).
2
,
otherwise specified. CH Cl was distilled from CaH . All commer-
2
2
2
cially available reagents were used without further purification.
TLC was performed on 0.2 mm Merck 60F254 silica gel aluminum
sheets, which were visualized with a vanillin/MeOH–H O–H SO
mixture. ACROS 80–230 silica gel 60 was employed for column
chromatography. A Perkin–Elmer RX-FTIR System was used to re-
cord IR spectra (neat or film). Bruker DPX 300 and DRX 500 spec-
13
C NMR (75 MHz, CDCl ): δ = 167.4, 163.8, 160.9, 157.8, 152.6,
3
137.2, 136.7, 129.7, 126.7, 103.8, 95.4, 93.8, 55.9, 54.5, 53.2, 38.5,
20.9.
2
2
4
+
ESI-HRMS: m/z calcd for C H O [M + H] : 357.13382; found:
20 21
6
3
57.1332.
trometers were employed for the NMR spectra (CDCl solutions)
3
Methyl 5,7-Dimethoxy-4-(m-tolyl)-2-oxochroman-3-carboxyl-
ate (7c)
Yield: 310 mg (87%); white solid; mp 90–92 °C.
1
using TMS as internal reference for H and CDCl as an internal ref-
3
1
3
erence for C NMR spectra.
Multicomponent Reaction of Dimethyl Malonate, 3,5-Dimeth-
oxyphenol, and Benzaldehyde Derivatives with NbCl5;
General Procedure
IR (neat): 1776, 1735, 1621, 1593, 1506, 1469, 1434, 1423, 1332,
1280, 1267, 1226, 1193, 1130, 1099 cm .
–
1
1
H NMR (300 MHz, CDCl ): δ = 7.16 (t, J = 7.5 Hz, 1 H), 7.03 (d,
3
To a solution of NbCl (270 mg, 1 mmol) in anhyd CH Cl (2 mL),
5
2
2
J = 7.5 Hz, 1 H), 6.90 (m, 2 H), 6.35 (d, J = 2.2 Hz, 1 H), 6.27 (d,
J = 2.2 Hz, 1 H), 4.94 (s, 1 H), 3.94 (d, J = 1.5 Hz, 1 H), 3.82 (s, 3
H), 3.73 (s, 3 H), 3.69 (s, 3 H), 2.28 (s, 3 H).
maintained at r.t. under N atmosphere, were added a solution of the
2
dimethyl malonate (132 mg, 1.0 mmol), 3,5-dimethoxyphenol (154
mg, 1.0 mmol), and the respective aldehyde 6a–k (1 mmol) in an-
hyd CH Cl (5 mL). After completion of the addition, stirring was
13
C NMR (75 MHz, CDCl ): δ = 167.4, 163.8, 160.9, 157.8, 152.6,
2
2
3
continued at the same temperature for 48 h. The reaction mixture
139.6, 138.7, 128.9, 128.3, 127.5, 123.9, 103.6, 95.4, 93.8, 55.9,
was quenched by the addition of H O (3 mL). The mixture was ex-
55.4, 54.5, 53.2, 38.8, 21.4.
2
tracted with CH Cl (10 mL). The organic layer was separated and
+
2
2
ESI-HRMS: m/z calcd for C H O [M + H] : 357.13382; found:
2
0
21
6
washed with sat. aq NaHCO (3 × 10 mL), brine (2 × 10 mL), and
3
3
57.1333.
dried (MgSO ). The solvent was removed under vacuum and the
4
products 7a–k were purified by column chromatography through
silica gel using mainly a mixture of hexane and EtOAc (7:3) as elu-
ent.
Methyl5,7-Dimethoxy-4-(o-tolyl)-2-oxochroman-3-carboxylate
(7d)
Yield: 349 mg (98%); white solid; mp 155–159 °C.
IR (neat): 1774, 1739, 1622, 1593, 1506, 1452, 1434, 1330, 1280,
Methyl 5,7-Dimethoxy-4-phenyl-2-oxochroman-3-carboxylate
–1
1263, 1222, 1195, 1135, 1097 cm .
(7a)
Yield: 273 mg (88%); white solid; mp 110–112 °C.
1
H NMR (300 MHz, CDCl ): δ = 7.20 (d, J = 7.5 Hz, 1 H), 7.16 (t,
3
J = 7.5 Hz, 1 H), 7.02 (t, J = 7.5 Hz, 1 H), 6.71 (d, J = 7.5 Hz, 1 H),
6.38 (d, J = 2.2 Hz, 1 H), 6.26 (d, J = 2.2 Hz, 1 H), 5.16 (s, 1 H),
IR (neat): 1778, 1737, 1627, 1595, 1502, 1454, 1437, 1423, 1319,
–1
1255, 1215, 1157, 1134, 1097 cm .
3
2
.83 (s, 3 H), 3.77 (d, J = 1.1 Hz, 1 H), 3.71 (s, 3 H), 3,69 (s, 3 H),
.54 (s, 3 H).
1
H NMR (500 MHz, CDCl ): δ = 7.28–7.22 (m, 3 H), 7.11 (d, J =
3
7
4
3
.3 Hz, 2 H), 6.35 (d, J = 2.2 Hz, 1 H), 6.27 (d, J = 2.2 Hz, 1 H),
.97 (s, 1 H), 3.95 (d, J = 1.4 Hz, 1 H), 3.81 (s, 3 H), 3.72 (s, 3 H),
.69 (s, 3 H).
13
C NMR (75 MHz, CDCl ): δ = 167.5, 163.6, 161.0, 157.6, 153.1,
3
137.6, 135.2, 131.0, 127.5, 126.7, 126.1, 103.6, 95.4, 93.6, 55.9,
55.5, 53.2, 53.1, 35.6, 19.2.
13
C NMR (125 MHz, CDCl ): δ = 167.7, 164.1, 161.4, 158.2, 153.0,
3
+
ESI-HRMS: m/z calcd for C H O [M + H] : 357.13382; found:
1
40.2, 129.4, 127.9, 127.3, 104.1, 95.9, 94.3, 56.3, 55.9, 54.8, 53.6,
20 21
6
3
57.1307.
39.2.
+
ESI-HRMS: m/z calcd for C H O [M + H] : 343.11816; found:
1
9
19
6
Methyl 5,7-Dimethoxy-4-(2,4,6-trimethylphenyl)-2-oxochro-
man-3-carboxylate (7e)
343.1145.
Yield: 215 mg (56%); white solid; mp 96–98 °C.
Methyl5,7-Dimethoxy-4-(p-tolyl)-2-oxochroman-3-carboxylate
IR (neat): 1766, 1737, 1621, 1594, 1504, 1469, 1450, 1434, 1421,
(7b)
–
1
1
324, 1261, 1242, 1222, 1201, 1164, 1145, 1097 cm .
Yield: 331 mg (93%); white solid; mp 75–76 °C.
1
H NMR (300 MHz, CDCl ): δ = 6.88 (s, 1 H), 6.67 (s, 1 H), 6.29
IR (neat): 1774, 1734, 1623, 1593, 1502, 1454, 1432, 1423, 1328,
3
–1
(d, J = 2.2 Hz, 1 H), 6.21 (d, J = 2.3 Hz, 1 H), 5.28 (d, J = 2.2 Hz, 1
H), 3.80 (s, 3 H), 3.76 (d, J = 2.2 Hz, 1 H), 3.73 (s, 3 H), 3.61 (s, 3
H), 2.51 (s, 3 H), 2.22 (s, 3 H), 1.86 (s, 3 H).
1
261, 1213, 1157, 1135, 1097 cm .
1
H NMR (300 MHz, CDCl ): δ = 7.11 (d, J = 8.0 Hz, 2 H), 7.03 (d,
J = 8.0 Hz, 2 H), 6.36 (d, J = 2.3 Hz, 1 H), 6.28 (d, J = 2.3 Hz, 1 H),
3
©
Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3361–3365

3364
W. H. dos Santos, L. C. da Silva-Filho
PAPER
13
13
C NMR (75 MHz, CDCl ): δ = 168.3, 164.4, 160.7, 158.4, 152.6,
C NMR (75 MHz, CDCl ): δ = 167.5, 163.9, 162.5 (J = 245.7
3
3
C,F
136.4, 134.8, 131.4, 129.7, 103.5, 95.4, 93.6, 55.9, 55.5, 53.3, 52.0,
Hz), 161.6, 158.2, 152.9, 135.9, 130.0, 129.0, 128.9, 116.4, 116.2,
35.6, 21.1, 20.6, 19.6.
103.9, 95.9, 94.3, 56.3, 55.9, 54.8, 53.7, 38.6.
+
+
ESI-HRMS: m/z calcd for C H O [M + H] : 385.16512; found:
ESI-HRMS: m/z calcd for C H FO [M + H] : 361.10874; found:
2
2
25
6
19 18
6
385.1628.
361.1080.
Methyl 5,7-Dimethoxy-4-(4-tert-butylphenyl)-2-oxochroman-3-
carboxylate (7f)
Yield: 310 mg (78%); white solid; mp 115–118 °C.
Methyl 5,7-Dimethoxy-4-(4-chlorophenyl)-2-oxochroman-3-
carboxylate (7j)
Yield: 301 mg (80%); white solid; mp 110–114 °C.
IR (neat): 1774, 1743, 1625, 1591, 1500, 1461, 1434, 1421, 1369,
IR (neat): 2848, 2925, 1772, 1737, 1627, 1591, 1502, 1488, 1461,
1432, 1423, 1321, 1292, 1259, 1216, 1205, 1186, 1159, 1137, 1095
cm .
–
1
1359, 1319, 1215, 1159, 1141, 1095 cm .
–1
1
H NMR (300 MHz, CDCl ): δ = 7.22 (d, J = 8.1 Hz, 2 H), 6.98 (d,
3
1
J = 8.1 Hz, 2 H), 6.29 (d, J = 2.3 Hz, 1 H), 6.22 (d, J = 2.3 Hz, 1 H),
H NMR (300 MHz, CDCl ): δ = 7.22 (d, J = 9.6 Hz, 2 H), 7.02 (d,
3
4
.90 (d, J = 1.5 Hz, 1 H), 3.91 (d, J = 1.5 Hz, 1 H), 3.76 (s, 3 H),
J = 9.6 Hz, 2 H), 6.32 (d, J = 2.3 Hz, 1 H), 6.24 (d, J = 2.3 Hz, 1 H),
4.92 (d, J = 1.4 Hz, 1 H), 3.88 (d, J = 1.7 Hz, 1 H), 3.79 (s, 3 H),
3.71 (s, 3 H), 3.67 (s, 3 H).
3.69 (s, 3 H), 3.64 (s, 3 H), 1.21 (s, 9 H).
13
C NMR (75 MHz, CDCl ): δ = 167.4, 164.0, 160.9, 157.8, 152.5,
3
13
150.3, 136.5, 126.5, 125.9, 104.0, 95.4, 93.8, 55.9, 55.5, 54.4, 53.2,
C NMR (75 MHz, CDCl ): δ = 167.0, 165.3, 161.2, 157.7, 152.5,
3
3
8.3, 34.4, 31.2.
139.6, 138.7, 133.4, 129.2, 128.3, 103.1, 95.5, 93.8, 55.9, 55.6,
54.2, 38.2.
+
ESI-HRMS: m/z calcd for C H O [M + H] : 399.18077; found:
2
3
27
6
+
399.1797.
ESI-HRMS: m/z calcd for C H ClO [M + H] : 377.07919; found:
1
9
18
6
3
77.0794.
Methyl 5,7-Dimethoxy-4-(3-methoxyphenyl)-2-oxochroman-3-
carboxylate (7g)
Methyl 5,7-Dimethoxy-4-(4-bromophenyl)-2-oxochroman-3-
carboxylate (7k)
Yield: 358 mg (85%); white solid; mp 107–110 °C.
Yield: 297 mg (80%); white solid; mp 133–135 °C.
IR (neat): 2956, 1776, 1735, 1623, 1593, 1500, 1456, 1434, 1423,
–
1
1
324, 1286, 1213, 1159, 1134, 1097 cm .
IR (neat): 1776, 1735, 1625, 1591, 1504, 1485, 1461, 1434, 1423,
1400, 1369, 1324, 1292, 1261, 1242, 1218, 1184, 1159, 1137, 1095
cm .
1
H NMR (300 MHz, CDCl ): δ = 7.19 (t, J = 7.9 Hz, 1 H), 6.77–6.65
3
–1
(
(
(
1
m, 3 H), 6.34 (d, J = 2.3 Hz, 1 H), 6.27 (d, J = 2.3 Hz, 1 H), 4.94
s, 1 H), 3.95 (d, J = 1.5 Hz, 1 H), 3.82 (s, 3 H ), 3.75 (s, 3 H), 3.74
s, 3 H), 3.69 (s, 3 H).
1
H NMR (300 MHz, CDCl ): δ = 7.40 (d, J = 8.4 Hz, 2 H), 6.69 (d,
3
J = 8.4 Hz, 2 H), 6.34 (d, J = 2.2 Hz, 1 H), 6.27 (d, J = 2.2 Hz, 1 H),
4.93 (s, 1 H), 3.90 (d, J = 1.4 Hz, 1 H), 3.82 (s, 3 H), 3.73 (s, 3 H),
3
C NMR (75 MHz, CDCl ): δ = 167.3, 161.0, 160.0, 157.8, 152.6,
3
3.70 (s, 3 H).
141.3, 130.1, 119.1, 113.1, 112.6, 103.5, 95.5, 93.8, 55.9, 55.5,
13
55.1, 54.4, 53.2, 38.8.
C NMR (75 MHz, CDCl ): δ = 167.0, 163.4, 161.2, 152.5, 138.8,
3
+
132.1, 128.7, 121.5, 103.4, 95.5, 93.8, 55.9, 55.5, 54.1, 53.3, 38.3.
ESI-HRMS: m/z calcd for C H O [M + H] : 373.12873; found:
2
0
21
7
+
373.1283.
ESI-HRMS: m/z calcd for C H BrO [M + H] : 421.02868; found:
19
18
6
4
21.0280.
Methyl 5,7-Dimethoxy-4-(2-methoxyphenyl)-2-oxochroman-3-
carboxylate (7h)
Yield: 346 mg (93%); white solid; mp 140–144 °C.
Dimethyl Benzylidenepropanedioate (8)
Isolated as a side product from the reaction of benzaldehyde (6a),
3
,5-dimethoxyphenol (4), and dimethyl malonate (5), following the
IR (neat): 2921, 1772, 1735, 1627, 1593, 1504, 1456, 1434, 1423,
–1
general procedure with a reaction time of 24 h; yield: 32 mg (14 %);
viscous yellow oil.
1282, 1263, 1220, 1159, 1137, 1110, 1095 cm .
1
H NMR (300 MHz, CDCl ): δ = 7.22 (ddd, J = 8.2, 7.5, 1.8 Hz, 1
3
1
H NMR (300 MHz, CDCl ): δ = 7.79 (s, 1 H), 7.42 (m, 5 H), 3.86
H), 6.88 (d, J = 8.2 Hz, 1 H), 6.81 (dt, J = 7.5, 1.0 Hz, 1 H) 6.74 (dd,
J = 7.5, 1.8 Hz, 1 H), 6.34 (d, J = 2.3 Hz, 1 H), 6.26 (d, J = 2.3 Hz,
3
(s, 3 H), 3.85 (s, 3 H).
13
1
3
H), 5.17 (s, 1 H), 4.08 (d, J = 1.5 Hz, 1 H), 3.88 (s, 3 H), 3.82 (s,
H), 3.70 (s, 3 H), 3.69 (s, 3 H).
C NMR (75 MHz, CDCl ): δ = 167.1, 164.5, 142.9, 132.8, 130.7,
3
129.4, 128.9, 125.5, 52.7.
13
C NMR (75 MHz, CDCl ): δ = 167.8, 164.1, 160.8, 157.9, 156.8,
3
1
53.2, 128.8, 128.2, 127.2, 120.6, 110.5, 103.1, 95.3, 93.7, 55.8,
Acknowledgment
55.5, 55.1, 53.1, 51.9, 34.5.
+
The authors would like to thank Fundação de Amparo à Pesquisa do
Estado de São Paulo (FAPESP) (Procs. 2010/18022-2), Conselho
Nacional de Desenvolvimento Científico e Tecnológico (CNPq),
Coordenadoria de Aperfeiçoamento de Pessoal do Nível Superior
ESI-HRMS: m/z calcd for C H O [M + H] : 373.12873; found
2
0
21
7
373.1283.
Methyl 5,7-Dimethoxy-4-(4-fluorophenyl)-2-oxochroman-3-
carboxylate (7i)
Yield: 331 mg (92%); white solid; mp 75–76 °C.
(
CAPES), and Pró-Reitoria de Pesquisa da UNESP (PROPe-
UNESP) for their financial support. We would also like to thank
CBMM (Companhia Brasileira de Mineralogia e Mineração) for the
IR (neat): 1778, 1739, 1631, 1591, 1502, 1463, 1454, 1436, 1425,
321, 1297, 1261, 1213, 1184, 1153, 1128, 1091 cm .
–
1
1
NbCl samples. We express our special thanks to N. P. Lopes, A. M.
5
1
Crotti, and J. N. Mendonça at the University of São Paulo in Ri-
beirão Preto for the HRMS analyses.
H NMR (300 MHz, CDCl ): δ = 7.09 (m, 2 H), 6.97 (m, 2 H), 6.34
d, J = 2.1 Hz, 1 H), 6.27 (d, J = 2.1 Hz, 1 H), 4.95 (s, 1 H), 3.91 (d,
3
(
J = 1.3 Hz, 1 H), 3.81 (s, 3 H), 3.74 (s, 3 H), 3.69 (s, 3 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
Synthesis 2012, 44, 3361–3365
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 4-Aryl-3,4-dihydrocoumarins
3365
References
Elem. 2011, 186, 88. (f) Hou, J. T.; Liu, Y. H.; Zhang, Z. H.
J. Heterocycl. Chem. 2010, 47, 703. (g) Shimada, N.;
Hanari, T.; Kurosaki, Y.; Anada, M.; Nambu, H.;
Hashimoto, S. Tetrahedron Lett. 2010, 51, 6572. (h) Yadav,
J. S.; Ganganna, B.; Dinesh, C. B.; Srihari, P. Tetrahedron
Lett. 2009, 50, 4318. (i) Gao, S. T.; Zhao, Y.; Li, C.; Ma, J.
J.; Wang, C. Synth. Commun. 2009, 39, 2221. (j) Oh, K.;
Knabe, W. E. Tetrahedron 2009, 65, 2966. (k) Yadav, J. S.;
Bhunia, D. C.; Singh, V. K.; Srihari, P. Tetrahedron Lett.
(
1) (a) Audisio, D.; Messaoudi, S.; Brion, J. D.; Alami, M. Eur.
J. Org. Chem. 2010, 1046. (b) Trost, B. M.; Toste, F. D.;
Greenman, K. J. Am. Chem. Soc. 2003, 125, 4518.
(2) Ribeiro, C. V. C.; Kaplan, M. A. C. Quim. Nova 2002, 25,
5
33; Chem. Abstr. 2002, 742733.
3) (a) Jung, J.-C.; Park, O.-S. Molecules 2009, 14, 4790.
b) Hamdi, N.; Sauod, M.; Romerosa, A. Top. Heterocycl.
(
(
Chem. 2007, 11, 283. (c) Gudasi, K. B.; Vadavi, R. S.; Patil,
M. S. Eur. J. Med. Chem. 2004, 45, 5139. (d) Marcu, M. G.;
Chadli, A.; Bouhouche, I.; Catelli, M.; Neckers, L. M. J.
J. Biol. Chem. 2000, 275, 37181. (e) Spino, C.; Dodier, M.;
Sotheeswaran, S. Bioorg. Med. Chem. Lett. 1998, 8, 3475.
2
009, 50, 2470. (l) Majhi, A.; Kim, S. S.; Kim, H. S. Appl.
Organomet. Chem. 2008, 22, 466. (m) Wang, R.; Li, B.-G.;
Huang, T.-K.; Shi, L.; Lu, X.-X. Tetrahedron Lett. 2007, 48,
2
071. (n) Yadav, J. S.; Narsaiah, A. V.; Basak, A. K.;
Sreenu, G. D.; Nagaiah, B. K. J. Mol. Catal. A: Chem. 2006,
55, 78. (o) Narsaiah, A. V.; Sreenu, D.; Nagaiah, K. Synth.
(f) Beckley-Kartey, S. A. J.; Hotchkiss, S. A. M.; Capel, M.
2
Toxicol. Appl. Pharmacol. 1997, 145, 34.
Commun. 2006, 36, 3183. (p) Leelavathi, P.; Kumar, S. R.
J. Mol. Catal. A: Chem. 2005, 240, 99. (q) Yadav, J. S.;
Reddy, B. V. S.; Eeshwaraiah, B.; Reddy, P. N. Tetrahedron
(
4) (a) Pagona, G.; Katerinopoulos, H. E.; Tagmatarchis, N.
Chem. Phys. Lett. 2011, 516, 76. (b) Jacquemin, D.; Perpete,
E. A.; Ciofini, I.; Adamo, C. Acc. Chem. Res. 2009, 42, 326.
2
005, 61, 875. (r) Constantino, M. G.; de Oliveira, K. T.;
Polo, E. C.; da Silva, G. V. J.; Brocksom, T. J. J. Org. Chem.
006, 71, 9880. (s) Arai, S.; Sudo, Y.; Nishida, A.
(c) Cho, Y. H.; Kim, J. H.; Park, S. M.; Lee, B. C.; Pyo, H.
B.; Park, H. D. J. Cosmet. Sci. 2006, 57, 11. (d) Ammar, H.;
Fery-Forgues, S.; Gharbi, R. Dyes Pigm. 2003, 57, 259.
5) (a) Maheswara, M.; Siddaiah, V.; Damu, G. L. V.; Rao, Y.
K.; Rao, C. V. J. Mol. Catal. A: Chem. 2006, 255, 49.
2
Tetrahedron 2005, 61, 4669. (t) Yadav, J. S.; Narsaiah, A.
V.; Reddy, B. V. S.; Basak, A. K.; Nagaiah, K. J. Mol. Catal.
A: Chem. 2005, 230, 107. (u) Nagaiah, K.; Reddy, B. V. S.;
Sreenu, D.; Narsaiah, A. V. ARKIVOK 2005, (iii), 192.
10) (a) Lacerda, V. Jr.; dos Santos, D. A.; da Silva-Filho, L. C.;
Greco, S. J.; dos Santos, R. B. Aldrichimica Acta 2012, 45,
(
(
b) Valizadeh, H.; Shockravi, A. Tetrahedron Lett. 2005, 46,
501. (c) Sharma, G. V. M.; Reddy, J. J.; Lakshmi, P. S.;
Krishna, P. R. Tetrahedron Lett. 2005, 46, 6119.
d) Bahekar, S. S.; Shinde, B. D. Tetrahedron Lett. 2004, 45,
999. (e) Bose, D. S.; Rudradas, A. P.; Babu, M. H.
3
(
(
7
1
9. (b) Constantino, M. G.; Lacerda, V. Jr.; da Silva-Filho,
L. C.; da Silva, G. V. J. Lett. Org. Chem. 2004, 1, 360.
c) Constantino, M. G.; da Silva-Filho, L. C.; Cunha Neto,
Tetrahedron Lett. 2002, 43, 9195. (f) Trost, B. M.; Toste, F.
D. J. Am. Chem. Soc. 1996, 118, 6305.
(
A.; Heleno, V. C. G.; da Silva, G. V. J.; Lopes, J. L. C.
Spectrochim. Acta, Part A 2004, 61, 171. (d) da Silva-Filho,
L. C.; Lacerda, V. Jr.; Constantino, M. G.; da Silva, G. V. J.;
Invernize, P. R. Beilstein J. Org. Chem. 2005, 1, 14.
(
6) (a) Donnelly, D. M. X.; Boland, G. M. Nat. Prod. Rep. 1995,
1
(
1
2, 321. (b) Reher, G.; Kraus, L. J. Nat. Prod. 1984, 47, 172.
c) Ulubelen, A.; Kerr, R. R.; Mabry, T. J. Phytochemistry
982, 21, 1145. (d) Thebtaranonth, C.; Imraporn, S.;
(
e) Constantino, M. G.; Lacerda, V. Jr.; Invernize, P. R.; da
Silva-Filho, L. C.; da Silva, G. V. J. Synth. Commun. 2007,
7, 3529. (f) da Silva-Filho, L. C.; Lacerda, V. Jr;
Constantino, M. G.; da Silva, G. V. J. Synthesis 2008, 16,
527. (g) Polo, E. C.; da Silva-Filho, L. C.; da Silva, G. V.
Padungkul, N. Phytochemistry 1981, 20, 2305.
(
7) (a) Dhooghe, L.; Maregesi, S.; Mincheva, I.; Ferreira, D.;
Marais, J. P. J.; Lemière, F.; Matheeussen, A.; Cos, P.; Maes,
L.; Vlietinck, A.; Apers, S.; Pieters, L. Phytochemistry 2010,
3
2
7
1, 785. (b) Hokkanen, J.; Mattila, S.; Jaakola, L.; Pirttila, A.
M.; Tolonen, A. J. Agric. Food. Chem. 2009, 57, 9437.
c) Tabanca, N.; Pawar, R. S.; Ferreira, D.; Marais, J. P. J.;
Khan, S. I.; Joshi, V.; Wedge, D. E.; Khan, I. A. Planta Med.
007, 73, 1107. (d) Zhang, X.-F.; Wang, H.-M.; Song, Y.-L.;
J.; Constantino, M. G. Quim. Nova 2008, 31, 763; Chem.
Abstr. 2008, 792174.
(
(
(
(
11) (a) Zhu, J.; Bienaymé, H. Multicomponent Reactions;
Wiley-VCH: Weinheim, 2005. (b) Bienaymé, H.; Hulme,
C.; Oddon, G.; Schimitt, P. Chem.–Eur. J. 2000, 6, 3321.
12) (a) Isambert, N.; Lavilla, R. Chem.–Eur. J. 2008, 14, 8444.
2
Nie, L.-H.; Wang, L.-F.; Liu, B.; Shen, P.; Liu, Y. Bioorg.
Med. Chem. Lett. 2006, 16, 949. (e) Yao, C.-S.; Lin, M.;
Wang, L. Chem. Pharm. Bull. 2006, 54, 1053.
(b) D’Souza, D. M.; Muller, T. J. J. Chem. Soc. Rev. 2007,
3
6, 1095.
(
8) (a) Chattopadhyay, K.; Jana, R.; Day, V. W.; Douglas, J. T.;
Tunge, J. A. Org. Lett. 2010, 12, 3042. (b) Duan, S.; Jana,
R.; Tunge, J. A. J. Org. Chem. 2009, 74, 4612.
13) (a) Cordier, C.; Morton, D.; Murrison, S.; Nelson, A.;
O’Leary-Steele, C. Nat. Prod. Rep. 2008, 25, 719.
(
b) Kalinski, C.; Lemoine, H.; Schmidt, J.; Burdack, C.;
(c) Rodrigues-Santos, C. E.; Echevarria, A. Tetrahedron
Kolb, J.; Umkehrer, J. Synthesis 2008, 4007. (c) Jain, S. L.;
Prasad, V. V. D. N.; Sain, B. Catal. Commun. 2008, 9, 499.
Lett. 2007, 48, 4505. (d) Roelens, F.; Huvaere, K.; Dhooge,
W.; Van Cleemput, M.; Comhaire, F.; De Keukeleire, D.
Eur. J. Med. Chem. 2005, 40, 1042. (e) Shchepin, V. V.;
Korzun, A. E.; Shurov, S. N.; Valhrin, M. I. Russ. J. Org.
Chem. 2004, 40, 1487. (f) Yamamura, T.; Onishi, J.;
Nishiyama, T. Arch. Dermatol. Res. 2002, 294, 349.
(
d) Wang, S.-X.; Wang, M.-X.; Wang, D.-X.; Zhu, J. Angew.
Chem. Int. Ed. 2008, 47, 388. (e) Wang, R.; Li, B.; Huang,
T.; Shi, L.; Lu, X. Tetrahedron Lett. 2007, 48, 2071.
(f) Dondoni, A.; Massi, A. Acc. Chem. Res. 2006, 39, 451.
(
g) Kusebauch, U.; Beck, B.; Messer, K.; Herdtweck, E.;
(
g) Raboin, J. C.; Beley, M.; Kirsch, G. Tetrahedron Lett.
000, 41, 1175.
9) (a) Andrade, C. K. Z.; Rocha, O. R. Mini-Rev. Org. Chem.
Dömling, A. Org. Lett. 2003, 5, 4021. (h) Hulme, C.; Gore,
V. Curr. Med. Chem. 2003, 10, 51. (i) Fu, N.-Y.; Yuan, Y.-
F.; Cao, Z.; Wang, S.-W.; Wang, J.-T.; Peppe, C.
Tetrahedron 2002, 58, 4801. (j) Lu, J.; Bai, Y.; Wang, Z.;
Yang, B.; Ma, H. Tetrahedron Lett. 2000, 41, 9075.
2
(
2
006, 3, 271. (b) Andrade, C. K. Z. Curr. Org. Synth. 2004,
1
, 333. (c) Hou, J. T.; Gao, J. W.; Zhang, Z. H. Appl.
Organomet. Chem. 2011, 25, 47. (d) Hou, J. T.; Gao, J. W.;
Zhang, Z. H. Monatsh. Chem. 2011, 142, 495. (e) Hou, J. T.;
Chen, H. L.; Zhang, Z. H. Phosphorus, Sulfur Silicon Relat.
(k) Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65,
6
270.
©
Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3361–3365