Synthesis and DPPH radical scavenging activity of novel compounds obtained from tyrosol and cinnamic acid derivatives

Article abstract of DOI:10.1039/c3nj01180a

Tyrosol, a naturally occurring phenolic compound poorly attractive as an antioxidant because of its weak efficacy, was used as starting material to obtain novel compounds. The synthesis is based on a trifluoroacetic acid-mediated hydroarylation of cinnamic esters with tyrosol to produce 4-aryl-3,4-dihydrocoumarins, molecules of biological interest, followed by a basic hydrolysis to give the corresponding ring opening products. Unreported mechanistic investigations confirmed that the first step resulted from an electrophilic aromatic substitution and an intramolecular transesterification. Final products exhibited DPPH radical scavenging activity significantly higher than tyrosol.

Full text of DOI:10.1039/c3nj01180a

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Synthesis and DPPH radical scavenging activity of
novel compounds obtained from tyrosol and
cinnamic acid derivatives
Cite this:DOI: 10.1039/c3nj01180a
Maurizio Barontini,a Roberta Bernini,*a Isabella Carastro,a Patrizia Gentilib and
Annalisa Romanic
Tyrosol, a naturally occurring phenolic compound poorly attractive as an antioxidant because of its weak
efficacy, was used as starting material to obtain novel compounds. The synthesis is based on a trifluoroacetic
acid-mediated hydroarylation of cinnamic esters with tyrosol to produce 4-aryl-3,4-dihydrocoumarins,
molecules of biological interest, followed by a basic hydrolysis to give the corresponding ring opening
products. Unreported mechanistic investigations confirmed that the first step resulted from an
electrophilic aromatic substitution and an intramolecular transesterification. Final products exhibited
DPPH radical scavenging activity significantly higher than tyrosol.
Received (in Montpellier, France)
29th September 2013,
Accepted 2nd December 2013
DOI: 10.1039/c3nj01180a
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acid 5 (caffeic acid) and 4-hydroxy-3,5-dimethoxycinnamic acid 6
(sinapic acid), responsible for the beneficial health effects associated
Introduction
It is well known that the human body is susceptible to the attack with cereal consumption (Fig. 1).11 In contrast, 2-(4-hydroxyphenyl)-
of free radicals and reactive oxygen species (ROS) having harmful ethanol 2 (tyrosol) shows a weak anti-oxidative efficacy.12 Despite
effects on human health. Under normal conditions, this action is this property, in the last few years tyrosol has attracted the attention
controlled by endogenous defence systems which intercept ROS of organic chemists and pharmacologists as a versatile substrate for
or repair the damage that has already been caused by them. In the synthesis of a variety of esters exhibiting diverse biological effects
contrast, if there is an imbalance between these systems because including antioxidant, anti-cancer, antimicrobial and antileishmania
of overproduction of free radicals in the organism or a deficit in activities.13 In this context, in our laboratory we utilized tyrosol for
the defence system, a pathological mechanism called oxidative the preparation of biologically and industrially-relevant catechols
stress ensues.1 Epidemiological studies demonstrated that this that showed antioxidant and antiproliferative effects on human
condition is related to the occurrence of many chronic degen- colon cancer cells.14 Continuing this research, we describe here
erative diseases including neurovegetative pathologies,2 cancer,3 the synthesis of novel DPPH (2,2-diphenyl-1-picrylhydrazyl) radical
cerebral ischemia,4 hypertension,5 diabetes,6 rheumatic diseases,7 scavengers. As shown in Scheme 1, the key step of our strategy is
and multiple sclerosis.8 In addition to endogenous defence systems, the preparation of 4-aryl-3,4-dihydrocoumarins. In the literature
exogenous antioxidants taken up from the diet may counteract
the dangerous effects of ROS. Among them, phenolic com-
pounds are well-recognized powerful antioxidants present in
plant food.9 Representative compounds are 2-(3,4-dihydroxyphenyl)-
ethanol 1 (hydroxytyrosol), present in extra-virgin olive oil;10
4-hydroxycinnamic acid
3 ( p-coumaric acid), 4-hydroxy-3-
methoxycinnamic acid 4 (ferulic acid); 3,4-dihydroxycinnamic
a Dipartimento di Scienze e Tecnologie per l’Agricoltura, le Foreste,
`
la Natura e l’Energia (DAFNE), Universita degli Studi della Tuscia,
Via S. Camillo De Lellis, 01100 Viterbo, Italy. E-mail: berninir@unitus.it;
Fax: +39 0761 357242; Tel: +39 0761 357452
b Dipartimento di Chimica and IMC-CNR Sezione Meccanismi di Reazione,
`
Universita degli Studi La Sapienza, P. le A. Moro 5, 00185 Roma, Italy.
Fax: +39 06 49913692; Tel: +39 06 49913082
c Dipartimento di Statistica, Informatica, Applicazioni ‘‘G. Parenti’’ (DiSIA) Viale
Morgagni 65, 50134 Firenze, Italy. Fax: +39 055 4223560; Tel: +39 055 2751500
Fig. 1 Representative naturally occurring phenolic compounds.
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Scheme 2 Carboxymethylation of tyrosol 1 with DMC/DBU.
Scheme 1 Synthetic strategy to obtain novel tyrosol derivatives.
several synthetic methods have been described for the synthesis of
this class of compounds including catalytic hydrogenation of
coumarins,15 reaction of alkenyl carbene chromium(0) complexes
with ketene acetals,16 reaction of Meldrum’s acid or 5-alkylidene
Meldrum’s acid with phenols,17 rhodium-mediated reaction of
3-(2-hydroxyphenyl)-cyclobutanones,18 Lewis acid catalyzed reac-
tion of acrylonitrile with phenols,19 hydroarylation of cinnamic
acid derivatives with alkyl phenols under acidic conditions20 or
microwave irradiation.21 Among them, hydroarylation reaction
seems to be of interest allowing the formation of C–C bonds with
high atom economy from simple phenol substrates.22 A mild and
convenient version is the trifluoroacetic acid-mediated hydro-
arylation.23 On the basis of these literature data, we firstly
explored the potentiality of this procedure using tyrosol and
cinnamic acid derivatives as starting materials in order to
obtain novel 4-aryl-3,4-dihydrocoumarins, precursors of our
target compounds.
Scheme 3 Methylation and acetylation reactions of cinnamic acids 3–6.
the phenolic moiety with acetic anhydride in dry pyridine followed
by methylation of the carboxylic group with potassium carbo-
nate and dimethyl sulfate (Scheme 3).
Results and discussion
Firstly, we selectively protected the alcoholic functionality of
tyrosol 2, the carboxylic and phenolic moieties of cinnamic
acids 3–6. Thus, tyrosol was converted into the corresponding tyrosol
methyl carbonate 7 by an efficient and simple procedure using
dimethyl carbonate (DMC) in the presence of 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU), as shown in Scheme 2.24
Cinnamic acids 3–6 were converted into the corresponding
methyl cinnamates 8–10 by reaction with potassium carbonate
and an excess of dimethyl sulfate. The yields of the final products
were comparable to those obtained by the Wittig reactions
between the corresponding benzaldehydes and the appropriate
phosphorane derivatives.25–27 Finally, cinnamic acids 3–6 were
converted into p-acetoxy methyl cinnamates 15–18 by reaction of
Scheme 4 TFA-mediated reaction of tyrosol methyl carbonate 7 with
cinnamic esters 8–10 and 15–18.
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Table 1 Experimental conditions of the reaction depicted in Scheme 4
ester on the phenolic substrate, followed by the intramolecular
transesterification to afford the dihydrocoumarin.20 In order to
confirm this hypothesis, we carried out the reactions of ester 8 in
combination with 2,6-dimethylphenol 26 and 2,4-dimethylphenol
27 in trifluoroacetic acid (Scheme 5). According to the proposed
mechanism, phenol 26, exhibiting two methyl groups in both
the ortho-positions and the free para-position, gave 28 as the
only product; in contrast, phenol 27, showing one free ortho-
position, produced the dihydrocoumarin 29. Both at 25 1C and
reflux temperature, compounds 28 and 29 were obtained as the
only reaction products.
Novel 4-aryl-3,4-dihydrocoumarins 19–25 appear to be interesting
molecules from the biological point of view. As a matter of fact,
several compounds of these class have been shown to possess many
biological properties such as antiherpetic,25 estrogenic,26 anti-
microbial,27 anti-inflammatory,28 cytotoxic,29 and antifungal
activities.30 In addition, many dihydrocoumarins are used as
synthetic intermediates of pharmaceuticals and flavoring
Entry Cinnamic ester Experimental conditionsa Productb (yield%)
1
2
3
4
5
6
7
8
8
8
9
25 1C, 24 h
Reflux, 5 h
25 1C, 24 h
Reflux, 5 h
25 1C, 24 h
Reflux, 5 h
25 1C, 24 h
Reflux, 6 h
25 1C, 24 h
Reflux, 6 h
25 1C, 24 h
Reflux, 6 h
25 1C, 24 h
Reflux, 5 h
19: 76
19: 78
20: 70
20: 74
21: 68
21: 64
22: 42
22: 52
23: 40
23: 50
24: 38
24: 42
25: 40
25: 44
9
10
10
15
15
16
16
17
17
18
18
9
10
11
12
13
14
a
Tyrosol methyl carbonate 7 (0.5 mmol); esters 8–10 and 15–18
b
(0.5 mmol); trifluoroacetic acid: 2 mL. Calculated after chromato-
graphic purification.
Hydroarylation reactions of cinnamic esters 8–10 and 15–18 agents of foods such as drinks, yogurt, and cakes.31
with tyrosol methyl carbonate 7 in trifluoroacetic acid are depicted in Finally, we carried out the basic hydrolysis of compounds
Scheme 4. Experimental results showed that 4-aryl-3,4-dihydro- 19–25. Under these conditions both the opening of the lactonic
coumarins 19–21 derived from cinnamic esters bearing electron- ring and deprotection of the carbonate moiety of the tyrosol
donating groups were obtained in satisfactory yields both at room skeleton were observed to produce tyrosol derivatives 30, 31, 32,
temperature and reflux temperature (Table 1, entries 1–6); 4-aryl-3,4- 33, 34 and 36 (Scheme 6). Unfortunately, we were not able to
dihydrocoumarins 22–25 derived from cinnamic esters bearing isolate a pure sample of tyrosol derivative 35, probably due to
an electron-withdrawing group at the para-position (an acetoxy its high polarity.
group) were also isolated in lower yields at reflux temperature
(Table 1, entries 7–14).
Compounds 30, 31, 32, 33, 34 and 36 were evaluated for their
radical scavenging capacity by using the DPPH radical test assay.32
In the literature the hypothesized mechanism of the TFA- The antioxidant activity was defined as the amount of compound
hydroarylation reaction, suggested on the basis of the electronic necessary to decrease the initial DPPH concentration by 50%
substituent effects on cinnamic ester derivatives, consists of the and expressed as EC50 (efficient concentration = mmol tyrosol
aromatic electrophilic substitution by the protonated cinnamic derivative/mmol DPPH). As shown in Table 2, all novel products
Scheme 5 Mechanistic investigations with cinnamic ester 8 and phenols 26 and 27.
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Scheme 6 Basic hydrolysis of 4-aryl-3,4-dihydrocoumarins 19–25.
Table 2 DPPH radical-scavenging effect of tyrosol 2 and compounds 30–34 and 36
Compound
a
EC50
21 Æ 1.0
2.32 Æ 0.03
2.49 Æ 0.03
3.00 Æ 0.03
Compound
a
EC50
2.04 Æ 0.02
0.86 Æ 0.01
0.24 Æ 0.01
a
Mmol isochroman/mmol DPPH radical.
showed a significant radical-scavenging activity. Among them, the the DPPH radical scavenging activity. Experimental results demon-
most active was compound 36; as a general trend, the substitution strated that all compounds showed an effect significantly higher
of a methoxy group with an hydroxyl group in the acidic frame than tyrosol and their efficacy increased with the presence of one
produced an increase of activity (compare compound 30 with 33; hydroxyl group in the aromatic ring of the acidic frame.
31 with 34; and 32 with 36) as already reported in the literature
and also observed by us.14
Experimental section
Materials and methods
Conclusions
Reagents and solvents were supplied by Sigma Aldrich (Milan, Italy)
Tyrosol, a naturally occurring phenolic compound poorly attractive and used without further purification. Tyrosol methyl carbonate 7
as an antioxidant because of its weak efficacy, was used as starting was prepared according to the procedure already reported by us.24
material for the preparation of novel bioactive compounds by a two- Silica gel 60 F254 plates and silica gel 60 were obtained from Merck
1
step procedure: (1) a trifluoroacetic acid-mediated hydroarylation of (Milan, Italy). H NMR and 13C NMR spectra were recorded on a
cinnamic esters and (2) a basic hydrolysis of the corresponding Bruker 200 MHz spectrometer using CDCl3 and CD3OD as solvents.
4-aryl-3,4-dihydrocoumarins. Unreported mechanistic investi- Chemical shifts are expressed in parts per million (d scale) and
gations confirmed that the hydroarylation process proceeded coupling constants in Hertz. GC-MS analyses were performed on a
by an electrophilic substitution followed by an intramolecular Shimadzu VG 70/250S apparatus equipped with a Supelco SLBt-
esterification. Pure samples of final compounds were evaluated for 5ms column (30 m, 0.25 mm and 0.25 mm film thickness).
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The analyses were performed using an isothermal temperature
(E)-Methyl 3-(3,4-diacetoxyphenyl)acrylate (17). Yield 88%;
profile of 100 1C for 2 min, followed by a 10 1C minÀ1 temperature colorless oil; H NMR (CDCl3, 200 MHz) d: 7.57 (d, J = 16.0 Hz,
gradient until 280 1C for 15 min. The injector temperature was 1H, CHQCH), 7.14–7.37 (m, 3H, Ph-H), 6.33 (d, J = 16.0 Hz, 1H,
280 1C. High Resolution Mass Spectrometry (HRMS) analyses CHQCH), 3.74 (3H, s, CO2CH3), 2.25 (6H, s, 2OCOCH3);
were performed using a Micromass Q-TOF micro Mass Spectro- 13C NMR (50 MHz, CDCl3) d: 168.0 (2C), 166.9, 143.5, 142.8,
1
meter (Waters).
142.4, 133.2, 126.3, 123.9, 122.6, 118.9, 51.7, 20.5 (2C); GC-MS:
278 (M+), 236, 194, 163, 134. C14H14O6 requires C, 60.43; H,
5.07; found C, 60.54; H, 5.10.
Synthesis
Methylation of cinnamic acids (3)–(6). Cinnamic acid 3, 4 or 6
(E)-Methyl 3-(4-acetoxy-3,5-dimethoxyphenyl)acrylate (18).
(1.0 mmol) was solubilized in acetone (5 mL) at room tempera- Yield 92%; colorless oil; 1H NMR (CDCl3, 200 MHz) d: 7.54
ture; then, potassium carbonate (2.0 mmol) and dimethyl sulfate (d, J = 16.0 Hz, 1H, CHQCH), 6.70 (s, 2H, Ph-H), 6.32
(2.0 mmol) were added. The mixture was kept under magnetic (d, J = 16.0 Hz, 1H, CHQCH), 3.76 (s, 6H, 2OCH3), 3.74
stirring at room temperature for 24 h. After the work-up, the final (s, 3H, CO2CH3), 2.23 (s, 3H, OCOCH3); 13C NMR (50 MHz, CDCl3)
product (8, 9 or 10) was purified on a silica gel chromatographic d: 168.4, 167.1, 152.4 (2C), 144.5, 132.6, 130.4, 118.0, 104.6 (2C),
column using hexane–ethyl acetate = 9/1 as an eluent.
(E)-Methyl 3-(4-methoxyphenyl)acrylate (8). Yield: 92%; color- 119. C14H16O6 requires C, 59.99; H, 5.75; found C, 60.19; H 5.70.
less oil; spectroscopic data are according to the literature.33
Reaction of tyrosol methyl carbonate (7) with cinnamates
56.1 (2C), 51.6, 20.3; GC-MS: 280 (M+), 238, 207, 175, 163, 147, 135,
(E)-Methyl 3-(3,4-dimethoxyphenyl)acrylate (9). Yield: 90%; (8)–(10) or (15)–(18). Tyrosol methyl carbonate 7 (0.3 mmol) and
colorless oil; spectroscopic data are according to the literature.34 the appropriate cinnamate derivative 8, 9, 10, 15, 16, 17 or 18
(E)-Methyl 3-(3,4,5-trimethoxyphenyl)acrylate (10). Yield: 88%; (0.5 mmol) were kept in trifluoroacetic acid (2.5 mL) under
colorless oil; spectroscopic data are according to the literature.35 magnetic stirring at room or reflux temperature for 5–24 h
Acetylation of cinnamic acids (3)–(6). To a solution of depending on the experiment. In the end, the crude was neutralized
cinnamic acid 3, 4, 5 or 6 (1.0 mmol) in dry pyridine (1.5 mL) with aqueous NaHCO3 and extracted with ethyl acetate. Organic
was added acetic anhydride (1.5 mL). The mixture was stirred at phases were washed with a saturated NaCl solution and dried on
room temperature overnight. Then, the reaction mixture was anhydrous Na2SO4. After evaporation of the solvent, the final product
poured into ice-water (5 mL) and treated with 3 M HCl. The (19, 20, 21, 22, 23, 24, or 25) was purified in a silica gel chromato-
precipitated product was filtered and washed with water and graphic column using hexane–ethyl acetate (8/2 or 7/3) as an eluent
diethyl ether. Pure samples of compounds (11, 12, 13, and 14) depending on the substrate.
were obtained after purification in a silica gel chromatographic
column using hexane–ethyl acetate = 8/2 as an eluent.
2-[4-(4-Methoxyphenyl)-2-oxochroman-6-yl]ethyl methyl car-
bonate (19). Yield 76 and 78%; colorless oil; H NMR (CDCl3,
1
(E)-3-(4-Acetoxyphenyl)acrylic acid (11). Yield: 95%; colorless 200 MHz) d: 7.02–7.16 (4H, m, Ph-H), 6.72–6.87 (m, 3H, Ph-H),
oil; spectroscopic data are according to the literature.36
4.20–4.27 (m, 3H, CH2 and CH), 3.78 (s, 3H, OCH3), 3.72 (s, 3H,
(E)-3-(4-Acetoxy-3-methoxyphenyl)acrylic acid (12). Yield: 90%; CO2CH3), 2.87–3.00 (m, 2H, CH2), 2.86 (t, J = 6.7 Hz, 2H, CH2);
colorless oil; spectroscopic data are according to the literature.37 13C NMR (50 MHz, CDCl3) d: 167.7, 159.0, 155.6, 150.5,
(E)-3-(3,4-Diacetoxyphenyl)acrylic acid (13). Yield: 92%; color- 133.8, 132.1, 130.1, 129.1, 128.7, 128.6, 126.2, 117.2, 115.4,
less oil; spectroscopic data are according to the literature.38
114.5, 68.1, 55.3, 54.7, 39.9, 37.2, 34.4; GC-MS: 356 (M+), 280,
(E)-3-(4-Acetoxy-3,5-dimethoxyphenyl)acrylic acid (14). Yield: 90%; 262, 237, 207. C20H20O6 requires C, 67.41; H, 5.66; found C,
colorless oil; spectroscopic data are according to the literature.37
67.50; H, 5.60.
Methylation of cinnamic acid derivatives (11)–(14). Cinnamic
2-[4-(3,4-Dimethoxyphenyl)-2-oxochroman-6-yl]ethyl methyl
acid 11, 12, 13 or 14 (1.0 mmol) was solubilized in acetone (5 mL) carbonate (20). Yield 70 and 74%; colorless oil; 1H NMR (CDCl3,
at room temperature. Then potassium carbonate (1.0 mmol) and 200 MHz) d: 7.02–7.16 (m, 2H, Ph-H); 6.63–6.83 (m, 4H, Ph-H),
dimethyl sulfate (1.0 mmol) were added and the mixture was 4.20–4.27 (m, 3H, CH2 and CH), 3.81 (3H, s, OCH3), 3.77 (3H, s,
kept under magnetic stirring at room temperature for 8 h. After OCH3), 3.71 (3H, s, CO2CH3), 2.96–3.01 (m, 2H, CH2), 2.88 (t, J =
the work-up, the final product (11, 12, 13, or 14) was purified in a 7.1 Hz, 2H, CH2); 13C NMR (50 MHz, CDCl3) d: 167.6, 155.6, 150.5,
silica gel chromatographic column using hexane–ethyl acetate = 149.5, 148.6, 133.8, 132.6, 129.2, 128.6, 126.1, 119.7, 117.2, 111.6,
8/2 as an eluent.
110.5, 68.1, 55.9 (2C), 54.7, 40.4, 37.1, 34.4; GC-MS: 386 (M+), 310,
(E)-Methyl 3-(4-acetoxyphenyl)acrylate (15). Yield: 92%; color- 292, 277, 237. C21H22O7 requires C, 65.28; H 5.74; found C, 65.42;
less oil; spectroscopic data are according to the literature.39
H, 5.84.
Methyl [2-(2-oxo-4-(3,4,5-trimethoxyphenyl)chroman)-6-yl-]ethyl
(E)-Methyl 3-(4-acetoxy-3-methoxyphenyl)acrylate (16). Yield:
90%; colorless oil; 1H NMR (CDCl3, 200 MHz) d: 7.66 (d, J = carbonate (21). Yield 68 and 64%; colorless oil; 1H NMR
16.0 Hz, 1H, CHQCH), 6.96–7.09 (m, 3H, Ph-H), 6.34 (d, J = (CDCl3, 200 MHz) d: 6.87–7.17 (m, 3H, Ph-H), 6.32 (s, 2H,
16.0 Hz, 1H, CHQCH), 3.84 (s, 3H, OCH3), 3.77 (s, 3H, Ph-H), 4.19–4.29 (m, 3H, CH2 and CH), 3.84 (s, 3H, 2OCH3),
CO2CH3), 2.29 (s, 3H, OCOCH3); 13C NMR (50 MHz, CDCl3) d: 3.78 (s, 3H, OCH3), 3.71 (3H, s, CO2CH3), 2.97–3.03 (m, 2H,
168.7, 167.2, 151.4, 144.1, 141.4, 133.2, 123.2, 121.1, 118.0, CH2), 2.81 (2H, t, J = 6.8 Hz, CH2); 13C NMR (50 MHz, CDCl3) d:
111.3, 55.8, 51.7, 20.6; GC-MS: 250 (M+), 208, 177, 145. 167.7, 155.6, 150.5 (2C), 146.9, 145.1, 133.8, 132.0, 129.2, 128.7,
C
13H14O5 requires C, 62.39; H, 5.64; found: C, 62.45; H, 5.60.
126.2, 120.5, 117.2, 114.9, 109.7, 68.1, 55.9, 54.7, 40.5, 37.2,
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34.4, 29.7; GC-MS: 416 (M+), 340, 322, 307, 281, 267. C22H24O8 using dichloromethane–methanol (8/2, 7/3 or 6/4 depending on
requires C, 63.45; H, 5.81; found C 65.08; H, 5.80. the polarity of the product), compounds 30, 31, 32, 33, 34 and
2-[4-(4-Hydroxyphenyl)-2-oxochroman-6-yl]ethyl methyl car- 36 were isolated as pure samples.
1
bonate (22). Yield 42 and 52%; colorless oil; H NMR (CDCl3,
3-(2-Hydroxy-5-(2-hydroxyethyl)phenyl)-3-(4-methoxyphenyl)-
1
200 MHz) d: 6.93–7.15 (m, 5H, Ph-H), 6.71–6.83 (m, 2H, Ph-H), propanoic acid (30). Yield 90%; colorless oil; H NMR (CDCl3/
4.19–4.27 (m, 3H, CH2 and CH), 3.72 (s, 3H, CO2CH3), 2.94–2.99 CD3OD, 200 MHz) d: 7.1 (d, J = 7.1 Hz, 2H, Ph-H), 6.61–6.84
(m, 2H, CH2), 2.86 (t, J = 6.9 Hz, 2H, CH2); 13C NMR (50 MHz, (m, 5H, Ph-H), 4.72 (t, J = 7.5 Hz, 1H, CH), 3.78 (s, 3H, OCH3),
CDCl3) d: 168.2, 155.4, 150.4, 148.2, 133.9, 131.9, 129.1, 128.7 3.63 (t, J = 6.9 Hz, 2H, CH2), 2.94–3.02 (m, 2H, CH2), 2.70
(2C), 128.5, 126.2, 117.2, 116.0 (2C), 68.1, 54.1, 39.8, 37.2, 34.3; (t, J = 6.7 Hz, 2H, CH2); 13C NMR (50 MHz, CDCl3) d: 177.6,
GC-MS: 342 (M+), 266, 248, 223, 207. C19H18O6 requires C, 159.0, 151.8, 133.1, 130.6 (2C), 129.2, 130.1, 126.2, 123.2, 117.5
66.66; H, 5.30; found C, 66.46; H 5.20.
(2C), 115.9, 63.0, 54.2, 42.4, 39.2, 38.5. C18H20O5 requires C,
2-[4-(4-Hydroxy-3-methoxyphenyl)-2-oxochroman-6-yl]ethyl 68.34; H, 6.37; found C, 68.42; H, 6.45.
methyl carbonate (23). Yield 40 and 50%; colorless oil; 1H NMR
3-(3,4-Dimethoxyphenyl)-3-(2-hydroxy-5-(2-hydroxyethyl)phenyl)-
(CDCl3, 200 MHz) d: 7.02–7.16 (m, 2H, Ph-H); 6.83–6.88 (m, 2H, propanoic acid (31). Yield 92%; colorless oil; 1H NMR (CDCl3/
Ph-H), 6.60–6.65 (m, 2H, Ph-H), 5.60 (s, br, 1H, OH), 4.18–4.27 CD3OD, 200 MHz) d: 6.63–6.85 (m, 6H, Ph-H), 4.71 (t, J = 7.8 Hz,
(m, 3H, CH2 and CH), 3.82 (s, 3H, OCH3), 3.72 (s, 3H, CO2CH3), 1H, CH), 3.78 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.63
2.98–3.01 (m, 2H, CH2), 2.87 (t, J = 6.9 Hz, 2H, CH2); 13C NMR (t, J = 6.9 Hz, 2H, CH2), 2.85–3.10 (m, 2H, CH2), 2.62
(50 MHz, CDCl3) d: 167.7, 155.6, 150.4, 146.9, 145.1, 133.8, (t, J = 6.6 Hz, 2H, CH2); 13C NMR (50 MHz, CDCl3) d: 177.6,
132.0, 129.1, 128.6, 126.1, 120.5, 117.2, 114.8, 109.7, 68.1, 55.9, 151.7, 149.6, 147.6, 130.6, 129.4, 128.5, 126.2, 123.8, 123.0,
54.7, 40.4, 37.2, 34.4. GC-MS: 386 (M+), 372, 296, 278, 253, 223. 115.9, 115.0, 112.0, 63.0, 56.0 (2C), 42.4, 39.7, 39.2. C19H22O6
C
20H20O7 requires C, 64.51; H, 5.41; found C, 64.61; H, 5.31.
requires C, 65.88; H, 6.40; found C, 68.48; H, 6.32.
2-[4-(3,4-Dihydroxyphenyl)-2-oxochroman-6-yl]ethyl methyl
3-(2-Hydroxy-5-(2-hydroxyethyl)phenyl)-3-(3,4,5-
carbonate (24). Yield 38 and 42%; colorless oil; 1H NMR (CDCl3, trimethoxyphenyl)propanoic acid (32). Yield 92%; colorless oil;
200 MHz) d: 6.78–7.14 (m, 4H, Ph-H), 6.57 (d, J = 6.7 Hz, 2H, 1H NMR (CDCl3/CD3OD, 200 MHz) d: 6.77–6.86 (m, 2H, Ph-H),
Ph-H), 4.05–4.34 (m, 3H, CH2 and CH), 3.72 (s, 3H, CO2CH3), 6.65 (d, J = 8.0 Hz, 1H, Ph-H), 6.45 (s, 2H, Ph-H), 4.68
2.85–3.03 (m, 2H, CH2), 2.87 (t, J = 6.8 Hz, 2H, CH2); 13C NMR (t, J = 7.8 Hz, 1H, CH), 3.70 (s, 6H, 2OCH3), 3.68 (s, 3H,
(50 MHz, CDCl3) d: 168.2, 155.6, 150.4, 144.1, 143.4, 133.8, OCH3), 3.59 (t, J = 6.7 Hz, 2H, CH2), 2.81–3.07 (m, 2H, CH2),
132.7, 128.9, 128.7, 125.9, 119.9, 117.0, 115.6, 114.4, 68.3, 54.9, 2.61 (t, J = 6.7 Hz, 2H, CH2); 13C NMR (50 MHz, CDCl3) d: 177.6,
39.8, 36.9, 34.4; GC-MS: 358 (M+), 382, 296, 278, 253, 194. 151.5, 152.2, 151.4, 140.4, 137.0, 131.4, 130.1, 126.2, 124.0,
C
19H18O7 requires C, 63.68; H, 5.06; found C, 63.88; H, 5.16.
115.9, 108.0 (2C), 63.0, 60.6, 56.1 (2C), 42.4, 40.9, 39.2.
2-[4-(4-Hydroxy-3,5-dimethoxyphenyl)-2-oxochroman-6-yl]ethyl
methyl carbonate (25). Yield 40 and 44%; colorless oil; 1H NMR
C
20H24O7 requires C, 63.82; H, 6.43; found C, 63.72; H, 6.38.
3-(2-Hydroxy-5-(2-hydroxyethyl)phenyl)-3-(4-hydroxyphenyl)-
1
(CDCl3, 200 MHz) d: 6.73–7.02 (m, 3H, Ph-H), 6.34 (s, 2H, Ph-H), propanoic acid (33). Yield 88%; colorless oil; H NMR (CDCl3/
4.17–4.28 (m, 3H, CH2 and CH), 3.80 (6H, s, 2OCH3), 3.71 (3H, CD3OD, 200 MHz) d: 7.12 (d, J = 8.7 Hz, 2H, Ph-H), 6.51–6.73
s, CO2CH3), 2.90–3.01 (m, 2H, CH2), 2.86 (t, J = 6.8 Hz, 2H, CH2); (m, 5H, Ph-H), 4.65 (t, J = 7.6 Hz, 1H, CH), 3.57 (t, J = 6.7 Hz, 2H,
13C NMR (50 MHz, CDCl3) d: 167.6, 155.6, 150.5, 147.4 (2C), CH2), 2.78–3.01 (m, 2H, CH2), 2.56 (t, J = 6.7 Hz, 2H, CH2);
134.2, 133.9, 131.2, 130.1, 129.2, 128.7, 126.1, 117.2 (2C), 104.3 13C NMR (50 MHz, CDCl3) d: 177.6, 154.0, 151.8, 139.7, 130.2
(2C), 68.1, 56.3, 54.7, 40.9, 37.1; GC-MS: 402 (M+), 326, 308, 293, (2C), 130.1, 129.3, 126.2, 123.2, 117.9 (2C), 115.9, 63.0, 42.4, 39.2,
253. C21H22O8 requires C, 62.68; H, 5.51; found C, 62.48; 38.5. C17H18O5 requires C, 67.54; H, 6.00; found C, 67.74; H, 6.10.
H, 5.59.
3-(4-Hydroxy-3-methoxyphenyl)-3-(2-hydroxy-5-(2-
Methyl 3-(4-hydroxy-3,5-dimethylphenyl)-3-(4-methoxyphenyl)- hydroxyethyl)phenyl)propanoic acid (34). Yield 90%; colorless
propanoate (28). Yield 80 and 82%; colorless oil; 1H NMR oil; 1H NMR (CDCl3/CD3OD, 200 MHz) d: 6.59–6.86 (m, 6H,
(CDCl3, 200 MHz) d: 7.16–7.19 (d, J = 8.0 Hz, 2H, Ph-H), Ph-H), 4.70 (t, J = 7.5 Hz, 1H, CH), 3.66 (t, J = 6.6 Hz, 2H, CH2),
6.83–6.86 (m, 4H, Ph-H), 4.42 (t, J = 8.0 Hz, 1H, CH), 4.01 2.88–3.10 (m, 2H, CH2), 2.58 (t, J = 6.6 Hz, 2H, CH2); 13C NMR
(s, br, 1H, OH), 3.98 (s, 3H, OCH3), 3.61 (s, 3H, CO2CH3), 3.02 (50 MHz, CDCl3) d: 177.6, 151.7, 149.2, 143.6, 135.1, 130.1, 129.5,
(d, J = 8.0 Hz, 2H, CH2), 2.22 (6H, s, 2CH3); 13C NMR (50 MHz, 128.2, 124.7, 123.0, 117.9, 115.9 (2C), 63.0, 55.9, 42.4, 39.7, 39.5.
CDCl3) d: 172.2, 157.5, 150.3, 135.7, 134.9, 127.9 (2C), 127.1 C18H20O6 requires C, 65.05; H, 6.07; found: C, 65.25; H, 6.12.
(2C), 122.6, 113.4 (2C), 54.7, 51.2, 44.9, 40.5, 15.7, 15.6 (2C);
GC-MS: 314 (M+), 299, 281, 271, 254, 241. C19H22O4 requires C, ethyl)phenyl)propanoic acid (36). Yield 92%; colorless oil;
72.59; H, 7.05; found C, 72.37; H, 7.15.
1H NMR (CDCl3/CD3OD, 200 MHz) d: 6.58–6.95 (m, 4H, Ph-H),
4-(4-Methoxyphenyl)-6,8-dimethylchroman-2-one (29). Color- 6.43 (s, 2H, Ph-H), 4.65 (t, J = 7.5 Hz, 1H, CH), 3.75 (s, 6H,
less oil. Spectroscopic data are according to the literature.20a
2OCH3), 3.66 (t, J = 6.6 Hz, 2H, CH2), 2.87–2.96 (m, 2H, CH2),
3-(4-Hydroxy-3,5-dimethoxyphenyl)-3-(2-hydroxy-5-(2-hydroxy-
Hydrolysis of compounds (19)–(25). Dihydrocoumarin 20, 2.61 (t, J = 6.6 Hz, 2H, CH2); 13C NMR (50 MHz, CDCl3) d: 177.6,
21, 22, 23, 24 or 25 (0.2 mmol) was treated with 1 N KOH in THF 151.5, 148.4 (2C), 136.5, 133.8 (2C), 131.5, 130.1, 126.2, 124.0,
(2 mL) at room temperature. After the work-up and chromato- 115.9, 108.2 (2C), 63.0, 56.1, 42.4, 40.9, 39.2. C19H22O7 requires
graphic purification in a silica gel chromatographic column C, 62.97; H, 6.12; found: C, 63.42; H, 6.10.
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Determination of the antioxidant activity
The antioxidant activity of tyrosol 1 and compounds 30, 31, 32,
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methanol.32 This ability was expressed as Efficient Concen-
tration (EC50 = mmol of antioxidant/mmol DPPH) that is the
concentration of antioxidant needed to decrease the initial
DPPH concentration by 50%. Aliquots of methanol solution
containing different concentrations of the tested compound
expressed as the number of mmoles of antioxidant/mmol
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From these graphs the percentage of remaining DPPH at the
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