Hydroxyl substitutional effect on selective synthesis of CIS, trans stilbenes and 3-arylcoumarins through perkin condensation

Article abstract of DOI:10.1080/00397911.2010.538889

The substitutional effect in the selective synthesis of cis, trans stilbenes and 3-arylcoumarins has been described. The regio- and geometrical selectivity for synthesis of stilbene derivatives under the Perkin strategy strongly depends on the presence or absence of hydroxyl group as well as their positions in the phenyl ring. As a result, practical synthetic strategies were established for preparing various natural stilbenes including combretastatin A-4, pterostilbene, and resveratrol with satisfactory yields (49.2-63.7%). Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.538889

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Hydroxyl Substitutional Effect on
Selective Synthesis of cis, trans Stilbenes
and 3-Arylcoumarins Through Perkin
Condensation
Chun-Fen Xiao a b , Yong Zou a , Jian-Li Du a , Hong-Yi Sun a b & Xian-
Ke Liu a b
a Guangzhou Institute of Chemistry, Chinese Academy of Sciences,
Guangzhou, China
b Graduate School of Chinese Academy of Sciences, Beijing, China
Accepted author version posted online: 07 Oct 2011.Published
online: 11 Jan 2012.
To cite this article: Chun-Fen Xiao , Yong Zou , Jian-Li Du , Hong-Yi Sun & Xian-Ke Liu (2012) Hydroxyl
Substitutional Effect on Selective Synthesis of cis, trans Stilbenes and 3-Arylcoumarins Through Perkin
Condensation, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 42:9, 1243-1258, DOI: 10.1080/00397911.2010.538889
To link to this article: http://dx.doi.org/10.1080/00397911.2010.538889
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Synthetic Communications1, 42: 1243–1258, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.538889
HYDROXYL SUBSTITUTIONAL EFFECT ON
SELECTIVE SYNTHESIS OF CIS, TRANS STILBENES
AND 3-ARYLCOUMARINS THROUGH PERKIN
CONDENSATION
Chun-Fen Xiao,1,2 Yong Zou,1 Jian-Li Du,1 Hong-Yi Sun,1,2
and Xian-Ke Liu1,2
1Guangzhou Institute of Chemistry, Chinese Academy of Sciences,
Guangzhou, China
2Graduate School of Chinese Academy of Sciences, Beijing, China
GRAPHICAL ABSTRACT
Abstract The substitutional effect in the selective synthesis of cis, trans stilbenes and
3-arylcoumarins has been described. The regio- and geometrical selectivity for synthesis
of stilbene derivatives under the Perkin strategy strongly depends on the presence or absence
of hydroxyl group as well as their positions in the phenyl ring. As a result, practical
synthetic strategies were established for preparing various natural stilbenes including
combretastatin A-4, pterostilbene, and resveratrol with satisfactory yields (49.2–63.7%).
Keywords 3-Arylcoumarins; isomerization; Perkin reaction; polyphenolic stilbenes;
selectivity
Received September 23, 2009.
Address correspondence to Yong Zou, Guangzhou Institute of Chemistry, Chinese Academy of
Sciences, Guangzhou 510650, China. E-mail: zou_jinan@163.com
1243

1244
C.-F. XIAO ET AL.
INTRODUCTION
Polyphenolic stilbenes, which often exist as geometrical isomers in cis and trans
forms, have received much attention in recent years because of their great potential
of medical applications. Studies have showed that the cis-stilbenes exhibited potent
antitubulin, antivascular, and anticancer activities in various assays.[1] The typical
compound of cis-stilbene, combretastatin A-4, is regarded as the lead compound
of novel vascular disrupting agents (VDA), and its water-soluble derivative
(CA4P) has undergone phase II=III clinical trials in the United States and Europe.
Trans-stilbenes, such as resveratrol and pterostilbene, are even more renowned for
their protecting properties in various disease conditions, such as cancers,[2] heart
disease, stroke, Alzheimer disease, inflammations, and infections,[3] and they even
show antiaging effects by activating SIRT1 in various organisms.[4] 3-Arylcoumarins,
which belong to a minor class of naturally derived isoflavonoids, were scarcely
documented previously in terms of bioactivity and structure modifications.[5] These
compounds are structurally similar to classical stilbenes except for a heterocyclic ring
existing between two phenyl groups and are commonly derived via the phenylpropa-
noid pathway.[6] Recently, a few studies showed that 3-arylcoumarins, such as glycy-
coumarin, glycyrin, and asphodelin A, exerted antimicrobial, antidiabetic, anti-HIV,
antiaggregatory, and anti-inflammatory activities,[7,8] and demonstrated inhibitory
effect on horseradish peroxidase (HRP).[9]
The remarkable medical importance and the scarcity in nature of polyphenolic
stilbenes prompted studies for their synthesis. The protocols for establishing ethene
bridge between the two phenyl rings are mainly associated with diverse reactions,
such as the Wittig reaction,[10] Pd-catalyzed Heck reaction,[11] Lindlar-catalyzed
semihydrogenation,[12] Perkin condensation,[13] and Ramberg–Backlund reaction.[14]
Among them, the Perkin condensation has proved to be more convenient in terms of
procedure, yield, and cis-selectivity, and protection or deprotection of hydroxyl group
is not needed in most cases. However, when one or more free hydroxyl groups exist in
phenolic stilbenes, such as combrestatatin A-4, pterostilbene, resveratrol, and
glycyrin, previous synthetic approaches have failed to investigate the substitutional
effect of hydroxyl groups and subsequent applicability under the Perkin method-
ology. This study demonstrates the important role of hydroxyl groups in selective
synthesis of cis, trans-stilbenes and 3-arylcoumarins. Practical methodologies for
the synthesis of various stilbenoids have been established. Representative compounds,
including combretastatin A-4, pterostilbene, resveratrol, and some 3-arylcoumarins,
have been successfully synthesized with satisfactory yields (49.2–63.7%).
RESULTS AND DISCUSSION
In the course of our studies searching for the synthetic methodologies to pro-
duce stilbene derivatives,[15] some meaningful results were obtained with respect to
substitutional effect of hydroxyl group under the Perkin methodology (Scheme 1).
Conventionally, the Perkin reactions between substituted phenyl acetic acids (1a–f)
and non-ortho-hydroxylated benzaldehydes (2a–g) predominantly gave E-2,3-diaryl-
acrylic acids (3a–k) with cis relationship of phenyl rings (Table 1). However, the reac-
tion between 1a–f and ortho-hydroxylated benzaldehydes (2h–l) specifically afforded

HYDROXYL GROUP IN PERKIN REACTION
1245
Scheme 1. Substitution effects in the selective synthesis of cis, trans-stilbenes and 3-arylcoumarins through
Perkin condensation. Reagents and conditions: (a) Ac2O, Et3N, reflux; (b) Cu, quinoline, N2, reflux; (c)
10% K2CO3=H2O=C2H5OH, rt or 10%HCl=H2O=C2H5OH, 80 ꢀC.
a series of cyclic stilbenes (4a–j), namely 3-arylcoumarins, and almost no
E-2,3-diarylacrylic acids were obtained. Hydrolysis of 4a–j in the presence of HCl=
EtOH could afford phenolic products 7a–j (Table 2). In order to investigate the
relationship between the ring-closing selectivity and ortho-substitutional pattern for
benzaldehydes (2), we then transformed 2,3-dihydroxy-4-methoxybenzaldehyde (2j)
into 2,3-diacetyloxy-4-methoxybenzaldehyde (2k) and found that the Perkin conden-
sation between 1a and 2k still gave 4a as the sole product. Further, we replaced 2j with
a more inert substrate such as 2,3,4-trimethoxybenzaldehyde (2e) and finally obtained
E-2,3-diarylacrylic acids (3f) as we expected. The 3-arylcoumarins were most
probably formed from isomerization of E-2,3-diarylacrylic acids and subsequent in
situ lactonization between carboxyl group and the adjacent ortho-hydroxyl or
ortho-acetyloxyl group. Owing to the appropriate distance between the carboxyl
group and the hydroxyl=acetyloxyl group, an intramolecular cyclization occurred,
affording the six-member heterocyclic 3-arylcoumarins, which were more energeti-
cally and geometrically favorable.
The configuration of E-2,3-diarylacrylic acids (3) can be clearly elucidated by
1H NMR spectroscopy. The field effects of carboxylic group in 3a–3k result in a
remarkable downfield shift of the acrylic alkene proton, and similarly, a noticeable
field effect of carboxylic group can also be found in the adjacent 20-H in the B ring.
This can be confirmed by chemical shift of the acrylic alkene proton and the 20-H in
the B ring of the corresponding cis and trans isomers. For example, compound 3g

1246
C.-F. XIAO ET AL.
Table 1. Perkin condensations between substituted phenyl acetic acids (1a–e) and non-ortho-hydroxylated
benzaldehydes (2a–g) give E-2,3-diarylcrylic acids (3a–k) as the main products
Substrate
1
2
Producta
Yieldb (%)
Mp (ꢀC)
235–237
80
79
182–184
140–142
208–209
218–220
86.4
84
75
78
85
75
187–189
225–227
182–184
(Continued )

HYDROXYL GROUP IN PERKIN REACTION
1247
Table 1. Continued
Substrate
1
2
Producta
Yieldb (%)
Mp (ꢀC)
207–209
70
81
82
294–295
215–217
aE-2,3-diarylcrylic acids were obtained as the sole products after single crystallization. All products were
characterized by 1H NMR, IR, and MS spectra.
bIsolated yields.
showed diagnostic signals at dHa7.67 and dHb7.02 respectively, and its trans-isomer
gave corresponding signals at dHa6.84 and dHb6.87 respectively. Moreover, the
3-arylcoumarins were readily recognized by their characteristic chemical shift of
4-H, for 7f dHa ¼ 8.07 (Fig. 1), indicating the existence of a strong magnetic aniso-
tropic effect of conjugated aryl system.
In addition, geometrical selectivity can be found in the decarboxylation process
of E-2,3-diarylacrylic acids (3a–k). Results showed that the compounds 3a–d kept the
original configuration, giving cis-stilbenes (5a–d) through decarboxylation. However,
3g–k, which possesses a para-hydroxyl or para-acetyloxyl group, readily underwent cis
to trans isomerization in decarboxylation process to afford trans-stilbenes (6a–e)
(Table 3). The formation of a quinoline-induced para-quinone intermediate, which
is associated with 3g–k, was the key step for cis to trans isomerization: The intermedi-
ate underwent a rapid rotation around the single bond to give the corresponding trans-
stilbene (Fig. 2). The cis to trans isomerization process could also be found in various
conditions in recent publications,[16–19] which reinforced the point of view that the
para-hydroxyl group in phenyl rings or the subsequent para-quinone intermediates
played a key role on the geometrical selectivity for synthesis of trans-stilbenes. The
results demonstrate that the presence or absence of para-hydroxyl group in the sub-
strates is crucial for geometrical selectivity of decarboxylation reaction. However, it
is mainly for this reason that the synthesis of cis-stilbenes with a para-hydroxyl group
could not be accomplished at this stage. The configuration of cis and trans-stilbene
(5a–d, 6a–e) are previously established by coupling constant of alkene protons, that
is J(CH¼CH) ¼ 12.4 Hz for cis-stilbenes, and J(CH¼CH) ¼ 16 Hz for trans-stilbenes.[13]

1248
C.-F. XIAO ET AL.
Table 2. Perkin condensations between substituted phenyl acetic acids (1) and ortho-hydroxylated benzal-
dehydes (2h–l) selectively afford 3-arylcoumarins
Substrate
1
2
Product (4a–4f)a
Product (7a–7f)a
Yieldb (%) Mp (ꢀC)
85c
95d
187–188c
222–224d
88c
187–188c
88c
89d
154–155c
230–232d
90c
85d
200–201c
235–237d
ND
ND
80c
161–162c
82c
147–149c
(Continued )

HYDROXYL GROUP IN PERKIN REACTION
1249
Table 2. Continued
Substrate
1
2
Product (4a–4f)a
Product (7a–7f)a
Yieldb (%) Mp (ꢀC)
91c
95d
162–164c
221–223d
74c
90d
189–191c
>280d
88c
94d
236–238c
>280d
75c
91d
168–170c
>280d
76c
90.5d
204–206c
249–251d
Note. ND, not done.
aFree hydroxyl groups in reactants have been acetylated during the reaction to give 4, followed by
hydrolysis to give 7. All products were characterized by 1H NMR, IR, and MS spectra.
bIsolated yields.
cData for compound 4.
dData for compound 7.
Figure 1. Characteristic proton and chemical shift of corresponding cis, trans-stilbene and 3-arylcoumarin.

1250
C.-F. XIAO ET AL.
Table 3. Hydroxyl group induced selectivity in decarboxylation process
Substrate
Producta
Yieldb (%)
Mp (ꢀC)
71c
116–117 (lit.[13] 115–116)
69c
91–93
70.6c
Pale yellow oil
70c
75d
70d
Pale yellow oil
93–94 (lit.[20] 92–94)
122–123
65d
148–150 (lit.[21] 150–152)
60.8d
260–262 (lit.[22] 255–260)
(Continued )

HYDROXYL GROUP IN PERKIN REACTION
1251
Table 3. Continued
Substrate
Producta
Yieldb (%)
Mp (ꢀC)
184–185
67d
aAll products were characterized by 1H NMR, IR, and MS spectroscopy.
bIsolated yields.
cZ-isomer was obtained as the dominant product (Z-isomers > 95%, determined by 1H NMR) before
crystallization.
dE-isomer was the only product obtained.
Figure 2. Mechanism of decarboxylation=isomerization of E-2,3-diaryl acrylic acids, which possess a para-
hydroxyl group.
Our findings with respect to the substitutional effects on the stereoselective syn-
thesis of stilbenes utilizing the Perkin methodology have been reinforced by successful
synthesis of several representative natural stilbenes, including combretastatin A-4 (5a),
pterostilbene (6a), and resveratrol (6d) with overall yields of 56.8%, 63.7%, and 49.2%,
respectively. Moreover, the selected 3-arylcoumarin hybrids (7f–j), which bear close
structural resemblance with pterostilbene, resveratrol, oxyresverstrol, piceatannol,
and rhapontigenin, have also been synthesized through hydrolysis of 4f–j (90–95%).
Biological studies of these compounds are currently under way in our laboratory.
CONCLUSION
In conclusion, we have revealed the dramatic effect of hydroxyl groups in the
selective synthesis of polyphenolic cis-, trans-stilbenes and 3-arylcoumarins under

1252
C.-F. XIAO ET AL.
Perkin methodology. Reactions between substituted phenyl acetic acids and
non-ortho-hydroxylated benzaldehydes give E-2,3-diarylcrylic acids, whereas the
reactions between substituted phenyl acetic acids and ortho-hydroxylated benzalde-
hydes specifically afford 3-arylcoumarins. Moreover, para-hydroxyl or acetyloxy
groups in either phenyl ring of E-2,3-diarylcrylic acids will lead to an unambiguous
cis to trans isomerization in decarboxylation process, while other substrates still
dominantly afford the cis products in the same conditions. In accordance with these
findings, some scarce natural products with important medical interests, including
combretastatin A-4 (cis-stilbene), pterostilbene, resveratrol (trans-stilbene), and
3-arylcoumarins, were successfully synthesized in a straightforward and practical
manner with satisfactory yields. Our finding paves the way for large-scale synthesis
of cis- and trans-stilbenes in the future.
EXPERIMENTAL
All melting points were determined on an X-4 TaiKe melting-point apparatus
and are uncorrected. Infrared (IR) spectra were recorded on an Analect RFX-65A
1
IR spectrometer. H NMR were obtained from a Brucker DRX 400-MHz spec-
trometer with tetramethylsilane (TMS) as an internal standard. Electron impact
mass spectrometry (EIMS) analyses were performed using a Shimadzu GCMS-
QP5050A and Thermo GCMS-MAT95XP mass spectrometer. Elemental analyses
were carried out on a Elementar Vario EL element analyzer.
Preparation of E-2,3-Diaryl Acrylic Acid (3)
Triethylamine (11 ml) was added to a solution of substituted phenyl acetic acid
(1a–e, 40 mmol) and non-ortho-hydroxylated benzaldehyde (2a–g, 40 mmol) in acetic
anhydride (11 ml). The mixture was heated to 110 ꢀC and stirred for 6 h. After cool-
ing, the mixture was acidified with concentrated hydrochloric acid, poured into ice
water, stirred, and stored for 4 h. A fuscous yellowish solid was obtained, filtered,
dissolved in 10% aqueous NaOH (40 ml), washed, and discolored with ethyl acetate.
The organic layers were separated. Hydrochloric acid was added to the aqueous
phase until pH 3–4. The precipitated solid was filtered and recrystallized from ethyl
acetate to afford E-2,3-diaryl acrylic acid (3).
Compound
3a,
E-2-(3,4,5-trimethoxyphenyl)-3-(3’-hydroxyl-4’-
methoxyphenyl) acrylic acid. IR (KBr) (T%): 3342 (48), 2941 (47), 2838 (55),
2628 (62), 1672 (28), 1587 (29), 1508 (21), 1457 (37), 1409 (35), 1342 (58), 1307
(37), 1267 (12), 1238 (21), 1170 (42), 1126 (10), 1058 (68), 1024 (49), 1003 (53),
1
974 (62), 923 (64); H NMR (400 MHz, CD3COCD3) d: 3.72 (s, 6H, 3, 5-OCH3),
3.75 (s, 3H, 4-OCH3), 3.79 (s, 3H, 40-OCH3), 6.51 (s, 2H, 2,6-ArH), 6.63 (d, 1H,
J ¼ 2.0 Hz, 20-ArH), 6.71 (dd, 1H, J1 ¼ 8.4 Hz, J2 ¼ 2.0 Hz, 60-ArH), 6.81 (d, 1H,
þ
þ
0
=
J ¼ 8.4 Hz, 5 -ArH), 7.69 (s, 1H, CH ); EIMS m=z: 360(M ), 345(M -CH3).
Compound 3b, E-2-(3,5-dimethoxyphenyl)-3-(3’-hydroxyl-4’-methoxy-
phenyl) acrylic acid. IR (KBr) (T%): 3359 (57), 3012 (65), 2933 (60), 2840 (61),
2638 (66), 1673 (42), 1598 (31), 1508 (43), 1461 (53), 1446 (53), 1423 (49), 1388
(64), 1346 (67), 1297 (46), 1267 (22), 1201 (48), 1149 (35), 1060 (61), 1025 (57),

HYDROXYL GROUP IN PERKIN REACTION
1253
1
968 (67), 927 (68); H NMR (400 MHz, CDCl3) d: 3.74 (s, 6H, 3, 5-OCH3), 3.84 (s,
3H, 40-OCH3), 6.37 (d, 2H, J ¼ 2.4 Hz, 2, 6-ArH), 6.46 (t, 1H, J ¼ 2.4 Hz, 4-ArH),
6.65 (d, 1H, J ¼ 8.4 Hz, 50-ArH), 6.67 (dd, 1H, J1 ¼ 8.4 Hz, J2 ¼ 2.4 Hz, 60-ArH),
þ
0
=
6.68 (d, 1H, J ¼ 2.4 Hz, 2 -ArH), 7.78 (s, 1H, CH ); EIMS m=z: 330 (M ), 311
(Mþ-H2O), 285 (Mþ-CO2).
Compound 3g, E-2-(4-hydroxyphenyl)-3-(3’, 5’-dimethoxyphenyl) acrylic
acid. IR (KBr) (T%): 3397 (52), 3062 (57), 3016 (56), 2952 (52), 2838 (55), 1670 (22),
1590 (29), 1513 (54), 1457 (56), 1427 (37), 1382 (65), 1344 (62), 1286 (35), 1234 (48),
1
1205 (37), 1155 (38), 1060 (57), 997 (750, 929 (70), 906 (70), 865 (74), 831 (54); H
NMR (400 Hz, CD3COCD3) d: 3.56 (s, 6H, 30,50-OCH3), 6.32 (m, 3H, 20,40,60-ArH),
6.84 (d, 2H, J ¼ 8.4 Hz, 3,5-ArH), 7.02 (d, 2H, J ¼ 8.4 Hz, 2,6-ArH), 7.67 (s, 1H,
þ
þ
=
CH ); EIMS m=z: 300 (M ), 255 (M -CO2).
Compound 3i, E-2-(3-hydroxy-4-methoxyphenyl)-3-(3’,5’-dimethoxy-4’-
hydroxyphenyl) acrylic acid. IR (KBr) (T%): 3428 (37), 2940 (49), 1675 (36),
1610 (44), 1590 (44), 1511 (27), 1457 (43), 1427 (44), 1263 (23), 1236 (27), 1110
(31), 1018 (59), 985 (66), 925 (63); 1H NMR(400 Hz, CDCl3) d: 3.62 (s, 6H,
30,50-OCH3), 3.89 (s, 3H, 4-OCH3), 5.52 (s, 1H, OH), 6.39(s, 2H, 20,60-ArH), 6.75
(dd, 1H, J1 ¼ 8.0 Hz, J2 ¼ 2.0 Hz, 6-ArH), 6.86 (d, 1H, J ¼ 2.0 Hz, 2-ArH),þ6.89 (d,
þ
=
1H, J ¼ 8.0 Hz, 5-ArH), 7.77 (s, 1H, CH); EIMS m=z: 346 (M ), 302 (M -CO2).
Compound 3j, E-2-(4-hydroxyphenyl)-3-(3’,5’-dihydroxyphenyl) acrylic
acid. IR (KBr) (T%): 3419 (49), 3056 (64), 1668 (33), 1617 (52), 1593 (45), 1516
1
(56), 1429 (88), 1280 (38), 1253 (48), 1203 (54), 1176 (60), 1153 (46), 1006 (69); H
NMR (400 Hz, CD3COCD3,) d: 6.19 (d, 2H, J ¼ 2.0 Hz, 2, 6-ArH), 6.26 (t, 1H,
J ¼ 2.0 Hz, 4-ArH), 6.82 (d, 2H, J ¼ 8.4 Hz, 20,60-ArH), 7.04 (d, 2H, J ¼ 8.4 Hz,
30,50-ArH), 7.63 (s, 1H, CH), 8.27 (s, 2H, 2 ꢁ OH), 8.43 (s, 1H, OH), 10.8 (s,
=
1H, COOH); ESIMS m=z: 272 (Mþ).
Decarboxylation
A mixture of E-2,3-diacrylic acid (3) (10 mmol) and copper powder (80 mmol)
in 20 ml quinoline was stirred at 200 ꢀC for 3 h under N2 atmosphere. After cooling,
ethyl acetate was added, and the copper powder was filtered off. The filtrate was
washed with 2 M hydrochloric acid, and the water layer was extracted with ethyl
acetate. The organic layers were combined and washed with brine, dried (MgSO4),
and evaporated in vacuum to afford a brown viscous solid, which was re-extracted
with hot petroleum ether (60–90 ꢀC) and recrystallized from ethyl acetate=petroleum
ether (60–90 ꢀC) to give the product (5 or 6) as a colorless crystal.
Compound 5a, Z-3’-hydroxyl-3,4,4’,5-tetramethoxystilbene (Combre-
tastatin A-4). IR (KBr) (T%): 3424 (6), 3002 (w, 10), 2938 (9), 2836 (11), 1579
(11), 1508 (6), 1459 (15), 1419 (15), 1328 (23), 1274 (14), 1238 (11), 1182 (36),
1
1126 (4) 1025 (37), 1004 (35), 944 (56), 881 (48), 854 (47); H NMR (400 MHz,
CDCl3) d: 3.68 (s, 6H, 3, 5-OCH3), 3.84 (s, 3H, 4-OCH3), 3.89 (s, 3H, 40-OCH3),
=
=
5.49 (s, 1H, OH), 6.42 (d, 1H, J ¼ 12.4 Hz, CH ), 6.45 (d, 1H, J ¼ 12.4 Hz, CH ),
6.51 (s, 2H, 2, 6-ArH), 6.71 (d, 1H, J ¼ 8.0 Hz, 50-ArH), 6.79 (dd, 1H, J1 ¼ 8.0 Hz,

1254
C.-F. XIAO ET AL.
J2 ¼ 2.0 Hz, 60-ArH), 6.91 (d, 1H, J ¼ 2.0 Hz, 20-ArH); EIMS m=z: 316 (Mþ), 301
(Mþ-CH3). Anal. calc. for C18H20O5: C, 68.35; H, 6.33%. Found: C, 68.26; H, 6.27%.
Compound 5b, Z-3’-hydroxyl-3,4’,5-trimethoxylstilbene. IR (KBr) (T%):
3436 (10), 3073 (31), 2996 (24), 2965 (24), 2938 (24), 2839 (26), 2040 (49), 1662 (68),
1587 (6), 1514 (8), 1461 (10), 1444 (14), 1402 (28), 1344 (22), 1268 (3), 1203 (9), 1155
1
(4), 1126 (15), 1052 (13), 1024 (17), 964 (32), 924 (21), 887 (22); H NMR(400 Hz,
CDCl3) d: 3.56 (s, 6H, 3, 5-OCH3), 3.84 (s, 3H, 40-OCH3); 5.50 (s, 1H, OH), 6.30
=
(t, 1H, J ¼ 2.0 Hz, 4-ArH), 6.43 (d, 1H, J ¼ 12.4 Hz, CH), 6.44 (d, 2H, J ¼ 2.0 Hz,
0
=
3,5-ArH), 6.48 (d, 1H, J ¼ 12.4 Hz, CH), 6.69 (d, 1H, J ¼ 8.0 Hz, 5 -ArH), 6.77 (d,
1H, J ¼ 8.0 Hz, 60-ArH), 6.87 (d, 1H, J ¼ 2.0 Hz, 20-ArH); EIMS m=z: 286 (Mþ), 271
(Mþ-CH3); HREIMS m=z: 286.1197, calculated for C17H18O4: 286.1200.
Compound 6a, E-4’-hydroxy-3,5-dimethoxylstilbene (pterostilbene). IR
(KBr) (T%): 3224 (24), 2933 (32), 2830 (32), 2364 (39), 1589 (14), 1511 (30), 1454
(32), 1421 (34), 1359 (36), 1295 (34), 1238 (25), 1203 (25), 1182 (38), 1151 (18),
1
1062 (30), 964 (36); H NMR (400 MHz, CDCl3) d: 3.81 (s, 6H, 3, 5-OCH3), 6.36
(t, 1H, J ¼ 2.0 Hz, 4-ArH), 6.63 (d, 2H, J ¼ 2.0 Hz, 2, 6-ArH), 6.81 (dd, 2H,
0
0
=
J1 ¼ 8.4 Hz, J2 ¼ 2.0 Hz, 2 ,6 -ArH), 6.87 (d, 1H, J ¼ 16 Hz, CH ), 7.01 (d, 1H,
0
0
=
J ¼ 16 Hz, CH ), 7.38 (dd, 2H, J1 ¼ 8.4 Hz, J2 ¼ 2.0 Hz, 3 ,5 -ArH); EIMS m=z:
256 (Mþ); HREIMS m=z: 256.1092 calculated for C16H16O3: 256.1094.
Compound 6c, E-3’,4-dihydroxyl-3,4’,5-trimethoxystilbene. IR (KBr)
(T%): 3502 (50), 3467 (46), 3001 (65), 2937 (62), 2840 (63), 1604 (59), 1513 (35),
1462 (55), 1425 (61), 1328 (50), 1294 (57), 1271 (51), 1249 (54), 1217 (46), 1112
1
(43), 1026 (61), 964 (66); H NMR (400 MHz, CDCl3) d: 3.89 (s, 3H, 40-OCH3),
3.92 (s, 6H, 3, 5-OCH3), 5.52 (s, 1H, OH), 5.58 (s, 1H, OH), 6.69 (d, 1H, J ¼ 16 Hz
0
=
=
CH ), 6.73 (d, 1H, J ¼ 16 Hz CH ), 6.81 (d, 1H, J ¼ 8.4 Hz, 5 -ArH), 6.85 (s, 2H, 2,
6-ArH), 6.94 (dd, 1H, J1 ¼ 8.4 Hz, J2 ¼ 2.0 Hz, 60-ArH), 7.10 (d, 1H, J ¼ 2.0 Hz,
20-ArH); EIMS m=z: 302 (Mþ), 287 (Mþ-CH3); HREIMS m=z: 302.1147, calculated
for C17H18O5: 302.1149.
Compound 6d, E-3,4’,5-trihydroxylstilbene (Resveratrol). IR (KBr)
(T%): 3292 (15), 3020 (37), 1606 (29), 1587 (18), 1512 (29), 1461 (42), 1444 (38), 1384
(34), 1326 (36), 1301 (50), 1265 (45), 1247 (43), 1214 (50), 1174 (49), 1151 (23), 1107
1
(60), 1010 (46), 987 (41), 966 (38); H NMR (400MHz, CD3COCD3) d: 6.26 (t, 1H,
=
J ¼ 2.0 Hz, 4-ArH), 6.54 (d, 2H, J ¼ 2.0 Hz, 3, 5-ArH), 6.86 (d, 1H, J ¼ 16Hz, CH ),
0
0
=
6.87 (dd, 2H, J1 ¼ 8.0 Hz, J2 ¼ 4.0 Hz, 2 ,6 -ArH), 7.02 (d, 1H, J ¼ 16Hz, CH ), 7.41
(dd, 2H, J1 ¼ 8.0 Hz, J2 ¼ 4.0 Hz, 30,50-ArH), 8.21 (s, 2H, 3,5-OH, D2O exchangeable),
8.43 (s, 1H, 40-OH, D2O exchangeable); EIMS m=z: 288 (Mþ), 211, 181, 152, 115.
Preparation of 3-Arylcoumarin (4)
Triethylamine (4 ml) was added to a solution of ortho-hydroxylated benzal-
dehyde (2h–l, 10 mmol) and substituted phenyl acetic acid (1, 10 mmol) in acetic
anhydride (6 ml). The mixture was heated to 120 ꢀC and stirred for 8 h. After cooling,
it was poured into ice water, stirred, and stored for 4 h. The precipitated yellowish
solid was filtered, washed with water, dried, and recrystallized from ethyl acetate
to give the title compound.

HYDROXYL GROUP IN PERKIN REACTION
1255
Compound 4f, 7-acetyloxy-3-(3’,5’-dimethoxyphenyl) coumarin. IR
(KBr) (T%): 3064 (64), 2994 (63), 2969 (61), 2940 (60), 2840 (63), 1758 (25), 1712
(13), 1594 (23), 1461 (47), 1427 (33), 1351 (49), 1209 (12), 1153 (24), 1122 (46), 1058
1
(41), 1012 (44), 916 (52), 881 (65), 848 (45); H NMR (400 MHz, CDCl3) d: 2.32 (s,
3H, 7-OAc), 6.49 (t, 1H, J ¼ 2.0 Hz, 40-ArH), 6.80 (d, 2H, J ¼ 2.0 Hz, 20,60-ArH),
7.05 (dd, 1H, J1 ¼ 8.4 Hz, J2 ¼ 2.0 Hz, 6-H), 7.12 (d, 1H, J ¼ 2.0 Hz, 8-H), 7.51
(d, 1H, J ¼ 8.4 Hz, 5-H), 7.77 (s, 1H, 4-H); EIMS m=z: 340 (Mþ), 298 (Mþ-Ac).
Compound 4g, 7-acetoxy-3-(3’,5’-diacetoxyphenyl) coumarin. IR (KBr)
(T%): 3079 (50), 2362 (56), 1764 (25), 1724 (28), 1614 (37), 1500 (58), 1434 (49), 1369
1
(44), 1307 (55), 1201 (19), 1151 (43), 1122 (33), 1022 (42), 950 (60), 921 (51); H
NMR (400 MHz, CDCl3) d: 2.29 (s, 6H, 30,50-OAc), 2.33 (s, 3H, 7-OAc), 6.97 (t,
1H, J ¼ 2.0 Hz, 40-ArH), 7.06 (dd, 1H, J1 ¼ 8.4 Hz, J2 ¼ 2.0 Hz, 6-H), 7.13 (d, 1H,
J ¼ 2.0 Hz, 8-H), 7.36 (d, 2H, J ¼ 2.0 Hz, 20,60-ArH), 7.52 (d, 1H, J ¼ 8.4 Hz, 5-H),
7.83 (s, 1H, 4-H); EIMS m=z: 396 (Mþ), 354 (Mþ-Ac), 312 (Mþ-2Ac), 270 (Mþ-3Ac).
Compound 4h, 5,7-diacetoxy-3-(3’,5’-diacetoxyphenyl) coumarin. IR
(KBr) (T%): 3120 (64), 3087 (64), 2938 (68), 1762 (21), 1733 (25), 1614 (35), 1488
(65), 1434 (51), 1373 (43), 1297 (55), 1209 (19), 1182 (16), 1130 (28), 1101 (49),
1
1076 (46), 1024 (43), 904 (50), 858 (68); H NMR (400 MHz, CDCl3) d: 2.29 (s,
6H, 30,50-OAc), 2.31 (s, 3H, 7-OAc), 2.40 (s, 3H, 5-OAc), 6.99 (d, 2H, J ¼ 1.6 Hz,
20,60-ArH), 7.05 (t, 1H, J ¼ 1.6 Hz, 40-ArH), 7.30 (d, 2H, J ¼ 2.0 Hz, 6, 8-H), 7.78
(s, 1H, 4-H); EIMS m=z: 454 (Mþ), 412 (Mþ-Ac), 370 (Mþ-2Ac), 328 (Mþ-3Ac),
286 (Mþ-4Ac).
Compound 4i, 7,8-diacetoxy-3-(3’,5’-diacetoxyphenyl) coumarin. IR
(KBr) (T%): 3085 (56), 2940 (61), 2362 (65), 1783 (21), 1735 (18), 1612 (38), 1492
(55), 1436 (42), 1373 (30), 1322 (49), 1253 (38), 1201 (8), 1157(28), 1130 (26), 1108
(34), 1078 (42), 1052 (28), 1025 (30), 917 (43), 879 (43); 1H NMR (400 MHz, CDCl3)
d: 2.28 (s, 6H, 30,50-OAc), 2.31 (s, 3H, 8-OAc), 2.40 (s, 3H, 7-OAc), 6.98 (t, 1H,
J ¼ 2.0 Hz, 40-ArH), 7.12 (d, 1H, J ¼ 8.4 Hz, 6-H), 7.32 (d, 2H, J ¼ 2.0 Hz, 20,60-ArH),
7.39 (d, 1H, J ¼ 8.4 Hz, 5-H), 7.80 (s, 1H, 4-H); EIMS m=z: 454 (Mþ), 412 (Mþ-Ac),
370 (Mþ-2Ac), 328 (Mþ-3Ac), 286 (Mþ-4Ac).
Compound 4j, 7-methoxy-8-acetoxy-3-(3’,5’-diacetoxyphenyl) coumarin.
IR (KBr) (T%): 3093 (59), 2938 (60), 2844 (63), 2362 (66), 1772 (14), 1741 (21), 1616
(29), 1581 (48), 1506 (46), 1463 (48), 1438 (44), 1369 (38), 1324 (50), 1297 (31), 1193
1
(9), 1120 (24), 1068 (40), 1024 (37), 914 (50); H NMR (400 MHz, CD3COCD3) d:
2.27 (s, 6H, 30,50-OAc), 2.40 (s, 3H, 8-OAc), 3.94 (s, 3H, OCH3), 7.00 (t, 1H,
J ¼ 2.0 Hz, 40-ArH), 7.19 (d, 1H, J ¼ 8.8 Hz, 6-H), 7.43 (d, 2H, J ¼ 2.0 Hz, 20,60-ArH),
7.66 (d, 1H, J ¼ 8.8 Hz, 5-H), 8.199 (s, 1H, 4-H); EIMS m=z: 426 (Mþ), 384 (Mþ-Ac),
342 (Mþ-2Ac), 300 (Mþ-3Ac) (100%), 285 (Mþ-3Ac-CH3).
Preparation of Phenolic 3-Arylcoumarin (7)
Compound 4 (1.25 mmol) was added to a 10% solution of HCl (15 ml) and
ethanol (5 ml). The mixture was heated to 80 ꢀC and stirred for 5–12 h. After cooling,
it was poured into ice water, and the precipitated solid was filtered, washed with
water, dried, and recrystallized from ethanol=water to give the title compound.

1256
C.-F. XIAO ET AL.
Compound 7f, 7-hydroxy-3-(3’,5’-dimethoxyphenyl) coumarin. IR (KBr)
(T%): 3284 (36), 2958 (58), 2836 (61), 1697 (27), 1598 (26), 1571 (35), 1508 (46), 1457
(49), 1425 (56), 1346 (45), 1303 (31), 1259 (57), 1234 (56), 1199 (38), 1157 (28), 1128
1
(46), 1064 (58), 1010 (52), 952 (72), 925 (68); H NMR (400 MHz,CD3COCD3) d:
3.80 (s, 6H, 30,50-OCH3), 6.49 (t, 1H, J ¼ 2.0 Hz, 40-ArH), 6.77 (d, 1H, J ¼ 2.4 Hz,
8-H), 6.85 (dd, 1H, J1 ¼ 8.4 Hz, J2 ¼ 2.4 Hz, 6-H), 6.90 (d, 2H, J ¼ 2.4 Hz, 20,60-ArH),
7.56 (d, 1H, J ¼ 8.4 Hz, 5-H), 8.07 (s, 1H, 4-H); 13C NMR (400 MHz, CD3COCD3)
d: 55.7, 100.8, 102.8, 107.5, 113.5, 114.0, 124.1, 130.7, 138.2, 141.5, 156.3, 160.6,
161.6, 161.9; EIMS m=z: 298 (Mþ), 269.
Compound 7g, 7-hydroxy-3-(3’,5’-dihydroxyphenyl) coumarin. IR (KBr)
(T%): 3168 (W, 18), 2362 (35), 1683 (16), 1616 (12), 1571 (16), 1509 (24), 1469 (26),
1380 (34), 1326 (20), 1301 (18), 1241 (29), 1201 (27), 1160 (15), 1133 (22), 1031 (40),
1
1002 (33), 931 (42), 887 (40), 840 (28); H NMR (400 MHz, CD3COCD3) d: 6.36 (t,
1H, J ¼ 2.4 Hz, 40-ArH), 6.70 (d, 2H, J ¼ 2.4 Hz, 20,60-ArH), 6.75 (d, 1H, J ¼ 2.0 Hz,
8-H), 6.85 (dd, 1H, J1 ¼ 8.4 Hz, J2 ¼ 2.0 Hz, 6-H), 7.55 (d, 1H, J ¼ 8.4 Hz, 5-H), 7.93
(s, 1H, 4-H); 13CNMR (400 MHz, CD3COCD3) d: 102.7, 103.3, 107.9, 113.4, 114.0,
124.3, 130.6, 138.1, 1411.0, 156.1, 159.1, 160.7, 161.8; ESIMS m=z: 270.3 (Mþ), 269.2
(Mþ-H).
Compound 7h, 5,7-dihydroxy-3-(3’,5’-dihydroxyphenyl) coumarin. IR
(KBr) (T%): 3259 (w, 26), 1691 (24), 1612 (20), 1519 (39), 1482 (35), 1413 (33),
1344 (29), 1294 (31), 1253 (37), 1209 (35), 1157 (23), 1083 (37), 1039 (46), 1004
(38), 943 (51), 892 (49); 1H NMR (400 MHz, CD3COCD3) d: 6.30(d, 1H, J ¼ 2.0 Hz,
40-ArH), 6.35(d, 1H, J ¼ 2.4 Hz, 6-H), 6.37(d, 1H, J ¼ 2.4 Hz, 8-H), 6.74 (d, 2H,
J ¼ 2.0 Hz, 20,60-ArH), 8.09 (s, 1H, 4-H), 8.30(s, 2H, 30,50-OH), 9.32 (s, 1H, 5-OH),
9.63 (s, 1H, 7-OH); 13CNMR (400 MHz, CD3COCD3) d: 95.0, 99.1, 99.2, 103.7,
107.8, 108.2, 113.7, 117.2, 120.4, 122.0, 135.3, 135.8, 138.5, 156.7, 157.1, 159.1,
160.8, 162.6; ESIMS m=z: 286.2 (Mþ), 285.2 (Mþ-H), 269.2.
Compound 7i, 7,8-dihydroxy-3-(3’,5’-dihydroxyphenyl) coumarin. IR
(KBr) (T%): 3208 (W, 29), 1695 (26), 1612 (25), 1517 (48), 1467 (36), 1402 (49),
1351 (33), 1295 (41), 1263 (41), 1207 (42), 1157 (35), 1120 (43), 1083 (55), 1054
1
(49), 1004 (51), 943 (65), 836 (53); H NMR (400 MHz, CD3COCD3) d: 6.36 (t,
1H, J ¼ 2.0 Hz, 40-ArH), 6.69 (d, 2H, J ¼ 2.0 Hz, 20,60-ArH), 6.87 (d, 1H, J ¼ 8.4 Hz,
5-H), 7.10 (d, 1H, J ¼ 8.4 Hz, 6-H), 7.91 (s, 1H, 4-H); 13C NMR (400 MHz,
CD3COCD3) d: 103.3, 107.9, 113.4, 114.1, 120.2, 124.2, 132.4, 138.2, 141.6, 143.9,
149.8, 159.1, 160.3; ESIMS m=z: 286.2 (Mþ), 285.2 (Mþ-H).
Compound 7j, 7-methoxy-8-hydroxy-3-(3’,5’-dihydroxyphenyl) coumarin.
IR (KBr) (T%): 3558 (35), 3486 (33), 3261 (W, 24), 2842 (39), 1679 (22), 1604 (18),
1508 (33), 1446 (26), 1394 (40), 1342 (28), 1284 (24), 1203 (34), 1155 (28), 1126 (27),
1103 (36), 1074 (31), 1004 (37), 946 (50), 852 (41); 1H NMR (400 MHz, CD3COCD3)
d: 3.95 (s, 3H, 7-OCH3), 6.38 (t, 1H, J ¼ 2.0 Hz, 40-ArH), 6.73 (d, 2H, J ¼ 2.0 Hz,
20,60-ArH), 7.03 (d, 1H, J ¼ 8.8 Hz, 6-H), 7.20 (d, 1H, J ¼ 8.8 Hz, 5-H), 7.94 (s, 1H,
4-H), 8.33 (s, 2H, 30,50-OH), 8.34 (s, 1H, 8-OH); 13CNMR (400 MHz, CD3COCD3)
d: 55.8, 103.4, 108.0, 109.2, 115.2, 119.5, 125.2, 134.2, 138.1, 141.2, 142.9, 151.1,
159.1, 160.3; ESIMS m=z: 300.1 (Mþ), 299.0 (Mþ-H), 284.1 (Mþ-H-CH3).

HYDROXYL GROUP IN PERKIN REACTION
1257
ACKNOWLEDGMENTS
This project was supported by the Science and Technology Program of
Guangdong Province, Strategic Cooperation Program between Guangdong Province
and Chinese Academy of Sciences, and National Key Technology Research and
Development Program, China (2003B31603, 2006B35604002, 2009B091300125 and
2007BAD82B02).
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