Reductive ring opening of 3,5-bis(2-arylethenyl)isoxazoles with molybdenum hexacarbonyl: A novel route to symmetrical and unsymmetrical curcumin derivatives

Article abstract of DOI:10.13005/ojc/320113

Curcumin derivatives were successfully synthesized from 3,5-dimethylisoxazole by lateral metalation and condensation with various aromatic aldehydes sequentially at C₅- and C₃-methyl groups. After dehydration, further transformation of isoxazole ring to β-diketone moiety was accomplished by reductive ring opening using molybdenum hexacarbonyl [Mo(CO)₆] and subsequent simple acidic hydrolysis.

Full text of DOI:10.13005/ojc/320113

ISSN: 0970-020 X
CODEN: OJCHEG
2016, Vol. 32, No. (1):
Pg. 127-135
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
Reductive Ring Opening of 3,5-Bis(2-arylethenyl)isoxazoles
with Molybdenum Hexacarbonyl: A Novel Route to
Symmetrical and Unsymmetrical Curcumin Derivatives
VIwAT HAHNVAJANAwONg*,THANApHAT THAIMA,
RUCHANOk TEARAVARICH and pARINYA THERAMONgkOL
Department of Chemistry and Center for Innovation in Chemistry, Faculty of Science,
Khon Kaen University, Khon Kaen 40002, Thailand.
*Corresponding author E-mail: viwhah@kku.ac.th
http://dx.doi.org/10.13005/ojc/320113
(Received: December 04, 2015; Accepted: February 02, 2016)
ABSTRACT
Curcumin derivatives were successfully synthesized from 3,5-dimethylisoxazole by lateral
metalation and condensation with various aromatic aldehydes sequentially at C5- and C3-methyl
groups. After dehydration, further transformation of isoxazole ring to b-diketone moiety was
accomplished by reductive ring opening using molybdenum hexacarbonyl [Mo(CO)6] and subsequent
simple acidic hydrolysis.
key words : Curcumin derivatives, Reductive ring opening,
Molybdenum hexacarbonyl, Lateral metalation
INTRODUCTION
by solid-phase synthetic strategy.7 Both syntheses
proceeded through acetylacetone-boric anhydride
complex which methyl terminals of this complex were
allowed to undergo aldol condensation.
Curcumin, 1,7-bis(4-hydroxy-3-
methoxyphenyl)-1,6-heptadien-3,5-dione, is a
bioactive compound isolated from Curcuma longa
rhizomes. Curcumin has been reported to possess
antioxidant, anti-inflammatory, antitmicrobial and
anticarcinogenic activities.1 Various curcumin
derivatives have been synthesized for testing their
biological activities.Synthetic symmetrical curcumin
derivatives reported in literature2-5 were obtained
from Pabons procedure.6 Unsymmetrical curcumin
derivatives, on the other hand, were synthesized
Isoxazoles can be employed as masked
1,3-dicarbonyl compounds because reductive
cleavage of the N-O bond in isoxazoles produce
b-aminoenones which are readily transform to
their corresponding b-hydroxyenones. We have
envisioned for using this N-O bond cleavage in our
strategy for the synthesis of symmetrical as well as
a wide range of unsymmetrical curcumin derivatives

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HAHNVAJANAWONG et al., Orient. J. Chem., Vol. 32(1), 127-135 (2016)
1, i.e., using isoxazole rings of 3,5-bis(2-arylethenyl) an additional1 hour. A solution of aromatic aldehyde
isoxazoles 2 as masked 1,3-dicarbonyl moieties of (30.0 mmol) in THF (6 ml) was then added. The
curcumin derivatives 1 (Scheme 1). The synthetic resulting mixture was allowed to warm up to room
direction to obtain 2 involves transformation of methyl temperature and treated with water.The phases were
groups of 3,5-dimethylisoxazole (5) into 2-aryl-2- separated and the aqueous layer was extracted with
hydroxyethyl groups sequentially at C5 and C3 to ethyl acetate (3x120 ml).The combined organic layer
get 5-(2-aryl-2-hydroxyethyl)-3-methylisoxazoles was dried (Na2SO4) and concentrated under reduce
4 and 3,5-bis(2-aryl-2-hydroxyethyl)isoxazoles 3 pressure. Purification of the residue using column
respectively. Subsequent dehydration of3,5-bis(2- chromatography on silica gel with a gradient of 10-
aryl-2-hydroxyethyl)isoxazoles 3 provides the route 50% ethyl acetate in hexane as eluent gave 5-(2-aryl-
to 3,5-bisstyrylisoxazoles 2.
2-hydroxyethyl)-3-methylisoxazoles 4a-c (70-84%)
as yellow oils or as white crystalline solids.
Experimental Section
general
5-(2-phenyl-2-hydroxyethyl)-3-methylisoxazole
Melting points were determined by usinga (4a)
Sanyo Gallenkamp melting point apparatus and are
Yield: 4.69 g (77%); yellow oil; IR (thin
uncorrected. IR spectra were taken with a Perkin film) nmax: 3370, 3031, 2931, 1604, 1493, 1450,
Elmer Spectrum One FT-IR Spectrometer. 1H and 1415,1051, 742, 700 cm-1; 1H NMR (CDCl3, 400 MHz)
13C NMR spectra were recorded using a VARIAN d: 7.33-7.20 (5H, m, ArH), 5.80 (1H, s, =CH), 4.96
MERCURY plus (400 MHz FT NMR).
(1H, dd, J = 8.2 and 5.1 Hz, OCH ), 3.10 (1H, dd, J
= 15.2 and 8.2 Hz, HCH), 3.01 (1H, dd, J = 15.2 and
n-BuLi and s-BuLi were prepared and 5.0 Hz, HCH), 2.12 (3H, s, CH3);13C NMR (CDCl3) d:
their concentration were determined following the 11.3, 36.6, 72.1, 103.4, 125.7, 128.0, 128.6, 143.0,
standard procedure.8,9
159.8, 169.6.
preparation of 3,5-dimethylisoxazole (5)10
[2-(4-Methoxyphenyl)-2-hydroxyethyl]-3-
A solution of hydroxylamine hydrochloride methylisoxazole (4b)
(8.34 g, 0.12 mole) in water (10 ml) was added a
solution of 2,4-pentanedione (6) (10.2 g, 0.1 mole) in
Yield: 4.90 g (70%); yellow oil; IR (thin film)
nmax: 3376, 2934, 2838, 1608, 1513, 1416, 1246,
ethanol (10 ml).The mixture was heated under reflux 1177, 1032, 833 cm-1; 1H NMR (CDCl3, 400 MHz) d:
temperature for 3 hours, then allowed to cool to room 7.21 (2H, d, J = 8.7 Hz, ArH), 6.82 (2H, d, J = 8.6 Hz,
temperature and poured into cold water (60 ml). The ArH), 5.80 (1H, s, =CH), 4.92 (1H, dd, J = 8.0 and
resulting mixture was extracted with ether (3x40 ml). 5.4 Hz, OCH), 3.74 (3H, s, OCH3), 3.10 (1H, dd, J =
The combined organic layer was dried (Na2SO4) and 15.2 and 8.1 Hz, HCH), 2.99 (1H, dd, J = 15.2 and
evaporated to dryness under reduced pressure. The 5.3 Hz, HCH), 2.15 (3H, s, CH3); 13C NMR (CDCl3)
brown oily residue was purified by distilling under d: 11.2, 36.5, 55.2, 71.4, 103.2, 113.8, 127.0, 135.4,
reduce pressure to give 3,5-dimethylisoxazole (5) 159.1, 159.7, 169.9.
(8.10g, 82%) as a colourless liquid (bp 85- 86 °C [2-(3,4-Dimethoxyphenyl)-2-hydroxyethyl]-3-
at 150 mmHg);IR (thin film) nmax: 3132, 2934, 1611, methylisoxazole (4c)
1
1455, 1414, 1258, 1011, 886, 795 cm-1; H NMR
Yield: 6.63 g (84%); white crystals; mp 63-
(CDCl3, 400 MHz) d: 5.82 (1H, s, H-4), 2.36 (3H, s, 64 °C; IR (thin film) nmax: 3382, 2936, 1603, 1513,
1
C=CCH3), 2.23 (3H, s, N=CCH3); 13C NMR (CDCl3) 1416, 1260, 1233, 1137, 1023, 809, 763 cm-1; H
d: 11.3, 12.1, 102.3, 159.9, 169.1.
NMR (CDCl3, 400 MHz) d: 6.90-6.78 (3H, m, ArH),
5.83 (1H, s, =CH), 4.98 (1H, m, OCH), 3.83 (6H, s,
general procedure for preparation of 5-(2-aryl-2- 2xOCH3), 3.14 (1H, dd, J = 15.1 and 8.2 Hz, HCH),
hydroxyethyl)-3-methylisoxazoles 4a-c 3.04 (1H, dd, J = 15.1 and 5.1 Hz, HCH), 2.20 (3H,
To a stirred solution of 3,5-dimethylisoxazole s, CH3); 13C NMR (CDCl3) d: 11.3, 36.7, 55.9, 71.7,
(5) (2.91 g, 30.0 mmol) in dryTHF (60 ml) was added 103.5, 109.1, 111.2, 118.1, 136.1, 148.6 149.1,
n-BuLi (1.0 M in hexane;30 ml, 30.0 mmol) dropwise 160.0, 170.0.
under N2 at -78 °C and the mixture was stirred for

HAHNVAJANAWONG et al., Orient. J. Chem., Vol. 32(1), 127-135 (2016)
129
general procedure for preparation of 3,5-bis(2-
aryl-2-hydroxyethyl)isoxazoles 3a-f
36.6, 55.3, 71.7, 72.1, 103.3, 113.9, 114.0, 127.0,
127.1, 135.1, 135.4, 159.2, 159.4, 161.4, 169.9.
To a solution of 5-(2-aryl-2-hydroxyethyl)-
3-methylisoxazole(4.0 mmol) in THF (20 ml) was
added s-BuLi (1.0 M in hexane, 10.0 ml, 10.0 mmol)
dropwise under N2 at -78 °C. After being stirred at
-78 °C for 1 hour, a solution of aromatic aldehyde
(5.0 mmol) in THF (2 ml) was then added. The
reaction mixture was allowed to warm up to room
temperature and treated with water. The phases
were separated and the aqueous layer was extracted
with ethyl acetate (3 x 50 ml).The combined organic
layer was dried (Na2SO4) and concentrated under
reduced pressure. Purification of the residue using
column chromatography on silica gel with agradient
of 30-70% ethyl acetate in hexane as an eluent
gave3,5-bis(2-aryl-2-hydroxyethyl)isoxazoles 3a-f
(46-65%) as crystalline solids or as oils.
3,5-Bis[2-(3,4-dimethoxyphenyl)-2-hydroxyethyl]
isoxazole (3c)
Yield: 1.12 g (65%); yellow crystals; mp
89-91 °C;IR (thin film) nmax:3384, 2937, 1599, 1513,
1
1420, 1260, 1138, 1022, 811, 762 cm-1; H NMR
(CDCl3, 400 MHz) d: 6.89 (1H, s, ArH), 6.85 (1H, s,
ArH), 6.84-6.74 (4H, m, ArH), 5.90 and 5.87 (1H,
2s, =CH), 4.93-4.81 (2H, m, 2"- and 2'-OCH), 3.81
and 3.80 (12H, 2s, 4xOCH3), 3.08 (1H, d d, J = 15.2
and 8.7 Hz, 1"-HCH), 3.03-2.86 (3H, m, 1"-HCH and
1'-CH2);13C NMR (CDCl3) d: 36.0, 36.8, 55.8, 55.9,
71.7, 72.3, 103.3, 108.9, 109.1, 111.0, 117.9, 118.0,
135.8, 136.0, 148.4, 148.5, 148.9, 161.4, 169.9.
3-[2-p henyl-2-hydroxyethyl]-5-(2-(4-
methoxyphenyl)-2-hydroxyethyl)isoxazole (3d)
Yield: 0.77 g (57%); brown crystals; mp
3,5-bis(2-phenyl-2-hydroxyethyl)isoxazole (3a)
Yield: 0.59 g (48%); white crystals; mp 97-
63-64°C; IR (thin film) nmax: 3365, 2896, 1606, 1513,
1437, 1246, 1176, 833, 701 cm-1; 1H NMR (CDCl3,
400 MHz) d: 7.34-7.20 (5H, m, ArH), 7.16 (2H, d, J
= 8.7 Hz, ArH), 6.80 (2H, d, J = 8.7 Hz, ArH), 5.85
and 5.84 (1H, 2s, =CH), 4.91-4.80 (2H, m, 2"-and
2'-OCH), 3.72 (3H, s, OCH3), 3.03 (1H, dd,J = 15.2
and 8.6 Hz, 1"-HCH), 2.99-2.83 (3H, m, 1"-HCH
and 1'-CH2); 13C NMR (CDCl3) d: 36.2, 36.6, 55.3,
71.8, 72.5, 103.3, 114.0, 125.8, 127.0, 127.8, 128.5,
135.0, 143.2, 159.4, 161.3, 169.9.
98°C; IR (thin film) nmax: 3377, 3031, 1601, 1428,
1
1052, 754, 700 cm-1; H NMR (CDCl3, 400 MHz)
d: 7.38-7.16 (10H, m, ArH), 5.89 and 5.88 (1H, 2s,
=CH), 5.03-4.84 (2H, m, 2"-and2'-OCH), 3.09 (1H,
dd,J= 15.2 and 8.7 Hz, 1"-HCH), 3.02 (1H, dd, J =
15.2 and 4.6 Hz, 1"-HCH), 2.98-2.89 (2H, m, 1'-CH2);
13C NMR (CDCl3) d: 36.0, 36.7, 71.9, 72.4, 103.3,
125.7, 125.8, 127.8, 128.0, 128.5, 128.6 , 142.9,
143.2, 161.4, 169.9.
3,5-Bis(2-(4-methoxyphenyl)-2-hydroxyethyl)
isoxazole (3b)
3-[2-phenyl-2-hydroxyethyl]-5-(2-(3,4-
dimethoxyphenyl)-2-hydroxyethyl)
isoxazole (3 e)
Yield: 0.72 g (49 %); white crystals; mp 97-
99 °C; IR (thin film) nmax: 3377, 2957, 1608, 1514,
1253, 1175, 1033, 825 cm-1; 1H NMR (CDCl3, 400
MHz) d:7.27 (4H, d, J = 8.4 Hz, ArH), 6.88 (4H, d, J =
8.4 Hz, ArH) 5.88 and 5.87 (1H, 2s, =CH), 5.03-4.91
(2H, m, 2"- and 2'-OCH), 3.80 (6H, s, 2xOCH3), 3.16
(1H, dd, J = 15.2 and 8.4 Hz, 1"-HCH),3.10-2.92 (3H,
m, 1"-HCH and 1'-CH2); 13C NMR (CDCl3) d: 36.1,
Yield: 0.75 g (51%); yellow oil; IR (thin film)
n
max: 3381, 2938, 1600, 1514, 1421, 1260, 1138,
1022, 810, 760, 701 cm-1; 1H NMR (CDCl3, 400 MHz)
d: 7.33-7.19 (5H, m, ArH), 6.84 (1H, s, ArH), 6.80
(1H, d, J = 8.5 Hz, ArH), 6.76 (1H, d, J = 8.2 Hz,
ArH), 5.87 and 5.85 (1H, 2s, =CH), 4.92-4.84 (2H,
m, 2"- and 2'-OCH), 3.80 and 3.79 (6H, 2s, 2xOCH3)
3.07 (1H, dd, J = 15.1, 8.7 Hz, 1"-HCH), 3.02-2.86
(3H, m, 1'-HCH and 1'-CH2);13C NMR (CDCl3) d:
35.9, 36.7, 55.8, 71.6, 72.4, 103.2, 108.9, 111.0,
O
O
NH2OH.HCl
EtOH/H2O
reflux 3 h
O
N
6
5; 82%
1
2
2
1
2
1
Ar
1
Ar
Ar Ar
Ar Ar
Ar
O
N
O
N
OH
O
N
OH
O
N
OH
OH
O
5
1
4
2
3
Scheme 1:

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HAHNVAJANAWONG et al., Orient. J. Chem., Vol. 32(1), 127-135 (2016)
117.9, 125.7, 127.7, 128.4, 135.7, 143.2, 148.5, =CH); 13C NMR (CDCl3) d:98.5, 113.0, 116.1, 127.0,
148.9, 161.3, 169.9.
127.1, 128.9, 129.2, 134.9, 135.5, 135.8, 162.0,
168.3.
3-[2-(4-Methoxyphenyl)-2-hydroxyethyl]-5-(2-
(3,4-dimethoxyphenyl)-2-hydroxyethyl) isoxazole 3,5-Bis(2-(4-methoxyphenyl)ethenyl)isoxazole
(3f) (2b)
Yield: 0.74 g (46%); green crystals; mp
Yield:0.20 g (61%);yellow crystals;mp 194-
76-77°C; IR (thin film) nmax: 3383, 2935, 1604, 1513, 196 °C (lit.11 180-181 °C); IR (thin film) nmax: 2934,
1
1421, 1238, 1139, 1024, 811, 763 cm-1; H NMR 1644, 1604, 1577, 1512, 1431, 1257, 1175, 1029,
(CDCl3, 400 MHz) d: 7.21 (2H, d, J = 8.2 Hz, ArH), 967, 823, 753 cm-1; 1H NMR (CDCl3, 400 MHz) d:7.48
6.85 (1H, s, ArH), 6.84-6.79 (3H, m,ArH), 6.77 (1H, (4H, d, J = 8.7 Hz, ArH), 7.31 (1H, d, J = 16.4 Hz,
d, J = 8.2 Hz, ArH), 5.89 and 5.86 (1H, 2s, =CH), Ar1CH=CH-), 7.13 (1H, d, J = 16.5 Hz, Ar2CH=CH-),
4.93-4.80 (2H, m, 2"- and 2'-OCH), 3.82 and 3.81 7.00 (1H, d, J = 16.5 Hz, Ar2CH=CH-), 6.92 (4H, d, J
(6H, 2s, 2xOCH3), 3.75 (3H, s, OCH3), 3.08 (1H, dd, = 8.5 Hz, ArH), 6.83 (1H, d, J = 16.4 Hz, Ar1CH=CH-),
J = 15.2 and 8.7 Hz, 1"-HCH), 3.03- 2.85 (3 H, m, 6.43 (1H, s, =CH), 3.84 (6H, s, 2xOCH3);13C NMR
1"-HCH and 1'-CH2);13C NMR (CDCl3) d: 35.9, 36.7, (CDCl3) d: 55.4, 97.7, 111.0 114.0, 114.3, 128.3,
55.2, 55.8, 55.9, 71.7, 72.1, 103.2, 108.9, 111.0, 128.6, 128.7, 134.4, 135.2, 160.2, 160.5, 162.2,
113.8, 117.9, 127.0, 135.4, 135.8, 148.5, 149.0, 168.5.
159.1, 161.4, 169.9.
general procedure for dehydration of 3,5-Bis(2- 3,5-Bis[2-(3,4-dimethoxyphenyl)ethenyl]
aryl-2-hydroxyethyl) isoxazoles 3a-f
isoxazole (2c)
Yield:0.22 g (56%);white crystals;mp 169-
A mixture of 3,5-bis(2-aryl-2-hydroxyethyl)
isoxazole (1.0 mmol), P2O5 (0.4 mmol) in benzene 171 °C (lit.11 159-160 °C); IR (thin film) nmax: 2937,
(5 ml) was heated under reflux temperature for 2 1644, 1584, 1561, 1512, 1428, 1264, 1139, 1024,
hours. The benzene layer was decanted and the 963, 805, 735 cm-1;1H NMR (CDCl3, 400 MHz) d:7.22
residue was washed once with hot benzene. The (1H, d, J = 16.4 Hz, Ar1CH=CH-), 7.09-6.93 (6H, m,
combined benzene layer was washed with water, ArH, Ar2CH=CH- and Ar2CH=CH-), 6.83 - 6.73 (3H,
dried (Na2SO4) and concentrated under reduced m, ArH and Ar1CH=CH-), 6.36 (1H, s, =CH), 3.90
pressure. The residue was purified using column and 3.89 (6H, 2s, 2xOCH3), 3.86 and 3.85 (6H, 2s,
chromatography on silica gel with CH2Cl2 as eluent 2xOCH3); 13C NMR (CDCl3) d: 55.8, 97.8, 108.8,
to give 5-(2-arylethenyl)-3-methylisoxazoles 2a-f 109.1, 110.0, 111.1, 113.9, 120.9, 121.0, 128.5,
(52-66%) as crystalline solids.
128.8, 134.5, 135.4, 149.1, 149.8, 150.1, 162.1,
168.4.
3,5-Bis(2-Phenylethenyl) isoxazole (2a)
Yield:0.18 g (66%);white crystals;mp 186- 5-(2-(4-Methoxyphenyl)ethenyl)-3-[2-
187°C; IR (thin film) nmax:3033, 1644, 1579, 1559, phenylethenyl] isoxazole (2d)
1
1429, 1292, 960, 751, 693 cm-1; H NMR (CDCl3,
Yield: 0.18 g (60%); yellow crystals; mp
400 MHz) d: 7.56-7.48 (4H, m, ArH), 7.42-7.29 (7H, 155-156°C; IR (thin film) nmax: 3035, 2928, 1643,
m, ArH and Ar1CH=CH-), 7.19 (1H, d, J = 16.6 Hz, 1603, 1509, 1430, 1254, 1173, 1032, 963, 822, 754,
1
Ar2CH=CH-), 7.13 (1H, d, J = 16.5 Hz, Ar2CH=CH-), 695 cm-1; H NMR (CDCl3, 400 MHz) d: 7.53 (2H,
6.96 (1H, d, J = 16.4 Hz, Ar1CH=CH-), 6.49 (1H, s, d, J = 7.2 Hz, ArH), 7.47 (2H, d, J = 8.7 Hz, ArH),
Ar1
1. n-BuLi, -78 oC
2. Ar1CHO
O N
O N
OH
7a-c
5
4a; Ar1 = C6H5, 77%
4b; Ar1 = 4-OMeC6H4, 70%
4c; Ar1 = 3,4-diOMeC6H3, 84%
Scheme 2:

HAHNVAJANAWONG et al., Orient. J. Chem., Vol. 32(1), 127-135 (2016)
131
7.42-7.28 (4H, m, ArH and Ar1CH=CH-), 7.18 (1H,
d, J = 16.6 Hz, Ar2CH=CH-), 7.13 (1H, d, J = 16.5
Hz, Ar2CH=CH-), 6.92 (2H, d, J = 8.7 Hz, ArH), 6.83
(1H, d, J = 16.4 Hz, Ar1CH=CH-), 6.44 (1H, s, =CH),
3.84 (3H, s, OCH3); 13C NMR (CDCl3) d: 55.4, 97.7,
110.9, 114.3, 116.2, 127.0, 128.3, 128.6, 128.8,
135.5, 135.6, 135.9, 160.5, 162.0, 168.7.
gel with 30% ethyl acetate/ hexane as an eluent
gave1,7-diaryl-5-amino-1,4,6-heptatrien-3-ones 8a-f
(43-56%) as yellow crystalline solids or as yellow
oils.
5-Amino-1,7-diphenylhepta-1,4,6-trien-3-one
(8a)
Yield: 61.5 mg (56%); yellow crystals; mp
145-147°C; IR (thin film) nmax: 3388, 3196, 1634,
1
5-(2-(3,4-Dimethoxyphenyl)ethenyl)-3-[2-
phenylethenyl]isoxazole (2e)
1570, 1519, 1149, 966, 754, 694 cm-1; H NMR
(CDCl3, 400 MHz) d: 7.60-7.54 (3H, m, ArH and
Ar1CH=CH-), 7.49 (2H, d, J = 7.1 Hz, ArH) 7.41-7.30
(6H, m, ArH), 7.11 (1H, d, J = 16.4 Hz, Ar2CH=CH-),
6.79 (1H, d, J = 15.9 Hz, Ar2CH=CH-), 6.53 (1H, d,
J = 16.4 Hz, Ar1CH=CH-), 5.53 (1H, s, =CHCO); 13C
NMR (CDCl3) d: 98.7, 124.8, 127.4, 127.9, 128.6,
128.8, 129.0, 129.4, 129.5, 134.5,135.2, 135.7,
138.7, 157.7, 188.4.
Yield: 0.19 g (58%); white crystals; mp
153-154 °C; IR (thin film) nmax: 2936, 1644, 1583,
1561, 1513, 1433, 1269, 1140, 1025, 964, 754,
1
697 cm-1; H NMR (CDCl3, 400 MHz) d:7.47 (2H,
d, J = 7.5 Hz, ArH), 7.39-7.28 (3H, m, ArH), 7.25
(1H, d, J = 16.4 Hz, Ar1CH=CH-), 7.13 (1H, d, J
= 16.6 Hz, Ar2CH=CH-), 7.08 (1H, d, J = 16.6 Hz,
Ar2CH=CH-), 7.05-6.98 (2H, m, ArH), 6.78 (2H, m,
ArH and Ar1CH=CH-), 6.39 (1H, s, =CH), 3.90 (3H,
s, OCH3), 3.85 (3H, s, OCH3); 13C NMR (CDCl3) d:
55.8, 55.9, 97.9, 109.1, 111.0, 111.2, 116.1, 121.1,
126.9, 128.5, 128.8, 134.7, 135.6, 135.8, 149.2,
150.1, 161.9, 168.5.
5-Amino-1,7-bis(4-methoxyphenyl)-1,4,6-
heptatrien-3-one (8b)
Yield: 66.8 mg (50%); yellow crystals; mp
158-160°C; IR (thin film) nmax: 3393, 3006, 1630,
1601, 1565, 1515, 1256, 1174, 754 cm-1; 1H NMR
(CDCl3, 400 MHz) d: 7.56-7.47 (3H, m, ArH and
Ar1CH=CH-), 7.43 (2H, d, J = 8.5 Hz, ArH), 7.05 (1H,
d, J = 16.3 Hz, Ar2CH=CH-), 6.93-6.86 (4H, m, ArH),
6.66 (1H, d, J = 15.8 Hz, Ar2CH=CH-), 6.39 (1H, d, J
= 16.3 Hz, Ar1CH=CH-), 5.47 (1H, s, =CHCO), 3.83
(6H, s, 2xOCH3);13C NMR (CDCl3) d:55.3, 55.4, 98.4,
114.2, 114.4, 122.4, 126.6, 128.0, 128.5, 128.8,
129.4, 134.0, 138.2, 158.1, 160.7, 188.3.
5-(2-(3,4-Dimethoxyphenyl)ethenyl)-3-[2-(4-
methoxyphenyl)ethenyl] isoxazole (2f)
Yield: 0.19 g (52%); white crystals; mp
169-171 °C; IR (thin film) n max: 2962, 1643, 1603,
1581, 1512, 1430, 1264, 1174, 1140, 1026, 965,
821, 750 cm-1; 1H NMR (CDCl3, 400 MHz) d: 7.45
(2H, d, J = 8.6 Hz, ArH), 7.27 (1H, d, J = 16.4 Hz,
Ar1CH=CH-), 7.10 (1H, d, J = 16.6 Hz, Ar2CH=CH-),
7.05 (2H, d, J = 7.7 Hz, ArH), 6.98 (1H, d, J = 16.4
Hz, Ar2CH=CH-), 6.93-6.84 (3H, m, ArH), 6.81 (1H,
d, J = 16.4 Hz, Ar1CH=CH-), 6.40 (1H, s, =CH),
3.93(3H, s, OCH3), 3. 90 (3H, s, OCH3), 3.82 (3H, s,
OCH3);13C NMR (CDCl3) d: 55.3, 55.9, 97.8, 109.1,
111.1, 111.2, 113.9, 114.3, 121.1, 128.3, 128.6,
134.6, 135.2, 149.2, 150.2, 160.2, 162.2, 168.4.
5-Amino-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-
heptatrien-3-one (8c)
Yield: 76.2 mg (48%); yellow oil; IR (thin
film) nmax:3417, 2937, 1629, 1587, 1513, 1461, 1263,
1139, 1024, 758 cm-1; 1H NMR (CDCl3, 400 MHz)
d: 7.51 (1H, d, J = 15.7 Hz, Ar1CH=CH-), 7.14-7.01
(5H, m, ArH and Ar2CH=CH-), 6.85 (2H, d, J = 8.3
Hz, ArH), 6.67 (1H, d, J = 15.8 Hz, Ar2CH=CH-),
6.39 (1H, d, J = 16.3 Hz, Ar1CH=CH-), 5.52 (1H, s,
=CHCO),3.92 and 3.90 (12H, 2s, 4xOCH3);13C NMR
(CDCl3) d: 55.9, 56.0, 98.3, 109.3, 109.7, 111.1,
111.2, 121.5, 122.2, 122.6, 126.7, 128.3, 128.8,
134.4, 138.5, 149.1, 149.3, 150.4, 158.1, 188.2.
general procedure for reductive ring opening of
3,5-bis(2-arylethenyl) isoxazoles 2a-f
A solution of a 3,5-bis(2-arylethenyl)
isoxazole (0.4 mmol), water (0.4 mmol) and
[Mo(CO)6] (0.2 mmol) in acetonitrile (8 ml) was
heated under reflux temperature for 24 hours and
cooled to room temperature. The reaction mixture
was filtered through Celite and evaporated to
dryness under reduced pressure. Purification of
the residue using column chromatography on silica
5-Amino-1-(4-methoxyphenyl)-7-phenyl-1,4,6-
heptatrien-3-one (8d)
Yield: 66.0 mg (54%); yellow crystals; mp
161-162 °C; IR (thin film) nmax: 3364, 3008, 1631,

132
HAHNVAJANAWONG et al., Orient. J. Chem., Vol. 32(1), 127-135 (2016)
1602, 1564, 1515, 1256, 1145, 752 cm-1; 1H NMR 5-Amino-1-(3,4-dimethoxyphenyl)-7-(4-
(CDCl3, 400 MHz) d: 7.56-7.45 (5H, m, ArH and methoxyphenyl)-1,4,6-heptatrien-3-one (8f)
Ar1CH=CH-), 7.42-7.29 (3H, m, ArH), 7.09 (1H, d, J
= 16.4 Hz, Ar2CH=CH-), 6.88 (2H, d, J = 8.4 Hz, ArH),
Yield:62.7 mg (43%);yellow oil;IR (thin film)
max:3394, 2964, 1597, 1514, 1262, 1141, 1027, 755
n
6.67 (1H, d, J = 15.8 Hz, Ar2CH=CH-), 6.51 (1H, d,J cm-1; 1H NMR (CDCl3, 400 MHz) d: 7.51 (1H, d, J =
= 16.4 Hz, Ar1CH=CH-), 5.49 (1H, s, =CHCO), 3.81 15.7 Hz, Ar1CH=CH-), 7.43 (2H, d, J = 8.6 Hz, ArH),
(3H, s, OCH3); 13C NMR (CDCl3) d:55.3, 98.8, 114.2, 7.15-7.02 (3H, m, ArH and Ar2CH=CH-), 6.92-6.82
124.9, 126.5, 127.3, 128.4, 128.9, 129.3, 129.5, (3H, m,ArH), 6.67 (1H, d, J = 15.7 Hz, Ar2CH=CH-),
134.3, 135.3, 138.5, 157.5, 160.8, 188.6.
6.39 (1H, d, J = 16.3 Hz, Ar1CH=CH-), 5.50 (1H, s,
=CHCO), 3.92 (3H, s, OCH3), 3.90 (3 H, s, OCH3),
5-Amino-1-(3,4-dimethoxyphenyl)-7-phenyl-1,4,6- 3.83 (3H, s, OCH3); 13C NMR (CDCl3) d:55.3, 55.9,
heptatrien-3-one (8e)
98.1, 109.7, 111.1, 114.4, 122.2, 122.3, 126.9, 128.0,
Yield:62.6mg (47%);yellow oil;IR (thin film) 128.8, 134.2, 138.4, 149.1, 150.4, 158.3, 160.7,
max:3395, 2959, 1631, 1575, 1516, 1264, 1139, 756 188.1.
n
cm-1; 1H NMR (CDCl3, 400 MHz) d:7.55-7.47 (3H, m,
ArH and Ar1CH=CH-), 7.41-7.31 (3H, m, ArH), 7.14- general procedure for hydrolysis of 5-amino-1,7-
7.08 (3H, m, ArH and Ar2CH=CH-), 6.85 (1H, d, J = diaryl-1,4,6-heptatrien-3-ones 8a-f
8.3 Hz, ArH), 6.68 (1H, d, J = 15.8 Hz, Ar2CH=CH-),
To a stirred solution of 5-amino-1-aryl-
6.52 (2H, d, J = 16.4 Hz, Ar1CH=CH-), 5.53 (1H, s, 1,4-hexadien-3-one (0.1 mmol) in ethanol (1.5 ml)
=CHCO),3.92(3H, s, OCH3), 3.90 (3H, s, OCH3); 13C was added concentrated HCl dropwise to adjust
NMR (CDCl3) d:55.9, 56.0, 98.6, 109.8, 111.2, 122.2, the pH between 4 and 5. The solution was then
124.9, 126.7, 127.3, 128.7, 128.9, 129.4, 134.3, stirred at 50°C. After 24 hours,the reaction mixture
135.3, 138.7, 149.2, 150.5, 157.5, 188.5.
was neutralized with a saturated K2CO3 solution.
1'
1''
Ar1
Ar2
OH
Ar1
2'
2''
1. s-BuLi 2 eq, -78 oC
O N
2. Ar2CHO
OH
O N
OH
7a-c
4a-c
3a; Ar1 = C6H5, Ar2 = C6H5, 48%
3b; Ar1 = 4-OMeC6H4, Ar2 = 4-OMeC6H4, 49%
3c; Ar1 = 3,4-diOMeC6H3, Ar2 = 3,4-diOMeC6H3, 65%
3d; Ar1 = 4-OMeC6H4, Ar2 = C6H5, 57%
3e; Ar1 = 3,4-diOMeC6H3, Ar2 = C6H5, 51%
3f; Ar1 = 3,4-diOMeC6H3, Ar2 = 4-OMeC6H4, 46%
Scheme 3:
1'
1''
Ar2
OH
Ar2
P2O5
2'
Ar1
Ar1
2''
benzene
reflux, 24h
O N
O N
OH
3a-f
2a; Ar1 = C6H5, Ar2 = C6H5, 66%
2b; Ar1 = 4-OMeC6H4, Ar2 = 4-OMeC6H4, 61%
2c; Ar1 = 3,4-diOMeC6H3, Ar2 = 3,4-diOMeC6H3, 56%
2d; Ar1 = 4-OMeC6H4, Ar2 = C6H5, 60%
2e; Ar1 = 3,4-diOMeC6H3, Ar2 = C6H5, 58%
2f; Ar1 = 3,4-diOMeC6H3, Ar2 = 4-OMeC6H4, 52%
Scheme 4:

HAHNVAJANAWONG et al., Orient. J. Chem., Vol. 32(1), 127-135 (2016)
133
The aqueous layer was extracted with diethyl ether
(3 × 25 mL). The combined organic layer was
dried (Na2SO4) and concentrated under reduce
pressure. Purification of the residue using column
chromatography on silica gel with a gradient of
30-50% ethyl acetate/hexane as eluent gave 1-aryl-
5-hydroxy-1,4-hexadien-3-ones 1a-f (48-63%) as
crystalline solids.
1628, 1600, 1574, 1512, 1461, 1253, 1173, 1138,
1
1031, 974, 828 cm-1; H NMR (CDCl3, 400 MHz)
d: 7.62 (2H, d, J = 15.8 Hz, Ar1CH=CH- and
Ar2CH=CH-), 7.50 (4H, d, J = 8.7 Hz, ArH), 6.91
(4H, d, J = 8.7 Hz, ArH), 6.49 (2H, d, J = 15.8 Hz,
Ar2CH=CH- and Ar1CH=CH-), 5.78 (1H, s, =CHCO),
3.84 (6H, s, 2xOCH3); 13C NMR (CDCl3) d: 55.4,
101.3, 114.4, 121.8, 127.8, 129.8, 140.1, 161.3,
183.3.
5-Hydroxy-1,7-diphenylhepta-1,4,6-trien-3-one
(1a)
5-Hydroxy-1,7-Bis(3,4-dimethoxyphenyl)-1,4,6-
heptatrien-3-one (1c)
Yield: 14.4 mg (52%); yellow crystals; mp
146-148°C; IR (thin film) nmax: 3057, 1627, 1581,
1445, 1275, 1139, 972, 753 cm-1; 1H NMR (CDCl3,
400 MHz) d: 7.67 (2H, d, J = 15.9 Hz, Ar1CH=CH-
and Ar2CH=CH-), 7.56 (4H, dd, J = 7.4 and 1.8
Hz, ArH), 7.44-7.34 (6H, m, ArH), 6.64 (2H, d, J =
15.9 Hz, Ar2CH=CH- and Ar1CH=CH-), 5.86 (1H, s,
=CHCO); 13C NMR (CDCl3) d: 101.8, 124.1, 128.1,
128.9, 130.1, 135.0, 140.6, 183.3.
Yield: 19.5 mg (49%); orange crystals;
mp115-117°C; IR (thin film) nmax:2935, 2837, 1624,
1583, 1512, 1462, 1262, 1136, 1023, 969, 808 cm-1;
1H NMR (CDCl3, 400 MHz) d: 7.61 (2H, d, J = 15.8
Hz, Ar1CH=CH- and Ar2CH=CH-), 7.14 (2H, d, J
= 8.3 Hz, ArH), 7.08 (2H, s, ArH), 6.88 (2H, d, J =
8.3 Hz, ArH), 6.50 (2H, d, J = 15.8 Hz, Ar2CH=CH-
and Ar1CH=CH-), 5.82 (1H, s, =CH), 3.93 (6 H, s,
2xOCH3), 3.92 (6H, s, 2xOCH3);13C NMR (CDCl3) d:
55.9, 56.0, 101.3, 109.8, 111.2, 122.1, 122.6, 128.1,
140.4, 149.3, 151.1, 183.3.
5-Hydroxy-1,7-Bis(4-methoxyphenyl)-1,4,6-
heptatrien-3-one (1b)
Yield: 21.2 mg (63%); orange crystals;mp
175-177°C; IR (thin film) nmax: 3037, 2933, 2838,
Mo(CO)6
Ar2
Ar1
Ar2
Ar1
MeCN/H2O
reflux, 24 h
O N
O
NH2
2a-f
8a; Ar1 = C6H5, Ar2 = C6H5, 56%
8b; Ar1 = 4-OMeC6H4, Ar2 = 4-OMeC6H4, 50%
8c; Ar1 = 3,4-diOMeC6H3, Ar2 = 3,4-diOMeC6H3, 48%
8d; Ar1 = 4-OMeC6H4, Ar2 = C6H5, 54%
8e; Ar1 = 3,4-diOMeC6H3, Ar2 = C6H5, 47%
8f; Ar1 = 3,4-diOMeC6H3, Ar2 = 4-OMeC6H4, 43%
Scheme 5:
Ar1
Ar2
Ar1
Ar2
conc.HCl
pH 4-5, 45 oC
24 h
O
NH2
O
OH
8a-f
1a; Ar1 = C6H5, Ar2 = C6H5, 52%
1b; Ar1 = 4-OMeC6H4, Ar2 = 4-OMeC6H4, 63%
1c; Ar1 = 3,4-diOMeC6H3, Ar2 = 3,4-diOMeC6H3, 49%
1d; Ar1 = 4-OMeC6H4, Ar2 = C6H5, 48%
1e; Ar1 = 3,4-diOMeC6H3, Ar2 = C6H5, 51%
1f; Ar1 = 3,4-diOMeC6H3, Ar2 = 4-OMeC6H4, 52%
Scheme 6:

134
HAHNVAJANAWONG et al., Orient. J. Chem., Vol. 32(1), 127-135 (2016)
5-Hydroxy-1-(4-methoxyphenyl)-7-phenyl-1,4,6-
heptatrien-3-one (1d)
RESULTS AND DISCUSSION
Yield: 14.7 mg (48%); yellow crystals; mp
3,5-Dimethylisoxazole (5) used in our
140-142°C; IR (thin film) nmax: 3050, 2933, 2836, study was readily prepared in 82% yield from
1623, 1601, 1576, 1512, 1447, 1255, 1175, 1140, condensation between 2,4-pentanedione (6) with
1
1028, 977, 826 cm-1; H NMR (CDCl3, 400 MHz) hydroxylamine hydrochloride in aqueous ethanol at
d:7.64 (1H, d, J = 15.9 Hz, Ar2CH=CH-), 7.63 (1H, reflux temperature for 3 hours.10
d, J = 15.8 Hz, Ar1CH=CH-), 7.55 (2H, d, J = 7.5 Hz,
ArH), 7.51 (2H, d, J = 8.7 Hz, ArH), 7.43-7.35 (3H,
Lateral metalation of 3,5-dimethylisoxazole
m, ArH), 6.91 (2H, d, J = 8.2 Hz, ArH), 6.61 (1H, (5) occurred regiospecifically at the C5-methyl
d, J = 15.9 Hz, Ar2CH=CH-), 6.51 (1H, d, J = 15.8 group upon treatment with either n-BuLi12 or
Hz, Ar1CH=CH-), 5.81 (1H, s, =CHCO), 3.83 (3H, NaNH2.13 Metalation at the 3-methyl group could
s, OCH3); 13C NMR (CDCl3) d: 55.4, 101.6, 114.4, be accomplished when metalating agent was either
121.8, 124.1, 127.7, 128.1, 128.9, 129.8, 135.1, s-BuLi or t-BuLi.14
140.1, 140.6, 161.4, 182.2, 184.4.
As expected, lateral metalation of 3,5-
5-Hydroxy-1-(3,4-dimethoxyphenyl)-7-phenyl- dimethylisoxazole (5) with n-BuLi in THF at -78°C
1,4,6-heptatrien-3-one (1e)
for 1 hour followed by quenching with aromatic
Yield: 17.1 mg (51%); orange crystals; mp aldehydes 7a-c gave the corresponding 5-(2-aryl-2-
138-139°C; IR (thin film) nmax: 2934, 2837, 1624, hydroxyethyl)-3-methylisoxazoles 4a-c in good yields
1581, 1511, 1446, 1420, 1261, 1136, 1023, 968 cm-1; (Scheme 2).
1H NMR (CDCl3, 400 MHz) d:7.65 (1H, d, J = 15.9 Hz,
Ar2CH=CH-), 7.62 (1H, d, J = 15.7 Hz, Ar1CH=CH-),
Further treatment of 5-(2-aryl-2-
7.55 (2H, d, J = 7.6, ArH), 7.43-7.34 (3H, m, ArH), hydroxyethyl)-3-methylisoxazoles 4a-c with 2
7.15 (1H, d, J = 8.3 Hz, ArH), 7.08 (1H, s, ArH), 6.88 equivalents of s-BuLi at -78 °C followed by quenching
(1H, d, J = 8.3 Hz, ArH), 6.62 (1H, d, J = 15.8 Hz, with aromatic aldehydes 7a-c led to the formation of
Ar2CH=CH-), 6.52 (1H, d, J = 15.8 Hz, Ar1CH=CH-), four diastereomers of the corresponding 3,5-bis(2-
5.84 (1H, s, =CHCO), 3.94(3H, s, OCH3), 3.92 (3 aryl-2-hydroxyethyl)isoxazoles 3a-f in moderate
H, s, OCH3); 13C NMR (CDCl3) d: 55.9, 56.0, 101.5, yields (Scheme 3).
109.9, 111.2, 122.1, 122.8, 124.1, 128.0, 128.1,
128.9, 130.0, 135.1, 140.2, 140.8, 149.3, 151.2,
182.4, 184.2.
Since P2O5 is a very efficient dehydrating
agent, it was used as such in dehydration of 3,5-
bis(2-aryl-2-hydroxyethyl)isoxazoles 3a-f.In benzene
5-Hydroxy-1-(3,4-dimethoxyphenyl)-7-(4- at reflux temperature15 (Scheme 4), the reaction
methoxyphenyl)-1,4,6-heptatrien-3-one (1f) between carbinols 3a-f and P2O5 furnished the
Yield: 19.0 mg (52%); orange crystals; mp corresponding 3,5-bis(2-arylethenyl) isoxazoles 2a-f
155-157°C; IR (thin film) nmax: 3002, 2935, 1625, in moderate yields.
1595, 1512, 1461, 1256, 1172, 1136, 1025, 970,
1
829 cm-1; H NMR (CDCl3, 400 MHz) d: 7.62 (1H,
The weak N–O bond of isoxazole ring is
d, J = 15.8 Hz, Ar2CH=CH-), 7.60 (1H, d, J = 15.8 easily cleaved into b-aminoenone by either catalytic
Hz, Ar1CH=CH-), 7.50 (2H, d, J = 8.7 Hz, ArH), 7.13 hydrogenolysis with platinum or palladium and Raney
(1H, d, J = 8.3 Hz, ArH), 7.08 (1H, d, J = 1.5 Hz, nickel under normal pressure and temperature16,17
ArH), 6.91 (2H, d, J = 8.7 Hz, ArH), 6.87 (1H, d, J = or by treatment with transition metal carbonyls
8.3 Hz, ArH), 6.49 (2H, d, J = 15.8 Hz, Ar1CH=CH- such as molybdenum hexacarbonyl [Mo(CO)6].18
and Ar2CH=CH-), 5.80 (1H, s, =CHCO), 3.93(3H, s, To avoid catalytic hydrogenation at the two styryl
OCH3), 3.91 (3 H, s, OCH3), 3.84 (3H, s, OCH3); 13C groups, 3,5-bisstyrylisoxazoles 2a-f were treated
NMR (CDCl3) d:55.4, 55.9, 56.0, 101.3, 109.8, 111.2, with molybdenum hexacarbonyl in moist acetonitrile
114.4, 121.8, 122.1, 122.6, 127.8, 128.1, 129.8, at reflux temperature. This treatment successfully
140.2, 140.3, 149.3, 151.1, 161.3, 183.1, 183.4.
provided the corresponding 1,7-diaryl-5-amino-1,4,6-

135
HAHNVAJANAWONG et al., Orient. J. Chem., Vol. 32(1), 127-135 (2016)
heptatrien-3-ones 8a-f in moderate yields ( Scheme unsymmetrical curcumin derivatives. Good to
5).
moderate yields of expected products were obtained
b-Aminoenones are easily transformed into from each step.
b-hydroxyenones by simple acidic hydrolysis.19,20
In our final step, hydrolysis of b-aminoenones 8a-f
was carried out by treatment with hydrochloric acid
in ethanol at pH 4-5. The corresponding curcumin
ACkNOwLEDgEMENT
We are pleased to acknowledge financial
derivatives, in their enol forms 1a-f were obtained support from the Natural Products Research Unit,
in satisfied yields (Scheme 6).
Department of Chemistry, Faculty of Science, Khon
Kaen University, and the Center for Innovation in
Chemistry (PERCH-CIC) and the Commission
of Higher Education (CHE-RG), Ministry of
CONCLUSIONS
The present six steps procedure provides Education.
a novel alternative route to symmetrical and
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