Synthesis and Tautomerism of Curcumin Derivatives
227
4,6-dimethyl-2-(20,20,20-trifluoroethoxy)ethoxy-pyrimidine (5)
was prepared by replacement of the methylsulfonyl group of
4,6-dimethyl-2-methylsulfonyl-pyrimidine with 2-(20,20,20-
trifluoroethoxy)ethanol. Condensation of the pyrimidine deriva-
tive 5 with 3-methoxy-4-tetrahydropyranyloxybenzaldehyde in
5 M sodium hydroxide in the presence of tetra-n-butylammonium
hydrogen sulfate gave the bis-phenylethenyl-pyrimidine 6a.[15]
Acid hydrolysis of the pyrimidine derivative 6a afforded the
desired compound 6b that is a coplanar molecule in which the
conjugated double bonds are fixed in the cis configuration as in
the enol form of curcumins.
with 0.5 M HCl and brine, and dried over magnesium sulfate.
The solvent was removed and the residue was purified by
column chromatography (silica gel, ethyl acetate (EtOAc)/
hexane) to give the corresponding series of products 2.
Compound 2a: (54 % yield), mp 173–1748C. RF 0.55 (1 : 1
EtOAc/hexane). lmax/nm (e/Mꢀ1 cmꢀ1) 408 (57000), 240
(19000). dH (DMSO[D6]) 6.09 (1H, s), 6.83 (2H, d, J 15.8),
7.07 (2H, d, J 8.4), 7.58 (2H, d, J 15.8), 7.61 (2H, dd, J 2.2, 8.4),
7.72 (2H, brs), 10.84 (2H, s), 16.22 (1H, brs). dF (DMSO[D6])
ꢀ57.75 (s).
Compound 2b: (48 % yield), mp 179–1808C. RF 0.35 (1 : 2
EtOAc/hexane). lmax/nm (e/Mꢀ1 cmꢀ1) 407 (68000), 245
(25000). dH (DMSO[D6]) 1.31 (3H, t, J 7.0), 4.37 (2H, q, J
7.0), 7.09 (2H, d, J 8.4), 7.14 (2H, d, J 15.9), 7.61 (2H, dd, J 8.6,
1.6), 7.70 (2H, brs), 7.74 (2H, d, J 15.9), 10.96 (1H, brs), 18.16
(1H, brs). dF (DMSO[D6]) ꢀ58.39 (s).
Conclusion
The syntheses of the derivatives of curcumin where the two
OCH3 groups are replaced by OCF3 groups and substituted at
position C-4 are reported here. It is found that enolisation of the
diketone moiety at C-3,4,5 was decreased probably by the þI
effect of alkyl groups, and the extent of enolisation depended on
the group which is attached to the alkyl group. Attempted syn-
thesis of the derivative with a 4-hydroxypropyl group at position
C-4 led to the formation of new rings (see compounds 3 and 4).
A pyrimidine derivative was prepared in order to fix the enol
form at C-3,4,5 of a curcumin. The binding of such curcumins to
Ab amyloid aggregates should be interesting and is currently
under investigation in our group (H. Taguchi and I. Tooyama,
unpubl. data).
Compound 2c: (53 % yield), mp 140–1418C. RF 0.30 (1 : 2
EtOAc/hexane). lmax/nm (e/Mꢀ1 cmꢀ1) 420 (23000), 326
(30000), 235 (22000). dH (DMSO[D6]) 2.92 (1.2H, d, J 6.8),
3.59 (1.8H, s), 3.62 (1.2H, s), 3.91 (0.8H, brs), 4.95 (0.6H, m),
7.0–7.2 (4H), 7.5–7.8 (6H), 10.88 (2H, brs), 17.89 (0.4H, s). dF
(DMSO[D6]) ꢀ58.48 (s), ꢀ58.33 (s).
Compound 2e: (68 % yield), mp 142–1438C. RF 0.30 (1 : 2
EtOAc/hexane). dH (DMSO[D6]) 2.07 (m), 2.32 (m), 2.4–2.55,
2.98 (m), 3.54 (s, enol), 3.59 (s, keto), 4.60 (0.6H, t, J 6.8), 6.98
(1.1H, d, J 15.9), 7.05 (d, J 8.4), 7.07 (d, J 8.4), 7.21 (0.9H, d, J
15.7), 7.55–7.7 (4H, arom), 7.77 (2H, brd, J 15.7), 10.89 (2H,
br), 17.87 (s). dF (DMSO[D6]) ꢀ58.06 (s), ꢀ57.93 (s). dH
(CDCl3) 2.55 (2H, m), 2.94 (2H, m), 3.69 (3H, s), 6.70 (0.3H,
d, J 15.9), 6.99 (1.7H, d, J 15.4), 7.08 (1.7H, d, J 8.1), 7.4–7.5
(4H, ArH), 7.61 (0.3H, d, J 15.9), 7.68 (1.7H, d, J 15.4), 17.52
(0.8H, s). dF (CDCl3) ꢀ59.05 (s, very weak), ꢀ59.01 (s).
Compound 2f: (53 % yield), mp 155–1568C. RF 0.25 (1 : 2
EtOAc/hexane). lmax/nm (e/Mꢀ1 cmꢀ1) 424.5 (35000), 330
(18000), 241 (17000). dH (DMSO[D6]) 1.13 (t, J 7.0), 1.15
(t, J 7.0), 2.03 (m), 2.30 (m), 2.46 (m), 2.98 (m), 4.00 (q, J 7.0),
4.05 (q, J 7.0), 4.60 (t, J 6.5), 6.98 (d, J 15.9), 7.05 (d, J 8.6),
7.07 (d, J 8.4), 7.21 (d, J 15.4), 7.55–7.70 (4H), 7.76 (2H, brd,
J 15.7), 10.87 (2H, br), 17.84 (s). dF (DMSO[D6]) ꢀ57.84 (s),
ꢀ57.71 (s).
Experimental
Reactions requiring anhydrous conditions are performed under a
nitrogen atmosphere. Unless otherwise noted, commercially
available compounds are used in this work without further
purification.
4-Hydroxy-3-(trifluoromethoxy)benzaldehyde
was purchased from Melford Laboratories Ltd. Ethyl diaceto-
acetate (1b) and methyl 4-acetyl-5-oxohexanoate (1e) were
bought from Sigma–Aldrich. The purity of all new compounds
has been checked by silica gel thin layer chromatography and
their spectral data are consistent with their structures, and also
showed that they were free from impurities.
Proton and fluorine nuclear magnetic resonance spectra are
recorded at 270 MHz on a JNM-GX270 spectrometer (JEOL,
Tokyo, Japan). 1H NMR spectra are referenced to tetramethyl-
silane as the internal standard, and 19F NMR signals are
referenced to C6F6 at ꢀ163 ppm as the external standard. UV–
visible absorption spectra are recorded in MeOH, unless other-
wise stated, on Shimadzu UV-3100 PC and mass spectra are
measured by negative mode using a FINNIGAN LCQ Advan-
tage MAX spectrometer.
Compound 2g: (55 % yield), mp 1918C. RF 0.30 (1 : 2 EtOAc/
hexane). lmax/nm (e/Mꢀ1 cmꢀ1) 425 (28000), 329 (15000), 235
(15000). dH (DMSO[D6]) 1.13 (d, J 6.2), 1.19 (d, J 6.2), 2.07
(m), 2.26 (m), 2.43 (m), 2.98 (m), 4.59 (t, J 6.7), 4.86 (1H, m),
6.98 (d, J 15.9), 7.0–7.1 (2H), 7.21 (d, J 15.9), 7.55–7.7 (4H, m),
7.76 (2H, d, J 15.9), 10.88 (2H, brs), 17.83 (s). dF (DMSO[D6])
ꢀ58.34 (s), ꢀ58.21 (s).
Compound 2h: (48 % yield), mp 1758C. RF 0.33 (1 : 2 EtOAc/
hexane). lmax/nm (e/Mꢀ1 cmꢀ1) 425.5 (33000), 330 (13000),
238.5 (15000). dH (DMSO[D6]) 1.35 (s), 1.38 (s), 2.03 (m), 2.19
(m), 2.39 (m), 2.95 (m), 4.57 (t, J 6.5), 6.98 (d, 16.2), 7.05 (d, J
8.6), 7.07 (d, J 8.4), 7.21 (d, J 15.4), 7.55–7.70 (4H), 7.76
(2H, brd, J 15.4), 10.87 (2H, brs), 17.79 (s). dF (DMSO[D6])
ꢀ58.31 (s), ꢀ58.18 (s).
Preparation of 4-Substituted 1,7-Bis(40-hydroxy-30-
trifluoromethoxyphenyl)-1,6-heptadiene-3,5-
diones 2a–2c and 2e–2m
General Procedure
A mixture of the acetyl acetone derivative 1 (2.2 mmol) and
boric anhydride (1.76 mmol) in ethyl acetate (4.0 mL) were
heated at 608C for 40 min, and 4-hydroxy-3-(trifluoro-
methoxy)benzaldehyde (4.0 mmol) and tributyl borate
(4.0 mmol) were added; heating at the same temperature was
continued for 30 min. n-Butylamine (2.0 mmol) was added to
the mixture, which was heated at 608C for 4 h. After cooling the
mixture to room temperature, 1 M hydrochloric acid was added
and the mixture was stirred vigorously for 30 min. The mixture
was extracted with ethyl acetate, and the extract was washed
Compound 2i: (43 % yield), mp 192–1938C. RF 0.20 (1 : 1
EtOAc/hexane). dH (DMSO[D6]) 2.03 (m), 2.28 (m), 2.47 (m),
2.79 (s), 2.80 (s), 2.90 (s), 2.92 (s), 4.61 (t, J 7.0), 6.9–7.3 (4H,
ArH), 7.5–7.8 (6H, ArH), 10.83 (2H, brs), 17.77 (s). dF (DMSO
[D6]) ꢀ58.45 (s), ꢀ58.33 (s).
Compound 2j: (40 % yield), mp 147–1488C. RF 0.32 (1 : 2
EtOAc/hexane). lmax/nm (e/Mꢀ1 cmꢀ1) 427.5 (44000), 333
(13000), 243.5 (17000). dH (DMSO[D6]) 1.4–2.0 (2.6H), 2.2–
2.7 (3.4H), 3.57 (s), 3.64 (s), 6.95 (d, J 15.9), 7.05 (d, J 8.4), 7.07