SAR of 2-Benzoylbenzoic Acids
J. Agric. Food Chem., Vol. 45, No. 6, 1997 2049
ppm. Therefore the acetyl group must be in 3′ position, i.e.,
compound 15 is 2-(3-hydroxy-4-methoxybenzoyl)benzoic acid.
2-(4-Hyd r oxy-3-m eth oxyben zoyl)ben zoic Acid (16) a n d
2-(3,4-Dim eth oxyben zoyl)ben zoic Acid (17). AlCl3 (2.50
g, 17 mmol) and 1,2-dimethoxybenzene (0.7 mL, 7 mmol) were
added in portions to a solution of phthalic anhydride (1.00 g,
7 mmol) in dichloromethane (20 mL) cooled to 0 °C, and the
resulting solution was stirred at room temperature overnight.
The mixture was then acidified with HCl, extracted with ethyl
acetate, and chromatographed to give compounds 16 (180 mg)
and 17 (140 mg).
Compound 16 has a melting point of 194°C. NMR (DMSO-
d6): δ 3.8 (3 H, s, OMe), 6.78 (1 H, d, J ) 8, H-5′), 6.88 (1 H,
dd, J ) 8 and 1.5, H-6′), 7.35 (1 H, d, J ) 1.5, H-2′), 7.55-7.95
(4 H, m, arom.), 10.1 (1 H, s, COOH). MS m/ z (%): 272 (55),
197 (25), 151 (100). MS-CI m/ z (%): 273 (100), 255 (7). IR
(cm-1): 1650.
(42), 124 (100). Anal. Calcd for C14H12O4S: C, 60.92; H, 4.35.
Found: C, 60.93; H, 4.35.
2-H yd r oxym et h ylp h en yl-4-m et h oxyp h en ylm et h a n ol
(26). Methyl 2-(4-methoxybenzoyl)benzoate (0.14 g, 0.53
mmol) in 3 mL of THF was added dropwise to a solution of
LiAlH4 (1 M solution, 0.8 mL, 0.8 mmol) in dry THF (5 mL)
under nitrogen. The mixture was stirred at room temperature
for 3 h and quenched with a saturated solution of NH4Cl. The
solvent was removed, and the residue was acidified with
concentrated HCl and extracted with ethyl acetate. The crude
residue (90 mg) was crystallized from 5 mL of 96% ethanol to
give a white solid (57%), mp 55-57 °C. NMR (CDCl3): δ 3.80
(3 H, s, OMe), 5.25 (2 H, m, CH2), 6.15 (1 H, s, m, CH), 7.1-
7.3 (6 H, m, arom.). MS m/ z (%): 226 (71, M - H2O), 225
(90), 210 (24), 195 (100), 165 (33), 152 (51), 135 (77).
P h th a lic Acid Mon o(4-m eth oxyp h en yl) Ester (27).
This compound was prepared by melting together phthalic
anhydride (3.60 g, 24 mmol) and 4-methoxyphenol (3.00 g, 24
mmol) for 5 h. The mixture was then treated with 5% NaOH
(35 mL) and acidified with 10% HCl to separate unreacted
phthalic acid. Addition of hexane to the filtrate precipitated
the ester 27 as a white solid (0.37 g, 6%), mp 118-120 °C.
NMR (DMSO-d6): δ 3.8 (3 H, s, OMe), 7.0-7.2 (2 H, 2 d,
arom.), 7.5-7.9 (6 H, arom.). MS m/ z (%): 149 (7, M+), 124
(100). IR (cm-1): 1750 (COOH), 1700 (CO).
3-(4-Met h oxyp h en yl)b en zo[2]fu r a n -1-on e (28). 4,4-
Dimethyl-2-phenyloxazoline (1.9 mL, 11 mmol) in dry THF (5
mL) was added to a solution of n-BuLi (1.6 M in hexane, 10.2
mL, 16 mmol) in dry THF (40 mL) at -45 °C. After 1 h,
4-methoxybenzaldehyde (1.38 mL, 11 mmol) in THF (10 mL)
was added, and the temperature was kept at -45 °C for 5 h
and then at -23 °C for 48 h. The mixture was quenched with
an iced saturated solution of NH4Cl (10 mL). The organic layer
was dried and concentrated under reduced pressure, and the
crude residue (3.42 g) was chromatographed on silica gel
(hexane:ethyl acetate, 7:3). 2-[2-(4-Methoxyphenyl)hydroxy-
methylphenyl]-4,4-dimethyloxazoline 34 was obtained as a
yellow oil (1.46 g, 43%). NMR (CDCl3): δ 1.0 and 1.5 (2 × 3
H, 2 s, Me), 3.8 (3 H, s, OMe), 4.0 (2 H, dd, CH2), 5.9 (1 H, d
broad, CH), 6.8-7.9 (8 H, arom.). MS m/ z (%): 311 (80, M+),
280 (58), 240 (100), 181 (38), 152 (42), 137 (95), 135 (88), 105
(65). The lactone 28 was obtained by treating with HCl 3%
(70 mL) oxazoline 34 (0.50 g, 1.6 mmol) at reflux for 5 h. The
mixture was extracted with ethyl acetate, dried, evaporated,
and purified by column chromatography (hexane:ethyl acetate,
7:3). The solid residue (0.30 g) was crystallized from hexane/
cyclohexane to give 0.15 g (39%) of pure product, mp 110 °C.
NMR (CDCl3): δ 3.9 (3 H, s, OMe), 6.35 (1 H, s, CH), 6.8-8 (8
H, arom.). MS m/ z (%): 240 (100, M+), 135 (48), 104 (40). IR
(cm-1): 1760 (CO).
Ta stin g. Although some derivatives had already been
tasted (see references in Figure 1), the tasting procedures were
not exhaustively described. In most cases it was unspecified
whether the compounds had been tasted as solids or in water
solution, as free acids or as sodium salts and moreover the
overall taste was often described as a mixture of different
sensations (for instance as “sweet-bitter” or “first sweet, then
bitter”), preventing the use of these data even for a qualitative
correlation study.
The compounds assayed in this work result from minor
structural modifications of compound 1 and therefore were not
submitted to toxicological evaluation. However they were
tasted only once with the “sip and spit” procedure at a starting
concentration of 200 mg/L. The solutions for the tasting trials
were obtained by dissolving the compounds (10 mg) in freshly
distilled water (50 mL). Derivatives 1, 7, 15, 20, 22, 23, 26,
and 27 were tasted both as free acids and as the corresponding
sodium salts; in both cases the taste and the sweetness
intensity remained substantially unchanged, but the taste of
the sodium salts was a little less persistent. A panel of five
to seven untrained people tasted the solutions in comparison
with 3% sucrose in water to assess the sweet taste potency.
Compounds 3, 7, and 12 were described as sweet by Cohn
(1914): in our tasting trials they were tasteless at a concentra-
tion of 0.2 g/L but were perceived as sweet when tasted as a
solid.
Compound 17 has a melting point of 234 °C. NMR (DMSO-
d6): δ 3.85 (6 H, s, OMe), 6.9-9.1 (8 H, m, arom. and COOH).
MS m/ z (%): 286 (10), 165 (70), 91 (100). Anal. Calcd for
C16H14O5: C, 67.12; H, 4.93. Found: C, 67.29; H, 4.92.
Str u ctu r e Deter m in a tion of Com p ou n d 16. HPLC
analysis showed that compounds 16 and 15 were two single
isomers. Compound 16 was reacted with acetic anhydride and
pyridine to give the acetylated derivative 33. NMR (DMSO-
d6): δ 2.3 (3 H, s, MeCO), 3.85 (3 H, s, OMe), 6.98 (1 H, dd, J
) 8 and 2, H-6′), 7.18 (1 H, d, J ) 8, H-5′), 7.52 (1 H, d, J )
2, H-2′), 7.6-8.0 (4 H, arom.). In compound 16 the signal at
6.78 was attributed to H-5′ because it has only one vicinal
coupling; in the corresponding acetylated derivative this signal
was shifted downfield by 0.4 ppm, while the signals of H-2′
and H-6′ were shifted only slightly (0.16 and 0.1 ppm,
respectively). Thus the proton H-2′ is ortho to the acetyl group,
i.e., compound 16 contains a 4-hydroxy-3-methoxyphenyl
group. Also the acetylated isomeric compounds 32 and 33 have
been analyzed by HPLC and were shown to be pure.
2-(2,4-Dim eth oxyben zoyl)ben zoic Acid (18) a n d 2-(4-
Hydr oxy-2-m eth oxyben zoyl)ben zoic Acid (19). AlCl3 (2.30
g, 17.3 mmol) was added in portions at 0 °C to a solution of
phthalic anhydride (1.00 g, 7 mmol) dissolved in 20 mL of dry
CH2Cl2, and then 1,3-dimethoxybenzene was added dropwise.
After the addition was complete the mixture was stirred at
room temperature for 20 min and then poured into acid water
and ice and extracted with ethyl acetate. The organic layer
was washed to neutrality and dried, and the solvent was
evaporated. Addition of ethanol favored the separation of
crystalline phthalic acid which was eliminated by filtration.
The crude residue was purified by column chromatography on
silica gel (hexane:ethyl acetate, 7:3) to give separated 18 (0.76
g) and 19 (0.26 g).
The dimethyl derivative 18 was purified by crystallization
from aqueous ethanol to yield 0.48 g of white crystals (40%);
mp 159-160 °C. NMR (CDCl3): δ 3.5 (3 H, s, OMe), 3.83 (3
H, s, OMe), 6.25-6.60 (2 H, d, J ) 9, H-3′ and H-5′), 7.15-
8.04 (5 H, m, arom.), 8.75-9.1 (1 H, br, COOH). MS m/ z (%)
286 (20, M+), 165 (100), 122 (18).
Compound 19 was crystallized from aqueous ethanol to yield
a white solid (0.10 g, 5%), mp 154-156 °C. NMR (CDCl3): δ
3.88 (3 H, s, OMe), 6.25 (1 H, dd, J ) 9 and 2.5, H-5′), 6.5 (1
H, d, J ) 2.5, H-3′), 7 (1 H, d, J ) 9, H-6′), 7.2-8.2 (4 H, m,
arom.), 12.3 (1 H, s, COOH). MS m/ z (%): 272 (10, M+), 151
(100). Anal. Calcd for C15H12O5: C, 66.17; H, 4.93. Found:
C, 66.16; H, 4.48.
The position of the methoxy group was determined by NMR
with a nuclear Overhauser effect (NOE) experiment: the
irradiation of the methoxy group showed a 19% NOE on H-3′
easily recognizable for the meta J value.
2-(4-Meth oxyp h en ylth io)ben zoic Acid S-Oxid e (23).
2-(4-Methoxyphenylthio)benzoic acid 22 (0.30 g, 1 mmol) was
stirred in the presence of 3-chloroperoxybenzoic acid (0.30 g,
1.5 mmol) in dichloromethane, at room temperature, for 24 h.
The solvent was evaporated, and the residue was crystallized
from ethanol to give compound 23 (0.20 g, 73%), mp 228 °C.
NMR (DMSO-d6): δ 3.8 (3 H, s, OMe), 7.0-8.3 (9 H, arom.
and COOH). IR (Nujol) cm-1: 1700. MS m/ z (%) 276 (5), 155