356
G. Allegretta et al. / European Journal of Medicinal Chemistry 90 (2015) 351e359
(125 MHz, acetone-d6): 30.8, 36.6, þ51.5, 116.0, 130.1, 132.4, 156.7,
4.2.1.12. Methyl 2-(3,4-dihydroxyphenyl)acetate (28). The carbox-
ylic acid 18 (100 mg, 0.59 mmol) and MeOH (10 ml) were used.
60 mg (56%) of yellow crystalline solid were obtained. 1H NMR
(500 MHz, acetone-d6): 3.46 (s, 2H), 3.61 (s, 3H), 6.60 (dd, J ¼ 8.0,
173.5. MS (ESI) m/z: [M þ H2O]
¼ 198.02. Purity ¼ 97.02%.
Mp ¼ 46e48 ꢂC. HRMS: calculated m/z ¼ 181.08592, experimental
m/z ¼ 181.08604.
J ¼ 2.4, 1H), 6.75 (d, J ¼ 8.2, 1H), 6.78 (d, J ¼ 2.5, 1H), 7.78 (s, 2H). 13
C
NMR (125 MHz, acetone-d6): 40.7, 51.9, 116.0, 117.2,þ121.5, 127.0,
4.2.1.6. Methyl 3-(p-tolyl)propanoate (22). The carboxylic acid 14
(100 mg, 0.61 mmol) and MeOH (10 ml) were used. 80 mg (73%) of
yellow crystalline solid were obtained. 1H NMR (500 MHz, acetone-
d6): 2.27 (s, 3H), 2.58 (t, J ¼ 8.0, 2H), 2.86 (t, J ¼ 7.2, 2H), 3.60 (s, 3H),
7.07e7.12 (m, 4H). 13C NMR (125 MHz, acetone-d6): 21.1, 31.2, 36.3,
51.6, 129.1, 129.9, 136.3, 138.8, 173.5. MS (ESI) m/z: [M þ MeCN þ H]
144.9, 145.8, 172.6. MS (ESI) m/z: [M
þ
H2O]
¼
199.88.
Purity ¼ >99%. Mp ¼ 52e55 ꢂC. HRMS: calculated m/z ¼ 183.06519,
experimental m/z ¼ 183.06534.
4.2.1.13. Methyl 4-(3,4-dimethoxyphenyl)butanoate (29). The car-
boxylic acid 19 (1.00 g, 4.46 mmol) and MeOH (100 ml) were used.
900 mg (85%) of yellow crystalline solid were obtained. 1H NMR
(500 MHz, acetone-d6): 1.88 (qui, J ¼ 7.2, 2H), 2.30 (t, J ¼ 7.2, 2H),
2.57 (t, J ¼ 7.6, 2H), 3.61 (s, 3H), 3.76 (s, 3H), 3.79 (s, 3H), 6.71 (dd,
J ¼ 8.3, J ¼ 2.4, 1H), 6.82 (d, J ¼ 2.1, 1H), 6.84 (d, J ¼ 8.0, 1H). 13C NMR
(125 MHz, acetone-d6): 27.6, 33.7, 35.3, 51.5, 56.1, 56.2, 113.0, 113.5,
121.2, 135.2, 148.8, 150.4, 174.0. MS (ESI) m/z: [MþH]þ ¼ 238.97.
Purity ¼ >99%. Mp ¼ 32e34 ꢂC. Intermediate 29 was used as is for
the synthesis of 30.
þ
¼ 220.02. Purity ¼ 95.34%. Mp ¼ 40e42 ꢂC. HRMS: calculated m/
z ¼ 179.10666, experimental m/z ¼ 179.10687.
4.2.1.7. Methyl 3-(4-nitrophenyl)propanoate (23). The carboxylic
acid 15 (150 mg, 0.77 mmol) and MeOH (15 ml) were used. 142 mg
(88%) of yellow crystalline solid were obtained. 1H NMR (500 MHz,
acetone-d6): 2.72 (t, J ¼ 7.5, 2H), 3.07 (t, J ¼ 8.2, 2H), 3.61 (s, 3H),
7.55e7.57 (m, 2H), 8.15e8.17 (m, 2H). 13C NMR (125 MHz, acetone-
d6): 31.2, 35.2, 51.8, 124.3, 130.5, 147.6, 150.0, 173.0. MS (EI) m/z: [M]
þ
_
¼ 208.9. Purity ¼ >99%. Mp ¼ 67e70 ꢂC. HRMS: calculated m/
z ¼ 210.07608, experimental m/z ¼ 210.07588.
4.2.2. Synthesis of compound 30
4.2.2.1. Methyl 4-(3,4-dihydroxyphenyl)butanoate (30). After dis-
solving 29 (400 mg, 1.68 mmol) in CH2Cl2 (20 ml), the solution was
cooled with an ice-water bath. BBr3 1.0 N in CH2Cl2 (10 ml,
10 mmol) was added dropwise and the reaction mixture was stirred
for 2 h at 0 ꢂC under N2 atmosphere. Ice was added to the mixture
and the system was stirred overnight warming up to room tem-
perature. Brine was added to the mixture and, then, it was extracted
three times with CH2Cl2; the organic layers were collected, dried
over Na2SO4 and the solvent was evaporated under reduced pres-
sure. The crude extract was purified by column chromatography
(hexane/ethyl acetate 8:2) yielding 258 mg (73%) of 30 as a yellow
oil. 1H NMR (500 MHz, acetone-d6): 1.83 (qui, J ¼ 7.2, 2H), 2.28 (t,
J ¼ 7.5, 2H), 2.49 (t, J ¼ 7.8, 2H), 3.61 (s, 3H), 6.52 (dd, J ¼ 8.0, J ¼ 2.3,
1H), 6.68 (d, J ¼ 2.1, 1H), 6.72 (d, J ¼ 8.0, 1H), 7.62 (ws, 2H). 13C NMR
4.2.1.8. Methyl 3-(4-aminophenyl)propanoate (24). The carboxylic
acid 16 (150 mg, 0.91 mmol) and MeOH (15 ml) were used. The
crude dried reaction mixture was dissolved in anhydrous THF
(2 ml) and cooled with an ice-water bath. HCl 4N in dioxane (2 ml)
was added dropwise to the solution until the formation of a pre-
cipitate isolated by filtration. 98 mg (74%) of a yellow crystalline
solid were obtained. 1H NMR (500 MHz, acetone-d6): 2.68 (t, J ¼ 7.6,
2H), 2.99 (t, J ¼ 8.0, 2H), 3.62 (s, 3H), 7.45 (s, 4H). 13C NMR (125 MHz,
acetone-d6): 31.0, 35.6, 51.7, 125.4, 130.3, 135.0, 143.8, 173.2. MS
(ESI) m/z: [MþH]þ ¼ 180.12. Purity ¼ >99%. Mp ¼ 178e180 ꢂC.
HRMS: calculated m/z ¼ 180.10191, experimental m/z ¼ 180.10197.
4.2.1.9. Methyl 3-(3,4-dihydroxyphenyl)propanoate (25). The car-
boxylic acid 17 (500 mg, 2.74 mmol) and MeOH (50 ml) were used.
433 mg (80%) of yellow crystalline solid were obtained. 1H NMR
(500 MHz, acetone-d6): 2.53 (t, J ¼ 7.9, 2H), 2.76 (t, J ¼ 8.0, 2H), 3.60
(s, 3H), 6.54 (dd, J ¼ 8.0, J ¼ 2.0, 1H), 6.70e6.73 (m, 2H), 7.60 (ws,
1H), 7.65 (ws, 1H). 13C NMR (125 MHz, acetone-d6): 31.0, 36.5, 51.5,
116.0, 116.2,þ 120.3, 133.4, 144.2, 145.8, 173.5. MS (ESI) m/z:
(125 MHz, acetone-d6): 27.7, 33.6, 35.0, 51.5, 116.0, 116.3, 120.5,
þ
134.2, 144.0, 145.8, 174.0. MS (ESI) m/z: [M-OMe]
¼ 179.09.
Purity ¼ 98.10%. HRMS: calculated m/z ¼ 211.09649, experimental
m/z ¼ 211.09649.
4.2.3. Synthesis of compound 32
4.2.3.1. 3-(3,4-Bis((tert-butyldimethylsilyl)oxy)phenyl)propanoic
acid (32). After dissolving 17 (1.00 g, 5.48 mmol) in DMF (11 ml),
imidazole (3.73 g, 54.80 mmol) and TBDMSCl (3.72 g, 24.66 mmol)
were added and the reaction mixture was stirred for 48 h at room
temperature. Saturated solution of NH4Cl (40 ml) was added to the
reaction and the mixture was extracted three times with ethyl ac-
etate. The organic layers were collected together, washed with
brine, dried over Na2SO4 and the solvent was evaporated under
reduced pressure. The crude extract was dissolved in a mixture of
THF/MeOH/H2O 1:3:1 (25 ml), K2CO3 (757 mg, 5.48 mmol) was
added in the solution and the system was stirred for 30 min at room
temperature. The mixture was concentrated under vacuum at room
temperature. Water was added to the crude mixture and drops of
HCl 1 N were added until the pH ¼ 7. The aqueous solution was
diluted with brine and extracted three times with ethyl acetate. The
organic layers were collected together, dried over Na2SO4 and the
solvent was evaporated under reduced pressure. The crude extract
was purified by column chromatography (hexane/ethyl acetate 9:1)
yielding 2.14 g (95%) of 32 as a white crystalline solid. 1H NMR
(500 MHz, acetone-d6): 0.21 (s, 6H), 0.22 (s, 6H), 0.99e1.01 (m,
18H), 2.56 (t, J ¼ 7.8, 2H), 2.80 (t, J ¼ 7.7, 2H), 6.72 (dd, J ¼ 8.1, J ¼ 2.3,
1H), 6.79 (d, J ¼ 8.1, 1H), 6.81 (d, J ¼ 2.1, 1H), 10.53 (ws, 1H). 13C NMR
(125 MHz, acetone-d6): ꢃ3.86, ꢃ3.81, 19.02, 19.04, 26.35, 26.37,
[M þ H2O]
¼ 213.95. Purity ¼ >99%. Mp ¼ 77e79 ꢂC. HRMS:
calculated m/z ¼ 197.08084, experimental m/z ¼ 197.08106.
4.2.1.10. Ethyl 3-(3,4-dihydroxyphenyl)propanoate (26). The car-
boxylic acid 17 (150 mg, 0.82 mmol) and EtOH (15 ml) were used.
145 mg (84%) of yellow oil were obtained. 1H NMR (500 MHz,
acetone-d6): 1.18 (t, J ¼ 6.9, 3H), 2.52 (t, J ¼ 7.4, 2H), 2.75 (t, J ¼ 7.9,
2H), 4.06 (qua, J ¼ 7.3, 2H), 6.55 (dd, J ¼ 7.9, J ¼ 2.0, 1H), 6.71 (m,
2H), 7.63 (s, 1H), 7.68 (s, 1H). 13C NMR (125 MHz, acetone-d6): 14.5,
31.0, 36.8, 60.5,116.0,116.3,120.4,133.4,144.2,145.8,173.0. MS (ESI)
m/z: [MþH]þ ¼ 210.88. Purity ¼ 95.11%. HRMS: calculated m/
z ¼ 211.09649, experimental m/z ¼ 211.09626.
4.2.1.11. Isopropyl
3-(3,4-dihydroxyphenyl)propanoate
(27).
The carboxylic acid 17 (250 mg, 1.37 mmol) and iPrOH (25 ml) were
used. 270 mg (88%) of yellow oil were obtained. 1H NMR (500 MHz,
acetone-d6): 1.17 (d, J ¼ 6.2, 6H), 2.49 (t, J ¼ 7.3, 2H), 2.75 (t, J ¼ 7.9,
2H), 4.93 (hep, J ¼ 6.3, 1H), 6.55 (dd, J ¼ 7.9, J ¼ 2.2, 1H), 6.71e6.73
(m, 2H), 7.64 (ws, 1H). 13C NMR (125 MHz, acetone-d6): 22.0, 31.1,
37.1, 67.8, 116.0, 116.3, 120.4, 133.4, 144.2, 145.7, 172.6. MS (ESI) m/z:
[MþH]þ
¼
225.10. Purity ¼ >99%. HRMS: calculated m/
z ¼ 225.11214, experimental m/z ¼ 225.11201.