Journal of Medicinal Chemistry
Article
1625, 1605, 1536, 1515, 1433, 1387, 1307, 1277, 1237, 1192, 1156,
1045, 969. HPLC purity (λ = 254 nm): 98% (retention time 12.4
min).
NMR (MeOD-d4, 75 MHz) δ = 115.1 + 116.5 + 117.8 + 122.3
(PhCHCHCON + 3 CHarom), 128.2 + 146.8 + 149.0 (3 Cqarom),
143.4 (PhCHCHCON), 171.7 (CONH2). IR (cm-1) νmax = 3330,
1680, 1649, 1626, 1564, 1528, 1451, 1207, 1196, 1137, 1109, 969.
HRMS calcd for C9H9NO3 ([M + Na]+), 202.0480; found, 202.0486.
HPLC purity (λ = 320 nm): 98% (retention time 7.1 min).
(E)-Ethyl 3-(3,4-Dihydroxyphenyl)acrylate (Caf-CO2Et). White
solid (85% yield); Rf = 0.45 (cyclohexane/EtOAc 5/5); mp 146−
148 °C (lit. 149−151 °C).21 1H NMR (acetone-d6, 300 MHz) δ = 1.13
(t, 3J = 7.2 Hz, 3H, CO2CH2CH3), 4.05 (q, 3J = 7.1 Hz, 2H,
3-(3,4-Dihydroxyphenyl)propanoic Acid (α,β-diH-Caf-CO2H). To
a solution of Caf-CO2H (81 mg, 0.45 mmol, 1 equiv) in MeOH (4
mL) was added catalytic amount of Pd/C. After stirring at room
temperature overnight under an hydrogen atmosphere (1 atm), the
mixture was filtered over Celite, washed with MeOH, and the filtrate
concentrated to yield α,β-diH-Caf-CO2H as a white solid (80.5 mg,
99% yield); Rf = 0.21 (cyclohexane/EtOAc 5/5); mp 134−136 °C (lit.
137−139 °C).44 1H NMR (MeOD-d4, 300 MHz) δ = 2.42 (t, 3J = 7.5
Hz, 2H, PhCH2-CH2CO2), 2.65 (t, 3J = 7.7 Hz, 2H, PhCH2-CH2CO2),
6.42 (dd, 3J = 7.8 Hz, 4J = 1.5 Hz, 1H, CHarom), 6.56 (d, 4J = 1.8 Hz,
1H, CHarom), 6.57 (d, 3J = 8.4 Hz, 1H, CHarom). 13C NMR (MeOD-
d4, 75 MHz) δ = 31.5 (PhCH2-CH2CO2), 37.4 (PhCH2-CH2CO2),
116.4 + 116.5 + 120.6 (3 CHarom), 133.9 + 144.5 + 146.2 (3
Cqarom). IR (cm−1) νmax = 3300, 1713, 1604, 1518, 1444, 1362, 1284,
1194, 1149, 1113. HPLC purity (λ = 240 nm) > 99% (retention time
9.2 min).
3
CO2CH2CH3), 6.14 (d, J = 15.9 Hz, 1H, PhCHCHCO2), 6.73 (d,
3
4
3J = 8.4 Hz, 1H, CHarom), 6.90 (dd, J = 8.1 Hz, J = 1.8 Hz, 1H,
4
3
CHarom), 7.03 (d, J = 1.8 Hz, 1H, CHarom), 7.40 (d, J = 15.9 Hz,
1H, PhCHCHCO2), 8.02 + 8.28 (2 bs, 2 × 1H, 2 OH). 13C NMR
(acetone-d6, 75 MHz) δ = 14.7 (CO2CH2CH3), 60.6 (CO2CH2CH3),
115.2 + 115.8 + 116.4 + 122.5 (PhCHCHCO2 + 3 CHarom), 127.7
+ 146.3 + 148.7 (3 Cqarom), 145.6 (PhCHCHCO2), 167.5 (CO2).
IR (cm−1) νmax = 3430, 2960, 2581, 1658, 1610, 1596, 1515, 1453,
1307, 1281, 1219, 1173, 1118, 1051, 973. HPLC purity (λ = 254 nm):
99% (retention time 13.7 min).
(E)-3-(3,4-Dihydroxyphenyl)-N-ethylacrylamide (Caf-CONHEt).
To a solution of caffeic acid Caf-CO2H (108 mg, 0.60 mmol, 1
equiv) in DMF (1 mL), were added, at 0 °C, DIEA (110 μL, 0.63
mmol, 1 equiv), ethylamine 70 wt % in water (75 μL, 0.91 mmol, 1.1
equiv), then the solution of BOP (280 mg, 0.96 mmol, 1 equiv) in
DCM (1 mL). After stirring at room temperature for 24 h, the mixture
was concentrated and the residue poured into water and extracted
three times with EtOAc. The combined organic layers were then
washed with HCl 1 M and brine, dried over Na2SO4, filtered, and the
filtrate concentrated. The residue was finally purified by column
chromatography (cyclohexane/EtOAc 3/7) to yield Caf-CONHEt as
a white solid (72 mg, 58% yield); Rf = 0.15 (cyclohexane/EtOAc 3/7);
mp 178−181 °C (lit. 117−118 °C).43 1H NMR (MeOD-d4, 300
MHz) δ = 1.06 (t, 3J = 7.4 Hz, 3H, CONHCH2CH3), 3.21 (q, 3J = 7.2
Hz, 2H, CONHCH2CH3), 6.25 (d, 3J = 15.6 Hz, 1H, PhCH
CHCON), 6.67 (d, 3J = 8.4 Hz, 1H, CHarom), 6.79 (dd, 3J = 8.1 Hz, 4J
= 1.8 Hz, 1H, CHarom), 6.91 (d, 4J = 2.1 Hz, 1H, CHarom), 7.28 (d,
3J = 15.6 Hz, 1H, PhCHCHCON). 13C NMR (MeOD-d4, 75 MHz)
δ = 14.9 (CONHCH2CH3), 35.4 (CONHCH2CH3), 115.1 + 116.5 +
118.5 + 122.1 (PhCHCHCON + 3 CHarom), 128.4 + 146.7 +
148.7 (3 Cqarom), 142.1 (PhCHCHCON), 168.6 (CON). IR
(cm−1) νmax = 3312, 2359, 1651, 1592, 1555, 1514, 1482, 1469, 1421,
1388, 1369, 1347, 1300, 1265, 1239, 1205, 1172, 1116, 992, 969.
HPLC purity (λ = 320 nm): 95.5% (retention time 9.8 min).
(E)-4-(3-Hydroxyprop-1-enyl)benzene-1,2-diol (Caf-CH2OH). To a
solution of LiAlH4 (31 mg, 0.8 mmol, 1.9 equiv) in anhydrous THF (4
mL) was added dropwise a solution of benzyl chloride (94 μL, 0.8
mmol, 1.9 equiv) in anhydrous THF (1 mL), and the mixture was
stirred at room temperature for 30 min to allow formation of AlH3. To
this solution was added dropwise a solution of Caf-CO2Me (83 mg,
0.4 mmol, 1 equiv) in anhydrous THF (1 mL). After further stirring at
room temperature for 5 h, the mixture was successively treated with
NaHCO3 5% (10 mL) and HCl 1 M (10 mL) then extracted with
DCM (3 × 10 mL). The combined organic layers were washed with
brine (15 mL), dried over Na2SO4, filtered, and concentrated. The
residue was finally purified by column chromatography (cyclohexane/
EtOAc 5/5) to yield Caf-CH2OH as a brownish solid (25 mg, 35%
yield); Rf = 0.15 (cyclohexane/EtOAc 5/5); mp 147 °C (lit. 144−145
°C).45 1H NMR (MeOD-d4, 300 MHz) δ = 16 (dd, J = 1.5 Hz, J =
6.0 Hz, 2H, CH2OH), 6.11 (td, 3J = 6.0 Hz, 3J = 15.6 Hz, 1H,
2
3
3
PhCHCHCH2), 6.43 (d, J = 15.6 Hz, 1H, PhCHCHCH2), 6.72
4
(m, 2H, CHarom), 6.87 (d, J = 1.5 Hz, 1H, CHarom). 13C NMR
(MeOD-d4, 75 MHz) δ = 64.0 (CH2OH), 114.0 + 116.3 + 119.9 +
126.7 (PhCHCHCH2 + 3 CHarom), 130.7 + 146.4 + 146.4 (3
Cqarom), 132.2 (PhCHCHCH2). IR (cm−1) ν max 3600−3300,
2928, 1652, 1591, 1458, 1416, 1058, 968. HPLC purity (λ = 254 nm):
86% (retention time 8.8 min).
(E)-3-(3,4-Dihydroxyphenyl)acrylamide (Caf-CONH2). To a sol-
ution of caffeic acid Caf-CO2H (200 mg, 1.1 mmol, 1 equiv) in DMF
(1 mL), were added, at 0 °C, DIEA (195 μL, 1.1 mmol, 1 equiv),
tritylamine (738 mg, 2.8 mmol, 2.5 equiv), and then the solution of
BOP (475 mg, 1.1 mmol, 1 equiv) in DCM (2 mL). After stirring at
room temperature for 96 h, the mixture was concentrated and the
residue poured into water and extracted three times with EtOAc. The
combined organic layers were then washed with HCl 1 M and brine,
dried over Na2SO4, filtered, and the filtrate concentrated. The residue
was finally purified by column chromatography (cyclohexane/EtOAc
5/5 to 3/7) to yield Caf-CONHTr as a white solid (132 mg, 28%
(E)-N-Methoxycinnamamide (Cin-CONHOMe). To a solution of
Cin-CO2H (300 mg, 2 mmol, 1 equiv) in anhydrous DCM (10 mL)
was added dropwise thionyl chloride (365 μL, 5 mmol, 2.5 equiv).
After refluxing for 2 h and cooling, the mixture was concentrated and
diluted with anhydrous DCM (20 mL). O-Methylhydroxylamine
hydrochloride (126 mg, 2.3 mmol, 1.1 equiv) and pyridine (390 μL,
4.9 mmol, 2.4 equiv) were added at 0 °C. After stirring at rt overnight,
the reactive medium was washed with water, and the organic layer was
then dried over Na2SO4, filtered, and the filtrate concentrated. The
residue was finally purified by column chromatography (cyclohexane/
EtOAc 5/5) to yield Cin-CONHOMe as a white solid (250 mg, 70%
yield); Rf = 0.30 (cyclohexane/EtOAc 5/5); mp = 87−90 °C (lit. 93−
95 °C).25 1H NMR (CDCl3, 300 MHz) δ 3.75 (s, 3H, OCH3), 6.56
(m, 1H, PhCHCHCO), 7.20 (m, 4H, CHarom), 7.39 (m, 1H,
CHarom), 7.65 (d, 3J = 15.6 Hz, 1H, PhCHCHCO), 10.70 (bs, 1H,
NH). 13C NMR (CDCl3, 75 MHz) δ 64.3 (OCH3), 117.3 (PhCH
CHCO), 127.9 + 128.8 + 129.9 (3 CHarom), 134.7 (Cqarom), 144.8
(PhCHCHCO), 164.7 (CO). IR (cm−1) ν max 3130, 1649, 1617,
1522, 1342, 1220, 1059, 972, 929. HPLC purity (λ = 254 nm): 98%
(retention time 12.3 min).
1
yield); Rf = 0.35 (cyclohexane/EtOAc 5/5); mp 84−86 °C. H NMR
(MeOD-d4, 300 MHz) δ = 7.20−7.30 (m, 20H, CHarom). 13C NMR
(MeOD-d4, 75 MHz) δ = 67.7 (CPh3), 115.4 + 116.5 + 119.3 + 122.3
(PhCHCHCON + 3 CHarom), 127.9 (CHtrityl), 146.2 + 149.4 (2
Cqarom), 128.8 + 129.0 + 129.5 + 130.1 (CHtrityl), 142.7 (PhCH
CHCON), 168.7 (CONH). IR (cm-1) νmax = 3473, 1595, 1488, 1444,
1285, 1201, 1180, 1117, 1032, 946. HPLC purity (λ = 320 nm): 70%
(retention time 18.3 min). To a solution of Caf-CONHTr (66 mg,
0.16 mmol, 1 equiv) in anhydrous DCM (300 μL) was added TFA
(600 μL). After stirring at room temperature for 3 h, addition of
triethylsilane (75 μL, 0.47 mmol, 3 equiv) and further stirring at room
temperature for 30 min, the mixture was concentrated and the residue
purified by column chromatography (EtOAc 100) to yield Caf-
CONH2 as a white solid (19 mg, 68% yield); Rf = 0.45 (EtOAc 100);
2-Benzylidenemalonic Acid (Cin-(CO2H)2). A mixture of benzalde-
hyde (200 μL, 2.0 mmol, 1 equiv), malonic acid (206 mg, 2.0 mmol, 1
equiv), and L-proline (24 mg, 0.2 mmol, 0.1 equiv) was heated at 95
°C for 2 h then cooled and diluted in DCM. The organic layer was
washed with HCl 1M, and then the aqueous layer was extracted with
1
mp 165−169 °C. H NMR (MeOD-d4, 300 MHz) δ = 6.40 (d, 3J =
15.6 Hz, 1H, PhCHCHCON), 6.76 (dd, 3J = 8.1 Hz, 4J = 1.5 Hz,
1H, CHarom), 6.91 (d, 3J = 8.4 Hz, 1H, CHarom), 7.01 (d, 4J = 1.8
Hz, 1H, CHarom), 7.41 (d, 3J = 15.9 Hz, 1H, PhCHCHCON). 13C
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dx.doi.org/10.1021/jm400374q | J. Med. Chem. 2013, 56, 4619−4630