1020
E. GABRIELE AL.
(E)-2-(allyldisulfanyl)ethyl 3-(3,4-bis((2-methoxyethoxy)methoxy)- The organic layer was dried with anhydrous Na2SO4, filtered and
the solvent was removed under reduced pressure to obtain a yel-
low oil, which crystallised spontaneously in the fridge during the
night. The solid was rinsed with ethyl ether to give ash gray crys-
tals. Yield: 80%. Melting point 62.3–64.6 ꢀC. 1H-NMR (300 MHz,
DMSO-d6): d ¼ 8.38 (s, 1H, NH collapsed with D2O), 7.38–7.30 (m,
2H, ArH and CH ¼ CH), 7.17 (m, 2H, ArH), 6.46 (d, 1H, J ¼ 15.6 Hz,
CH ¼ CH), 5.26 (s, 4H, OCH2O), 3.78–3.69 (m, 4H, CH2), 3.60–3.39
(m, 9H, CH3 and CH2), 3.32 (t, 2H, J ¼ 6.3 Hz, CH2S), 3.20 (s, 6H,
OCH3) ppm. 13C-NMR (75 MHz, CD3OD): d ¼ 167.6, 149.0, 147.4,
140.4, 129.3, 122.9, 118.6, 116.7, 116.0, 94.3, 94.0, 71.4, 71.3, 67.7,
phenyl)acrylate (43) and N-acylurea by-product (45)
(a) The raw yellow oil initially obtained was partially crystallised in
freezer; after dilution with ether and filtration, white crystals have
been obtained, which resulted to be the N-acylurea (45). (b) The
ethereal mothers, evaporated to dryness were purified through CC
(CH2Cl2/MeOH; in gradient up to 99:1) to achieve compound (43).
(E)-3-(3,4-bis((2-methoxyethoxy)methoxy)phenyl)-N-cyclohexyl-N-
(cyclohexylcarbamoyl) acrylamide (45)
1H-NMR (300 MHz, CDCl3): d ¼ 7.58 (d, 1H, J ¼ 15.6 Hz, CH ¼ CH), 67.6, 57.7, 57.6, 49.3, 38.7, 35.1 ppm. HRMS (ESI) m/z Calcd for
7.34 (d, 1H, J ¼ 1.4 Hz, ArH), 7.21 (d, 1H, J ¼ 8.2 Hz), 7.10 (dd, 1H, C18H28NO9S2 [M þ H]þ: 494.15185; found: 494.15112.
J ¼ 1.4 and 8.2 Hz, ArH), 7.05 (br s, 1H, NH collapsed with D2O),
6.61 (d, 1H, J ¼ 15.6 Hz, CH ¼ CH), 5.33 (s, 2H, CH2), 5.30 (s, 2H,
3-(3,4-Dihydroxyphenyl)acrylate esters (21, 23, 24) and amide (22)
(general method)
CH2) 4.10–4.09 (m, 1H, CH), 3.87–3.83 (m, 4H, CH2), 3.75–3.73 (m,
1H, CH), 3.57–3.36 (s, 6H, OCH3), 1.99–1.58 (m, 10H, CH), 1.41–1.14
(m, 10H, CH) ppm. 13C-NMR (75 MHz, CDCl3): d ¼ 167.1, 154.1,
149.0, 147.3, 143.1, 129.2, 122.9, 118.06, 116.3, 116.2, 94.6, 94.1,
77.0, 71.5, 71.4, 67.9, 59.0, 56.2, 49.8, 32.8, 30.9, 26.2, 26.2, 25.4,
25.3, 24.66 ppm. HRMS (ESI) m/z Calcd for C30H47N2O8 [M þ H]þ:
563.33324; found: 563.33222.
To a solution of the appropriate 3-(3,4-dihydroxyphenyl)acrylate
derivative (28, 29, 43, 44; 0.42 mmol) in anhydrous CH2Cl2 or
CHCl3 (2 ml), trifluoroacetic acid (0.32 ml, 4.21 mmol) was added
and the reaction mixture was stirred, under argon, at r.t. for 5–8 h.
After the completion of reaction, the solvent and the trifluoroace-
tic acid were evaporated to dryness. The residue was washed with
the solvents indicated for each compounds or purified by CC (sil-
ica, eluent as indicated).
(E)-2-(Allyldisulfanyl)ethyl 3-(3,4-bis((2-methoxyethoxy)methoxy)-
phenyl)acrylate (43)
Yellow oil. Yield: 40%. 1H-NMR (300 MHz, DMSO-d6): d ¼ 7.56 (d,
1H, J ¼ 15.6 Hz, CH ¼ CH), 7.48 (d, 1H, J ¼ 1.2 Hz, ArH), 7.30 (dd, 1H,
J ¼ 1.2 mand 8.2 Hz, ArH), 7.11 (d, 1H, J ¼ 8.2 Hz, ArH), 6.49 (d, 1H,
J ¼ 15.6 Hz, CH ¼ CH), 5.90–5.70 (m, 1H, CH ¼ CH2), 5.40–5.00 (m,
6H, OCH2O and CH ¼ CH2), 4.35 (d, 2H, J ¼ 6.3 Hz, CH2), 3.85–3.60
(m, 4H, CH2), 3.52–3.35 (m, 6H, CH2), 3.20 (s, 6H, OCH3), 3.01 (d,
2H, J ¼ 6.3 Hz, CH2) ppm. 13C-NMR (75 MHz, CDCl3): d ¼ 166.8,
149.2, 147.2, 144.8, 133.2, 128.7, 123.6, 118.8, 116.1, 115.9, 109.9,
94.5, 94.0, 71.4, 71.3, 68.0, 67.9, 62.4, 59.1, 59.0, 42.3, 37.2 ppm.
(E)-2-(methylsulfonylthio)ethyl 3-(3,4-dihydroxyphenyl)acrylate (21)
Solid residue washed with CH2Cl2/petroleum ether (1:1) and dried
in vacuo to afford the title compound as a white solid. Yield: 64%.
Melting point 133.1–134.8 ꢀC. 1H-NMR (300 MHz, DMSO-d6):
d ¼ 9.61 (br s, 1H, OH collapsed with D2O), 9.13 (br s, 1H, OH col-
lapsed with D2O), 7.50 (d, 1H, J ¼ 15.9 Hz, CH ¼ CH), 7.04–7.00 (m,
2H, ArH), 6.47 (d, 1H, J ¼ 8.9 Hz, ArH), 6.25 (d, 1H, J ¼ 15.9 Hz,
CH ¼ CH), 4.39 (t, 2H, J ¼ 6.3 Hz, CH2), 3.56 (s, 3H, CH3), 3.51 (t, 2H,
J ¼ 6.3 Hz, CH2) ppm. 13C-NMR (75 MHz, d6-DMSO): d ¼ 166.9, 149.3,
146.5, 146.2, 126.0, 122.2, 116.4, 115.6, 113.9, 62.8, 50.8, 35.1.
HRMS (ESI) m/z Calcd for C12H15O6S2 [M þ H]þ: 319.03100; found:
319.03052.
(E)-4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl 3-(3,4-bis((2-methoxye-
thoxy)methoxy)phenyl) acrylate (44)
CC (EtOAc/cyclohexane; in gradient up to 37:63). A red oil was
obtained which crystallized spontaneously in the fridge during the
night. The solid was rinsed with petroleum ether to give orange
crystals. Yield: 60%. Melting point 81.4–84.0 ꢀC. 1H-NMR (300 MHz,
(E)-S-2-(3-(3,4-dihydroxyphenyl)acrylamido)ethyl methanesulfono-
thioate (22)
DMSO-d6): d ¼ 7.98 (d, 2H, J ¼ 8.8 Hz, ArH), 7.84–7.76 (m, 2H, The obtained residue was purified by CC (silica gel; CH2Cl2/MeOH;
CH ¼ CH and ArH), 7.59 (d, 1H, J ¼ 1.2 Hz, ArH), 7.47–7.32 (m, 3H, in gradient up to 99:1). The title compound was obtained as a tan
ArH), 7.17 (d, 1H, J ¼ 8.8, ArH), 6.76 (d, 1H, J ¼ 15.9 Hz, CH ¼ CH), oil. Yield: 9%. 1H-NMR (300 MHz, DMSO-d6): d ¼ 8.25 (s, 2H, –OH
5.30 (s, 4H, OCH2O), 3.78–3.70 (m, 4H, CH2), 3.50–3.41 (m, 4H, CH2), collapsed with D2O), 7.54 (s, 1H, NH collapsed with D2O), 7.42 (d,
3.21 (s, 6H, OCH3) ppm. 13C-NMR (75 MHz, DMSO-d6): d ¼ 215.9, 1H, J ¼ 15.6 Hz, CH ¼ CH), 7.08 (d, 1H, J ¼ 1.1 Hz, ArH), 6.95 (dd, 1H,
173.2, 165.1, 154.0, 150.1, 147.3, 147.2, 136.2, 129.1, 128.2, 124.9,
123.6, 117.2, 116.7, 115.3, 94.3, 93.9, 71.4, 71.3, 68.1, 68.0, 58.5,
68.4 ppm.
J ¼ 1.1 and 8.2 Hz, ArH), 6.84 (d, 1H, J ¼ 8.2 Hz, ArH), 6.44 (d, 1H,
J ¼ 15.6 Hz, CH ¼ CH), 3.78–3.60 (m, 2H, NHCH2), 3.49 (s, 3H, CH3),
3.41 (t, 2H, J ¼ 6.3 Hz, CH2S) ppm. 13C-NMR (75 MHz, DMSO-d6):
d ¼ 166.2, 147.9, 145.9, 140.1, 126.6, 120.9, 118.2, 116.1, 114.2, 50.6,
38.8, 35.8 ppm. HRMS (ESI) m/z Calcd for C12H16NO5S2 [M þ H]þ:
(E)-S-2-(3-(3,4-bis((2-methoxyethoxy)methoxy)phenyl)acrylami-
do)ethyl methanesulfonothioate (29)
318.04699; found: 318.04643.
S-2-aminoethyl methanesulfonothioate hydrobromide (3, 101 mg,
0.65 mmol) and DIPEA (0.11 ml, 0.65 mmol) were mixed together in
anhydrous CHCl3 (4 ml) and (E)-3-(3,4-bis((2-methoxyethoxy)me-
thoxy)phenyl)acrylic acid (212 mg, 0.59 mmol), EDAC (107 mg,
0.89 mmol) and DMAP (7.3 mg, 0.06 mmol) were added at r.t. The
reaction mixture was stirred for 4 h under argon and it was moni-
tored by TLC. The obtained residue was poured into a separation
(E)-2-(allyldisulfanyl)ethyl 3-(3,4-dihydroxyphenyl)acrylate (23)
The obtained residue was taken up with CH2Cl2 and washed twice
with iced-brine. The organic layer was dried with anhydrous
Na2SO4, filtered and evaporated to dryness to obtain a residue
that was purified by preparative TLC (silica; eluent mixture:
CH2Cl2/MeOH 10:0.4). The title compound was obtained as a
funnel, firstly washed with a cold solution of 0.5 N HCl, then with green-gray oil. Yield: 42%. 1H-NMR (300 MHz, acetone-d6): d ¼ 8.45
a cold solution of 5% (w/w), NaHCO3 and finally with cold brine. (s, 1H, OH collapsed with D2O), 8.17 (s, 1H, OH collapsed with