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Chem. Pharm. Bull.
Vol. 65, No. 12 (2017)
(s). FT-IR (wavenumber, cm−1) 2995, 2954, 2902, 2832, 1724, solvent was evaporated to get the crude product as yellow oil.
1577, 1509, 1438, 1280.
The crude product was then purified by column chromatogra-
Synthesis of N-Ethylacrylamide-2-(4-(dimethoxymethyl)- phy using silica gel as stationary phase and a mixture of ethyl
benzamide)
acetate–cyclohexane (15:85, v/v) as eluent. The purification
Methyl-4-(dimethoxymethyl)benzoate (700.0mg) and 1,2-di- was monitored by TLC, the fraction with Rf=0.33 was col-
aminoethane (10.0mL) were mixed and heated up to 80°C for lected and the solvent was removed to get the desired product
1
24h and then evaporated to dryness under vacuum. The yel- as pale yellow oil. Yield: 68%. H-NMR (300MHz, CDCl3)
low solid obtained was dissolved in dry CH2Cl2 (20.0mL) and δ: 8.50 (d, J=4.1Hz, 1H), 7.57 (td, J=7.7, 1.8Hz, 1H), 7.40
triethylamine (Et3N) (20.0mL) was added. The solution was (d, J=8.0Hz, 1H), 7.14 (dd, J=6.9, 5.5Hz, 1H), 3.82–3.77 (m,
cooled to 0°C in an ice bath. Acryloyl chloride (520.0mg) in 2H), 2.98–2.91 (m, 2H).
CH2Cl2 (10.0mL) was added dropwise for a period of 30min.
The reaction was stirred overnight at room temperature and
Synthesis of Pyridyldisulfide Ethylacrylate (M2)41)
To a solution of HPDS (V) (1.5g) in dry CH2Cl2 (20.0mL),
then transferred to a separating funnel with saturated NaHCO3 Et3N (1.0g) was added and the mixture was cooled in an ice
(aq) (30.0mL). The aqueous layer was extracted with CH2Cl2 bath. After that, a solution of acryloyl chloride (1.0g) in dry
(3×30.0mL). The organic extracts were combined and dried CH2Cl2 (10.0mL) was added during 30min. The mixture was
over Na2SO4, filtered, and evaporated to dryness under vac- stirred at room temperature for 12h. The stirring was stopped
uum to afford a crude solid, which was purified by column and the solid was removed by filtration. The obtained product
chromatography using silica gel as stationary phase and a was mixed with water (20.0mL). The aqueous layer was ex-
mixture of CH2Cl2–MeOH (90:10 v/v) as eluent to obtain a tracted with CH2Cl2 (3×30.0mL). The organic extracts were
1
white solid. H-NMR (300MHz, CDCl3) δ: 7.81 (d, J=8.3Hz, combined and dried over Na2SO4, filtered, and evaporated to
1H), 7.50 (d, J=8.2Hz, 1H), 6.27 (dd, J=17.0, 1.6Hz, 1H), 6.13 dryness under vacuum to afford a crude product as brown oil,
(dd, J=17.0, 10.0Hz, 1H), 5.63 (dd, J=10.0, 1.6Hz, 1H), 5.41 which was purified by column chromatography using silica
(s, 1H), 3.59 (s, 2H), 3.31 (s, 3H). 13C-NMR (75MHz, CDCl3) gel as stationary phase and a mixture of ethyl acetate–cy-
δ: 168.23 (s), 167.17 (s), 141.59 (s), 133.99 (s), 130.61 (s), 127.00 clohexane (25:75, v/v) as eluent to afford a pale yellow oil.
1
(s), 126.78 (s), 102.43 (s), 52.69 (s), 41.10 (s), 39.98 (s). FT-IR Yield: 78wt%. The reaction is shown in the Chart 1. H-NMR
(wavenumber cm−1) 3300, 3072, 2986, 2942, 2903, 2831, 1643, (300MHz, CDCl3) δ: 8.52–8.40 (m, 1H), 7.72–7.57 (m, 2H),
1544, 1505, 1436, 1250.
7.12–7.05 (m, 1H), 6.40 (dd, J=17.3, 1.4Hz, 1H), 6.09 (dd,
Synthesis of N-Ethylacrylamide-2-(4-formylbenzamide) (M1) J=17.3, 10.4Hz, 1H), 5.83 (dd, J=10.4, 1.4Hz, 1H), 4.41 (t,
A solution of N-ethylacrylamide-2-(4-(dimethoxymethyl)- J=6.4Hz, 2H), 3.08 (t, J=6.4Hz, 2H). 13C-NMR (101MHz,
benzamide) (500.0mg) in 1.0M HCl(aq) (5mL) was stirred CDCl3) δ: 165.93 (s), 159.82 (s), 149.88 (s), 137.14 (s), 131.40
at room temperature for 2h and then neutralized with satu- (s), 128.16 (s), 120.98 (s), 119.96 (s), 62.42 (s), 37.51 (s). The
rated NaHCO3(aq) (30.0mL). The aqueous layer was extracted final product was also analyzed by COSY, HSQC, HMBC and
with EtOAc (50.0mL) 3 times and the organic extracts were NOESY NMR spectroscopy as supplementary characteriza-
combined and dried over MgSO4, filtered, and evaporated to tion and is available in the Supplementary Materials from S14
dryness under vacuum to obtain a pale yellow solid which to S17.
was purified by column chromatography using silica gel as
Synthesis of Bi-functionalized Acrylic Copolymer (P1)
stationary phase and a mixture of CH2Cl2–MeOH (96:4 v/v) The copolymer P1 was made by RAFT polymerization fol-
1
as eluent to afford a white solid. H-NMR (300MHz, dimethyl lowing a procedure described in the literature.22) S-1-Dodecyl-
sulfoxide (DMSO)) δ: 10.14 (s, 1H), 8.84 (s, 1H), 8.32 (s, 1H), S′-(α,α-dimethyl-α″-acetic acid)trithiocarbonate (DDMAT)
8.13–8.02 (m, 4H), 6.27 (dd, J=17.1, 9.8Hz, 1H), 6.15 (dd, (20.8mg) and AIBN (1.9mg) were added to a small Schlenk
J=17.1, 2.3Hz, 1H), 5.65 (dd, J=9.8, 2.3Hz, 1H), 3.41 (dd, tube. N,N′-Dimethylacrylamide (910mg, 9,18mmol), N-
J=11.0, 6.1Hz, 4H). 13C-NMR (101MHz, DMSO) δ: 192.87 ethylacrylamide-2-(4-formylbenzamide) (281.0mg, 1,14mmol),
(s), 165.56 (s), 164.90 (s), 139.49 (s), 137.73 (s), 131.77 (s), and 2-pyridyl disulfide ethylacrylate (276,0mg, 1,14mmol)
129.35 (s), 127.92 (s), 125.07 (s), 38.15 (s). FT-IR (wavenumber, were then added followed by N,N-dimethylformamide (DMF)
cm−1) 3270, 3094, 2986, 2940, 2820, 2783, 2773, 1702, 1643, (4mL). The reaction mixture was degassed by 5 cycles of
1547, 1503, 1447, 1382. The final product was also analyzed freeze-vacuum-thaw and then it was bubbled for 30min with
by COSY, HSQC, HMBC and NOESY NMR spectroscopy as argon. The vessel was backfilled with argon and allowed to
supplementary characterization and is available in the Supple- warm to room temperature. The reaction mixture was then
mentary Materials from S7 to S10.
placed in an oil bath at 70°C with constant magnetic stirring,
General Procedure for the Preparation of the Acrylic and the polymerization was quenched after 21h with liquid
Monomer with Disulfide Functionality (M2)
Synthesis of Hydroxyethyl Pyridyldisulfide
nitrogen. The reaction mixture was dissolved in a minimal
amount of tetrahydrofuran (THF) and added dropwise to a
Hydroxyethyl pyridyldisulfide (HPDS) (V) was synthesized large excess of ice-cold diethyl ether. The solid polymer was
according to the literature.40) The reaction is shown in the then isolated by filtration, and the precipitation was repeated
Chart 1. Briefly, dithiodipyridine (DTDP) (IV) (5.0g) was dis- once before drying under high vacuum. Polymer P1 was
solved in methanol (25.0mL) and glacial acetic acid (350µL) obtained as a pale yellow solid. A schematic reaction can be
1
was then added. After that, a solution of mercaptoethanol seen in Chart 2. H-NMR (400MHz, CDCl3) δ: 10.06 (s), 8.44
(530 µL) in methanol (5.0mL) was added dropwise at room (s), 8.11 (s), 7.91 (s), 7.66 (s), 7.09 (s), 4.30 (s), 3.72 (s), 3.09 (s),
temperature during 30min under continuous stirring. Once 2.87 (s), 2.62 (s), 2.14 (s), 1.83 (s), 1.61 (s), 1.23 (s), 0.85 (s). P1
the addition was over, the reaction mixture was stirred at was also analyzed by size exclusion chromatography (SEC) to
room temperature for 4h. The stirring was stopped and the evaluate the molecular weight and differential scanning calo-