The Journal of Organic Chemistry
Article
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2:1 → 1:1; Hex/EtOAc) to obtain 5 (6.72 g, 13.37 mmol) as a clear
viscous oil in an 81% yield.
145−148 °C. H NMR (400 MHz, chloroform-d) δ 7.73 (d, J = 8.3
Hz, 4H), 7.31 (d, J = 8.3 Hz, 4H), 4.83 (s, 2H), 3.02 (t, J = 6.1 Hz,
6H), 2.43 (s, 4H), 1.67 (p, J = 6.2 Hz, 2H); 13C{1H} NMR (101
MHz, chloroform-d) δ 143.6, 136.8, 129.8, 127.0, 39.7, 29.9, 21.5.
HRMS (ESI) m/z [M + H]+ calcd for C17H23O4N2S2 383.1094, found
383.1097.
Method C. A 250 mL round-bottom flask equipped with a
magnetic stir bar, a nitrogen inlet, and a condenser was charged with
THF/H2O (5:1, 75 mL) and degassed with nitrogen via gas
dispersion frit for 20 min. The addition of tosyl-cystamine (7.60 g,
16.50 mmol) and tributyl phosphine (4.89 mL, 19.83 mmol) was
followed, and the reaction was refluxed for 2 h via a heating mantle.
The solution was then cooled down to room temperature, and
degassed 2 M NaOH (17.4 mL, 34.80 mmol) was added in one
portion. The solution was stirred at room temperature for 5 min, 1,3-
dibromopropane (0.76 mL, 7.43 mmol) was added, and the solution
was refluxed for 12 h via a heating mantle. The reaction mixture was
diluted with EtOAc (150 mL), washed with 1 M HCl (2 × 20 mL),
water (20 mL), and brine (15 mL), dried with sodium sulfate, filtered,
concentrated in vacuo, and subjected to column chromatography (3:1
→ 1:1, Hex/EtOAc). Compound 5 (7.30 g, 14.52 mmol) was
obtained in an 88% yield as an opaque oil.
N,N′-(Propane-1,3-diyl)bis(N-(2-hydroxyethyl)-4-methyl-
benzenesulfonamide) (8a). Method A. A 25 mL round-bottom
flask equipped with a condenser, a nitrogen inlet, and a magnetic stir
bar was charged with N,N′-(propane-1,3-diyl)bis(4-methylbenzene-
sulfonamide) (7) (0.82 g, 2.14 mmol), potassium carbonate (0.65 g,
4.71 mmol), ethylene carbonate (0.75 g, 8.56 mmol), and DMF (0.5
M, 4.3 mL). This solution was maintained at 110−120 °C for 4 h in
an oil bath controlled with a thermocouple and then cooled to 23 °C.
The DMF was removed, and the yellow residue was taken up in ethyl
acetate (50 mL) and washed with 0.5 M HCl (10 mL), water (10
mL), and brine (10 mL). The organic layer was dried with sodium
sulfate, filtered, and concentrated in vacuo to afford a thick yellow oil.
The residue was subjected to column chromatography (2:1, ethyl
acetate/hexane) to afford 8a (0.473 g, 1.01 mmol) as a clear viscous
oil in a 47% yield.
Method B. A 50 mL round-bottom flask was charged with N,N′-
(propane-1,3-diyl)bis(4-methylbenzenesulfonamide) (7) (5.00 g, 13.1
mmol), ethylene carbonate (2.88 g, 32.8 mmol), and potassium
hydroxide (0.050 g, 0.891 mmol). The mixture was stirred for 4 h at
115 °C in an oil bath controlled with a thermocouple, at which time,
the residue was cooled to 0 °C via an external ice bath and diluted
with MilliQ water (10 mL). The solution was extracted with ethyl
acetate (20 mL × 3), and the combined organic layers were washed
with 1 M HCl (10 mL), water (10 mL), and brine (5 mL), dried with
sodium sulfate, filtered, and concentrated in vacuo. The remaining
residue was purified via flash chromatography (3:2 EtOAc/Hex)
providing 8a (5.47 g, 11.66 mmol) in an 89% yield as a clear oil. Rf =
0.40 (EtOAc); 1H NMR (400 MHz, chloroform-d) δ 7.63 (d, J = 8.4
Hz, 4H), 7.25 (d, J = 8.1 Hz, 4H), 3.74−3.64 (m, 4H), 3.42−3.33 (m,
4H), 3.20−3.09 (m, 8H), 2.35 (s, 6H), 1.90 (p, J = 7.4 Hz, 2H);
13C{1H} NMR (101 MHz, chloroform-d) δ 143.6, 135.5, 129.8,
Method D. A 500 mL two-neck round-bottom flask equipped with
a magnetic stir bar, a pressure-equalizing drop funnel, a condenser,
and a nitrogen inlet was charged with THF/H2O (5:1, 217 mL) and
degassed with nitrogen via gas dispersion frit for 20 min. At which
time, NaOH (0.95 g, 23.87 mmol) followed by TCEP·HCl (6.84 g,
23.87 mmol) was added, and the mixture was degassed with nitrogen
via gas dispersion frit for 10 min. Tosyl-cystamine (10.0 g, 21.7
mmol) was added in one portion, and the solution was refluxed with a
heating mantle until the disappearance of a starting material via TLC
(∼15 min). The solution was cooled down to room temperature, at
which time, nitrogen-degassed 2 M NaOH (54 mL, 27.00 mmol) was
added in one portion, and the pressure-equalizing drop funnel was
charged with 1,3-dibromopropane in nitrogen-degassed THF (10
mL). The solution was stirred at room temperature for 5 min followed
by the dropwise addition of 1,3-dibromopropane over 15 min and
refluxed with a heating mantle for 12 h. The reaction mixture was
diluted with EtOAc (300 mL), washed with 1 M HCl (2 × 30 mL),
water (30 mL), and brine (20 mL), dried with sodium sulfate, filtered,
concentrated in vacuo, and subjected to column chromatography (3:1
→ 1:1, Hex/EtOAc) to afford compound 5 (9.82 g, 19.53 mmol) in a
127.2, 61.4, 51.7, 47.9, 28.6, 21.5. IR νmax 3524, 2927, 1597, 1455,
1331, 1155, 1088, 815, 728, 656 cm−1; HRMS (ESI) m/z [M + H]+
calcd for C21H31O6N2S2 471.1618, found 471.1619.
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90% yield as an opaque oil. Rf = 0.5 (Hex/EtOAc, 1:1). H NMR
(400 MHz, chloroform-d) δ 7.70 (d, J = 8.3 Hz, 4H), 7.25 (d, J = 8.2
Hz, 4H), 5.54−5.34 (m, 2H), 3.04 (t, J = 7.0 Hz, 4H), 2.52 (t, J = 6.8
Hz, 4H), 2.41 (t, J = 7.1 Hz, 8H), 2.36 (s, 6H), 1.65 (p, J = 7.1 Hz,
2H); 13C{1H} NMR (101 MHz, chloroform-d) δ 143.6, 136.8, 129.8,
127.0, 42.3, 31.6, 30.2, 28.9, 21.5. IR νmax 3277, 2921, 2256, 1597,
1494, 1409, 1321, 1185, 1092, 1019, 813 cm−1. HRMS (ESI) m/z [M
+ Na]+ calcd for C21H30O4N2NaS4 525.0981, found 525.0985.
2,2′-(Propane-1,3-diylbis(sulfanediyl))diacetyl Chloride (6).
A 50 mL flame-dried round-bottom flask equipped with a magnetic
stir bar, a condenser, and a calcium sulfate drying tube was charged
with 2,2′-(propane-1,3-diylbis(sulfanediyl))diacetic acid (2) (0.400 g,
1.78 mmol), methylene chloride (17.8 mL), and thionyl chloride
(0.320 mL, 1.78 mmol) in the indicated order. This mixture was
refluxed with an external heating mantle for 12 h and then
concentrated in vacuo. To the yellow oil, trituration from toluene
(3 × 10 mL) afforded the final bis-acid chloride 6 (0.428 g, 1.64
N-(2-Hydroxyethyl)-4-methyl-N-(3-((4-methylphenyl)-
sulfonamido)propyl)benzenesulfonamide (8b). A 50 mL round-
bottom flask was charged with N,N′-(propane-1,3-diyl)bis(4-methyl-
benzenesulfonamide) (7) (5.00 g, 13.1 mmol), ethylene carbonate
(2.88 g, 32.8 mmol), and potassium hydroxide (0.050 g, 0.891 mmol).
The mixture was stirred for 2 h at 110 °C in an oil bath controlled
with a thermocouple, at which time, the residue was cooled to 0 °C
via an external ice bath and diluted with MilliQ water (10 mL). The
solution was extracted with ethyl acetate (20 mL × 3), and the
combined organic layers were washed with 1 M HCl (10 mL), water
(10 mL), and brine (5 mL), dried with sodium sulfate, filtered, and
concentrated in vacuo. The remaining residue was purified via flash
chromatography (3:2 EtOAc/Hex) providing 8b (2.18 g, 5.11 mmol)
in a 39% yield as a clear oil. Rf = 0.50 (EtOAc); 1H NMR (400 MHz,
chloroform-d) δ 7.71 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H),
7.31−7.21 (m, 4H), 5.64 (t, J = 6.4 Hz, 1H), 3.68 (q, J = 5.3 Hz, 2H),
3.28−3.10 (m, 4H), 2.99 (q, J = 6.3 Hz, 2H), 2.83 (s, 1H), 2.39 (s,
3H), 2.38 (s, 3H), 1.77 (p, J = 6.5 Hz, 2H); 13C{1H} NMR (101
MHz, chloroform-d) δ 143.8, 143.3, 136.9, 135.3, 129.9, 129.7, 127.2,
127.0, 61.5, 51.8, 47.5, 39.9, 28.9, 21.5. IR νmax 3475, 3217, 2932,
2873, 1597, 1493, 1451, 1326, 1151, 1091, 741 cm−1. HRMS (ESI)
m/z [M + Na]+ calcd for C19H26O5N2NaS2 449.1175, found
449.1176.
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mmol) in a 92% yield as a viscous light-yellow oil. H NMR (300
MHz, chloroform-d) δ 3.71 (s, 1H), 2.78 (t, J = 7.1 Hz, 1H), 1.93 (p,
J = 7.1 Hz, 1H); 13C{1H} NMR (75 MHz, chloroform-d) δ 170.2,
45.2, 31.2, 27.8.
N,N′-(Propane-1,3-diyl)bis(4-methylbenzenesulfonamide)
(7). A 500 mL round-bottom flask equipped with a magnetic stir bar
and a pressure-equalizing drop funnel was charged with water (80
mL) and potassium carbonate (13.82 g, 100.0 mmol) followed by 1,3-
propanediamine (4.2 mL, 50.0 mmol). The pressure-equalizing drop
funnel was charged with THF (85 mL) and para-toluenesulfonyl
chloride (19.06 g,100.0 mmol) and was added over a 4.5 h period to
the carbonate solution. Once added, the solution was stirred for 10 h
at 23 °C and poured over water (40 mL) at 0 °C. The white solid was
filtered, washed with ethanol (50.0 mL, 0 °C), and dried in vacuo to
afford bis-sulfonamide 7 (18.17 g, 47.50 mmol) in a 95% yield. Mp =
N-(2-(2-Hydroxyethoxy)ethyl)-N-(3-((N-(2-hydroxyethyl)-4-
methylphenyl)sulfonamido)propyl)-4-methylbenzenesulfo-
namide (8c). A 50 mL round-bottom flask was charged with N,N′-
(propane-1,3-diyl)bis(4-methylbenzenesulfonamide) (7) (5.00 g, 13.1
mmol), ethylene carbonate (2.88 g, 32.8 mmol), and potassium
hydroxide (0.050 g, 0.891 mmol). The mixture was stirred for 4 h at
190 °C in an oil bath controlled with a thermocouple, at which time,
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J. Org. Chem. XXXX, XXX, XXX−XXX