602
D. S. Baldwin et al.
7.19, m, 1H, Ar; 7.32–7.46, m, 3H, Ar; 7.9, m, 3H, Ar. 13C NMR
(CDCl3) δ 14.4, 31.7, 41.7, 51.5, 61.2, 110.4, 110.9, 115.0, 124.4,
126.4, 129.2, 131.0, 131.7, 132.0, 134.5, 139.7, 150.3, 166.4, 168.8.
in dimethylformamide (100 mL) for 4 h. The resulting mixture was
poured into water (500 mL) and the mixture extracted with diethyl ether
(3 × 200 mL). The combined organic extracts were washed with water
(3 × 100 mL), dried over sodium sulfate, and then evaporated to yield
the ester (18) as a viscous oil (17.8 g, 81%) (Found (ES): [M + Na]+,
322.1048. C17H17NO4 requires [M + Na]+, 322.1050). 1H NMR
(CDCl3) δ 3.73, br t, J 5.7 Hz, 2H, NCH2; 3.86, s, 3H, OCH3; 4.33, t, J
5.7 Hz, 2H, OCH2; 6.64, dt, J 1, 7 Hz, 1H, Ar; 6.78, d, J 7.9 Hz, 1H, Ar;
6.99, d, J 8.1 Hz, 1H, Ar; 7.05, br t, J 7.5 Hz, 1H, Ar; 7.39, dt, J 1.6, 8.5
Hz, 1H, Ar; 7.53, dt, J 1.8, 8.8 Hz, 1H, Ar; 7.85, dd, J 1.8, 7.7 Hz, 1H,
Ar; 7.92, dd, J 1.7, 8.1 Hz, 1H, Ar; 8.11, br s, NH, 1H; 10.52, s, CHO.
13C NMR (CDCl3) δ 42.0, 51.6, 67.1, 110.7, 111.0, 112.5, 115.2, 121.0,
125.2, 128.3, 131.8, 134.5, 135.6, 150.6, 160.8, 189.4.
Synthesis of Diol (15)
A suspension of the diester (14) (33.5 g, 0.09 mol) was slowly added to
a stirred suspension of lithium aluminium hydride (7.8 g, 0.2 mol) in
dry, freshly distilled tetrahydrofuran (500 mL) under a nitrogen
atmosphere, at 0°C. The mixture was stirred overnight and cooled, after
which the excess lithium aluminium hydride was hydrolysed by
dropwise addition of water (7.8 mL), 10% sodium hydroxide (12.3 mL)
and water (12.3 mL). The mixture was stirred at room temperature for
1 h. The solution was filtered and the precipitate washed several times
with dichloromethane. Evaporation of the filtrate yielded a pale yellow
oil, which was dissolved in dichloromethane and eluted with the same
solvent through a short silica gel column. Removal of the solvent
yielded the product (15) as an off-white solid that was recrystallized
from a mixture of dichloromethane/cyclohexane (24.2 g, 90%) (Found
(ES): [M + Na]+, 312.1025. C16H19NO2S requires [M + Na]+,
312.1029). 1H NMR (CDCl3) δ 3.12, br t, J 6.0 Hz, 2H, SCH2; 3.26, br
t, J 6.0 Hz, 2H, NHCH2; 4.46, s, 2H, CH2OH; 4.65, s, 2H, CH2OH;
6.53, br d, J 8.1 Hz, 1H, Ar; 6.62, dt, J 7.2, 0.9 Hz, 1H, Ar; 6.95, dd, J
7.2, 1.5 Hz, 1H, Ar; 7.10–7.22, m, 3H, Ar; 7.30, dd, J 6.6, 2.7 Hz, 1H,
Ar; 7.38, dd, J 6.9, 1.5 Hz, 1H, Ar. 13C NMR (CDCl3) δ 34.3, 42.1, 63.5,
64.5, 110.6, 116.9, 124.7, 127.1, 128.3, 128.8, 129.2, 129.5, 131.1,
133.5, 141.5, 146.7.
Synthesis of Diol (19)
The ester (18) (10.09 g, 0.034 mol) in dry tetrahydrofuran (50 mL) was
slowly added to a stirred suspension of lithium aluminium hydride
(1.8 g, 0.047 mol) in dry tetrahydrofuran (500 mL) under a nitrogen
atmosphere. The reaction mixture was stirred for 1 h, then cooled in an
ice bath, and the excess lithium aluminium hydride quenched by
successive dropwise additions of water (1.8 mL), 10% sodium
hydroxide (2.9 mL) and again water (2.9 mL). The mixture was stirred
overnight, then filtered through a small plug of Celite and the
precipitate was washed several times with dichloromethane.
Evaporation of the filtrate yielded the product as an oil. Rapid column
chromatography on silica gel, using dichloromethane as eluent, yielded
the pure diol (19) as a white, crystalline solid (5.0 g, 54%) (Found: C,
70.4; H, 7.0; N, 5.0. C16H19NO3 requires C, 70.3; H, 7.0; N, 5.1%). 1H
NMR (CDCl3) δ 3.56, br t, J 5.1 Hz, 2H, NCH2; 4.26, t, J 5.1 Hz, 2H,
OCH2CH2; 4.59, s, 4H, CH2OH; 6.67–6.73, m, 2H Ar; 6.88, d, J 8.1 Hz,
1H, Ar; 6.94, dt, J 0.8, 7.6 Hz, 1H, Ar; 7.02, dd, J 1.5, 7.3 Hz, 1H, Ar;
7.21–7.28, m, 3H, Ar. 13C NMR (CDCl3) δ 42.8, 61.1, 64.3, 66.3, 110.8,
111.3, 117.1, 121.0, 125.1, 129.1, 129.2, 129.3, 129.4, 129.7, 147.3,
156.5.
Synthesis of Dialdehyde (16)
Barium manganate (66.0 g, 0.26 mol) was added to a stirred solution of
diol (15) (4.4 g, 0.015 mol) in dry, freshly distilled dichloromethane
(150 mL). The mixture was stirred overnight, then filtered through a
small amount of silica gel and the black residue was washed several
times with dichloromethane. Evaporation of the combined filtrates
yielded (16) as an orange solid, which was recrystallized from a mixture
of ethanol/chloroform (2.7 g, 62%) (Found: C, 66.9; H, 5.4; N, 5.0.
Synthesis of Dialdehyde (17)
1
C16H15NO2S requires C, 67.3; H, 5.3; N, 4.9%). H NMR (CDCl3) δ
Barium manganate (45.0 g, 0.18 mol) was added to a stirred solution of
the diol (19) (3.0 g, 0.01 mol) in dry dichloromethane (120 mL). After
4 h, a further 10 g of barium manganate was added and the reaction
mixture was stirred overnight, then filtered through silica gel. The
residue was washed well with dichloromethane. Evaporation of the
filtrates yielded the product (17) as a pale yellow solid (2.2 g, 74%)
(Found: C, 71.0; H, 5.9; N, 5.3. C16H15NO3 requires C, 71.4; H, 5.6; N,
5.2%). 1H NMR (CDCl3) δ 3.76, m, 2H, NCH2; 4.31, br t, J 5.6 Hz, 2H,
OCH2; 6.75, t, J 7.4 Hz, 1H, Ar; 6.78, d, J 8.5 Hz, 1H, Ar; 6.98, d, J 8.4
Hz, 1H, Ar; 7.05, t, J 7.5 Hz, 1H; 7.41–7.56, m, 3H, Ar; 7.85, dd, J 1.8,
7.7 Hz, 1H, Ar; 8.65, br s, 1H, NH; 9.82, s, 1H, CHO; 10.50, s, 1H,
CHO. 13C NMR (CDCl3) δ 41.4, 66.9, 110.6, 112.4, 115.6, 118.8,
121.2, 125.1, 128.4, 135.8, 135.9, 136.8, 150.3, 160.7, 189.6, 194.1.
3.23, m, 2H, SCH2; 3.55, m, 2H, NHCH2; 6.64, br d, J 9.0 Hz, 1H, Ar;
6.73, t, J 7.2 Hz, 1H, Ar; 7.33–7.56, m, 5H, Ar; 7.86, dd, J 7.8, 1.2 Hz,
1H, Ar; 8.54 br s, 1H, NH; 9.81, s, 1H, CHO; 10.42, s, 1H, CHO. 13
C
NMR (CDCl3) δ 32.8, 41.2, 110.3, 115.4, 118.6, 126.1, 129.3, 131.4,
133.8, 134.6, 135.7, 136.6, 139.8, 149.7, 191.0, 193.7.
Synthesis of Macrocycle (5)
2,2′-Diaminodiethylamine (0.93 g, 0.009 mol) in methanol (20 mL)
was added very slowly to a stirred solution of dialdehyde (16) (2.56 g,
0.009 mol) in methanol (140 mL) with heating. The mixture was
refluxed for 1 h, and then allowed to cool. Excess sodium borohydride
(2.0 g, 0.053 mol) was added rapidly, followed by slow addition of ice,
resulting in a total volume of 500 mL. The mixture was left stirring
overnight, during which time an off-white gum separated out. The
mixture was extracted with dichloromethane (3 × 100 mL) followed by
a water wash (100 mL) of the combined extracts. The dichloromethane
extract was then dried with anhydrous sodium sulfate. Removal of the
solvent on the rotary evaporator yielded the macrocycle (5) as a solid,
which was subsequently recrystallized from acetonitrile (2.1 g, 65%)
(Found: C, 66.7; H, 7.5; N, 15.3. C20H28N4S requires C, 67.4; H, 7.9; N,
15.7%) (Found (ES): [M + H]+, 357.2124. C20H28N4S requires [M +
Synthesis of Macrocycle (6)
2,2′-Diaminodiethylamine (0.38 g, 0.004 mol) was dissolved in
methanol (5 mL) and added dropwise to a solution of the dialdehyde
(17) (1.0 g, 0.004 mol) in methanol (100 mL). The reaction mixture was
refluxed for 10 min and then sodium borohydride (0.45 g, 0.012 mol)
was added slowly. Following the reduction, ice water (400 mL) was
slowly added and the product separated out as a pale cream gum. The
gum was extracted into dichloromethane (3 × 100 mL), followed by a
water back-wash (50 mL) and dried over anhydrous sodium sulfate.
Removal of the dichloromethane on the rotary evaporator yielded (6) as
a white solid, which was recrystallized from acetonitrile (0.7 g, 56%)
(Found: C, 70.4; H, 8.4; N, 16.0. C20H28N4O requires C, 70.6; H, 8.3;
N, 16.5%). 1H NMR (CDCl3) δ 2.59–2.62, m, 4H, NCH2; 2.72–2.75, m,
4H, NCH2; 3.58, br m, 2H, NCH2; 3.79, s, 2H; 3.80, s, 2H; 4.28, br t, J
4.3Hz, 2H, OCH2; 6.47, br s, 1H, NH; 6.63–6.67, m, 2H, Ar; 6.68–6.93,
1
H]+, 357.2107). H NMR (CDCl3) δ 1.75, br s, 4H, NH; 2.7, m, 4H,
NCH2; 2.8–2.9, m, 4H, NCH2; 3.37, m, 2H, SCH2; 3.52, m, 2H,
ArNHCH2; 3.79, s, 2H, ArCH2; 3.78, s, 2H, ArCH2; 6.63, m, 2H, Ar;
7.02, dd, J 7.8, 1.8 Hz, 1H, Ar; 7.10–7.25, m, 4H, Ar; 7.33, dd, J 8.1,
0.1 Hz, 1H, Ar. 13C NMR (CDCl3) δ 32.0, 41.9, 48.4, 49.5, 49.6, 49.8,
53.4, 54.3, 109.9, 116.4, 124.2, 125.2, 126.9, 127.9, 128.5, 129.7,
130.1, 137.3, 138.5, 147.7.
m, 2H, Ar; 7.03, dd, J 7.2, 1.5 Hz, 1H, Ar; 7.16–7.25, m, 3H, Ar. 13
C
Synthesis of Intermediate (18)
NMR (CDCl3) δ 43.2, 47.4, 48.4, 48.5, 48.5, 50.2, 53.7, 67.5, 109.9,
111.5, 116.5, 120.6, 124.2, 128.3, 128.5, 128.5, 129.9, 130.9, 147.7,
157.5.
The mesylate (13) (20.0 g, 0.073 mol) and salicylaldehyde (10.7 g,
0.088 mol) were heated with potassium carbonate (20.2 g, 146 mmol)