Inorganic Chemistry
Article
were separated via centrifuge and the supernatant was removed. The
pellet was resuspended in CH2Cl2 (10 mL) and subjected to
centrifuge extraction a further three times. The combined organic
phase was evaporated in vacuo, and the residue was purified via silica
gel chromatography (CombiFlash automated purification system; A:
CH2Cl2, B: MeOH; 100% A to 10% B). The title compound was
−CH2), 3.20 (4H, q, J = 5.5 Hz, 6 −CH2). 13C{1H} NMR (75 MHz,
CDCl3, 298 K) 148.1, 134.0, 133.5, 133.1, 131.1, 125.8, 69.1, 43.5.
ESI-MS (MeOH) 475.7 [M + H]+.
Di-tert-butyl 2,2′-((Oxybis(ethane-2,1-diyl))bis(((2-nitrophenyl)-
sulfonyl)azanediyl)) Diacetate (8). Compound 7 (2.45 g, 5.16
mmol) was dissolved in dry MeCN (50 mL), and K2CO3 (2.85 g, 20.6
mmol, 4.0 equiv) was added. To the solution was added tert-butyl
bromoacetate (1.52 mL, 2.01 g, 10.3 mmol, 2.0 equiv) at RT, and the
resulting mixture was heated at 50 °C over 48 h. The solution was
then filtered, and the filtrate was evaporated in vacuo to yield a yellow
oil. The crude residue was purified via silica gel chromatography
(CombiFlash automated purification system; A: hexanes, B: EtOAc;
100% A to 100% B) to yield the title compound as a white fluffy solid
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isolated as a pale-yellow oil (210 mg, 99%). H NMR (300 MHz,
CDCl3, 298 K) 5.90 (1H br s, 2 −NH), 3.22 (4H, s, 7 −CH2), 3.07
(2H, br m, 3 −CH2), 2.81 (2H, br s, 9 −NH), 2.56 (4H, m, 6 −CH2),
2.52−2.44 (6H, m, 4− and 5 −CH2), 1.35 (18H, s, 8 −C(CH3)3),
1.32 (9H, s, 1 −C(CH3)3). 13C{1H} NMR (75 MHz, CDCl3, 298 K)
171.6, 156.4, 81.2, 78.6, 54.1, 53.9, 51.3, 47.1, 39.0, 28.5, 28.2. ESI-
MS (MeOH) 333.9 [M + H]+. Rf = 0.31 (CH2Cl2/MeOH, 95:5).
Methyl 6-(2-(2-(tert-Butoxy)-2-oxoethyl)-5-(2-((tert-
butoxycarbonyl)amino)ethyl)-8-((6-(methoxycarbonyl)pyridin-2-
yl)methyl)-12,12-dimethyl-10-oxo-11-oxa-2,5,8-triazatri-decyl)-
picolinate (5). Compound 4 (210 mg, 0.451 mmol) was dissolved in
dry MeCN (10 mL), and K2CO3 (250 mg, 1.80 mmol, 4.0 equiv)
added to the stirred solution at RT. Methyl (6-bromomethyl)-
picolinate (214 mg, 0.902 mmol, 2.0 equiv) was added over 10 min,
and the resulting mixture was heated at 60 °C for 48 h. Upon
completion of the reaction, the inorganic salts were separated via
centrifuge and washed with CH2Cl2 (3 × 10 mL). The product was
purified via silica gel chromatography (CombiFlash automated
purification system; A: CH2Cl2, B: MeOH; 100% A to 10% B).
The title compound was obtained as a pale-amber oil (260 mg, 85%).
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(3.23 g, 90%). H NMR (300 MHz, CDCl3, 298 K) 8.06−8.03 (2H,
m, 1 −CH), 7.72−7.67 (4H, m, 2− and 4 −CH), 7.64−7.61 (2H, m,
3 −CH), 4.14 (4H, s, 5 −CH2), 3.59−3.54 (8H, m, 6− and 7 −CH2),
1.36 (18H, s, 8 −C(CH3)3). 13C{1H} NMR (75 MHz, CDCl3, 298 K)
167.9, 148.1, 133.6, 133.5, 131.9, 131.0, 124.2, 82.4, 70.1, 50.2, 48.1,
28.0. ESI-MS (MeOH) 741.3 [M + K]+.
Di-tert-butyl 2,2′-((Oxybis(ethane-2,1-diyl))bis(azanediyl))-
diacetate (9). Compound 8 (3.23 g, 4.59 mmol) was dissolved in
dry MeCN (100 mL), and K2CO3 (2.10 g, 13.8 mmol, 3.0 equiv) was
added. Thiophenol (2.83 mL, 3.04 g, 27.6 mmol, 6.0 equiv) was
added to the solution, and the reaction mixture was heated at 50 °C
for 24 h. Upon completion of the reaction, the solution was allowed to
cool to RT, filtered, and evaporated in vacuo to yield a red-brown oil.
The crude residue was purified via silica gel chromatography
(CombiFlash automated purification system; A: CH2Cl2, B: MeOH,
100% A to 10% B) to yield the title compound as a pale-amber oil
3
1H NMR (300 MHz, CDCl3, 298 K) 7.87 (2H, d, J = 7.6 Hz, 12
3
3
−CH), 7.73 (2H, t, J = 7.6 Hz, 11 −CH), 7.64 (2H, d, J = 7.6 Hz,
10 −CH), 5.47 (1H, br s, 2 −NH), 3.92 (4H, s, 9 −CH2), 3.85 (6H,
s, 13 −CH3), 3.19 (4H, s, 7 −CH2), 3.06 (2H, q, J = 4.9 Hz, 3
3
1
(1.22 g, 81%). H NMR (300 MHz, CDCl3, 298 K) 3.53 (4H, t, J =
−CH2), 2.69−2.53 (10H, m, 4−, 5− and 6 −CH2), 1.32 (18H, s, 8
−C(CH3)3), 1.27 (9H, s, 1 −C(CH3)3). 13C{1H} NMR (75 MHz,
CDCl3, 298 K) 170.6, 165.8, 160.4, 156.1, 147.2, 137.7, 126.4, 123.7,
81.3, 78.8, 60.4, 56.4, 53.2, 52.9, 52.5, 52.3, 37.8. 28.5, 28.2. ESI-MS
(MeOH) 773.3 [M + H]+, 795.4 [M + Na]+. Rf = 0.40 (CH2Cl2/
MeOH, 95:5).
5.2 Hz, 1 −CH2), 3.30 (4H, s, 4 −CH2), 2.77 (4H, t, J = 5.2 Hz, 2
−CH2), 2.53 (2H, br s, 3 −NH), 1.42 (18H, s, 5 −C(CH3)3).
13C{1H} NMR (75 MHz, CDCl3, 298 K) 171.4, 81.2, 70.4, 51.6, 48.8,
28.2. ESI-MS (MeOH) 333.21 [M + H]+.
(Me)2(tBu)2noneunpa (10). Compound 9 (415 mg, 1.81 mmol)
was added to a solution of di-tert-butyl 2,2′-((oxybis(ethane-2,1-
diyl))bis(azanediyl))diacetate (300 mg, 0.902 mmol) and K2CO3
(499 mg, 3.61 mmol) in dry MeCN (20 mL). The reaction mixture
was heated to 60 °C with stirring overnight. Upon completion of the
reaction, the volatiles were removed in vacuo and the resulting residue
was redissolved in CH2Cl2 (30 mL). The organic phase was washed
with deionized H2O (3 × 20 mL), dried over Na2SO4, and evaporated
in vacuo. The crude residue was purified via silica gel chromatography
(CombiFlash automated purification system; A: CH2Cl2, B: MeOH;
100% A to 5% B) to give the title product as a white solid (512 mg,
H4neunpa-NH2 (6). Compound 5 (94.0 mg, 0.122 mmol) was
dissolved in 6 M HCl (4 mL) and heated at 60 °C overnight. The
crude reaction mixture was evaporated to dryness in vacuo and
redissolved in deionized H2O (5 mL). The product was purified via
RP-HPLC (A: H2O (0.1% TFA), B: MeCN; 95% A to 30% B, 25 min
gradient, 10 mL/min, tR = 14.5 min) and co-evaporated with 1 M
HCl (3 × 2 mL) to obtain the title compound as a white HCl salt. 1H
NMR (300 MHz, D2O, 298 K) 8.00 (4H, m, 8− and 9 −CH), 7.64
3
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(2H, dd, J = 5.5 Hz, J = 3.3 Hz, 7 −CH), 4.58 (4H, s, 6 −CH2),
4.06 (4H, s, 5 −CH2), 3.48 (4H, t, 3J = 6.6 Hz, 4 −CH2), 3.15 (2H, t,
3J = 6.5 Hz, 1 −CH2), 3.09 (4H, t, 3J = 6.6 Hz, 3 −CH2), 2.97 (2H, t,
3J = 6.5 Hz, 2 −CH2). 13C{1H} NMR (75 MHz, D2O, 298 K) 169.0,
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90%). H NMR (300 MHz, CDCl3, 298 K) 7.80 (4H, m, 1− and 3
−CH), 7.47 (2H, br t, 2 −CH), 4.14 (4H, s, 4 −CH2), 3.60 (6H, s, 8
−CH3), 3.35 (4H, br t, 7 −CH2), 3.25 (4H, s, 5 −CH2), 2.80 (4H, br
t, 6 −CH2), 1.21 (18H, s, 9 −C(CH3)3). 13C{1H} NMR (75 MHz,
CDCl3, 298 K) 171.4, 165.7, 158.6, 146.6, 138.8, 127.3, 123.7, 81.7,
67.3, 60.2, 54.7, 53.8, 52.8, 28.1. ESI-MS (MeOH) 631.4 [M + H]+,
316.3 [M + 2H]2+.
166.8, 149.9, 146.5, 140.8, 128.0, 126.2, 57.7, 55.3, 52.0, 49.7, 48.1,
36.3. ESI-MS (H2O) 533.3 [M + H]+. HR-ESI-MS calcd for
[C24H32N6O8 + H]+: 533.2276; found, [M + H]+: 533.2349.
Elemental analysis: calcd% for H4neunpa-NH2·6HCl·3H2O
(C24H32N6O8·6HCl·3H2O = 802.33 g/mol): C, 35.79; H, 5.51; N,
10.44. Found: C, 35.74; H, 5.49; N, 10.27.
H4noneunpa·4HCl (11). Compound 10 (512 mg, 0.813 mmol)
was dissolved in 4 M HCl (10 mL) and heated at 60 °C overnight.
Upon completion of the reaction, the volatiles were removed in vacuo
and the resulting off-white solid was purified via RP-HPLC (A: H2O
(0.1% TFA), B: MeCN; 100% A to 20% B, 30 min, tR ∼ 19.5 min).
Appropriate fractions were combined and co-evaporated with 3 M
N,N′-(Oxybis(ethane-2,1-diyl))bis(2-nitrobenzenesulfonamide)
(7). Bis-(2-aminoethyl) ether (1.20 g, 11.5 mmol) was dissolved in
dry CH2Cl2 (120 mL) and cooled to 0 °C. Triethylamine (6.4 mL,
4.65 g, 47.5 mmol) was added, followed by slow addition of 2-
nitrobenzenesulfonyl chloride (5.11 g, 23.7 mmol) over 15 min. The
pale-yellow solution was allowed to warm to RT and stirred for 5 h.
Upon completion of the reaction, the reaction mixture was diluted
with deionized H2O (100 mL) and the organic phase was separated.
The aqueous phase was extracted with CH2Cl2 (3 × 100 mL), and the
combined organic phase was evaporated in vacuo to give a pale-yellow
oil. The crude residue was purified via silica gel chromatography
(CombiFlash automated purification system; A: CH2Cl2, B: MeOH;
100% A to 10% B) to give the title compound as a white solid (4.60 g,
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HCl to yield the desired product as a white HCl salt. H NMR (300
MHz, D2O, 298 K) 7.97−7.90 (4H, m, 1− and 2 −CH), 7.60 (2H,
3
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dd, J = 6.5 Hz, J = 2.3 Hz, 3 −CH), 4.69 (4H, s, 4 −CH2), 4.13
(4H, s, 5 −CH2), 3.77 (4H, br t, 6 −CH2), 3.58 (4H, br t, 7 −CH2).
13C{1H} NMR (75 MHz, D2O, 298 K), 168.1, 167.1, 149.4, 146.6,
140.2, 128.2, 125.8, 64.9, 58.6, 55.4, 54.6. LR-ESI-MS (H2O) 491.2
[M + H]+, 489.1 [M − H]−. HR-ESI-MS (H2O) calcd for
[C22H26N4O9 + H]+: 491.1692; found, [M + H]+: 491.1769.
Elemental analysis: calcd% for H4noneunpa·4HCl·3.5H2O
(C22H26N4O9·4HCl·3.5H2O = 699.16 g/mol): C, 37.78; H, 5.33;
N, 8.01. Found: C, 37.70; H, 5.41; N, 8.00.
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84%). H NMR (300 MHz, CDCl3, 298 K) 8.12−8.07 (2H, m, 1
−CH), 7.90−7.84 (2H, m, 4 −CH), 7.77−7.72 (4H, m, 2− and 3
−CH), 5.67 (2H, t, J = 5.8 Hz, 5 −NH), 3.44 (4H, t, J = 5.0 Hz, 7
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Inorg. Chem. 2021, 60, 4076−4092