Molecules 2020, 25, 1959
17 of 23
+
+
4
4
9.52 (Cring), 48.89 (Cring), 48.60 (Cring) ESI -MS: C H N O [M + H] m/z 441.24963 m/zfound
calc
41.25100.
38
58
8
16
3
4
.2.7. Synthesis of Dibenzyl
,10-bis(2-(tert-Butoxy)-2-Oxoethyl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylate (7)
Compound
and tert-butyl bromoacetate (0.98 mL, 6.66 mmol) was added. The reaction mixture was refluxed for
0 min. The solvent was evaporated to yield an oil and solid mixture. The oil was taken up with Et O
6 (1.47 g, 3.33 mmol) was dissolved in MeCN (24 mL). DIPEA (11.59 mL, 66.55 mmol)
3
2
and washed with H O. After drying over Na SO , the solvent was evaporated under reduced pressure
2
2
4
1
to yield a light yellow oil as pure compound
7 (2.21 g, 3.30 mmol, 99%). H-NMR (500 MHz, CDCl ):
3
δ
7.37–7.28 (m, Har, 10H), 5.12 (s, CH , 4H), 3.52–3.15 (m, CH , 12H), 2.87 (bs, Hring, 8H), 1.43 (s, Ot-Bu,
2
2
1
8H) 13C-NMR (300 MHz, CDCl3):
δ 170.70, 156.62, 137.02 (Car),128.62 (Car), 128.03 (Car), 81.11, 67.14
+
+
(
O-C-bz), 56.14 (CH ), 54.18 (CH ), 46.72 (Cring), 28.35 (CtBut) ESI -MS: C H N O [M + H] m/z
2
2
38 58
8
16
calc
6
69.38579 m/zfound 669.38769.
0
3
.2.8. Synthesis of Di-tert-butyl 2,2 -(1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetate (8)
To a suspension of Pd/C 10% (442 mg, 20% wt) in iso-propanol (50 mL), a solution of compound
2.21 g, 3.30 mmol) in iso-propanol (30 mL) was added. Ammonium formate (9.57 g, 152 mmol) was
added and the mixture was refluxed for 15 min under constant wave irradiation (150 W). The catalyst
was filtered off through celite. The solvent was evaporated and the white solid residue was taken
up in 4M aq. NaOH (50 mL) and extracted with CHCl (100 mL 4). The combined organic layers
(1.30 g, 98%) as a yellow viscous oil
7
(
µ
×
3
were dried over Na SO and the solvent evaporated to yield
8
2
4
1
that became a white solid after a few days’ exposure to air. H-NMR (500 MHz, CDCl ):
OCCH , 4H), 2.80 (bs, Hring, 8H), 2.61 (t, Hring, 8H), 1.46 (s, Ot-Bu, 18H) C-NMR (300 MHz, CDCl ):
171.10, 81.15, 57.35 (CH ), 52.18 (CH ), 45.87 (Cring), 28.36 (CtBut) ESI -MS: C H N O [M + H]
2 2 20 40 4 4
δ
3.31 (s,
3
1
3
2
3
+
+
δ
m/zcalc 401.31223 m/zfound 401.31280.
3
2
.2.9. Synthesis of Di-tert-butyl
0
,2 -(4,10-bis(2-(4-((tert-butyldimethylsilyl)oxy)phenoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-
1
,7-diyl)diacetate (9)
Compound (350 mg, 0.87 mmol) was dissolved in MeCN (4 mL) and DIPEA (1.52 mL, 8.74 mmol)
was slowly added under a nitrogen atmosphere. After a few minutes, a solution of compound (550 mg,
.83 mmol) in MeCN (2.2 mL) was added and the mixture was refluxed for 2 h. After this time, the dark
brown mixture was concentrated and the resulting brown oil was dissolved in EtOAc and washed
three times with H O. After drying over Na SO , the solvent was removed under reduced pressure
8
2
1
2
2
4
to yield a brown oil. The residue was purified by column chromatography (9.25:0.75 DCM/MeOH)
1
to yield compound
9
as a pale yellow oil (451 mg, 0.48 mmol, 55%). H-NMR (500 MHz, CDCl ):
δ
3
6
.96 (d, Har, 4H), 6.75 (d, Har, 4H), 3.71–2.17 (m-bs, H + N-CH -CO, 24H), 1.25 (s, Ot-Bu, 18H), 0.98
ring 2
1
3
(
s, Si-C-CH , 18H), 0.19 (s, Si-CH , 12H) C-NMR (300 MHz, CDCl3):
δ
173.74, 173.01, 153.50, 144.44,
3
3
+
122.13 (Car), 120.38 (Car), 82.27, 55.86, 55.11, 27.83, 25.78,
−
4.34 (Si-CH ) ESI -MS: C H N O Si
3
48 80
4
10
2
+
[M + H] m/z
929.54857 m/zfound 929.55713.
calc
3
2
.2.10. Synthesis of
0
00
,2 ,2 -(10-(2-(4-Hydroxyphenoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-Triyl)triacetic
1
acid (L )
Compound
4
(100 mg, 0.13 mmol) was dissolved in DCM (0.32 mL) and TFA (0.22 mL, 3.47 mmol)
was slowly added to the mixture. The reaction was followed with MALDI-TOF (matrix: dithranol)
until the starting material could no longer be observed. The clear solution was stirred at room
temperature for 2 days, after which it was concentrated under reduced pressure. The resulting brown
oil was dissolved in the minimum amount of MeOH and triturated multiple times with Et O to yield
2