Inorganic Chemistry
Article
+
N,N′-[6-(Methoxycarbonyl)pyridin-2-yl]methyl-1,2-(1R,2R)-cyclo-
hexanediamine (3). To a solution of 2 (1.16 g, 1.48 mmol) in THF (10
mL) was added thiophenol (313 μL, 3.04 mmol, just over 2 equiv) and
potassium carbonate (1.22 g, 8.88 mmol, 6 equiv). The reaction mixture
was stirred at ambient temperature for 72 h, during which time a slow
color change from faint yellow to deep yellow occurred. The salts were
removed by filtration after centrifugation (4000 rpm for 10 min), and
the filtrate was concentrated in vacuo. The crude product was purified by
confirmed by MS (ES+) m/z = 291.4 [M + H] , and the reaction
mixture was cooled to ambient temperature and concentrated in vacuo.
The crude imine was purified by column chromatography (CombiFlash
Rf automated column system; 80 g of HP silica; A: dichloromethane, B:
methanol, 100% A to 10% B gradient) to yield the intermediate imine as
a faint yellow solid (1.28 g). The imine was then dissolved in ethanol (70
mL) at 0 °C, and NaBH (0.422 g, 11.2 mmol, ∼2.5 equiv) was added in
small portions. The mixture was stirred for 2 h, subsequently quenched
with saturated aqueous NH Cl (70 mL), and extracted with dichloro-
methane (3 × 90 mL). The organics were collected, dried over MgSO4,
and concentrated in vacuo to yield 7 as a yellow oil (1.336 g, 38% over
4
column chromatography (CombiFlash R automated column system; 24
f
4
g of HP silica; A: dichloromethane, B: methanol with 2% triethylamine,
1
1
00% A to 25% B gradient) to yield 3 as a yellow oil (0.606 g, 99%). H
1
NMR (400 MHz, CDCl ) δ 7.87 (d, J = 7.5 Hz, 2H), 7.69 (t, J = 7.7 Hz,
two steps). H NMR (400 MHz, MeOD) δ 7.39−7.25 (m, 10H), 3.96
3
2
H), 7.61 (d, J = 7.4 Hz, 2H), 4.06 (d, J = 14.9 Hz, 2H), 3.87 (d, J = 13.5
(d, J = 13.0 Hz, 2H), 3.76 (dd, J = 12.9, 7.4 Hz, 2H), 2.53−2.41 (m, 2H),
1
3
Hz, 2H), 3.84 (s, 6H), 2.67 (s, 2H), 2.28−2.19 (m, 2H), 2.05 (d, J = 13.1
2.21 (d, J = 12.0 Hz, 2H), 1.83−1.71 (m, 2H), 1.34−1.19 (m, 4H). C
Hz, 2H), 1.60 (d, J = 8.1 Hz, 2H), 1.17−1.04 (m, 2H), 1.03−0.87 (m,
NMR (101 MHz, MeOD) δ 139.3, 129.7, 129.7, 128.7, 60.9, 50.6, 30.8,
H). 13C NMR (101 MHz, CDCl ) δ 165.7, 161.4, 147.1, 137.3, 125.7,
23.3, 61.3, 52.7, 52.1, 31.5, 24.8. MS (ES+) m/z = 451.3 [M + K] .
+
2
1
25.7. MS (ES+) m/z = 295.5 [M + H] .
3
+
Dimethyl 6,6′-(((1R,2R)-Cyclohexane-1,2-diylbis-
H CHXdedpa·2HCl·2H O (4). Compound 3 (0.314 g, 0.76 mmol)
(benzylazanediyl))bis(methylene))dipicolinate (8). To a solution of
2
2
57
was dissolved in HCl (6 M, 5 mL) and refluxed overnight, during which
time a white precipitate formed. The resultant mixture was cooled on
ice, and the solid was isolated by vacuum filtration and washed with
7 (0.356 g, 1.21 mmol) and methyl-6-bromomethyl picolinate (0.585
g, 2.54 mmol, just over 2 equiv) in acetonitrile (20 mL), potassium
carbonate (0.836 g, 6.05 mmol, 6 equiv) was added, and the resultant
suspension was refluxed for 3 d. The mixture was cooled to ambient
temperature, excess salts were removed by filtration, and filtrate was
concentrated in vacuo. The crude yellow oil was purified by column
automated column system; 80 g of HP
silica; A: dichloromethane, B: methanol, 100% A to 10% B gradient) to
yield 8 as a yellow oil (0.537 g, 75%). H NMR (400 MHz, CDCl ) δ
3
1
acetone to yield 4 as a white crystalline solid (0.251 g, 67%). H NMR
(
300 MHz, D O) δ 8.15 (dt, J = 15.3, 7.1 Hz, 4H), 7.76 (d, J = 6.5 Hz,
2
2
2
H), 4.98 (d, J = 17.1 Hz, 2H), 4.85 (d, J = 15.9 Hz, 2H), 3.72−3.56 (m,
H), 2.50 (d, J = 12.5 Hz, 2H), 1.87 (d, J = 9.0 Hz, 2H), 1.61 (d, J = 8.7
chromatography (CombiFlash R
f
13
Hz, 2H), 1.27 (t, J = 9.9 Hz, 2H). C NMR (75 MHz, D O) δ 167.4,
2
1
1
51.6, 146.6, 140.1, 126.8, 125.7, 58.8, 47.8, 28.1, 22.7. Anal. Calcd
(
found) for C H N O ·2HCl·2H O: C, 48.69 (48.90); H, 6.13 (5.99);
7.97 (d, J = 7.6 Hz, 2H), 7.93 (d, J = 7.7 Hz, 2H), 7.65 (t, J = 7.6 Hz, 2H),
7.27 (d, J = 7.1 Hz, 4H), 7.15−7.07 (m, 6H), 3.98 (s, 6H), 3.84 (d, J =
15.2 Hz, 2H), 3.72−3.62 (m, 4H), 3.47 (d, J = 13.6 Hz, 2H), 2.73 (d, J =
7.0 Hz, 2H), 2.17 (d, J = 10.0 Hz, 2H), 1.73 (d, J = 5.4 Hz, 2H), 1.13−
20
24
4
4
2
+
N, 11.36 (11.37)%. HR-ESI-MS m/z for C H N O (M+H ) calcd.
(
20
25
4
4
found): 385.1876 (385.1881) (1.3 PPM).
Dimethyl 6,6′-(((1R,2R)-Cyclohexane-1,2-diylbis((2-(tert-butoxy)-
0.99 (m, 4H). 13C NMR (101 MHz, CDCl ) δ 165.8, 161.8, 147.0,
2
-oxoethyl)azanediyl))bis(methylene))dipicolinate (5). To a solution
3
of 3 (0.398 g, 0.96 mmol) in acetonitrile (8 mL), tert-butylbromoacetate
285 μL, 1.93 mmol, 2 equiv) and sodium carbonate (0.610 g, 5.76
139.4, 136.6, 128.9, 127.9, 126.8, 126.2, 123.2, 59.1, 55.1, 53.9, 52.7,
25.7, 24.3. (ES+) m/z = 593.4 [M + H] .
+
(
mmol, 6 equiv) were added. The reaction mixture was stirred at 60 °C
overnight. Excess salts were removed by filtration, and the filtrate was
concentrated in vacuo. The crude oil was purified by column
H2CHXdedpa-bb (9). Compound 8 (0.308 g, 0.52 mmol) was
dissolved in THF/water mixture (3:1, 12 mL), and lithium hydroxide
(0.062 g, 2.60 mmol, 5 equiv) was added. The mixture was stirred at
ambient temperature for 2 h, and solvent was removed in vacuo to yield
chromatography (CombiFlash R automated column system; 24 g of
f
1
HP silica; A: dichloromethane, B: methanol, 100% A to 20% B gradient)
the product as the lithium adduct. H NMR (400 MHz, MeOD) δ 7.95
1
to yield 5 as a faint yellow oil (0.423 g, 68%). H NMR (400 MHz,
(d, J = 7.5 Hz, 2H), 7.87 (d, J = 7.4 Hz, 2H), 7.77 (t, J = 7.5 Hz, 2H), 7.24
(d, J = 6.6 Hz, 4H), 7.14−7.04 (m, 6H), 3.76 (d, J = 14.5 Hz, 2H), 3.55
(t, J = 14.9 Hz, 4H), 3.36 (d, J = 13.4 Hz, 2H), 2.66 (d, J = 7.8 Hz, 2H),
2.11 (d, J = 10.3 Hz, 2H), 1.69 (d, J = 6.1 Hz, 2H), 1.11−0.94 (m, 4H).
CDCl ) δ 8.02 (d, J = 7.8 Hz, 2H), 7.91 (d, J = 7.5 Hz, 2H), 7.55 (t, J =
3
7
2
2
4
1
.7 Hz, 2H), 3.95 (s, 6H), 3.90 (d, J = 15.0 Hz, 2H), 3.77 (d, J = 15.0 Hz,
H), 3.36 (d, J = 16.8 Hz, 2H), 3.25 (d, J = 16.8 Hz, 2H), 2.61 (s, 2H),
.11 (d, J = 7.1 Hz, 2H), 1.71 (s, 2H), 1.40 (s, 18H), 1.08 (d, J = 5.8 Hz,
13
C NMR (101 MHz, MeOD) δ 172.8, 161.4, 155.2, 140.8, 138.9, 130.2,
H). 13C NMR (101 MHz, CDCl ) δ 171.5, 166.1, 161.8, 146.8, 137.0,
3
129.1, 128.0, 126.3, 123.4, 60.5, 56.1, 55.1, 26.9, 25.3. The product was
then purified via semipreparative RP-HPLC to remove lithium salts
27.7, 123.6, 80.5, 61.8, 56.1, 52.9, 52.7, 28.2, 26.3, 26.0. MS (ES+) m/z
+
=
641.6 [M + H] .
(gradient: A: 0.1% TFA (trifluoroacetic acid) in water, B: CH CN; 5 to
3
H CHXoctapa·3.5HCl·0.5H O (6). Compound 5 (0.336 g, 0.52
100% B linear gradient over 25 min, 10 mL/min, t = 17.9 min). The
4
2
R
mmol) was dissolved in HCl (6 M, 10 mL) and refluxed overnight. The
reaction mixture was concentrated in vacuo and purified via semi-
preparative RP-HPLC (gradient: A: 0.1% TFA (trifluoroacetic acid) in
HPLC fractions were pooled, concentrated in vacuo, redissolved in
CH CN (1 mL) and HCl (1 M, 3 mL), and concentrated again to drive
3
off trifluoroacetic acid. This process was repeated two more times, and
the last time solvent was removed on a lyphophilizer yielding the HCl
salt 9 as a faint yellow solid (0.143 g, 49%). Anal. Calcd (found) for
C H N O ·3.5HCl·0.5H O: C, 58.23 (58.58); H, 5.82 (5.93); N, 7.99
water, B: CH CN, 5 to 100% B linear gradient over 25 min, 10 mL/min,
3
tR = 12.5 min). Product fractions were pooled, concentrated in vacuo,
dissolved in CH CN (3 mL) and HCl (3 M, 3 mL), and then
3
34 36
4
4
2
+
concentrated in vacuo again to remove trifluoroacetic acid. This process
(7.96)%. HR-ESI-MS m/z for C H N O (M + H ) calcd. (found):
34 37 4 4
was repeated two more times; the last time, solvent was lyophilized to
565.2815 (565.2821) (1.1 PPM).
yield the HCl salt 6 as an off-white solid (0.136 g, 41% based on MW
[Ga(CHXdedpa)][ClO ]. H CHXdedpa·3HCl (4) (18.1 mg, 0.037
4 2
1
calculated from EA). H NMR (400 MHz, D O, 55 °C) δ 8.54 (t, J = 7.7
mmol) was dissolved in methanol/water (1:3, 2 mL); the pH of this
2
Hz, 2H), 8.48 (d, J = 7.1 Hz, 2H), 8.16 (d, J = 5.4 Hz, 2H), 4.74−4.57
solution was 2.5. To this clear solution Ga(ClO ) ·6H O (14.6 mg,
4
3
2
(
m, 4H), 4.19 (d, J = 17.4 Hz, 2H), 4.01 (d, J = 17.1 Hz, 2H), 3.83 (d, J =
0.040 mmol, 1.1 equiv) in water (500 μL) was added. The pH of this
solution was adjusted to 4.5 using NaOH (aq) (0.1 M), and the mixture
was stirred at room temperature for 1.5 h. The resultant murky solution
was concentrated in vacuo to a white solid. The crude product was
dissolved in water/acetonitrile (4 mL: 0.5 mL) and purified by
9
=
1
.2 Hz, 2H), 2.69 (d, J = 12.3 Hz, 2H), 2.31 (d, J = 8.5 Hz, 2H), 1.93 (d, J
13
8.9 Hz, 2H), 1.83−1.67 (m, 2H). C NMR (101 MHz, D O) δ 172.4,
2
65.3, 152.5, 146.2, 143.7, 129.1, 126.2, 100.1, 63.3, 52.3, 24.5, 24.4.
Anal. Calcd (found) for C H N O ·3.5HCl·0.5H O: C, 45.24 (45.26);
24
28
4
8
2
H, 5.14 (5.47); N, 8.79 (8.41)%. HR-ESI-MS m/z for C H N O (M +
semipreparative RP-HPLC (gradient: A: water, B: CH CN, 5 to 100% B
2
4
29
4
8
3
+
H ) calcd. (found): 501.1985 (501.1982) (−0.6 PPM).
linear gradient over 25 min, 10 mL/min, t = 11.3 min). Fractions were
R
1
2
(
1R,2R)-N ,N -dibenzylcyclohexane-1,2-diamine (7). A solution of
concentrated in vacuo and further dried under vacuum overnight to give
1
(
1R,2R)-(−)-1,2-diaminocyclohexane (1.381 g, 12.1 mmol) and
the product as a white solid (15.7 mg, 77%). H NMR (400 MHz,
benzaldehyde (2.46 mL, 24.2 mmol, 2 equiv) in ethanol (50 mL) was
dimethyl sulfoxide (DMSO)) δ 8.59 (t, J = 7.8 Hz, 2H), 8.27 (d, J = 7.6
Hz, 2H), 8.06 (d, J = 7.9 Hz, 2H), 5.92 (dd, J = 10.1, 5.2 Hz, 2H), 4.59
stirred at 0 °C for 4 h, then overnight at reflux. Formation of imine was
L
Inorg. Chem. XXXX, XXX, XXX−XXX