K. Kopecky et al. / Tetrahedron 67 (2011) 5956e5963
5961
crystallizing pale oil (1.34 g, 96%). [Found: C, 47.33; H, 3.76; N, 25.15.
C11H10N5O2Cl requires C, 47.24; H, 3.60; N, 25.04%]; Rf (hexane/
ethyl acetate/acetic acid 6:3:1) 0.35; nmax (ATR) 2928, 2357, 2341,
2226, 1709, 1555, 1420, 1389, 1352, 1291, 1263, 1197, 1120, 1045,
hexafluorophosphate (HBTU) (152 mg, 0.4 mmol) in dry DMF
(5 mL) was added to a solution of 5 (300 mg, 0.25 mmol) in dry
DMF (20 mL) followed by addition of 3-azidopropan-1-amine19
(160 mg, 1.6 mmol) in dry DMF (5 mL) and i-Pr2NEt (0.2 mL).
The mixture was stirred at room temperature for 1 h. Solvent
was evaporated under reduced pressure and the crude product
was suspended in water and filtered. The product was purified
by column chromatography (silica) using dichloromethane/ace-
tone/methanol (20:1:1) as eluent. Finally, the product was dis-
solved in dichloromethane (5 mL), dropped into hexane
(200 mL) and cooled to ꢂ30 ꢀC overnight. The precipitated fine
suspension was filtered and washed with hexane to give a purple
solid (250 mg, 79%), mp >300 ꢀC. [Found: C, 56.88; H, 7.53; N,
29.39. C63H92N28O2þ3H2O requires C, 56.99; H, 7.44; N, 29.54%];
Rf (dichloromethane/acetone/methanol 20:1:1) 0.30; nmax (ATR)
3301, 2967, 2929, 2871, 2093, 1640, 1422, 1341, 1283, 1158, 1132,
1022, 909 cmꢂ1
; dH (300 MHz, CDCl3) 3.84e3.76 (m, 2H, NCH2), 3.39
(s, 3H, NCH3), 2.45 (t, 2H, J 7 Hz, CH2COOH), 2.06 (p, 2H, J 7 Hz,
CH2CH2COOH); dC (75 MHz, CDCl3) 178.5, 152.1, 135.5, 129.2, 118.3,
113.1, 112.8, 52.1, 39.7, 30.8, 21.9.
4.2.2. 4-((5,6-Dicyano-3-(4-(2-hydroxyethyl)piperidin-1-yl)pyrazin-
2-yl)(methyl)amino)butanoic acid (3). A mixture of 2 (653 mg,
2.35 mmol) and 2-(piperidin-4-yl)ethanol (907 mg, 7.03 mmol) in
THF (20 mL) was stirred at room temperature for 3 h. Then, the
solvent was evaporated under reduced pressure to give crude
product. This was purified by column chromatography (silica) using
ethyl acetate/acetic acid (10:1) as an eluent to yield viscous pale
yellow oil (713 mg, 82%). Rf (ethyl acetate/acetic acid 10:1) 0.37; nmax
(ATR) 2929, 2853, 2225,1706,1517,1491,1434,1406,137,1240,1089,
1057, 1017 cmꢂ1
; dH (300 MHz, pyridine-d5) 13.73 (s, 2H, centr$NH),
8.65 (br s, 1H, CONH), 4.46 (d, 2H, J 12 Hz, piper$NCH2), 4.18 (t, 2H, J
7 Hz, NCH2), 4.00 (t, 2H, J 7 Hz, CH2OH), 3.96e3.79 (m, 24H, NCH2),
3.48 (q, 2H, J 7 Hz, NHCH2), 3.43 (3H, s, NCH3), 3.24 (t, 2H, J 7 Hz,
CH2N3), 3.01 (t, 2H, J 12 Hz, piper$CH2), 2.56 (t, 2H, J 7 Hz, CH2CONH),
2.56e2.40 (m, 2H, CH2CH2CONH), 2.02e1.82 (m, 3H, CHþpi-
per$NCH2), 1.81e1.51 (m, 6H, CH2CH2OHþpiper$CH2þCH2CH2N3),
1.26e1.12 (m, 36H, NCH3). dC (75 MHz, pyridine-d5) 172.5, 151.3, 151.0,
150.7, 150.6, 149.2, 147.6 (broad), 141.9, 141.2, 140.4, 59.6, 50.5, 49.3,
48.4, 43.0, 42.9, 40.3, 37.5, 37.0, 34.2, 33.3, 32.6, 29.4, 23.9, 13.1; UV/
1051, 985 cmꢂ1
; dH (300 MHz, acetone-d6) 5.12 (br s, 1H, OH), 4.05
(2H, d, J 13 Hz, piper$NCH2), 3.76e3.65 (m, 2H, NCH2), 3.61 (2H, t, J
7 Hz, CH2OH), 3.13 (3H, s, NCH3), 2.84 (t, 2H, J 13 Hz, piper$CH2), 2.22
(2H, t, J 7 Hz, CH2COOH), 1.91e1.66 (m, 5H, CHþCH2CH2COOHþ
piper$NCH2), 1.47 (q, 2H, J 7 Hz, CH2CH2OH), 1.42e1.26 (m, 2H,
piper$CH2); dC (75 MHz, acetone-d6) 174.1, 148.2, 147.7, 121.4, 120.0,
116.0, 115.9, 59.2, 47.9, 47.7, 40.0, 37.0, 33.2, 32.4, 31.3, 22.8. HRMS
(EI): MþHþ, found 373.1970, C18H25N6O3 requires 373.1988.
vis (THF): lmax (log 3) 368 (5.00), 515 (4.76), 650 (4.80), 680 nm
4.2.3. 2-[(4-Carboxypropyl)methylamino]-3-[(4-2-hydroxyethyl)-pi-
peridin-1-yl]-9,10,16,17,23,24-hexakis(diethylamino)-
(4.93 Mꢂ1 cmꢂ1); MS (MALDI-TOF, [Mþ]) calcd for C63H92N28O2,
1272.8; found, 1272.7; HRMS (MALDI): Mþ, found 1272.7931,
C63H92N28O2 requires 1272.7958.
1,4,8,11,15,18,22,25-(octaaza)phthalocyanine (5). A mixture of
3
(259 mg, 0.69 mmol) and 4 (568 mg, 2.09 mmol) in dry n-butanol
(10 mL) was heated to reflux and metal lithium (102 mg,14.6 mmol)
was added. The reaction mixture was heated to reflux for 3 h. The
solvent was evaporated under reduced pressure, diluted acetic acid
(50% v/v,100 mL) was added and the suspension was stirred at room
temperature for 30 min. The crude product was filtered and washed
thoroughly with water. The resulting mixture of congeners was
separated by column chromatography (silica) with dichloro-
methane/acetone/methanol 10:1:1 as mobile phase. The second
intense purple fraction (compound 5) was purified on silica once
more with dichloromethane/acetone/methanol 15:1:1. Finally, the
pure compound 5 was dissolved in 5 mL of dichloromethane,
dropped into 200 mL of hexane and cooled to ꢂ30 ꢀC overnight. The
precipitated fine suspensionwas filtered and washed with hexane to
give a purple solid (135 mg, 16%), mp >300 ꢀC. [Found: C, 58.46; H,
7.64; N, 27.12. C60H86N24O3þ2H2O requires C, 58.71; H, 7.39; N,
27.39%]; Rf (dichloromethane/acetone/methanol 15:1:1) 0.24; nmax
(ATR) 3300, 2967, 2930, 1726, 1641, 1423, 1376, 1340, 1283, 1250,
4.2.5. 2-{[(N-3-Azidopropyl)-4-carboxamidopropyl]methylamino}-
3-[4(-2-hydroxyethyl)-piperidin-1-yl]-9,10,16,17,23,24-
hexakis(diethylamino)-1,4,8,11,15,18,22,25-(octaaza)phthalocyani-
nato zinc(II) (7). Compound 6 (100 mg, 0.08 mmol) was dissolved
in dry DMF (10 mL) and anhydrous zinc acetate (74 mg, 0.4 mmol)
was added. The mixture was heated to reflux for 2 h. The solvent
was evaporated under reduced pressure and water was added. The
crude product was filtered and washed thoroughly with water.
The mixture was purified by column chromatography (silica) using
dichloromethane/acetone/methanol (15:1:1) as eluent to give dark
blue solid (60 mg, 56%), mp >300 ꢀC. [Found: C, 54.48; H, 7.14; N,
26.85. C63H90N28O2Znþ3H2O requires C, 54.40; H, 6.96; N, 28.19%];
Rf (dichloromethane/acetone/methanol 15:1:1) 0.25; nmax (ATR)
3500e3200 (br), 2966, 2929, 2871, 2094, 1642, 1515, 1420, 1318,
1253, 1159, 1109, 1056, 1019 cmꢂ1
; dH (300 MHz, pyridine-d5) 8.76
(br s, 1H, CONH), 6.00 (br s, 1H, OH), 4.44 (2H, d, J 12 Hz,
piper$NCH2), 4.15 (t, 2H, J 6 Hz, NCH2), 3.99 (t, 2H, J 6 Hz, CH2OH),
3.96e3.77 (m, 24H, NCH2), 3.50 (q, 2H, J 7 Hz, NHCH2), 3.41 (3H, s,
NCH3), 3.21 (t, 2H, J 7 Hz, CH2N3), 3.00 (t, 2H, J 12 Hz, piper$CH2),
2.71e2.60 (m, 2H, CH2CONH), 2.40e2.26 (m, 2H, CH2CH2CONH),
2.02e1.81 (m, 3H, CHþpiper$NCH2), 1.81e1.47 (m, 6H,
CH2CH2OHþpiper$CH2þCH2CH2N3), 1.35e1.02 (m, 36H, NCH3); dC
(75 MHz, pyridine-d5) 172.7, 151.6, 151.5, 151.46, 151.41, 151.3, 151.1,
150.9, 150.6, 143.6, 143.04, 142.97, 142.90, 142.8, 142.2, 59.7, 50.6,
49.3, 48.4, 43.0, 42.8, 40.4, 37.4, 37.0, 34.5, 33.3, 32.7, 29.4, 23.9,
1159, 1133, 1058, 1018 cmꢂ1
; dH (300 MHz, pyridine-d5) 13.72 (s, 2H,
centr$NH), 4.49 (2H, d, J 12 Hz, piper$NCH2), 4.21 (t, 2H, J 7 Hz, NCH2),
3.98 (2H, t, J 7 Hz, CH2OH), 3.95e3.83 (m, 24H, NCH2), 3.46 (3H, s,
NCH3), 3.03 (t, 2H, J 12 Hz, piper$CH2), 2.69 (2H, t, J 7 Hz, CH2COOH),
2.36e2.34 (m, 2H, CH2CH2COOH), 2.01e1.81 (m, 3H, CHþpi-
per$NCH2), 1.80e1.71 (m, 2H, CH2CH2OH), 1.69e1.53 (m, 2H,
piper$CH2), 1.27e1.13 (m, 36H, NCH3). dC (75 MHz, pyridine-d5)
175.4, 151.4, 151.2, 150.72, 150.68, 149.2, 147.6 (broad), 142.1, 141.3,
140.6, 59.6, 50.4, 48.4, 43.0, 42.8, 40.4, 37.6, 33.3, 32.7, 32.5, 30.2,
13.2, 13.13, 13.09; UV/vis (THF): lmax (log 3) 376 (4.99), 507 (4.47),
23.4, 13.2, 13.1; UV/vis (THF): lmax (log 3) 367 (4.98), 512 (4.73), 649
598 (4.40), 655 nm (5.04 Mꢂ1 cmꢂ1); MS (MALDI-TOF, [Mþ]) calcd
for C63H90N28O2Zn, 1334.7; found, 1334.6; HRMS (MALDI): Mþ,
found 1334.7107, C63H90N28O2Zn requires 1334.7093.
(4.78), 679 nm (4.91 Mꢂ1 cmꢂ1); MS (MALDI-TOF, [Mþ]) calcd for
C60H86N24O3, 1190.7; found, 1190.7; HRMS (MALDI): MþNaþ, found
1213.7206, C60H86N24NaO3 requires 1213.7212.
4.2.6. 2-{[(N-3-Azidopropyl)-4-carboxamidopropyl]methylamino}-3-
[4(-2-dimethoxytrityloxyethyl)-piperidin-1-yl]-9,10,16,17,23,24-
hexakis(diethylamino)-1,4,8,11,15,18,22,25-(octaaza)phthalocyaninato
zinc(II) (8). Compound 7 (241 mg, 0.18 mmol) was dissolved in dry
4.2.4. 22-{[(N-3-Azidopropyl)-4-carboxamidopropyl]methyl-
amino}-3-[4(-2-hydroxyethyl)-piperidin-1-yl]-9,10,16,17,23,24-
hexakis(diethylamino)-1,4,8,11,15,18,22,25-(octaaza)phthalocya-
nine
(6). O-(Benzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium