H. M. Kim, O. Kwon, B. R. Cho et al.
used in place of compound A. The crude product was purified by column
chromatography on silica gel (n-hexane/EtOAc, 1:1) as the eluent. Yield
0.38 g (56%); m.p. 2058C; 1H NMR (400 MHz, CDCl3): d=8.20 (1H, d,
J=1.6 Hz), 8.12 (1H, s), 7.82 (1H, dd, J=8.8, 1.6), 7.72 (1H, d, J=
9.2 Hz), 7.54 (1H, d, J=8.8.), 7.25 (2H, d, J=8.8), 6.98 (1H, dd, J=9.2,
2.4), 6.82 (1H, d, J=2.4), 6.53 (2H, d, J=8.8), 4.19 (1H, m), 3.79 (1H,
hancement factor and TP action cross-section by a factor of
3–5. This result provides a useful guideline for the design of
efficient TP probes.
m), 3.62ACHTUNTRGNEU(GN 6H, s), 3.41 (4H, t, J=7.6), 3.32 (1H, m), 3.14 (4H, s), 2.68
(4H, t, J=7.6), 2.54 (3H, s), 2.31 (2H, m), 2.04 ppm (2H, m); 13C NMR
(100 MHz, CDCl3): d=197.6, 171.1, 170.6, 147.0, 143.8, 137.1, 131.3,
131.0, 130.1, 127.0, 126.3, 125.9, 124.6, 122.2, 116.4, 112.2, 106.8, 64.6,
52.3, 50.8, 49.7, 33.2, 31.5, 29.5, 26.3, 24.0 ppm; IR (KBr): n˜ =1736, 1624,
1522 cmꢀ1; HRMS (EI): m/z calculated for [M+H]+ 638.2359; found:
638.2357.
Experimental Section
Synthesis: 6-Acyl-2-[N-methyl-N-(carboxymethyl)amino]naphthalene[27]
(acedane, A) and 2,2’-(4-nitrophenylazanediyl)bis(ethane-2,1-diyl)bis(4-
methylbenzenesulfonate)[28] (1) were prepared according to literature
methods. The synthesis of other compounds is described below.
Synthesis of ANi1: A solution of KOH in EtOH (1.0m, 4.1 mL) was
added to ANi1-Me (0.50 g, 0.82 mmol) in EtOH/CH2Cl2 (8:2, 10 mL) and
stirred for 2 h. The solution was evaporated until the volume had been
reduced by half. To this solution, dilute HCl (aq) was added slowly to
pH 3–4. The product precipitated as yellow–brown solid. The product
was collected, washed with distilled water, and purified by crystallization
from MeOH. Yield 0.21 g (44%); m.p.: 1018C; IR (KBr): n˜ =3423, 1716,
Synthesis of compound 2: A solution of compound 1 (3.0 g, 5.6 mmol) in
anhydrous DMF (35 mL) was added dropwise over 1 h to a mixture of
methyl thioglycolate (1.1 mL, 12 mmol) and Cs2CO3 (4.0 g, 12 mmol) in
anhydrous DMF (20 mL) at room temperature. The reaction mixture was
stirred overnight at 608C. The reaction mixture was filtered and the salts
were washed with DMF. The resulting solution was extracted with
EtOAc and washed three times with water and brine. The organic phase
was dried over Na2SO4, filtered, and evaporated. The product was puri-
fied by column chromatography on silica gel (n-hexane/EtOAc, 2:1) as
1618, 1516 cmꢀ1 1H NMR (400 MHz, CDCl3/[D4]MeOH 9:1): d=8.32
;
(1H, d, J=1.8 Hz), 7.93 (1H, dd, J=8.8, 1.8 Hz), 7.85 (1H, d, J=8.8 Hz),
7.68 (1H, d, J=9.0 Hz), 7.26 (2H, d, J=8.0 Hz), 7.14 (1H, dd, J=9.0,
2.7 Hz), 7.01 (1H, d, J=2.7 Hz), 6.60 (2H, d, J=8.0 Hz), 4.09 (2H, s),
3.50 (4H, t, J=7.5 Hz), 3.22 (7H, s), 2.75 (4H, t, J=7.5 Hz), 2.65 ppm
(3H, s); 13C NMR (100 MHz, CDCl3/[D4]MeOH 9:1): d=198.56, 172.92,
168.21, 148.99, 144.17, 137.18, 131.51, 131.16, 130.29, 126.63, 126.30,
126.08, 124.64, 122.43, 116.23, 112.22, 106.94, 58.42, 50.75, 39.90, 33.61,
29.30, 26.28 ppm; HRMS (EI): m/z calculated for [M+H]+ 584.1889;
found: 584.1885.
1
the eluent to obtain a yellow oil. Yield 1.7 g (77%); H NMR (300 MHz,
CDCl3): d=8.15 (2H, d, J=9.3 Hz), 6.70 (2H, d, J=9.3 Hz), 3.76 (6H,
s), 3.70 (4H, t, J=7.7 Hz), 3.30 (4H, s), 2.88 ppm (4H, t, J=7.7 Hz); IR
(NaCl): n˜ =1747, 1606, 1344 cmꢀ1; HRMS (EI): m/z calcd for [M+H]+
403.0998; found: 403.0998.
Synthesis of compound 3: A mixture of compound 2 (1.7 g, 4.3 mmol)
and SnCl2 (12 g, 52 mmol) in MeCN/EtOH (1/1, v/v, 150 mL) was heated
to reflux for 12 h. The mixture was concentrated and a small amount of
NaOH (aq) was added until a white precipitate had formed. The precipi-
tate was filtered and the product was extracted with CH2Cl2, dried over
MgSO4, and evaporated to obtain dark brown oil. Yield 1.4 g (85%);
1H NMR (300 MHz, CDCl3): d=6.75 (2H, d, J=8.4 Hz), 6.65 (2H, d, J=
8.4 Hz), 3.73 (6H, s), 3.45 (4H, t, J=7.8 Hz), 3.26 (4H, s), 2.77 ppm (4H,
t, J=7.8 Hz); IR (NaCl): n˜ =3439, 3358, 1732 cmꢀ1; HRMS (EI): m/z
calcd for [M]+ 372.1178; found: 372.1174.
Synthesis of ANi2: Synthesized by the same procedure as described for
ANi1 by using KOH in EtOH (1.0m, 2.1 mL) and ANi2-Me (0.27 g,
0.42 mmol) in EtOH/EtOAc (4/1, v/v, 5 mL). Yield, 0.15 g (58%); m.p.:
1138C; IR (KBr): n˜ =3431, 1714, 1616, 1522 cmꢀ1 1H NMR (400 MHz,
;
CDCl3/[D4]MeOH 9:1): d=8.32 (1H, d, J=1.6 Hz), 8.17 (1H, s), 7.89
(1H, dd, J=9.2, 1.6 Hz), 7.84 (1H, d, J=9.2 Hz), 7.65 (1H, d, J=9.2 Hz),
7.21 (2H, d, J=8.8 Hz), 7.05 (1H, dd, J=9.2, 2.4 Hz), 6.90 (1H, d, J=
2.4 Hz), 6.57 (2H, d, J=8.8 Hz), 4.24 (1H, m), 3.86 (1H, m), 3.49 (4H, t,
J=7.6 Hz), 3.43 (1H, m), 3.18 (4H, s), 2.73 (4H, t, J=7.6, Hz), 2.64 (3H,
s), 2.36 (2H, m), 2.11 ppm (2H, m); 13C NMR (100 MHz, CDCl3/
[D4]MeOH) d=198.50, 172.61, 171.76, 147.11, 143.90, 137.27, 131.45,
131.23, 130.44, 127.27, 126.44, 125.98, 124.63, 122.41, 116.46, 112.48,
106.83, 64.50, 51.21, 33.50, 31.48, 29.56, 29.17, 26.29, 24.03; HRMS (EI?
ESI?): m/z calculated for [M+H]+ 610.2046; found: 610.2045.
Synthesis of B:
A mixture of 2-acetyl-6-hydoxynaphthalene (1.5 g,
8.1 mmol), l-proline (4.5 g, 39 mmol), Na2S2O5 (3.1 g, 16 mmol), NaOH
(1.6 g, 39 mmol), and H2O (25 mL) was stirred in a steel-bomb reactor at
1408C for 96 h. The mixture was cooled to room temperature, washed
with water, and acidified with dilute HCl to pH 2–3 in an ice bath. The
precipitate was collected by filtration, washed with water, and purified by
column chromatography on silica gel (CHCl3/MeOH, 4:1). Yield 1.7 g
(76%); 1H NMR (300 MHz, CDCl3): d=8.39 (1H, d, J=1.8 Hz), 7.86
(1H, dd, J=8.4, 1.8 Hz), 7.85 (1H, d, J=8.4 Hz), 7.62 (1H, d, J=9.0 Hz),
7.05 (1H, dd, J=9.0, 2.4 Hz), 6.78 (1H, d, J=2.4 Hz), 4.37 (1H, dd, J=
8.4, 2.1 Hz), 3.72 (1H, m), 3.53 (1H, m), 2.30–2.45 (1H, m), 2.00–
2.26 ppm (3H, m); IR (KBr): n˜ =3427, 1654, 1618 cmꢀ1; HRMS (EI): m/z
calcd for [M+H]+ 284.1287; found: 284.1285.
Synthesis of ANi2-AM: A solution of bromomethyl acetate (0.040 mL,
0.41 mmol) in anhydrous DMF (0.4 mL) was added dropwise to a solu-
tion of ANi2 (63 mg, 0.10 mmol) and DIPEA (0.16 mL, 0.92 mmol) in
anhydrous DMF (2 mL). The reaction mixture was stirred overnight at
room temperature and water (10 mL) was added to quench the reaction.
The product was extracted with EtOAc, dried over Na2SO4, filtered, and
concentrated in vacuo. The crude product was purified by column chro-
matography on silica gel (MeOH/CHCl3, 1:20) to obtain a green solid.
Yield, 62 mg (82%); m.p.: 548C; IR (KBr): n˜ =1763, 1664, 1620,
Synthesis of ANi1-Me: A mixture of compound A (0.37 g, 1.5 mmol),
DCC (0.38 g, 1.8 mmol), and HOBt (0.23 g, 1.7 mmol) in CH2Cl2 (15 mL)
was stirred at room temperature for 30 min. To this mixture, compound 3
(0.63 g, 1.7 mmol) in CH2Cl2 (5 mL) were added and stirred overnight
under an Ar atmosphere. The resulting mixture was filtered and the fil-
trate was extracted with saturated NaHCO3 (aq), dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. The crude product was
purified by column chromatography on silica gel (CHCl3/MeOH, 40:1).
Yield 0.69 g (74%); m.p.: 1808C; 1H NMR (300 MHz, CDCl3): d=8.36
(1H, d, J=1.8 Hz), 8.02 (1H, s), 8.00 (1H, dd, J=8.7, 1.8 Hz), 7.90 (1H,
d, J=9.3 Hz), 7.73 (1H, d, J=8.7 Hz), 7.34 (2H, d, J=9.0 Hz), 7.20 (1H,
dd, J=9.3, 2.4 Hz), 7.07 (1H, d, J=2.4 Hz), 6.66 (2H, d, J=9.0 Hz), 4.12
(2H, s), 3.73 (6H, s), 3.54 (4H, t, J=7.2 Hz), 3.25 (4H, s), 3.25 (3H, s),
2.80 (4H, t, J=7.2 Hz), 2.69 ppm (3H, s); IR (KBr): n˜ =1626, 1578,
1
1518 cmꢀ1; H NMR (400 MHz, CDCl3): d=8.24 (1H, d, J=1.6 Hz), 8.03
(1H, S), 7.87 (1H, dd, J=8.8, 1.6 Hz), 7.77 (1H, d, J=8.8 Hz), 7.59 (1H,
d, J=8.8 Hz), 7.25 (2H, d, J=9.2 Hz), 7.01 (1H, dd, J=8.8, 2.0 Hz), 6.86
(1H, d, J=2.0 Hz), 6.55 (2H, d, J=9.2 Hz), 5.67 (4H, s), 4.21 (1H, m),
3.83 (1H, m), 3.44 (4H, t, J=7.6 Hz), 3.37 (1H, m), 3.19 (4H, s), 2.71
(4H, t, J=7.6 Hz), 2.58 (3H, s), 2.34 (2H, m), 2.07 (2H, m), 2.00 ppm
(6H, s); 13C NMR (100 MHz, CDCl3): d=197.6, 171.1, 169.4, 169.0,
147.1, 143.9, 137.2, 131.5, 131.2, 130.2, 127.2, 126.4, 126.1, 124.8, 122.3,
116.5, 112.6, 107.0, 79.6, 64.8, 50.9, 49.9, 33.1, 31.6, 29.6, 26.4, 24.1,
20.6 ppm; HRMS (EI): m/z calculated for [M+H]+ 754.2468; found:
754.2462.
1535 cmꢀ1
611.2153.
;
HRMS (EI): m/z calcd for [M+H]+ 611.2157; found:
Solubility of ANi1, ANi2, and ANi2-AM in HEPES buffer: A small
amount of dye was dissolved in DMSO to prepare the stock solution
(1.0ꢁ10ꢀ3 m). The solution was diluted to about 6.0ꢁ10ꢀ3–6.0ꢁ10ꢀ5 m and
added to a cuvette containing HEPES Buffer (3.0 mL, pH 7.1) using a
Synthesis of ANi2-Me: Synthesized according to the same procedure as
described for ANi1-Me, except that compound B (0.30 g, 1.1 mmol) was
1958
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 1953 – 1960