Fluorogenic Substrate of BoVine Plasma Amine Oxidase
8.8 Hz), 7.28 (d, 1H, J ) 2.4 Hz), 7.51 (dd, 1H, J ) 1.6, 8.4 Hz),
7.81 (d, 1H, J ) 8.8 Hz), 7.84 (d, 1H, J ) 8.8 Hz), 7.88 (s, 1H);
13C NMR (CD3OD) δ 40.3, 44.5, 65.4, 108.0, 120.5, 127.8, 129.2,
129.4, 130.0, 130.6, 130.9, 136.1, 158.2; HRMS (FAB) m/z calcd
C13H17N2O (MH+) 217.1341, found 217.1342.
evaluate BPAO inhibitors at nanomolar levels. Compounds of
this type could serve as sensors of copper amine oxidase
activities in biological tissues.
(2-(6-(Aminomethyl)naphthalen-2-yloxy)ethyl)methylamine Dihy-
drochloride (10 ·2HCl). The mixed anhydride of formic and acetic
acids was first prepared by stirring a mixture of acetic anhydride
(0.561 g, 5.5 mmol), formic acid (0.253 g, 5.5 mmol), and pyridine
(0.435 g, 5.5 mmol) in 10 mL of dry CH2Cl2 at room temperature
for 1 h. To the resulting mixture was added a solution of the abo-
ve crude 25·CF3CO2H (1.63 g, 5 mmol) and Et3N (2.02 g, 20
mmol) in CH2Cl2 (10 mL). The mixture was stirred at room
temperature for 1 h, diluted with Et2O to 200 mL, and then washed
with brine (3 × 50 mL). The organic layer was separated, dried
(Na2SO4), and evaporated to dryness to give crude 6-(2-formami-
doethoxy)naphthalene-2-carbonitrile (26) as a brown oil.
Experimental Section
6-Methoxy-2-naphthalenemethaneamine Hydrochloride (1 ·HCl).
To a suspension of 1.9 g (50 mmol) of LAH in 200 mL of Et2O
was slowly added with vigorous stirring at 0 °C a solution of
6-methoxy-2-naphthonitrile (3.66 g, 20 mmol) in 100 mL of Et2O.
The mixture was stirred at room temperature for 4 h, at which point
10 mL of EtOAc was added dropwise with cooling at -78 °C to
decompose excess LAH. The final mixture was slowly added to a
mixture of ice (500 g) and sodium tartrate (10 g) under stirring.
The organic layer was separated, and the aqueous layer was
saturated with solid NaCl and extracted with Et2O (3 × 100 mL).
The combined organic layers were dried (Na2SO4), the solvent was
evaporated, and the residue was dissolved in 20 mL of 12 N aqueous
HCl. Evaporation of solvent and crystallization of the residue from
EtOH/iPrOH afforded pure 1·HCl (3.89 g, 17 mmol, 85%): white
The above crude 26 was reduced with LAH in Et2O and worked
up exactly as for 25 above, including purification of the final HCl
salt, affording pure 10·2HCl as a white powder (0.62 g, 2.04 mmol,
1
an overall yield of 41%): mp 304-306 °C (decomp); H NMR
1
plates, mp 279-280 °C (decomp); H NMR (CD3OD) δ 3.86 (s,
(D2O/CD3OD) δ 2.84 (s, 3H), 3.54 (t, 2H, J ) 4.8 Hz), 4.29 (s,
2H), 4.41 (t, 2H, J ) 4.8 Hz), 7.30 (dd, 1H, J ) 2.4, 9.2 Hz), 7.36
(d, 1H, J ) 2.4 Hz), 7.52 (d, 1H, J ) 8.8 Hz), 7.86-7.92 (3H);
13C NMR (D2O/CD3OD) δ 33.8, 44.2, 49.0, 63.9, 107.9, 120.1,
127.7, 129.0, 129.2, 129.3, 129.9, 130.9, 135.3, 157.3; HRMS
(FAB) m/z calcd C14H19N2O (MH+) 231.1497, found 231.1492.
6-(2-(Dimethylamino)ethoxy)naphthalene-2-carbonitrile (27). To a
solution of 25·CF3CO2H (5.87 g, 18 mmol), glacial HOAc (10 mL),
and 37% aqueous CH2O (3 mL, 40 mmol) in 100 mL of MeOH
was added in small portions solid NaCNBH3 (3.15 g, 50 mmol)
with vigorous stirring and cooling to 0 °C. The mixture was then
stirred at room temperature for 2 h, and MeOH was evaporated.
The residual solution was diluted with 200 mL of brine, neutralized
with solid NaHCO3 to pH 7, basified with NaOH to pH 11, and
extracted with EtOAc (3 × 200 mL). The combined organic layers
were extracted with 200 mL of 0.5 N aqueous HCl. The aqueous
layer was separated, washed with Et2O (2 × 50 mL), neutralized
with solid NaHCO3 to pH 7, brought to pH 11 with NaOH, saturated
with solid NaCl, and extracted with EtOAc (3 × 100 mL). The
latter organic layers were collected, dried (Na2SO4), and evaporated
to dryness to give 27 as a brown viscous oil (2.64 g, 11.0 mmol,
61%): 1H NMR (CDCl3) δ 2.36 (s, 6H), 2.80 (t, 2H, J ) 5.6 Hz),
4.19 (t, 2H, J ) 5.6 Hz), 7.14 (d, 1H, J ) 2.0 Hz), 7.27 (dd, 1H,
J ) 2.0, 9.2 Hz), 7.53 (dd, 1H, J ) 1.2, 8.4 Hz), 7.74 (s, 1H), 7.75
(d, 1H, J ) 9.2 Hz), 8.10 (s, 1H); 13C NMR (CDCl3) δ 46.1, 58.3,
66.3, 106.7, 106.8, 119.8, 121.2, 127.2, 127.86, 127.94, 130.1,
133.9, 136.5, 159.4.
3H), 4.25 (s, 2H), 7.14 (dd, 1H, J ) 2.4, 8.8 Hz), 7.22 (d, 1H, J )
2.0 Hz), 7.52 (dd, 1H, J ) 1.6, 8.8 Hz), 7.79 (d, 1H, J ) 9.2 Hz),
7.82 (d, 1H, J ) 8.4 Hz), 7.87 (s, 1H); 13C NMR (CD3OD) δ 44.4,
56.0, 106.8, 120.2, 127.6, 129.0, 129.2, 129.3, 129.9, 130.6, 135.9,
159.4; HRMS (FAB) m/z calcd for C12H14NO (MH+) 188.1075,
found 188.1077.
2-(6-(Aminomethyl)naphthalen-2-yloxy)ethylamine Dihydrochlo-
ride (9 ·2HCl). A mixture of 2-bromoethylamine ·HBr (8.20 g, 40
mmol), di-tert-butyl dicarbonate (8.72 g, 40 mmol), and diiospro-
pylethylamine (DIEA, 20 mL) in 200 mL of CH2Cl2 was stirred at
room temperature overnight. The solvent was evaporated at room
temperature, and the residue was extracted with 200 mL of Et2O.
The solid material was filtered off and washed with Et2O. The
combined filtrates were evaporated to dryness to afford crude (2-
bromoethyl)carbamic acid tert-butyl ester as a light brown oil, which
solidified over time (7.6 g, 34 mmol, 85%).
A mixture of 6-cyano-2-naphthol (5.07 g, 30 mmol), (2-
bromoethyl)carbamic acid tert-butyl ester (6.72 g, 30 mmol),
anhydrous K2CO3 (4.14 g, 30 mmol), and KI (4.98 g, 30 mmol) in
100 mL of dry DMF was stirred under argon at 50 °C for 24 h.
The mixture was partitioned between 1 L of CH2Cl2 and 1 L of
5% aqueous K2CO3. The organic layer was separated, washed with
5% aqueous K2CO3 (3 × 100 mL), dried (Na2SO4), and evaporated
to dryness to give crude [2-(6-cyanonaphthalen-2-yloxy)ethyl]car-
bamic acid tert-butyl ester (24) as a light brown oil that solidified
on standing.
The latter was dissolved into 50 mL of dry trifluoroacetic acid
(TFA) with cooling at 0 °C. The solution was stirred at room
temperature for 20 min and then evaporated to dryness to give crude
6-(2-aminoethoxy)naphthalene-2-carbonitrile 25·CF3CO2H as a
brown oil (9.6 g, 29.4 mmol, 98%).
(2-(6-(Aminomethyl)naphthalen-2-yloxy)ethyl)dimethylamine Di-
hydrochloride (11 ·2HCl). A solution of 27 (2.00 g, 8.3 mmol) was
reduced with LAH (1.14 g, 30 mmol) in Et2O and worked up
exactly as for 25 above, including purification of the final HCl salt,
affording pure 11·2HCl as a white solid (2.02 g, 6.4 mmol, 77%):
mp 274-276 °C (decomp); 1H NMR (CD3OD) δ 3.03 (s, 6H), 3.70
(t, 2H, J ) 4.8 Hz), 4.27 (s, 2H), 4.52 (t, 2H, J ) 4.8 Hz), 7.33
(dd, 1H, J ) 2.8, 9.2 Hz), 7.43 (d, 1H, J ) 2.8 Hz), 7.56 (dd, 1H,
J ) 2.0, 8.4 Hz), 7.88 (d, 1H, J ) 8.8 Hz), 7.91 (d, 1H, J ) 8.8
Hz), 7.93 (s, 1H); 13C NMR (CD3OD) δ 44.0, 44.5, 58.0, 63.3,
108.3, 120.5, 127.9, 129.2, 129.5, 130.1, 130.7, 131.0, 136.0, 157.8;
HRMS (FAB) m/z calcd C15H21N2O (MH+) 245.1654, found
245.1642.
(2-(6-(Aminomethyl)naphthalen-2-yloxy)ethyl)trimethylammoni-
um Chloride Hydrochloride (12Cl- ·HCl). A mixture of 11·2HCl
(1.00 g, 3.15 mmol), Et3N (5 mL), and di-tert-butyl dicarbonate
(0.70 g, 3.21 mmol) in 50 mL of dry CH2Cl2 was stirred at room
temperature overnight. The solvent was evaporated at room
temperature, and the residue was partitioned between 100 mL of
Et2O and 100 mL of alkaline brine (pH 11). The organic layer was
separated, washed with alkaline brine (3 × 50 mL), dried (Na2SO4),
A suspension of 25·CF3CO2H (1.63 g, 5 mmol) in 100 mL of
absolute Et2O was treated with LAH (1.9 g, 50 mmol) as above.
The excess LAH was decomposed with EtOAc, and the resulting
mixture was further treated with ice and sodium tartrate. The organic
layer was separated. The aqueous layer was saturated with solid
NaCl and extracted with Et2O (3 × 50 mL). The combined organic
layers were extracted with 100 mL of 0.5 N aqueous HCl. The
aqueous layer was separated, washed with Et2O (2 × 50 mL),
brought to pH 11 with NaOH, saturated with solid NaCl, and
extracted with Et2O (3 × 100 mL). The latter organic layers were
collected, dried (Na2SO4), and evaporated to dryness. The residue
was dissolved in 10 mL of 12 N aqueous HCl and then evaporated
to dryness. The final residue was crystallized from EtOH/MeOH
to afford pure 9·2HCl as a white powder (0.67 g, 2.3 mmol, 46%):
mp >360 °C (decomp); 1H NMR (CD3OD) δ 3.45 (t, 2H, J ) 5.0
Hz), 4.26 (s, 2H), 4.39 (t, 2H, J ) 5.0 Hz), 7.23 (dd, 1H, J ) 2.4,
J. Org. Chem. Vol. 74, No. 1, 2009 347