Journal of Medicinal Chemistry
Article
(t, CH2), 101.2 (t, O−CH2−O), 107.6 (d), 108.6 (d), 120.7 (d), 124.8
(d), 124.9 (d), 127.4 (d), 128.8 (d), 134.8 (s), 137.9 (s), 141.1 (s),
147.3 (s), 148.2 (s), 171.6 (s, −CO−N). HR-MS [M + H]+ m/z
(pred) = 326.1751, m/z (meas) = 326.1749, difference = −0.61 ppm.
[5-(Benzo[d][1,3]dioxol-5-yl)naphthalen-1-yl](piperidin-1-yl)-
methanone (62). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (EDCI·HCl; 65 mg, 0.34 mmol, 2 equiv) was added
to a suspension of 62a (50 mg, 0.17 mmol, 1 equiv) and
hydroxybenzotriazole (HOBt; 52 mg, 0.34 mmol, 2 equiv) in dry
dichloromethane (2 mL) under argon at rt. After 2 h, the suspension
was transformed into an opaque solution and TLC indicated full
consumption of the starting material. Piperidine (0.5 mL) was added
at rt and stirring was continued overnight. After full conversion was
detected by TLC, the reaction mixture was diluted with EtOAc (30
mL); washed with 0.5 N HCl, saturated NaHCO3, and brine (20 mL
each); dried with sodium sulfate; and evaporated. The crude product
was purified by column chromatography with LP/EtOAc mixture as
eluent.
Yield 29% (48% based on recovered starting material, 874 mg, 2.9
mmol), colorless solid, mp 97−99 °C. TLC 0.18 (LP/EE 30:1). H
1
NMR (CDCl3, 200 MHz) δ 1.38 (s, 12H, CH3), 6.03 (s, 2H, O−
CH2−O), 7.10 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 8.2 Hz,
1H), 8.16 (s, 1H, H5). 13C NMR (CDCl3, 50 MHz) 24.9 (q, 4C,
CH3), 83.8 (s, B−O−CR3), 101.0 (t, O−CH2−O), 103.8 (d), 104.4
(d), 126.2 (d), 129.3 (d), 129.8 (s), 132.5 (s), 134.9 (d), 147.4 (s),
148.4 (s); C6 signal could not be detected due to low signal intensity.
6-Bromonaphtho[2,3-d][1,3]dioxole (68b). For synthesis of 68b, a
modification of a published procedure40 was used. In a three-necked
flask with magnetic stirrer and reflux condenser, 68a (700 mg, 2.35
mmol, 1 equiv) was dissolved in methanol. Copper(II) bromide (1.57
g, 7 mmol, 3 equiv) was dissolved in water (20 mL) and added. The
reaction was heated to reflux for 18 h and checked with TLC. The
reaction mixture was cooled, diluted with water (200 mL), and
extracted with 3 × 50 mL of DCM. The combined organic extracts
were washed with 50 mL each water and brine, dried with anhydrous
sodium sulfate, and evaporated.
Yield 62% (0.11 mmol, 38 mg), colorless solid, mp 150−153 °C.
TLC 0.09 (LP/EtOAc 4:1). 1H NMR (CDCl3, 200 MHz) δ 1.40−1.50
(m, 2H, CH2), 1.66−1.80 (m, 4H, CH2), 3.15−3.21 (m, 2H, N−
CH2), 3.87−3.93 (m, 2H, N−CH2), 6.04 (s, 2H, O−CH2−O), 6.93−
6.95 (m, 3H, ArH), 7.39−7.56 (m, 4H, ArH), 7.84 (d, J = 8.3 Hz, 1H,
ArH), 7.94 (dd, J1 = 7.2 Hz, J2 = 2.6 Hz, 1H, ArH). 13C NMR (CDCl3,
50 MHz) δ 24.6 (t, CH2), 25.9 (t, CH2), 26.7 (t, CH2), 42.7 (t, N−
CH2), 48.3 (t, N−CH2), 101.2 (t, O−CH2−O), 108.2 (d), 110.6 (d),
123.3 (d), 123.4 (d), 124.4 (d), 125.3 (d), 126.2 (d), 126.9 (d), 127.4
(d), 120.9 (s), 131.9 (s), 134.3 (s), 135.2 (s), 140.3 (s), 147.0 (s),
147.5 (s), 169.4 (s, CO−N). HR-MS [M + H]+ m/z (pred) =
360.1594, m/z (meas) = 360.1597, difference = 0.83 ppm.
Yield 94% (555 mg, 2.21 mmol), colorless solid, mp 135−138 °C.
TLC 0.40 (LP/EE 30:1). 1H NMR (CDCl3, 200 MHz) δ 6.04 (s, 2H,
O−CH2−O), 7.01 (s, 1H, ArH), 7.06 (s, 1H, ArH), 7.38 (dd, J1 = 8.7
Hz, J2 = 1.9 Hz, 1H, H7), 7.51 (d, J = 8.7 Hz, 1H, H8), 7.79 (d, J = 1.9
Hz, 1H, H5). 13C NMR (CDCl3, 50 MHz) 101.3 (t, O−CH2−O),
103.0 (d), 103.8 (d), 118.1 (s), 127.5 (d), 128.5 (d), 128.9 (d), 131.8
(s), 148.0 (s), 148.3 (s). One signal could not be detected due to low
signal intensity.
(E)-Methyl 3-(Naphtho[2,3-d][1,3]dioxol-6-yl)acrylate (68c). An
8-ml vial with magnetic stirrer, screw cap, and septum was charged
with 68b (300 mg, 1.2 mmol, 1 equiv), methyl acrylate (163 μL, 1.8
mmol, 1.5 equiv), palladium(II) acetate (8 mg, 0.036 mmol, 3 mol %),
and tri-o-tolylphosphine (22 mg, 0.072 mmol, 6 mol %) and flushed
with argon. Triethylamine (0.85 mL) was added via syringe and the
reaction was heated to 80 °C. TLC monitoring (eluent LP/EE 30:1)
showed full conversion after 8 h. The reaction mixture was diluted
with diethyl ether (30 mL). Due to low solubility of the product in
diethyl ether, it was necessary to add ethyl acetate (20 mL) and DCM
(10 mL) to obtain a clear solution. The organic phase was washed with
3 × 10 mL of 0.5 N HCl and 30 mL of brine and dried with sodium
sulfate. Evaporation of the solvent gave the pure product in
quantitative yield.
Yield 100% (310 mg, 1.2 mmol), colorless solid, mp 151−152 °C.
TLC 0.16 (LP/EE 30:1). 1H NMR (CDCl3, 200 MHz) δ 3.81 (s, 3H,
CH3), 6.06 (s, 2H, O−CH2−O), 6.49 (d, J = 16.0 Hz, 1H, H3), 7.10
(s, 1H, ArH), 7.12 (s, 1H, ArH), 7.50 (dd, J1 = 8.6 Hz, J2 = 1.6 Hz, 1H,
H7′), 7.64 (d, J = 8.6 Hz, 1H, H8′), 7.74−7.83 (m, 2H, H2, H5′). 13C
NMR (CDCl3, 50 MHz) δ 51.7 (q, CH3), 101.3 (t, O−CH2−O),
103.9 (d), 104.4 (d), 116.9 (d), 127.6 (d), 128.7 (d), 130.3 (s), 130.4
(s), 131.7 (s), 145.1 (d), 148.2 (s), 148.7 (s), 167.6 (d, COOR). HR-
MS [M + H]+ m/z (pred) = 257.0808, m/z (meas) = 257.0807,
difference = −0.39 ppm.
Naphtho[2,3-d][1,3]dioxole-5-carboxylic acid (71a). For synthesis
of 71a, a modification of a published procedure41 was used. In a two-
necked flask equipped with magnetic stirrer, septum, and balloon,
naphtho[2,3-d][1,3]dioxol-5-yl trifluoromethanesulfonate42 (96 mg,
0.3 mmol, 1 equiv), 1,3-bis(diphenylphosphino)propane (dppp; 7 mg,
0.018 mmol, 6 mol %), and palladium(II) acetate (2 mg, 0.009 mmol,
3 mol %) were suspended in DMF/water 3:1 (1 mL). A steel cannula
reaching to the bottom of the flask was used to bubble carbon
monoxide through the solution for 10 min; after that, the balloon was
filled with CO gas in order to maintain its supply throughout the
(E)-Methyl 3-(Naphtho[2,3-d][1,3]dioxol-5-yl)acrylate (65a). For
synthesis of 65a, a modification of a previously published method38
was employed. A 8-mL vial with magnetic stirrer, screw cap, and
septum was charged with naphtho[2,3-d][1,3]dioxol-5-yl trifluorome-
thanesulfonate (synthesized according to ref 37) (480 mg, 1.5 mmol, 1
equiv), 1,10-phenanthroline monohydrate (16 mg, 0.083 mmol, 5.5
mol %), palladium(II) acetate (17 mg, 0.075 mmol, 5 mol %), and
anhydrous N,N-dimethylformamide (DMF, 5 mL). Then triethyl-
amine (250 μL, 1.8 mmol, 1.2 equiv) and methyl acrylate (680 μL, 7.5
mmol, 5 equiv) were added successively. The vial was flushed with
argon and heated to 80 °C for 16 h. Reaction control by TLC showed
full conversion. The solvent was evaporated, and the residue was taken
up in DCM and adsorbed on silica. Column chromatography (45 g of
SiO2, eluent LP/EtOAc, 5% isocratic) yielded the pure product.
Yield 95% (364 mg, 1.425 mmol), colorless solid, mp 125−126 °C.
1
TLC 0.44 (LP/EtOAc 4:1). H NMR (CDCl3, 200 MHz) δ 3.82 (s,
3H, CH3), 5.99 (s, 2H, O−CH2−O), 6.43 (d, J = 15.7 Hz, 1H, H3),
7.04 (s, 1H, ArH), 7.25 (t, J = 7.7 Hz, 1H, H7′), 7.38 (s, 1H, ArH),
7.52 (d, J = 7.1 Hz, 1H, ArH), 7.61 (d, J = 8.1 Hz, 1H, ArH), 8.29 (d, J
= 15.7 Hz, 1H, H2). 13C NMR (CDCl3, 50 MHz) 51.7 (q, CH3), 99.9
(d), 101.4 (t, O−CH2−O), 104.4 (d), 119.9 (d), 123.5 (d), 124.0 (d),
128.7 (s), 129.5 (d), 130.7 (s), 130.9 (s), 142.1 (d), 147.6 (s), 148.6
(s), 167.3 (s, COOR). HR-MS [M − MeOH]+ m/z (pred) =
225.0546, m/z (meas) = 225.0553, difference = 3.11 ppm.
4,4,5,5-Tetramethyl-2-(naphtho[2,3-d][1,3]dioxol-6-yl)-1,3,2-di-
oxaborolane (68a). For synthesis of 68a, a modification of a
procedure published by Ishyama et al.39 was used. A three-necked flask
with magnetic stirrer, septum, reflux condenser, and balloon was
charged with naphtho[2,3-d][1,3]dioxole (1.72 g, 10 mmol, 1 equiv),
bis(pinacolato)diboron (1.27 g, 5 mmol, 0.5 equiv), [Ir(OMe)cod]2
(100 mg, 0.15 mmol, 1.5 mol %), and 4,4′-di-tert-butyl-2,2′-bipyridine
(81 mg, 0.3 mmol, 3 mol %) and flushed with argon. Then
cyclohexane (60 mL) was added and the reaction was heated to reflux
and monitored with GC/MS. After 24 h the reaction did not proceed
any further. After evaporation of the solvent, the residue was
redissolved in DCM, adsorbed on silica, and directly subjected to
column chromatography (45 g of SiO2, eluent LP/EE 30:1), which
yielded the pure product (683 mg of starting material could be
reisolated in this step).
reaction time. Hunig’s base (102 μL, 0.6 mmol, 2 equiv) was added via
̈
syringe and the reaction mixture was heated to 70 °C. After 3 h,
reaction control with TLC indicated complete consumption of the
starting material. The reaction mixture was diluted with ethyl acetate
(10 mL) and extracted with 3 × 5 mL of saturated NaHCO3. The
combined aqueous extracts were acidified to pH = 2 with 2 N HCl and
extracted with 3 × 10 mL of ethyl acetate. The combined organic
extracts were washed with 10 mL each water and brine and dried with
sodium sulfate. Evaporation of the solvent gave the pure product.
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dx.doi.org/10.1021/jm5002277 | J. Med. Chem. XXXX, XXX, XXX−XXX