BULLETIN OF THE
Article
Synthesis of Benzoisoxazole Derivatives and Evaluation
KOREAN CHEMICAL SOCIETY
further purification (880 mg, 40% yield). 1H NMR
(400 MHz, CDCl3) δ 1.66 (m, 2H), 1.90 (m, 2H), 2.71 (m,
5H), 7.24 (dd, J = 6.4, 2.0 Hz, 1H), 7.31 (dd, J = 6.4,
4.2 Hz, 1H), 7.77 (dd, J = 4.2, 2.0 Hz, 1H). 13C NMR
(400 MHz, CDCl3) δ 23.1 (2C), 27.4 (2C), 36.6, 118.0
(2C), 124.3, 148.8 (2C), 157.6, 161.8.
45.5, 56.2, 97.1, 112.6, 117.9, 122.5, 160.0, 162.3,
163.8, 171.8.
(E)-3-(3,4-Dimethoxyphenyl)-1-(4-(6-fluorobenzo[d]iso-
xazol-3-yl)piperidin-1-yl)prop-2-en-1-one (19). Com-
pound 19 was obtained as a yellow solid in 90% yield by
1
general procedure (A). H NMR (400 MHz, CDCl3) δ 2.00
2-Azido-1-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-
1-yl)ethanone (2). To a solution of 2-azidoacetic acid
(1.04 mL, 13.85 mmol) in 10 mL DCM, EDC (3.72 g,
19.4 mmol) was added at room temperature slowly. After
the reaction mixture was stirred for 15 min at room temper-
ature, free amine 1 (3.05 g, 13.85 mmol) was added and
then stirred for 1 h in additionally. The reaction was com-
pleted and then was quenched by adding water. The result-
ing solution was extracted with DCM thrice and dried over
with anhydrous MgSO4. After the solvent was removed
under vacuum, the crude product was purified by silica gel
column chromatography to give a desired product (2) as a
white solid product (2.8 g, 67% yield). 1H NMR
(400 MHz, CDCl3) δ 1.95 (m, 1H), 2.08 (m, 1H), 2.19 (m,
2H), 3.02 (dt, J = 4.3, 1.4 Hz, 1H), 3.30 (dt, J = 4.3,
1.4 Hz, 1H), 3.38 (q, J = 4.3 Hz, 1H), 3.85 (dt, J = 4.3,
1.4 Hz, 1H), 4.60 (dt, J = 4.3, 1.4 Hz, 1H), 7.10 (dd,
J = 6.4, 2.0 Hz, 1H), 7.28 (dd, J = 6.4, 4.2 Hz, 1H), 7.63
(dd, J = 4.2, 2.0 Hz, 1H). 13C NMR (400 MHz, CDCl3) δ
30.8 (2C), 34.5, 42.2, 45.8, 50.7, 98.1, 113.7, 117.6, 122.3,
160.8, 164.5, 165.9, 167.7.
6-Fluoro-3-(1-(prop-2-yn-1-yl)piperidin-4-yl)benzo[d]
iso-xazole (3). To a solution of free amine 1 (2.0 g,
9.08 mmol) in 50 mL DCM, triethylamine (4.45 mL,
31.78 mmol), propargyl chloride (0.72 mL, 9.99 mmol),
and potassium iodide (80 mg, 0.45 mmol) were added at
room temperature slowly. After the reaction mixture
was stirred for 2 h at room temperature, the reaction was
quenched by adding water. The resulting solution was
extracted with DCM thrice and dried over with anhydrous
MgSO4. After the solvent was removed under vacuum, the
desired propazyl product (3) was obtained by recrystalliza-
tion with DCM/hexane system as a white solid product
(1.8 g, 77% yield). 1H NMR (400 MHz, CDCl3) δ 1.66 (m,
2H), 1.90 (m, 2H), 2.50 (s, 1H), 2.71 (m, 7H), 7.20 (dd,
J = 6.4, 2.0 Hz, 1H), 7.31 (dd, J = 6.4, 4.2 Hz, 1H), 7.63
(dd, J = 4.2, 2.0 Hz, 1H). 13C NMR (400 MHz, CDCl3) δ
23.2 (2C), 27.3 (2C), 34.5, 36.7, 42.6 (2C), 118.4 (2C),
124.2, 148.6 (2C), 157.3, 161.8.
(m, 2H), 2.15 (m, 2H), 3.00 (br-s, 1H), 3.35 (m, 2H), 3.87
(s, 3H), 3.89 (s, 3H), 4.25 (br-s, 1H), 4.81 (br-s, 1H), 6.75
(d, J = 16.0 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 7.01 (s,
1H), 7.02 (d, J = 8.8 Hz, 1H), 7.07 (dt, J = 8.8, 2.4 Hz,
1H), 7.22 (dd, J = 8.4, 2.4 Hz, 1H), 7.60 (d, J = 16.0 Hz,
1H), 7.63 (dd, J = 8.4, 5.2 Hz, 1H).
(E)-4-(3-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-
1-yl)-3-oxoprop-1-en-1-yl)-2-methoxyphenyl acetate (20).
Compound 20 was obtained as a yellow solid in 82% yield
1
by general procedure (A). H NMR (400 MHz, CDCl3) δ
2.05 (m, 2H), 2.21 (m, 2H), 2.33 (s, 3H), 3.05 (br-s, 1H),
3.39 (m, 2H), 3.88 (s, 3H), 4.26 (br-s, 1H), 4.76 (br-s, 1H),
6.87 (d, J = 15.2 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 7.09
(m, 2H), 7.14 (dt, J = 8.4, 2.0 Hz, 1H), 7.27 (dd, J = 8.0,
2.0 Hz, 1H), 7.50 (d, J = 15.2 Hz, 1H), 7.52 (dd, J = 8.4,
4.8 Hz, 1H). 13C NMR (400 MHz, CDCl3) δ 20.2, 30.4,
34.1 (2C), 56.5 (2C), 66.9, 97.4, 111.8, 112.3, 117.7 (2C),
120.8, 122.0, 123.6, 134.4, 140.8, 142.2, 151.5, 160.7,
164.3 (2C), 165.7, 168.8.
(E)-4-(3-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-
1-yl)-3-oxoprop-1-en-1-yl)-1,2-phenylene diacetate (21).
Compound 21 was obtained as a yellow solid in 88% yield
1
by general procedure (A). H NMR (400 MHz, CDCl3) δ
2.03 (m, 2H), 2.18 (m, 2H), 2.30 (s, 3H), 2.31 (s, 3H), 3.04
(br-s, 1H), 3.39 (m, 2H), 4.25 (br-s, 1H), 4.73 (br-s, 1H),
6.88 (d, J = 15.2 Hz, 1H), 7.08 (dt, J = 8.8, 2.0 Hz, 1H),
7.21 (d, J = 8 Hz, 1H), 7.26 (dd, J = 8.4, 2.0 Hz, 1H),
7.37 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.63 (d,
J = 15.2 Hz, 1H), 7.64 (dd, J = 8.4, 4.8 Hz, 1H). 13C
NMR (400 MHz, CDCl3) δ 20.3 (2C), 30.4, 34.7 (2C),
53.9 (2C), 97.7, 112.8, 117.1, 118.2, 122.5 (2C), 123.9,
126.6, 134.1, 141.3, 142.7 (2C), 160.8, 162.4, 163.5,
165.9, 168.8 (2C).
4-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidine-1-car-
bon-yl)-2,6-dimethoxyphenyl acetate (22). Compound 22
was obtained as a yellow solid in 75% yield by general pro-
1
cedure (A). H NMR (400 MHz, CDCl3) δ 2.00 (br-s, 2H),
2.18 (br-s, 2H), 2.35 (s, 3H), 3.21 (br-s, 2H), 3.38 (m, 1H),
3.85 (s, 6H), 4.04 (br-s, 1H), 4.71 (br-s, 1H), 6.68 (s, 2H),
7.09 (dt, J = 8.8, 2.0 Hz, 1H), 7.28 (dd, J = 8.4, 2.0 Hz,
1H), 7.64 (dd, J = 8.4, 4.8 Hz, 1H). 13C NMR (400 MHz,
CDCl3) δ 20.2, 30.4, 34.5 (2C), 53.6 (2C), 56.8 (2C), 97.1,
103.1 (2C), 112.2, 117.5, 122.3, 129.5, 133.8, 152.4 (2C),
160.7, 163.5 (2C), 168.8, 169.0.
5-(1,2-Dithiolan-3-yl)-1-(4-(6-fluorobenzo[d]isoxazol-
3-yl)piperidin-1-yl)pentan-1-one (18). Compound 18 was
obtained as a yellow solid in 78% yield by general proce-
1
dure (A). H NMR (400 MHz, CDCl3) δ 1.50 (m, 2H),
1.72 (m, 4H), 1.96 (m, 3H), 2.15 (m, 2H), 2.40 (t,
J = 7.6 Hz, 2H), 2.48 (m, 1H), 2.90 (t, J = 13.6 Hz, 1H),
3.16 (m, 2H), 3.35 (m, 2H), 3.60 (m, 1H), 4.02 (br-d,
J = 13.6 Hz, 1H), 4.67 (br-d, J = 13.6 Hz, 1H), 7.08 (dt,
J = 8.8, 2.0 Hz, 1H), 7.26 (dd, J = 8.4, 2.0 Hz, 1H), 7.65
(dd, J = 8.8, 4.8 Hz, 1H). 13C NMR (400 MHz, CDCl3) δ
25.6, 29.2, 30.4 (2C), 33.6, 34.2 (2C), 38.4, 40.7, 41.3,
5-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidine-1-car-
bon-yl)benzene-1,2,3-triyl triacetate (23). Compound 23
was obtained as a yellow solid in 81% yield by general pro-
1
cedure (A). H NMR (400 MHz, CDCl3) δ 2.03 (m, 2H),
2.18 (m, 2H), 2.30 (s, 9H), 3.23 (br-s, 2H), 3.36 (m, 1H),
4.06 (br-s, 1H), 4.67 (br-s, 1H), 7.09 (dt, J = 8.4, 2.4 Hz,
Bull. Korean Chem. Soc. 2016, Vol. 37, 1464–1471
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim