Synthesis of benzo-fused spiropiperidines
7.36 (m, 10H, ArH), 7.42–7.56 (m, 4H, ArH), 7.80 (d, 2H,
J = 6.0 Hz, ArH), 8.02 (d, 2H, J = 6.0 Hz, ArH), 8.26–
8.32 (m, 2H, ArH) ppm; 13C NMR (75 MHz, CDCl3):
d = 13.8, 30.7, 31.8, 39.4, 39.8, 48.3, 49.2, 52.9, 55.6,
70.6, 103.5, 122.6, 122.8, 123.1, 123.8, 125.1, 125.2,
125.6, 125.9, 126.1, 126.7, 126.8, 126.9, 127.0, 127.3,
127.7, 127.9, 128.4, 128.7, 129.0, 132.3, 132.8, 136.3,
137.1, 154.6, 155.0, 167.0, 213.9, 214.0 ppm; FT-IR
4H-spiro[naphthalene-1,40-piperidin]-4-one (3c) (53 %)
and 14.4 mg 10-benzyl-3,4-dihydro-2H-spiro[naphthalene-
1,40-piperidin]-4-ol (3d) (10 %) as a mixture of the
reduction reaction.
Procedure B To a stirred solution of 150.0 mg 10-
benzyl-4H-spiro[naphthalene-1,40-piperidine]-20,4-dione
(3b, 0.47 mmol, 1.0 equiv.) in 2.0 cm3 THF at 0 °C, a
solution of 24.0 mg LiAlH4 (0.94 mmol, 2.0 equiv.) in
5.0 cm3 THF was added. The resulting mixture was MW
heated (100 W, 60 °C) for 10 min. Then, a second solution
of 12.0 mg LiAlH4 (0.47 mmol, 1.0 equiv.) in 2.0 cm3
THF was added at 0 °C and the resulting mixture was MW
heated (100 W, 60 °C) for 10 min. Then, 0.6 cm3 water
and 0.6 cm3 NaOH (4 N) were sequentially added and the
new solution was filtered through a Celite pad and
concentrated until dryness. The crude was purified by
silica gel column chromatography (hexanes/AcOEt/Et3N,
20:80:0.1, v/v/v) to afford 98.2 mg 10-benzyl-3,4-dihydro-
2H-spiro[naphthalene-1,40-piperidin]-4-ol (3d) (68 %).
Procedure C To a stirred solution of 50.0 mg 10-benzyl-
2,3-dihydro-4H-spiro[naphthalene-1,40-piperidin]-4-one
(3c, 0.16 mmol, 1.0 equiv.) in 2.0 cm3 THF at 0 °C, a
solution of 6.0 mg LiAlH4 (0.24 mmol, 1.5 equiv.) in
1.0 cm3 THF was added. The resulting mixture was MW
heated (100 W, 60 °C) for 10 min. Then, 0.3 cm3 water
and 0.3 cm3 NaOH (4 N) were sequentially added and the
new solution was filtered through a Celite pad and
concentrated until dryness. The crude was purified by
silica gel column chromatography (hexanes/AcOEt/Et3N,
20:80:0.1, v/v/v) to afford 49.7 mg 10-benzyl-3,4-dihydro-
2H-spiro[naphthalene-1,40-piperidin]-4-ol (3d) (quantita-
tive yield).
(ATR): vꢀ = 1,055, 1,225, 1,586, 1,647, 2,936 cm-1
;
?
HRMS: m/z calcd. for C25H27NO3S2 ([MH]?) 454.1511,
found 454.1508.
10-Benzyl-4H-spiro[naphthalene-1,40-piperidine]-20,4-
dione (3b, C21H19NO2)
To a stirred solution of 2.1 g S-[2-[benzyl[2-(4-meth-
oxynaphthalen-1-yl)ethyl]amino]-2-oxoethyl]
O-ethyl
carbonodithioate (4, 4.7 mmol, 1.0 equiv.) in 23.0 cm3
1,2-DCE, 2.24 g DLP (5.6 mmol, 1.2 equiv.) was added in
six cycles (0.2 equiv./cycle) of MW heating conditions
(100 W, 85 °C, 5 min) and then the solvent was removed
until dryness. The crude was purified by silica gel column
chromatography (AcOEt/hexanes, 1:1, v/v) to afford
744.8 mg
10-benzyl-4H-spiro[naphthalene-1,40-piperi-
dine]-20,4-dione (3b) (50 %) as colorless crystals (CCDC
1
1022815). Rf = 0.33 (hexanes/AcOEt, 1:1, v/v); H NMR
(300 MHz, CDCl3): d = 1.84–1.92 (m, 1H, 1 H of CH2),
2.23-2.33 (m, 1H, 1 H of CH2), 2.61 (dd, J = 2.4, 17.4 Hz,
1H, 1 H of CH2), 3.05 (d, J = 17.4 Hz, 1H, 1 H of CH2),
3.39–3.43 (m, 2H, NCH2), 4.73 (dd DAB, J = 14.4,
32.7 Hz, 2H, NCH2), 6.47 (d, J = 10.5 Hz, 1H, CH),
6.99 (d, J = 10.2 Hz, 1H, CH), 7.29 (m, 7H, ArH), 7.54–
7.60 (m, 1H, ArH), 8.19 (dd, J = 1.5, 7.9 Hz, 1H, ArH)
ppm; 13C NMR (75 MHz, CDCl3): d = 35.5, 39.5, 42.8,
44.3, 50.3, 125.8, 127.3, 127.7, 127.9, 128.5, 128.9, 129.0,
131.0, 133.2, 136.7, 146.3, 150.1, 167.6, 183.9 ppm; FT-IR
(ATR): vꢀ = 1,225, 1,596, 1,661, 2,966 cm-1; HRMS: m/
10-Benzyl-2,3-dihydro-4H-spiro[naphthalene-1,40-
piperidin]-4-one (3c, C21H22NO)
Pale yellow oil; Rf = 0.57 (hexanes/AcOEt, 1:1, v/v); H
1
?
z calcd. for C21H20NO2 ([MH]?) 318.1494, found
NMR (300 MHz, CDCl3): d = 1.67–1.72 (m, 2H, CH2),
2.13–2.23 (m, 4H, 2 CH2), 2.31–2.39 (m, 2H, CH2), 2.62–
2.67 (m, 2H, NCH2), 2.77–2.87 (m, 2H, NCH2), 3.60 (s,
2H, NCH2), 7.23–7.38 (m, 6H, ArH), 7.52–7.61 (m, 2H,
ArH), 8.02 (dd, J = 1.5, 7.8 Hz, 1H, ArH) ppm; 13C NMR
(75 MHz, CDCl3): d = 28.3, 33.8, 35.4, 36.0, 49.4, 63.4,
125.5, 126.5, 127.4, 128.3, 129.3, 132.0, 134.1, 138.2,
151.8, 198.4 ppm; FT-IR (ATR): vꢀ = 1,597, 1,685, 2,806,
2,923 cm-1; HRMS: m/z calcd. for C21H23NO? ([MH]?)
306.1858, found 306.1864.
318.1497.
10-Benzyl-2,3-dihydro-4H-spiro[naphthalene-1,40-
piperidin]-4-one (3c, C21H22NO) and 10-benzyl-3,4-
dihydro-2H-spiro[naphthalene-1,40-piperidin]-4-ol
(3d, C21H24NO)
Procedure A To a stirred solution of 150.0 mg 10-benzyl-
4H-spiro[naphthalene-1,40-piperidine]-20,4-dione
(3b,
0.47 mmol, 1.0 equiv.) in 2.0 cm3 THF at 0 °C, a solution
of 24.0 mg LiAlH4 (0.94 mmol, 2.0 equiv.) in 5.0 cm3
THF was added. The resulting mixture was MW heated
(100 W, 60 °C) for 10 min. Then, 0.6 cm3 water and
0.6 cm3 NaOH (4 N) were sequentially added and the
new solution was filtered through a Celite pad and
concentrated until dryness. The crude was purified by
silica gel column chromatography (hexanes/AcOEt/Et3N,
50:50:0.1, v/v/v) to afford 76.0 mg 10-benzyl-2,3-dihydro-
10-Benzyl-3,4-dihydro-2H-spiro[naphthalene-1,40-
piperidin]-4-ol (3d, C21H24NO)
Pale yellow oil; Rf = 0.28 (hexanes/AcOEt, 1:1, v/v); H
1
NMR (300 MHz, CDCl3): d = 1.52–1.63 (m, 2H, CH2),
1.74–2.37 (m, 8H, 4 CH2), 2.74–2.81 (m, 2H, CH2), 3.59
(s, 2H, NCH2), 4.72 (t, J = 6.0 Hz, 1H, CH), 7.17–7.44
(m, 8H, ArH), 7.53 (dd, J = 3.0, 9.0 Hz, 1H, ArH) ppm;
123