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Y. Laras et al.
1ꢀ-Benzyl-6-methoxyspiro[chromene-2,4ꢀ-piperidin]-
4(3H)-one Oxime 4a
cyclohexane/ethyl acetate (3:1, v/v) as eluent to give product 1ꢀ-
benzyl-7-methoxyspiro[chromene-2,4ꢀ-piperidin]- 4(3H)-one-O-[tert-
butyl(dimethyl)silyl] oxime 4i as yellow oil (0.4 g, 80%). (Found: C
69.76, H 8.44, N 5.68. Calc. for C27H38N2O3Si: C 69.49, H 8.21, N
6.00%). δH (CDCl3, 250 MHz) 0.26 (6H, s), 1.00 (9H, m), 1.68–1.79
(2H, m), 1.88–2.04 (2H, m), 2.40–2.45 (2H, m), 2.61–2.68 (2H, m),
2.87 (2H, s), 3.59 (2H, s), 3.84 (3H, s), 6.46 (1H, d, J 2.2), 6.55 (1H, dd,
J 8.7, 2.3), 7.26–7.38 (5H, m), 7.83 (1H, d, J 8.8). m/z (ES–MS) 467
[M + 1]+.
White solid (72%), mp 279–280◦C. (Found: C 71.61, H 6.92, N 8.05.
Calc. for C21H24N2O3: C 71.57, H 6.86, N 7.95%). δH ([D6]DMSO,
250 MHz) 1.93–2.13 (4H, m), 2.75 (2H, s), 3.02–3.16 (4H, m), 3.71
(3H, s), 4.39–4.42 (2H, m), 6.92–6.94 (2H, m), 7.22–7.26 (2H, m), 7.44
(3H, m), 7.70 (1H, m), 11.47 (1H, s). m/z (ES–MS) 353 [M + 1]+.
1ꢀ-Benzyl-6-methylspiro[chromene-2,4ꢀ-piperidin]-
4(3H)-one Oxime 4b
Typical Procedure for the Synthesis of Secondary Anilines:
White solid (93%), mp 268–269◦C. (Found: C 75.23, H 7.17, N 8.61.
Calc. for C21H24N2O2: C 74.97, H 7.19, N 8.33%). δH ([D6]DMSO,
250 MHz) 1.95–2.07 (4H, m), 2.15 (3H, s), 2.39–2.43 (2H, m), 6.86
(2H, s), 2.97–3.10 (4H, m), 6.79 (1H, d, J 8.3), 7.01 (1H, dd, J 8.5, 1.9),
7.29–7.41 (3H, m), 7.48–7.50 (1H, m), 7.58 (2H, m), 12.03 (1H, s). m/z
(ES–MS) 337 [M + 1]+.
1ꢀ-Benzyl-4,5-dihydro-3H-spiro[1,5-benzoxazepine-2,4ꢀ-piperidine] 5f
Oxime4f (3 g, 9.3 mmol)wassolubilizedinanhydrousdichloromethane
(20 mL). The mixture was stirred at 0◦C for 30 min, and diisobutylalu-
minium hydride in dichloromethane (54 mL, 1 M, 54 mmol) was added
dropwise during 1 h. The mixture was stirred for 3 h under nitrogen at
0◦C. The reaction was quenched by slowly adding MeOH (9 mL), fol-
lowed by distilled water (9 mL) and 20% sulfuric acid (50 mL). The
solution was stirred for a further 20 min. The solution was basified to
pH 9 using 30% sodium hydroxide solution. The resulting mixture was
extracted with ethyl acetate (2 × 100 mL). The organic layer was dried
(MgSO4) and concentrated to give a yellow oil.The residue was purified
by chromatography on alumina with cyclohexane/ethyl acetate (1:1, v/v)
to give product 5f as yellow oil (1.5 g, 52%). (Found: C 78.04, H 7.88,
N 9.25. Calc. for C20H24N2O: C 77.89, H 7.84, N 9.08%). δH (CDCl3,
250 MHz) 1.69 (2H, ddd, J 13.5, 9.6, 4.6), 1.96 (2H, t, J 5.4), 2.06–2.11
(2H, m), 2.55 (2H, td, J 11.4, 2.5), 2.65 (2H, dt, J 11.6, 3.8), 3.30 (2H,
t, J 5.4), 3.62 (2H, s), 6.65 (1H, dd, J 1.5, 7.8), 6.78 (1H, td, J 7.8, 1.5),
6.91 (1H, td, J 7.8, 1.5), 7.20 (1H, dd, J 7.8, 1.5), 7.28–7.40 (5H, m).
m/z (ES–MS) 309 [M + 1]+.
1ꢀ-Benzyl-6-(benzyloxy)spiro[chromene-2,4ꢀ-piperidin]-
4(3H)-one Oxime 4c
White solid (95%), mp 245–254◦C. (Found: C 75.71, H 6.54, N 6.25.
Calc. for C27H28N2O3: C 75.68, H 6.59, N 6.54%). δH ([D6]DMSO,
250 MHz) 2.02–2.07 (2H, m), 2.39–2.50 (2H, m), 2.95 (2H, s), 2.99–
3.13 (2H, m), 3.27–3.32 (2H, m), 4.20–4.21 (2H, m), 4.98 (2H, s),
6.74–6.77 (1H, m), 6.88–6.89 (1H, m), 7.29–7.52 (9H, m), 7.65–7.74
(2H, m), 12.03 (1H, s). m/z (ES–MS) 429 [M + 1]+.
1ꢀ-Benzyl-6-chlorospiro[chromene-2,4ꢀ-piperidin]-
4(3H)-one Oxime 4d
White solid (76%), mp 259–260◦C. (Found: C 67.07, H 5.66, N 7.98.
Calc. for C20H21ClN2O2: C 67.32, H 5.93, N 7.85%). δH ([D6]DMSO,
250 MHz) 1.94–2.08 (4H, m), 2.78 (2H, s), 3.10–3.17 (4H, m), 4.31–
4.36 (2H, m), 7.00–7.04 (1H, m), 7.36–7.45 (4H, m), 7.64–7.69 (3H,
m), 11.67 (1H, s). m/z (ES–MS) 357 [M + 1]+.
1ꢀ-Benzyl-7-methoxy-4,5-dihydro-3H-spiro[1,5-benzoxazepine-
2,4ꢀ-piperidine] 5a
Yellow oil (61%). (Found: C 74.68, H 7.57, N 8.41. Calc. for
C21H26N2O2: C 74.52, H 7.74, N 8.28%). δH (CDCl3, 250 MHz) 1.52
(2H, ddd, J 13.5, 9.6, 4.6), 1.81 (2H, t, J 5.4), 1.86–1.91 (2H, m), 2.40
(2H, td, J 11.4, 2.5), 2.50–2.55 (2H, m), 3.21 (2H, t, J 5.4), 3.47 (2H,
s), 3.64 (3H, s), 6.08 (1H, d, J 2.8), 6.16 (1H, dd, J 8.7, 2.9), 6.76 (1H,
d, J 8.7), 7.16–7.25 (5H, m). m/z (ES–MS) 339 [M + 1]+.
1ꢀ-Benzyl-6-fluorospiro[chromene-2,4ꢀ-piperidin]-
4(3H)-one Oxime 4e
White solid (29%), mp 212–214◦C. (Found: C 70.71, H 6.18, N 8.17.
Calc. for C20H21FN2O2: C 70.57, H 6.22, N 8.23%). δH ([D6]DMSO,
250 MHz) 1.91–2.08 (4H, m), 2.37 (2H, m), 2.64 (4H, m), 3.46 (2H, s),
7.12–7.57 (8H, m), 11.56 (1H, s). m/z (ES–MS) 341 [M + 1]+.
1ꢀ-Benzyl-7-methyl-4,5-dihydro-3H-spiro[1,5-benzoxazepine-
2,4ꢀ-piperidine] 5b
1ꢀ-Benzyl-7-methoxyspiro[chromene-2,4ꢀ-piperidin]-
4(3H)-one Oxime 4g
Yellow solid (16%), mp 64–65◦C. (Found: C 78.32, H 8.38, N 8.77. Calc.
for C21H26N2O: C 78.22, H 8.13, N 8.69%). δH (CDCl3, 250 MHz) 1.52
(2H, ddd, J 13.5, 9.6, 4.6), 1.81 (2H, t, J 5.4), 1.86–1.91 (2H, m), 2.16
(2H, s), 2.40 (2H, td, J 11.4, 2.5), 2.51–2.56 (2H, m), 3.21 (2H, t, J 5.4),
3.47 (2H, s), 6.10–6.18 (2H, m), 6.76–6.78 (1H, m), 7.24–7.32 (5H, m).
m/z (ES–MS) 323 [M + 1]+.
White solid (88%), mp 279–280◦C. (Found: C 71.49, H 6.76, N 8.23.
Calc. for C21H24N2O3: C 71.57, H 6.86, N 7.95%). δH ([D6]DMSO,
250 MHz) 1.93–2.14 (4H, m), 2.74 (2H, s), 3.10–3.25 (4H, m), 3.76 (3H,
s), 4.33–4.43 (2H, m), 6.48–6.61 (2H, m), 7.43–7.47 (3H, m), 7.64–7.67
(3H, m), 11.16 (1H, s). m/z (ES–MS) 353 [M + 1]+.
1ꢀ-Benzyl-7-(benzyloxy)-4,5-dihydro-3H-spiro[1,5-benzoxazepine-
2,4ꢀ-piperidine] 5c
1ꢀ-Benzyl-6-nitrospiro[chromene-2,4ꢀ-piperidin]-
4(3H)-one Oxime 4h
Yellow solid (52%), mp 101–103◦C. (Found: C 78.14, H 7.11,
N 6.54. Calc. for C27H30N2O2: C 78.23, H 7.29, N 6.76%). δH (CDCl3,
250 MHz) 1.66 (2H, ddd, J 13.5, 9.6, 4.6), 1.93 (2H, t, J 5.4), 2.02–2.06
(2H, m), 2.50–2.70 (2H, m), 2.29–2.39 (2H, m), 3.28 (2H, t, J 5.4), 3.61
(2H, s), 4.98 (2H, s), 6.29–2.30 (1H, d, J 2.8), 6.39 (1H, dd, J 8.5, 2.8),
6.91 (1H, d, J 8.7), 7.29–7.49 (10H, m). m/z (ES–MS) 415 [M + 1]+.
White solid (81%), mp 230–231◦C. (Found: C 65.57, H 5.69, N 11.62.
Calc. for C20H21N3O4: C 65.38, H 5.76, N 11.44%). δH ([D6]DMSO,
250 MHz) 2.00–2.25 (4H, m), 3.13–3.58 (8H, m), 7.25 (1H, d, J 9.1),
7.44–7.47 (3H, m), 7.65–7.74 (2H, m), 8.25 (1H, dd, J 9.1, 2.8), 8.56
(1H, d, J 2.7), 11.90 (1H, s). m/z (ES–MS) 368 [M + 1]+.
Typical Procedure for the Silylation of Oximes: 1ꢀ-Benzyl-
7-methoxyspiro[chromene-2,4ꢀ-piperidin]-4(3H)-one-
O-[tert-butyl(dimethyl)silyl] Oxime 4i
1ꢀ-Benzyl-7-chloro-4,5-dihydro-3H-spiro[1,5-benzoxazepine-
2,4ꢀ-piperidine] 5d
Yellow oil (32%). (Found: C 70.19, H 6.82, N 8.37. Calc. for
C20H23ClN2O: C 70.06, H 6.76, N 8.17%). δH (CDCl3, 250 MHz) 1.66
(2H, ddd, J 13.5, 9.6, 4.6), 1.92 (2H, t, J 5.4), 1.97–2.02 (2H, m), 2.50
(2H, td, J 11.4, 2.5), 2.63–2.68 (2H, m), 3.28 (2H, t, J 5.4), 3.60 (2H,
s), 6.60 (1H, d, J 2.6), 6.68 (1H, dd, J 8.4, 2.4), 6.89 (1H, d, J 6.5),
7.30–7.39 (5H, m). m/z (ES–MS) 343 [M + 1]+.
To a stirred solution of 4g (0.40 g, 1.1 mmol) and tert-butyldimethylsilyl
chloride (TBDMS-Cl) (0.17 g, 1.1 mmol) in CH2Cl2 (10 mL) was
added dropwise a solution of imidazole (0.15 g, 2.2 mmol) in CH2Cl2
at room temperature. The reaction was left overnight with stirring.
Purification was carried out by flash silica gel chromatography using