Synthesis of Acylpiperidines
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16 3413
N-(1-Ad a m a n ta n oyl)-4-[(2-m eth oxy-4-m eth oxyca r bon -
yl)ben zylid en e]p ip er id in e (18a ). 18a was synthesized from
N-(1-adamantanoyl)-4-piperidone (3b)8 and 2-methoxy-4-meth-
oxycarbonylbenzyltriphenylphosphonium bromide (30b). It
was purified by FCC (petrol ether/ethyl acetate 16:5). Yield
37%, white powder, mp 131-132 °C. 1H NMR (400 MHz,
CDCl3): δ 1.73 (s, 6H, ada H), 2.02, (s, 9H, ada H), 2.41 (t, 4H,
J ) 6 Hz, pip. H), 3.64 and 3.76 (2t, 4H, J ) 6 Hz, pip. H),
3.89 (s, 3H, -OCH3), 3.92 (s, 3H, -COOCH3), 6.37 (s, 1H,
vinyl-H), 7.17 (d, 1H, J ) 8 Hz, aromatic H), 7.53 (s, 1H,
aromatic H), 7.60 (dd, 1H, J ) 8 Hz, J ) 2 Hz, aromatic H).
IR (KBr): ν ) 3400, 2900, 2820, 1720, 1600, 1450, 1400, 1280,
1260, 1220, 1170, 1100, 1030, 980, 860, 750 cm-1. C26H33NO4
(423.55).
N-(Diph en yl)acetyl-4-[4-(m eth oxycar bon ylm eth yl)ben -
zylid en e]p ip er id in e (19a ). 19a was synthesized from
N-(diphenyl)acetyl-4-piperidone (6b)8 and [4-(methoxycarbo-
nylmethyl)benzyl]triphenylphosphonium bromide (29b). It was
purified by CC (hexane/ethyl acetate 7:3). Yield 16%, white
powder. 1H NMR (400 MHz, CDCl3): δ ) 2.04-2.47 (4s, broad,
4H, pip. H), 3.43-3.68 (m, 4H, pip. H, overlapped with 2H,
-CH2COOH), 3.70 (s, 3H, -COOCH3), 5.25 (s, broad, 1H,
-COCH-), 6.29 (s, broad, 1H, vinyl-H), 7.09 (s, broad, 2H,
aromatic H), 7.20-7.33 (m, 10H, aromatic H, overlapped with
2H, aromatic H). C29H29NO3 (439.55).
N-(Dicycloh exyl)acetyl-4-[4-(m eth oxycar bon ylm eth yl)-
ben zylid en e]p ip er id in e (20a ). 20a was synthesized from
N-(dicyclohexyl)acetyl-4-piperidone (7b)8 and [4-(methoxycar-
bonylmethyl)benzyl]triphenylphosphonium bromide (29b). It
was purified by FCC (hexane/ethyl acetate 8:2). Yield 15%,
white powder. 1H NMR (400 MHz, CDCl3): δ 0.93-1.69 (m,
22 H, cyclohexyl-H), 2.36 (s, broad, 1H, -COCH-), 2.48 (s,
broad, 4H, pip. H), 3.52-3.71 (m, 4H, pip. H), overlapped with
3.70 (s, 2H, -CH2COOH), 3.73 (s, 3H, -COOCH3), 6.35 (s, 1H,
vinyl-H), 7.15 and 7.23 (d, AA′BB′, 4H, J ) 8 Hz, aromatic
H). C29H41NO3 (451.64).
Syn th esis of Com p ou n d s 10-20. N-(Dip h en yl)a cetylp i-
p er id in e-4-(ben zylid en e-3-ca r boxylic a cid ) (10). A mix-
ture of N-(diphenyl)acetyl-4-[3-(methoxycarbonyl)benzylidene]-
piperidine (10a ) (0.50 g, 1.19 mmol) and potassium carbonate
(0.70 g) in methanol/water 9:1 (50 mL) was refluxed for 3 h at
90 °C. The solution was stirred overnight at room temperature.
After this, the reaction was acidified with 1 N hydrochloric
acid. The compound was extracted with CH2Cl2 (3 × 30 mL),
washed with water, and dried over MgSO4. The solvent was
evaporated in vacuo to yield 10 as a crude product that was
purified by recrystallization from hexane/ethyl acetate. Yield
53%, white powder, mp 136-137 °C. 1H NMR (400 MHz,
DMSO-d6): δ 1.98-2.40 (4s, broad, 4H, pip. H), 3.52 and 3.60
(2s, broad, 4H, pip. H), 5.57 (s, 1H, -COCH-), 6.38 (s, 1H,
vinyl-H), 7.21-7.33 (m, 10H, aromatic H), 7.37-7.45 (m, 2H,
aromatic H), 7.70-7.78 (m, 2H, aromatic H), 12.77 (s, 1H,
-COOH). IR (KBr): ν ) 3050-2900, 1710, 1690, 1640, 1440,
1280, 1210, 1080, 1000, 920, 850, 750 cm-1. Anal. (C27H25NO3
(411.50)) C, H, N.
broad, 4H, pip. H), 4.51 (t, 1H, J ) 7 Hz, -CH2CH-), 6.39 (s,
1H, vinyl-H), 7.14 and 7.89 (d, AA′BB′, 4H, J ) 8 Hz, aromatic
H), 7.23-7.32 (m, 10H, aromatic H), 12.87 (s, 1H, -COOH).
IR (KBr): ν ) 3400 (broad), 2650, 2520, 1680, 1640, 1600,
1420, 1310, 1250, 1170, 1100, 980, 870, 750, 700 cm-1. Anal.
(C28H27NO3 (425.52)) C, H, N.
N-(Dip h en yl)a cetylp ip er id in e-4-(2-flu or oben zylid en e-
4-ca r boxylic a cid ) (13). 13 was synthesized from N-(diphe-
nyl)acetyl-4-[(2-fluoro-4-methoxycarbonyl)benzylidene]pip-
eridine (13a ). It was purified by recrystallization from hexane/
ethyl acetate. Yield 52%, white powder, mp 217-218 °C. 1H
NMR (400 MHz, DMSO-d6): δ 1.98-2.29 (4s, broad, 4H, pip.
H), 3.53 and 3.61 (2s, broad, 4H, pip. H), 5.58 (s, 1H, -COCH-
), 6.29 (s, 1H, vinyl-H), 7.21-7.33 (m, 10H, aromatic H), 7.40
(t, 1H, J ) 8 Hz, aromatic H), 7.62 (d, 1H, J ) 8 Hz, aromatic
H), 7.71 (t, 1H, J ) 8 Hz, aromatic H), 13.18 (s, 1H, -COOH).
IR (KBr): ν ) 3440 (broad), 3050-2820, 1700, 1640, 1440,
1290, 1220, 1000, 940, 760, 700 cm-1. Anal. (C27H24NO3F
(429.49)) C, H, N.
N -(D ip h e n y l)a c e t y lp ip e r id in e -4-(2-m e t h o x y b e n z-
ylid en e-4-ca r boxylic a cid ) (14). 14 was synthesized from
N-(diphenyl)acetyl-4-[(2-methoxy-4-methoxycarbonyl)benz-
ylidene]piperidine (14a ). It was purified by recrystallization
from hexane/ethyl acetate. Yield 46%, white powder, mp 215
°C. 1H NMR (400 MHz, DMSO-d6): δ 1.97 and 2.28 (2s, broad,
4H, pip. H), 3.53 and 3.59 (2s, broad, 4H, pip. H), 3.80 (s, 3H,
-OCH3), 5.58 (s, 1H, -COCH-), 6.29 (s, 1H, vinyl-H), 7.13
(d, 1H, J ) 8 Hz, aromatic H), 7.21-7.33 (m, 10H, aromatic
H), 7.45-7.51 (m, 2H, aromatic H), 12.94 (s, 1H, -COOH). IR
(KBr): ν ) 2950, 2600 (broad), 1680, 1630, 1600, 1480, 1450,
1410, 1260, 1200, 1100, 1030, 980, 860, 750, 700 cm-1. Anal.
(C28H27NO4 (441.52)) C, H, N.
N -(Dicycloh e xyl)a ce t ylp ip e r id in e -4-(2-flu or ob e n z-
ylid en e-4-ca r boxylic a cid ) (15). 15 was synthesized from
N-(dicyclohexyl)acetyl-4-[(2-fluoro-4-methoxycarbonyl)benz-
ylidene]piperidine (15a ). It was purified by recrystallization
from hexane/ethyl acetate. Yield 65%, white powder, mp 195-
196 °C. 1H NMR (400 MHz, DMSO-d6): δ 0.95-1.69 (m, 22 H,
cyclohexyl-H), 2.36-2.50 (m, 4H, pip. H), 2.62 (s, broad, 1H,
-COCH-), 3.52-3.66 (m, 4H, pip. H), 6.35 (s, 1H, vinyl-H),
7.43 (t, 1H, J ) 8 Hz, aromatic H), 7.64 (d, 1H, J ) 10 Hz,
aromatic H), 7.73 (d, 1H, J ) 8 Hz, aromatic H), 13.20 (s, 1H,
-COOH). IR (KBr): ν ) 3400, 2940, 2860, 1720, 1580, 1460,
1430, 1260, 1210, 1080, 1000, 980, 900, 870, 750 cm-1. Anal.
(C27H36NO3F (441.58)) C, H, N.
N-(Dicycloh exyl)a cet ylp ip er id in e-4-(2-m et h oxyb en -
zylid en e-4-ca r boxylic a cid ) (16). 16 was synthesized from
N-(dicyclohexyl)acetyl-4-[(2-methoxy-4-methoxycarbonyl)ben-
zylidene]piperidine (16a ). It was purified by recrystallization
from hexane/ethyl acetate. Yield 72%, white powder, mp 197-
198 °C. 1H NMR (400 MHz, DMSO-d6): δ 0.90-1.65 (m, 22 H,
cyclohexyl-H), 2.27 and 2.32 (2s, broad, 4H, pip. H), 2.60 (s,
broad, 1H, -COCH-), 3.50-3.64 (4s, broad, 4H, pip. H), 3.83
(s, 3H, -OCH3), 6.35 (s, 1H, vinyl-H), 7.26 (d, 1H, J ) 8 Hz,
aromatic H), 7.47 (s, 1H, aromatic H), 7.51 (d, 1H, J ) 8 Hz,
aromatic H), 12.96 (s, 1H, -COOH). IR (KBr): ν ) 2940, 2840,
2600 (broad), 1720, 1680, 1630, 1600, 1450, 1410, 1250, 1200,
1110, 1040, 1000, 880, 760 cm-1. Anal. (C28H39NO4 (453.62))
C, H, N.
N-(1-Adam an tan oyl)piper idin e-4-(2-flu or oben zyliden e-
4-ca r boxylic a cid ) (17). 17 was synthesized from N-(1-
adamantanoyl)-4-[(2-fluoro-4-methoxycarbonyl)benzylidene]-
piperidine (17a ). It was purified by recrystallization from
hexane/ethyl acetate. Yield 62%, white powder, mp 250-251
°C. 1H NMR (400 MHz, DMSO-d6): δ 1.68 (s, 6H, ada H), 1.92,
(s, 6H, ada H), 1.98, (s, 3H, ada H), 2.31 and 2.35 (2s, broad,
4H, pip. H), 3.58 and 3.65 (2s, broad, 4H, pip. H), 6.33 (s, 1H,
vinyl-H), 7.42 (t, 1H, J ) 8 Hz, aromatic H), 7.64 (d, 1H, J )
10 Hz, aromatic H), 7.73 (d, 1H, J ) 9 Hz, aromatic H), 12.96
(s, 1H, -COOH). IR (KBr): ν ) 3200-2300, 1710, 1590, 1430,
1380, 1270, 1230, 1200, 1120, 1060, 980, 870, 740 cm-1. Anal.
(C24H28NO3F (397.48)) C, H, N.
N-(Dicycloh exyl)a cet ylp ip er id in e-4-(b en zylid en e-3-
ca r boxylic a cid ) (11). 11 was synthesized from N-(dicyclo-
hexyl)acetyl-4-[3-(methoxycarbonyl)benzylidene]piperidine (11a).
It was purified by recrystallization from hexane/ethyl acetate.
Yield 65%, white powder, mp 214 °C. 1H NMR (400 MHz,
DMSO-d6): δ 0.90-1.65 (m, 22H, cyclohexyl-H), 2.28-2.41 (3s,
broad, 4H, pip. H), 2.60 (s, broad, 1H, -COCH-), 3.56-3.65
(3s, broad, 4H, pip. H), 6.44 (s, 1H, vinyl-H), 7.47 (s, broad,
2H, aromatic H), 7.88 (s, broad, 2H, aromatic H), 12.99 (s, 1H,
-COOH). IR (KBr): ν ) 3400, 2920-2700 (broad), 2580, 1720,
1650, 1600, 1450, 1270, 1240, 1200, 1080, 980, 920, 850, 750,
700 cm-1. Anal. (C27H37NO3 (423.59)) C, H, N.
N-(3,3-Dip h en yl)p r op a n oylp ip er id in e-4-(ben zylid en e-
4-ca r boxylic a cid ) (12). 12 was synthesized from N-(3,3-
diphenyl)propanoyl-4-[4-(methoxycarbonyl)benzylidene]pip-
eridine (12a ). It was purified by recrystallization from hexane/
ethyl acetate. Yield 61%, white powder, mp 191-192 °C. 1H
NMR (400 MHz, DMSO-d6): δ 2.20 and 2.29 (2s, broad, 4H,
pip. H), 3.16 (t, 2H, J ) 7 Hz, -CH2CH-), 3.39-3.58 (4s,
N -(1-Ad a m a n t a n oyl)p ip e r id in e -4-(2-m e t h oxyb e n z-
ylid en e-4-ca r boxylic a cid ) (18). 18 was synthesized from