New synthesis of 3-aryl-N-n-propyl-piperidines

Article abstract of DOI:10.1016/S0040-4020(02)00282-X

The synthesis of 3-aryl-N-n-propyl-piperidines is described in six steps starting from α-sulfonyl acetamide via the formal [3+3] cycloaddition reaction.

Full text of DOI:10.1016/S0040-4020(02)00282-X

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 3623±3628
New synthesis of 3-aryl-N-n-propyl-piperidines
Meng-Yang Chang,a Shui-Tein Chena,p and Nein-Chen Changb,p
aInstitute of Biological Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan, ROC
bDepartment of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, ROC
Received 29 January 2002; accepted 4 March 2002
AbstractÐThe synthesis of 3-aryl-N-n-propyl-piperidines is described in six steps starting from a-sulfonyl acetamide via the formal [313]
cycloaddition reaction of the latter into glutarimide. The pathway involvesan ef®cient cycloaddition and regioselective reduction, and yields
useful building blocks for heterocyclic chemistry. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
propyl-piperidinesasillustrated in Scheme 1. There are two
remarkable steps for the synthesis of 1. One isthe rapid
access to produce a wide variety of 3-aryl-piperidin-2,6-
dionesby formal [3 13] cycloaddition reaction.6a The
other is the regioselective transformation from a-sulfonyl
piperidin-2,6-diones to vinyl sulfonyl pyridinones using
reduction followed by acidic dehydration.
3-Arylpiperidines have been investigated since the early
1,2
1980sin view of their therapeutic dopaminergic activities.
The most therapeutically active of these compounds is
3-(3-hydroxyphenyl)-N-(n-propyl)-piperidine (3-PPP, precla-
mol),3,4 reported to be the ®rst selective D2-like dopamine
autoreceptor agonist.4 The N-n-propyl substituent has been
suggested to be the most effective substitutions among
several 3-arylpiperidines with different substituents on the
aromatic ring.5 These potent dopaminergic substances could
be effective antipsychotic agents with therapeutic effect in
the treatment of schizophrenia and Parkinson's disease.
2.2. Synthesis of 3-aryl-N-n-propyl-piperidines
The synthesis began from the glutarimides 5a±d (5a RˆH;
5b Rˆ3-OMe; 5c Rˆ4-OMe; 5d 3,4-OMe2) which were
the cycloadductsof formal [3 13] cycloaddition reactions6
ashsown in Scheme 2.
N-n-Propylamine wastreated
2. Results and discussion
with chloroacetyl chloride and triethylamine to produce
a-chloride acetamide. Chloride compound wastreated
with p-toluenesulfonic acid sodium salt to give N-n-propyl
a-sulfonyl acetamide 3 asthe tsarting material of formal
[313] cycloaddition reaction in the synthesis of 3-aryl-N-
n-propyl-piperidines (85% two steps).
2.1. Retrosynthetic analysis of 3-aryl N-n-propyl-
piperidines
We describe the stepwise reduction leading to 3-aryl-N-n-
Scheme 1. Retrosynthetic analysis of 3-aryl-N-n-propyl-piperidines.
Keywords: formal [313] cycloaddition reaction; a-sulfonyl acetamide; 3-aryl-N-n-propyl-piperidines; preclamol.
Corresponding authors. Tel.: 1886-7-5292000x3913; fax: 1886-7-5253913; e-mail: ncchang@mail.nsysu.edu.tw
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00282-X

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M.-Y. Chang et al. / Tetrahedron 58 (2002) 3623±3628
Scheme 2. Synthesis of 3-aryl-N-n-propyl-piperidines.
Compound 3 wasdeprotonated with osdium hydride to
produce the dianion intermediate. The dianion of 3 was
reacted with a,b-unsaturated esters 4 to yield the glutari-
mides 5 in an ef®cient procedure. The key step in our
preparation of 3-aryl-N-n-propyl-piperidines 1 wasa formal
[313] cycloaddition reaction. We initially used glutarimide
5a as a model substrate to synthesize target 1a in two steps
(desulfonation [Na/Hg] then reduction [LAH]), but desulfo-
nation of glutarimide 5a with sodium amalgam produced
complex results. The six-membered ring of glutarimide 5a
might open, producing other compoundsasmonitored by
TLC in the basic desulfonation. The desired desulfonyl
glutarimide wasobtained in lessthan 5% yield. The
desulfonyl compound was treated with lithium aluminum
hydride to obtain 3-phenyl-N-n-propyl-piperidine in 62%
yield. This synthesis of 3-phenyl-N-n-propyl-piperidine
resulted in very low total yield in three steps.
of the sulfones with an excess of sodium amalgam in 80±
85% yield. Finally, the reduction of piperidinones 2a±d by
treatment with lithium aluminum hydride gave the 2-aryl-N-
n-piperidines 1a±d in 86±92% yield.
3. Conclusion
In summary, the synthesis of target 1 demonstrates the
utility of the formal [313] cycloaddition reaction of
a-sulfonyl acetamide and yields the skeleton of piperidine
ring. Formal synthesis of 3-PPP is also described by the
above method.8
4. Experimental
4.1. General
In order to prevent ring-opening of a-sulfonyl piperidin-2,6-
dionesthusto increase the total yield of 3-aryl- N-n-propyl-
piperidines, we regioselectively reduced the piperidin-2,6-
dionesinto 6-hydroxy piperidinone.s The glutarimides
5a±d treated with sodium borohydride followed by dehy-
dration with boron tri¯uoride etherate yielded the vinyl
ole®nic sulfones 6a±d. According to a related reported,7
regioselective reduction with sodium borohydride was
effected by the a-substituted group at glutarimide ring. In
our case, chelation between 5-sufonyl and 6-carbonyl group
position of glutarimides 5a±d wasinduced by sodium boro-
hydride to produce the regioselective 6-hydroxy piperidi-
nonesat 4±7 8C. When the temperature wasincreaesd
to 20±258C, the glutarimide ring wastsill opening as
determined by TLC. The 6-hydroxy piperidinoneswas
dehydrated with boron tri¯uoride etherate to give ole®ns
6a±d. The two steps from 5a±d to 6a±d gave 75±82%
overall yield.
Methylene chloride and tetrahydrofuran were distilled prior
to use. All other reagents and solvents were obtained from
commercial sources and used without further puri®cation.
Reactionswere routinely carried out under an atmosphere of
dry nitrogen with magnetic stirring. Products in organic
solvents were dried with anhydrous magnesium sulfate
before concentration in vacuo. All reported melting
temperatureswere uncorrected.
4.2. Synthesis of N-propyl-2-(4-methylphenyl)sulfonyl
acetamide (3)
A solution of chloroacetyl chloride (5.99 g, 53.0 mmol) in
tetrahydrofuran (40 mL) was added to a stirred solution of
N-n-propylamine (2.95 g, 50.0 mmol) and triethylamine
(5.57 g, 55.0 mmol) in tetrahydrofuran (100 mL) in an ice
bath for 1 h. The reaction mixture wastsirred at room
temperature for 4 h and concentrated under reduced
pressure. The residue was diluted with water (30 mL) and
extracted with ethyl acetate (3£100 mL). The combined
organic layerswere wahsed with brine (2 £50 mL), dried
After hydrogenation of ole®ns 6a±d by palladium hydrox-
ide under standard conditions, the resulting 2-aryl-N-n-
piperidinones 2a±d wasms oothly obtained by treatment

M.-Y. Chang et al. / Tetrahedron 58 (2002) 3623±3628
3625
over anhydrous magnesium sulfate, ®ltered and evaporated.
1H NMR (400 MHz, CDCl3) d 6.70 (br s, 1H), 4.03 (s, 2H),
3.26 (q, Jˆ6.9 Hz, 2H), 1.60±1.52 (m, 2H), 0.93 (t, Jˆ
7.4 Hz, 3H). Without further puri®cation, the crude product
wasre¯uxed with p-toluenesulfonic acid sodium salt
(TolSO2Na±2H2O, 16.05 g, 75.0 mmol) in dioxane
(150 mL) and water (150 mL) for 10 h. Then the mixture
was concentrated under reduced pressure. The residue was
extracted with ethyl acetate (3£150 mL). The combined
organic layerswere wahsed with brine (2 £50 mL), dried
over anhydrous magnesium sulfate, ®ltered and evaporated.
Recrystallization on hexane (60 mL) and ethyl acetate
with saturated ammonium chloride solution (2 mL) in an
ice bath, and concentrated under reduced pressure. The
residue was diluted with water (10 mL) and extracted with
ethyl acetate (3£20 mL). The combined organic layerswere
washed with brine (2£20 mL), dried over anhydrousmag-
nesium sulfate, ®ltered and evaporated. Puri®cation on
silica gel (hexane/ethyl acetateˆ4/1±2/1) produced 5a±d
in 56±63% yield.
4.4.1. N-1-Propyl-3-phenyl-5-[(4-methylphenyl)sulfonyl]-
piperidin-2,6-dione (5a). Yield 60%; mpˆ190±1928C; IR
(CHCl3) 2965, 2360, 1727, 1677, 1320, 1149 cm21; ESI-
MS: C21H24NO4S m/z (%)ˆ137 (48), 154 (58), 202 (25),
386 (M111, 100); HRMS (ESI, M111) calcd for
C21H24NO4S 386.1427, found 386.1422; 1H NMR
(400 MHz, CDCl3) d 7.90 (d, Jˆ8.3 Hz, 1/2H), 7.76 (d,
Jˆ8.3 Hz, 3/2H), 7.39±7.29 (m, 5H), 7.20±7.17 (m, 2H),
4.45 (dd, Jˆ5.6, 11.8 Hz, 3/4H), 4.31 (dd, Jˆ5.6, 13.0 Hz,
1/4H), 4.14 (dd, Jˆ3.9, 5.8 Hz, 3/4H), 3.87±3.76 (m, 3/2H),
3.72±3.66 (m, 3/4H), 3.00 (ddd, Jˆ3.9, 5.7, 14.9 Hz, 3/4H),
2.83 (dt, Jˆ5.1, 13.5 Hz, 1/4H), 2.68±2.53 (m, 1H), 2.46 (s,
3H), 1.60±1.48 (m, 2H), 0.90 (t, Jˆ7.5 Hz, 9/4H), 0.83 (t,
Jˆ7.5 Hz, 3/4H); Anal. calcd for C21H23NO4S C, 65.43; H,
6.01. Found C, 65.62; H, 6.06.
(30 mL) produced 10.83 g (85%) of 3 asa oslid: mp
ˆ
114±1178C; IR (CHCl3) 3293, 2970, 1662, 1568, 1321,
1159, 1088, 820 cm21; ESI-MS: C12H18NO3S m/z (%)ˆ
256 (M111, 100); HRMS (ESI, M111) calcd for
C12H18NO3S 256.1007, found 256.1014; 1H NMR (400
MHz, CDCl3) d 7.75 (d, Jˆ8.3 Hz, 2H), 7.34 (d, Jˆ
8.3 Hz, 2H), 6.75 (br s, 1H), 3.96 (s, 2H), 3.20 (q, Jˆ
6.9 Hz, 2H), 2.42 (s, 3H), 1.57±1.47 (m, 2H), 0.91 (t,
Jˆ7.4 Hz, 3H); Anal. calcd for C12H17NO3S C, 56.45; H,
6.71. Found C, 56.06; H, 6.67.
4.3. Synthesis of a,b-unsaturated esters (4)
4.4.2.
N-1-Propyl-3-(3-methoxyphenyl)-5-[(4-methyl-
A three-necked ¯ask with a dropping funnel, stirrer, and
re¯ux condenser, magnesium turnings (10.0 mmol) was
®lled with dry tetrahydrofuran (20 mL) and treated with
about 1/20 of a total of arylbromide (5.0 mmol) in tetra-
hydrofuran (20 mL) while stirring. After the reaction had
started, the remaining arylbromide was added dropwise with
further stirring in such a way that the ether boils gently.
When the Grignard reagent wasprepared, the reagent was
added dropwise via a syringe to a solution of methyl pyru-
vate (5.0 mmol). After the addition wascomplete, the
mixture isheated in a water bath (60 8C) with stirring for
30 min, then cooled, then hydrolyzed by the addition of
water (1 mL), and subsequently treated with 1N hydrogen
chloride (2£20 mL) to dissolve the precipitate that had been
formed. The mixture was®ltered and extracted with ethyl
acetate (3£50 mL). The combined organic layerswere
washed with brine (2£20 mL), dried by magnesium sulfate,
®ltered and evaporated. Without puri®cation, the resulting
alcohol was added to a stirred solution of p-toluenesulfonic
acid (100 mg) in benzene (50 mL) and the reaction mixture
wasstirred at re¯uxed temperature under a Dean±Stark trap
for 4 h. The cooled reaction mixture wasdiluted with ether
(30 mL) and washed successively with sodium bicarbonate
solution (10 mL). The combined organic layers were
washed with brine (2£20 mL), dried with magnesium sul-
fate, ®ltered and evaporated. Puri®cation on silica gel
(hexane/ethyl acetateˆ10/1±8/1) produced a,b-unsaturated
esters 4 in 36±45% yield.
phenyl)sulfonyl]-piperidin-2,6-dione (5b). Yield 63%;
mpˆ130±1328C; IR (CHCl3) 2964, 2360, 1729, 1678,
1149 cm21; ESI-MS: C22H26NO5S m/z (%)ˆ136 (25), 154
(30), 204 (33), 232 (72), 416 (M111, 100); HRMS (ESI,
M111) calcd for C22H26NO5S 416.1533, found 416.1528;
1H NMR (400 MHz, CDCl3) d 7.89 (d, Jˆ8.3 Hz, 4/7H),
7.76 (d, Jˆ8.3 Hz, 10/7H), 7.37 (d, Jˆ8.3 Hz, 2H), 7.30±
7.25 (m, 1H), 6.87±6.83 (m, 1H), 6.76±6.70 (m, 2H), 4.40
(dd, Jˆ5.6, 11.5 Hz, 5/7H), 4.31 (dd, Jˆ5.4, 13.2 Hz,
2/7H), 4.14 (dd, Jˆ4.1, 5.6 Hz, 5/7H), 3.83±3.76 (m,
10/7H), 3.79 (s, 3H), 3.73±3.67 (m, 4/7H), 3.66±3.60 (m,
2/7H), 3.00±2.95 (m, 5/7H), 2.83±2.78 (m, 2/7H), 2.65±
2.52 (m, 1H), 2.45 (s, 3H), 1.63±1.45 (m, 2H), 0.90 (t,
Jˆ7.4 Hz, 15/7H), 0.82 (t, Jˆ7.4 Hz, 6/7H); Anal. calcd
for C22H25NO5S C, 63.59; H, 6.06. Found C, 63.73; H, 6.20.
4.4.3.
N-1-Propyl-3-(4-methoxyphenyl)-5-[(4-methyl-
phenyl)sulfonyl]-piperidin-2,6-dione (5c). Yield 56%;
mpˆ208±2108C; IR (CHCl3) 2964, 2360, 1728, 1678,
1516, 1149 cm21; ESI-MS: C22H26NO5S m/z (%)ˆ136
(30), 154 (42), 204 (46), 232 (80), 416 (M111, 100);
HRMS (ESI, M111) calcd for C22H26NO5S 416.1533,
1
found 416.1531; H NMR (400 MHz, CDCl3) d 7.89 (d,
Jˆ8.3 Hz, 1/2H), 7.76 (d, Jˆ8.3 Hz, 3/2H), 7.37 (d, Jˆ
8.1 Hz, 2H), 7.12±7.08 (m, 2H), 6.91±6.87 (m, 2H), 4.39
(dd, Jˆ5.5, 11.7 Hz, 3/4H), 4.30 (dd, Jˆ5.5, 13.1 Hz,
1/4H), 4.13 (dd, Jˆ4.0, 5.8 Hz, 3/4H), 3.80±3.75 (m,
3/2H), 3.79 (s, 3H), 3.68 (t, Jˆ7.5 Hz, 1/2H), 3.63 (dd,
Jˆ4.7, 13.7 Hz, 1/4H), 2.97 (ddd, Jˆ4.0, 5.5, 14.8 Hz,
3/4H), 2.80 (d, t, Jˆ5.1, 13.4 Hz, 1/4H), 2.64±2.49 (m,
1H), 2.46 (s, 3H), 1.59±1.46 (m, 2H), 0.89 (t, Jˆ7.4 Hz,
9/4H), 0.82 (t, Jˆ7.4 Hz, 3/4H); Anal. calcd for
C22H25NO5S C, 63.59; H, 6.06. Found C, 63.67; H, 6.26.
4.4. Procedure of formal [313] cycloaddition reaction
A solution of acetamide 3 (1.28 g, 5.0 mmol) in tetrahydro-
furan (30 mL) was added to a rapidly stirred suspension of
sodium hydride (420 mg, 10.5 mmol, 60%) in tetrahydro-
furan (40 mL). After the reaction mixture wastsirred at
room temperature for 15 min, a solution of a,b-unsaturated
esters 4 (5.0 mmol) in tetrahydrofuran (10 mL) wasadded.
The resulting mixture was re¯uxed for 30 min, quenched
4.4.4. N-1-Propyl-3-(3,4-dimethoxyphenyl)-5-[(4-methyl-
phenyl)sulfonyl]-piperidin-2,6-dione (5d). Yield 63%;
mpˆ171±1738C; IR (CHCl3) 2964, 2360, 1727, 1677,

3626
M.-Y. Chang et al. / Tetrahedron 58 (2002) 3623±3628
1518, 1148 cm21; ESI-MS: C23H28NO6S m/z (%)ˆ136 (38),
154 (50), 262 (61), 445 (100), 446 (M111, 100); HRMS
(ESI, M111) calcd for C23H28NO6S 446.1638, found
446.1636; 1H NMR (400 MHz, CDCl3) d 7.89 (d, Jˆ
8.2 Hz, 1/4H), 7.76 (d, Jˆ8.2 Hz, 7/4H), 7.37 (d, Jˆ
8.2 Hz, 2H), 6.87±6.83 (m, 1H), 6.74±6.67 (m, 2H), 4.38
(dd, Jˆ5.5, 11.7 Hz, 7/8H), 4.30 (dd, Jˆ5.5, 13.0 Hz,
1/8H), 4.14 (dd, Jˆ4.0, 5.8 Hz, 7/8H), 3.86 (s, 6H), 3.78
(t, Jˆ7.5 Hz, 7/4H), 3.70 (t, Jˆ7.5 Hz, 1/4H), 3.62 (dd,
Jˆ4.7, 13.8 Hz, 1/8H), 3.00 (ddd, Jˆ4.1, 5.4, 14.8 Hz,
7/8H), 2.85±2.78 (m, 1/8H), 2.56 (ddd, Jˆ5.9, 11.7,
14.8 Hz, 1H), 2.46 (s, 3H), 1.60±1.53 (m, 2H), 0.90 (t, Jˆ
7.4 Hz, 21/8H), 0.83 (t, Jˆ7.4 Hz, 3/8H); Anal. calcd for
C23H27NO6S C, 62.00; H, 6.11. Found C, 61.93; H, 6.20.
(46), 154 (70), 307 (20), 400 (M111, 100); HRMS (ESI,
M111) calcd for C22H26NO4S 400.1584, found 400.1583;
1H NMR (400 MHz, CDCl3) d 7.64 (d, Jˆ8.3 Hz, 2H), 7.32
(s, 1H), 7.24 (d, Jˆ8.3 Hz, 2H), 7.11±7.07 (m, 1H), 6.74±
6.72 (m, 1H), 6.62±6.60 (m, 2H), 3.74 (t, Jˆ4.2 Hz, 1H),
3.72 (s, 3H), 3.55 (t, Jˆ7.4 Hz, 2H), 2.84 (ddd, Jˆ0.8, 7.4,
17.0 Hz, 1H), 2.67 (dd, Jˆ8.0, 17.0 Hz, 1H), 2.40 (s, 3H),
1.66±1.57 (m, 2H), 0.88 (t, Jˆ7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 168.95, 159.75, 144.13, 138.75,
138.34, 136.73, 129.89, 129.61, 127.58 (3£), 119.73,
116.16, 113.35, 113.03, 55.18, 49.51, 45.75, 27.01, 22.15,
21.56, 11.00; Anal. calcd for C22H25NO4S C, 66.14; H, 6.31.
Found C, 66.26; H, 6.33.
4.5.3.
N-1-Propyl-3-(4-methoxyphenyl)-5-[(4-methyl-
phenyl)sulfonyl]-1,2,3,4-tetrahydro-2-pyridinone (6c).
Yield 79%; gum; IR (CHCl3) 2963, 2360, 1691, 1649,
1513, 1138 cm21; ESI-MS: C22H26NO4S m/z (%)ˆ136
(35), 154 (62), 307 (31), 400 (M111, 100), 400 (M111,
100); HRMS (ESI, M111) calcd for C22H26NO4S 400.1584,
4.5. Procedure of regioselective reduction [NaBH4] and
acidic dehydration [BF3-OEt2]
A solution of compound 5 (2.0 mmol) in a co-solvent of
tetrahydrofuran (10 mL) and HPLC-grade methanol
1
found 400.1591; H NMR (400 MHz, CDCl3) d 7.66 (d,
(5 mL) watsisrred at 4±7
8C. Sodium borohydride
Jˆ8.2 Hz, 2H), 7.31 (s, 1H), 7.25 (d, Jˆ8.2 Hz, 2H), 6.95
(dd, Jˆ3.0, 8.7 Hz, 2H), 6.71 (dd, Jˆ3.0, 8.7 Hz, 2H), 3.74
(s, 3H), 3.71 (t, Jˆ7.7 Hz, 1H), 3.53 (t, Jˆ7.4 Hz, 2H), 2.82
(ddd, Jˆ0.9, 7.3, 16.8 Hz, 1H), 2.65 (dd, Jˆ7.9, 16.8 Hz,
1H), 2.41 (s, 3H), 1.65±1.56 (m, 2H), 0.87 (t, Jˆ7.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 169.38, 158.93,
144.14, 138.36, 136.83, 129.90, 129.23, 128.54 (2£),
127.65 (4£), 116.11, 114.05, 55.22, 49.50, 44.94, 27.00,
22.15, 21.57, 11.00; Anal. calcd for C22H25NO4S 66.14;
H, 6.31. Found C, 66.02; H, 6.12.
(150 mg, 4.0 mmol) wasadded at 4±7 8C. The mixture
was stirred for 2 h at that temperature. Saturated sodium
bicarbonate solution (1 mL) was added to the mixture and
concentrated under reduced pressure. The residue was
diluted with water (5 mL) and extracted with dichloro-
methane (3£10 mL). The combined organic layerswere
washed with brine (2£10 mL), dried over anhydrous
magnesium sulfate, ®ltered and evaporated. Without further
puri®cation, the crude hydroxy-lactam was dissolved in
dichloromethane (10 mL), and a catalytic amount of boron
tri¯uoride etherate (0.1 mL) and magnesium sulfate (0.5 g)
were added. The mixture wastsirred for 5 h at room
temperature. Saturated sodium bicarbonate solution
(5 mL) wasadded to the resulting mixture and concentrated
under reduced pressure. The residue was diluted with water
(5 mL) and extracted with dichloromethane (3£10 mL).
The combined organic layerswere wahsed with brine
(2£10 mL), dried over anhydrous magnesium sulfate,
®ltered and evaporated. Puri®cation on silica gel (hexane/
ethyl acetateˆ4/1±2/1) produced 6a±d in 75±82% yield.
4.5.4. N-1-Propyl-3-(3,4-dimethoxyphenyl)-5-[(4-methyl-
phenyl)sulfonyl]-1,2,3,4-tetrahydro-2-pyridinone (6d).
Yield 82%; mpˆ150±1528C; IR (CHCl3) 2963, 2360,
1690, 1651, 1517, 1138 cm21; ESI-MS: C23H28NO5S m/z
(%)ˆ136 (15), 154 (18), 178 (56), 429 (91), 430 (M111,
100); HRMS (ESI, M111) calcd for C23H28NO5S 430.1689,
1
found 430.1684; H NMR (400 MHz, CDCl3) d 7.65 (d,
Jˆ8.2 Hz, 2H), 7.30 (s, 1H), 7.25 (d, Jˆ7.4 Hz, 2H),
6.69±6.58 (m, 3H), 3.81 (s, 3H), 3.79 (s, 3H), 3.72 (t,
Jˆ7.2 Hz, 1H), 3.53 (td, Jˆ2.4, 7.0 Hz, 2H), 2.76 (qd,
Jˆ7.2, 16.8 Hz, 2H), 2.40 (s, 3H), 1.63±1.55 (m, 2H),
0.86 (t, Jˆ7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
169.32, 149.04, 148.51, 144.22, 138.26, 136.82, 129.87
(2£), 129.52, 127.60 (2£), 119.42, 116.06, 111.13, 110.89,
55.87 (2£), 49.48, 45.13, 26.70, 22.13, 21.56, 10.66; Anal.
calcd for C23H27NO5S C, 64.31; H, 6.34. Found C, 64.48; H,
6.62.
4.5.1. N-1-Propyl-3-phenyl-5-[(4-methylphenyl)sulfonyl]-
1,2,3,4-tetrahydro-2-pyridinone (6a). Yield 80%; gum; IR
(CHCl3) 2963, 2360, 1693, 1651, 1383, 1138 cm21; ESI-
MS: C21H24NO3S m/z (%)ˆ167 (20), 279 (8), 289 (10),
307 (16), 370 (M111, 100); HRMS (ESI, M111) calcd
for C21H24NO3S 370.1478, found 370.1481; 1H NMR
(400 MHz, CDCl3) d 7.66 (d, Jˆ8.2 Hz, 2H), 7.33 (s,
1H), 7.26 (d, Jˆ8.2 Hz, 2H), 7.21±7.18 (m, 3H), 7.05±
7.02 (m, 2H), 3.76 (t, Jˆ7.9 Hz, 1H), 3.55 (t, Jˆ7.2 Hz,
2H), 2.85 (dd, Jˆ7.3, 17.0 Hz, 1H), 2.68 (dd, Jˆ8.3,
17.0 Hz, 1H), 2.41 (s, 3H), 1.66±1.54 (m, 2H), 0.88 (t, Jˆ
7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 169.09,
144.17, 138.37, 137.28, 136.78, 129.92, 128.65 (2£),
127.64 (3£), 127.55 (2£), 127.48, 116.19, 49.53, 45.77,
27.02, 22.15, 21.58, 11.00; Anal. calcd for C21H23NO3S C,
68.27; H, 6.27. Found C, 68.46; H, 6.16.
4.6. Procedure of hydrogenation [H2/Pd(OH)2] and
desulfonation [Na/Hg]
Palladium hydroxide (100 mg) on activated carbon ascata-
lyst was added to a solution of ole®nic sulfone (1.0 mmol) in
acetic acid (10 mL). Hydrogen wasbubbled into the mixture
for 10 min, and the mixture stirred at room temperature for
3 h. Filtration through a short plug of Celite and washing
with ethyl acetate (3£10 mL) resulted in the crude sulfone.
Without further puri®cation, 6% sodium amalgam (Na/Hg,
1.5 g) and sodium phosphate (355 mg, 2.5 mmol) were
added to a stirred solution of crude sulfone (ca. 1.0 mmol)
in HPLC-grade methanol (15 mL), and vigorously stirred
4.5.2.
N-1-Propyl-3-(3-methoxyphenyl)-5-[(4-methyl-
phenyl)sulfonyl]-1,2,3,4-tetrahydro-2-pyridinone (6b).
Yield 75%; gum; IR (CHCl3) 2962, 2360, 1691, 1651,
1381, 1138 cm21; ESI-MS: C22H26NO4S m/z (%)ˆ136

M.-Y. Chang et al. / Tetrahedron 58 (2002) 3623±3628
3627
for 2 h at room temperature. The residue was ®ltered and
washed with methanol (2£10 mL). The combined organic
layerswere concentrated to obtain the crude deuslfonyl
compound. Puri®cation on silica gel (hexane/ethyl acetateˆ
1/1±1/2) produced 2a±d in 80±85% yield.
hydride (53 mg, 1.45 mmol) in tetrahydrofuran (20 mL)
via syringe at 08C. The mixture wasre¯uxed for 2 h,
quenched with saturated aqueous ammonium chloride
solution (2 mL) under cooling, and concentrated. The
residue was diluted with water (15 mL) and extracted with
ethyl acetate (3£30 mL). The organic layer waswahsed
with brine and water, dried (MgSO4), ®ltered and concen-
trated to produce crude compound 1. Puri®cation on silica
gel (ethyl acetate/methanolˆ4/1±2/1) produced 1a±d in
86±92% yield.
4.6.1. N-1-Propyl-3-phenyl-piperidin-2-one (2a). Yield
80%; oil; IR (CHCl3) 2933, 2360, 1634, 1248 cm21; ESI-
MS: C14H20NO m/z (%)ˆ218 (M111, 100); HRMS (ESI,
M111) calcd for C14H20NO 218.1546, found 218.1547; 1H
NMR (400 MHz, CDCl3) d 7.30±7.24 (m, 2H), 7.21±7.15
(m, 3H), 3.66 (t, Jˆ6.9 Hz, 1H), 3.53±3.36 (m, 2H), 3.36±
3.24 (m, 2H), 2.18±2.10 (m, 1H), 1.97±85 (m, 2H), 1.82±
1.75 (m, 1H), 1.67±1.58 (m, 2H), 0.92 (t, Jˆ7.4 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 170.36, 141.98, 128.42
(4£), 126.47, 49.20, 48.58, 48.21, 30.54, 20.98, 20.39,
11.39.
4.7.1. N-1-Propyl-3-phenyl-piperidine (1a).1,5a,b Yield
89%; oil; IR (CHCl3) 2932, 2360, 1453, 1089, 698 cm21
;
ESI-MS: C14H22N m/z (%)ˆ174 (21), 202 (25), 204
(M111, 100); HRMS (ESI, M111) calcd for C14H22N
204.1754, found 204.1745; H NMR (400 MHz, CDCl3) d
1
7.30±7.26 (m, 2H), 7.23±7.17 (m, 3H), 3.06±2.99 (m, 2H),
2.85 (tt, Jˆ3.5, 11.7 Hz, 1H), 2.36±2.31 (m, 2H), 2.02±1.90
(m, 3H), 1.79±1.72 (m, 2H), 1.58±1.39 (m, 3H), 0.88 (t,
Jˆ7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 144.67,
128.37 (2£), 127.30 (2£), 126.35, 61.17, 61.07, 53.82,
42.73, 31.54, 25.62, 19.87, 12.00; Anal. calcd for C14H21N
C, 82.70; H, 10.41. Found C, 82.61; H, 10.55.
4.6.2. N-1-Propyl-3-(3-methoxyphenyl)-piperidin-2-one
(2b).3i Yield 85%; oil; IR (CHCl3) 2935, 2360, 1637,
1261 cm21; ESI-MS: C15H22NO2 m/z (%)ˆ136 (16), 154
(23), 247 (25), 248 (M111, 100); HRMS (ESI, M111)
1
calcd for C15H22NO2 248.1652, found 248.1651; H NMR
(400 MHz, CDCl3) d 7.20 (t, Jˆ7.8 Hz, 1H), 6.77±6.72
(m, 3H), 3.76 (s, 3H), 3.63 (t, Jˆ6.8 Hz, 1H), 3.56±3.49
(m, 1H), 3.44±3.38 (m, 1H), 3.35±3.20 (m, 2H), 2.15±2.11
(m, 1H), 1.95±1.87 (m, 2H), 1.81±1.75 (m, 1H), 1.67±1.57
(m, 2H), 0.92 (t, Jˆ7.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 170.19, 159.60, 143.51, 129.36, 120.65, 113.67,
111.79, 55.15, 49.18, 48.56, 48.19, 30.42, 20.95, 20.38,
11.39.
4.7.2. N-1-Propyl-3-(3-methoxyphenyl)-piperidine (1b).1,3
Yield 86%; oil; IR (CHCl3) 2932, 2360, 1602, 1584, 1262,
1050 cm21; ESI-MS: C15H24NO m/z (%)ˆ204 (55), 232
(87), 234 (M111, 100); HRMS (ESI, M111) calcd for
C15H24NO 234.1859, found 234.1860; 1H NMR (400
MHz, CDCl3) d 7.20 (t, Jˆ7.9 Hz, 1H), 6.82±6.72 (m,
3H), 3.78 (s, 3H), 3.07±3.01 (m, 2H), 2.88 (t, Jˆ11.6 Hz,
1H), 2.38±2.34 (m, 2H), 2.04±1.91 (m, 3H), 1.81±1.77 (m,
2H), 1.60±1.40 (m, 3H), 0.89 (t, Jˆ7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 159.68, 146.68, 129.36, 119.60,
113.27, 111.50, 60.99, 60.93, 55.16, 53.81, 42.61, 31.43,
25.42, 19.73, 11.94; Anal. calcd for C15H23NO C, 77.21;
H, 9.93. Found C, 77.44; H, 10.06.
4.6.3. N-1-Propyl-3-(4-methoxyphenyl)-piperidin-2-one
(2c). Yield 85%; oil; IR (CHCl3) 2934, 2360, 1638,
1245 cm21; ESI-MS: C15H22NO2 m/z (%)ˆ136 (12), 154
(20), 247 (20), 248 (M111, 100); HRMS (ESI, M111)
1
calcd for C15H22NO2 248.1651, found 248.1662; H NMR
(400 MHz, CDCl3) d 7.10±7.06 (m, 2H), 6.84±6.81 (m,
2H), 3.75 (s, 3H), 3.59 (t, Jˆ7.4 Hz, 1H), 3.52±3.37 (m,
2H), 3.34±3.21 (m, 2H), 2.15±2.07 (m, 1H), 1.94±1.83 (m,
2H), 1.81±1.70 (m, 1H), 1.65±1.56 (m, 2H), 0.89 (t,
Jˆ7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 170.61,
158.66, 134.07, 129.16, 114.11 (3£), 55.24, 49.16, 48.19,
47.73, 30.50, 21.02, 20.38, 11.38.
4.7.3. N-1-Propyl-3-(4-methoxyphenyl)-piperidine (1c).1
Yield 90%; oil; IR (CHCl3) 2933, 2360, 1514, 1247,
1038 cm21; ESI-MS: C15H24NO m/z (%)ˆ204 (58), 232
(95), 234 (M111, 100); HRMS (ESI, M111) calcd for
C15H24NO 234.1859, found 234.1865; 1H NMR (400
MHz, CDCl3) d 7.12 (d, Jˆ8.7 Hz, 2H), 6.82 (d, Jˆ
8.7 Hz, 2H), 3.75 (s, 3H), 3.12±3.08 (m, 2H), 2.91 (tt, Jˆ
3.3, 11.9 Hz, 1H), 2.45±2.39 (m, 2H), 2.09±1.99 (m, 2H),
1.93±1.77 (m, 3H), 1.61±1.53 (m, 2H), 1.48±1.38 (m, 1H),
0.88 (t, Jˆ7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
158.25, 135.97, 128.06, 113.88 (3£), 60.68, 60.57, 53.43,
41.07, 31.26, 30.04, 24.94, 19.19, 11.86.
4.6.4. N-1-Propyl-3-(3,4-dimethoxyphenyl)-piperidin-2-
one (2d). Yield 83%; oil; IR (CHCl3) 2935, 2359, 1633,
1240 cm21; ESI-MS: C16H24NO3 m/z (%)ˆ58 (100), 91
(18), 154 (20), 278 (M111, 70); HRMS (ESI, M111)
1
calcd for C16H24NO3 278.1757, found 278.1750; H NMR
(400 MHz, CDCl3) d 6.80±6.78 (m, 1H), 6.72±6.69 (m,
2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.61±3.51 (m, 2H), 3.42
(ddd, Jˆ5.2, 7.6, 12.3 Hz, 1H), 3.35±3.29 (m, 1H), 3.25±
3.17 (m, 1H), 2.15±2.09 (m, 1H), 1.97±1.85 (m, 2H), 1.82±
1.72 (m, 1H), 1.61 (sext, Jˆ7.4 Hz, 2H), 0.92 (t, Jˆ7.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 170.52, 148.83,
147.73, 136.10, 120.11, 111.95, 111.32, 55.94, 55.88,
49.15, 48.19, 48.06, 30.36, 21.04, 20.38, 11.38.
4.7.4. N-1-Propyl-3-(3,4-dimethoxyphenyl)-piperidine
(1d).1k Yield 92%; oil; IR (CHCl3) 2933, 2360, 1517,
1263, 1030 cm21; ESI-MS: C16H26NO2 m/z (%)ˆ234 (57),
262 (80), 264 (M111, 100); HRMS (ESI, M111) calcd for
C16H26NO2 264.1965, found 264.1967; 1H NMR (400 MHz,
CDCl3) d 6.80±6.73 (m, 3H), 3.85 (s, 3H), 3.83 (s, 3H),
3.11±3.07 (m, 2H), 2.85 (dd, Jˆ3.5, 11.8 Hz, 1H), 2.45±
2.34 (m, 2H), 2.05±1.98 (m, 2H), 1.94±1.88 (m, 2H), 1.82±
1.76 (m, 2H), 1.60±1.47 (m, 1H), 1.46±1.37 (m, 1H), 0.88
(t, Jˆ7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 148.88,
147.65, 136.94, 118.85, 111.29, 110.83, 60.81, 60.61, 55.92,
55.89, 53.45, 41.77, 31.43, 25.11, 19.36, 11.91.
4.7. Reduction [LAH] of 3-arylpiperidinones
A solution of piperidinone 2 (0.7 mmol) in tetrahydrofuran
(10 mL) wasadded to a oslution of lithium aluminum

3628
M.-Y. Chang et al. / Tetrahedron 58 (2002) 3623±3628
Mastebroek, D.; Wikstrom, H.; Svensson, K.; Carlsson, A.;
Acknowledgements
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The authorswould like to thank the National Science
Council of the Republic of China for ®nancial support.
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8. Compound 1b wastreated with 48% hydrogen bromide to yield
the 3-PPP. The procedure wasshown in Ref. 3h.