Regioselective reduction of N-alkyl-3-sulfonylglutarimide. Formal synthesis of 1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine and homobaclofen

Article abstract of DOI:10.3987/com-02-9626

Reduction of N-alkyl-3-sulfonylglutarimides with (1) sodium hydride and then with lithium aluminum hydride, or (2) sodium borohydride yielded two different types of regioselectively reduced hydroxypiperidinones which were further dehydrated to two pyridin-2-ones in the presence of boron trifluoride etherate. Cycloaddition and regioselective reduction were combined to synthesize 1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine and homobaclofen.

Full text of DOI:10.3987/com-02-9626

HETEROCYCLES, Vol. 60, No. 1, 2003
99
HETEROCYCLES, Vol. 60, No. 1, 2003, pp. 99 - 112
Received, 12th September, 2002, Accepted, 18th November, 2002, Published online, 25th November, 2002
REGIOSELECTIVE REDUCTION OF N-ALKYL-3-SULFONYL-
GLUTARIMIDE. FORMAL SYNTHESIS OF 1,2,3,4,6,7,12,12b-
OCTAHYDROINDOLO[2,3-a]QUINOLIZINE AND HOMOBACLOFEN
Meng-Yang Chang,a Shui-Tein Chen,*a and Nein-Chen Changb
aInstitute of Biological Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan
bDepartment of Chemistry, National Sun Yat-Sen University, Kaohsiung 804,
Taiwan
Abstract—Reduction of N-alkyl-3-sulfonylglutarimides with (1) sodium hydride
and then with lithium aluminum hydride, or (2) sodium borohydride yielded two
different types of regioselectively reduced hydroxypiperidinones which were
further dehydrated to two pyridin-2-ones in the presence of boron trifluoride
etherate. Cycloaddition and regioselective reduction were combined to synthesize
1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine and homobaclofen.
1. INTRODUCTION
N-Acyliminium ions have been used extensively in the synthesis of alkaloids and compounds with
potential biological activities.1-3 Hydroxypiperidinones are reasonable precursors of N-acyliminium
ions.4-6 The regioselective reduction of asymmetrically substituted cyclic imides such as
piperidine-2,6-diones to their corresponding hydroxypiperidinones7-11 is an important pathway to the
formation of N-acyliminium ions. However, it is difficult to generate specific N-acyliminium ions from
imide systems.12,13 Thus, it is important to select appropriate piperidine-2,6-diones with α-sulfonyl group

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HETEROCYCLES, Vol. 60, No. 1, 2003
that features higher selectivity in reduction.
Recently we developed a facile method to produce a wide variety of α-sulfonylpiperidine-2,6-diones by
cycloaddition reaction.14,15 Here, we investigate the regioselective reduction of the
α-sulfonylpiperidine-2,6-diones (glutarimides) and use the technique to synthesize natural product (1)
and a class of potentially drug (2). The family of 1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine
(1), shown in Figure 1, possesses a wide range of biological activities16,17 and serves as an
pharmacological tool. Many synthetic methods for these compounds started with the tetracyclic ring
system.18-40 Krogsgaard-Larsen and Brauner-Osborne41,42 showed homobaclofen (2),41-44 a homologue of
classical GABAB receptor agonist baclofen,45-50 to exhibit a quite remarkable functional pharmacological
profile. Regioselective reduction is the key connection between α-sulfonylglutarimides (3) and the target
compounds (1) and (2) in our synthetic studies.
Cl
O
Tol S
O
R2
O
H
N
B
D
N
A
C
O
N
R1
2
6
O
NH2
OH
2
1
3
Figure 1. Structure of 1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine (1),
homobaclofen (2) and α-sulfonylglutarimides (3)
2. RESULTS AND DISCUSSION
2.1. Regioselective reduction of α-sulfonylglutarimides
Scheme 1 describes the production of α-sulfonylpiperidine-2,6-diones (3A) and (3B) and the two
respective stepwise reduction steps from compounds (3A) and (3B) to synthesis α-sulfonylpyridinones (6)
and (7). Compounds (4A) and (4B) were prepared by known procedures.14,15 Reactions of
α-sulfonylacetamides (4A) and (4B) having N-substituents (R1=Tryp and Bn) with the respective
acrylates (5A) and (5B) (R2=H and 4-ClC6H4) yielded products (3A) and (3B) via cycloaddition in basic
condition ( NaH/THF) at room temperature. The regioselective reduction of
α-sulfonylpiperidine-2,6-dione (3A) at the C-2 carbonyl group proceed by reduction with sodium
o
borohydride at 4~7 C, followed by acidic dehydration with boron trifluoride etherate to produce

HETEROCYCLES, Vol. 60, No. 1, 2003
101
pyridinone (6). The regioselective reduction of α-sulfonylpiperidine-2,6-dione (3B) at the C-6 carbonyl
o
group proceeded by proton abstraction using sodium hydride at 25 C, then reaction with lithium
aluminum hydride, followed by dehydration with boron trifluoride etherate to produce pyridinone (7). We
used 6 and 7 in the formal synthesis of 1 and 2.
O
Tol S
O
O
Tol S
O
O
Tol S
O
R2
O
R2
O
NaBH4
R2
O
NaH, THF
+
for 3A
O
N
R1
HO
2
N
2
6
MeO
O
NH
R1
R1
3A R1=Tryp, R2=H
3B R1=Bn, R2=4-ClC6H4
4A R1=Tryp 5A R2=H
4B R1=Bn
5B R2=4-ClC6H4
BF3-OEt2
O
NaH, then LAH
for 3B
O
O
BF3-OEt2
Tol S
O
R2
O
Tol S
R2
Tol S
O
R2
O
N
R1
N
R1
O
N
R1
OH
6
O
6
7
Scheme 1. Regioselective reduction of N-alkyl-3-sulfonylglutarimides
2.2. Formal synthesis of 1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine (1)
There are many strategies for the synthesis of 1.18-40 Our strategy used the key protocols of cycloaddition
to form the D-ring via α-sulfonylglutarimide (3A) and regioselective reduction followed by ring-closure
dehydration on the skeleton of compound (3A) to synthesize our target (1) as shown in Scheme 2.
Reaction of tryptamine with chloroacetyl chloride followed by substitution of p-toluenesulfonic acid
sodium salt gave N-tryptaminyl-α-sulfonylacetamide (4A)in 87% yield. Deprotonation of acetamide (4A)
using sodium hydride in THF at room temperature generated the dianion, this is followed by the addition
of methyl acrylate (5A)to produce cycloadducts (3A) and (3A-1). The two cycloadducts (3A) and (3A-1)
were formed by Michael addition/cycloaddition and double Michael addition/Dieckmann condensation,
respectively. The ratio of cycloadducts (3A) to its side product (3A-1) was controlled by the rate of
addition and the concentration of methyl acrylate in THF. When the rate of addition and concentration of
methyl acrylate were 1/10 mL/min and 1/50 g/mL in THF, the ratio of cycloadducts (3A) to (3A-1) was
3:1 for 72% total yield. Under conditions of 1/20 mL/min and 1/100 g/mL, the cycloadducts ratio was up

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HETEROCYCLES, Vol. 60, No. 1, 2003
to 8:1 for 80% total yield.
H
O
O
O
O
Tol S
O
O
Tol S
O
R2
O
R2
O
NaH, THF
OCH3
+
+
H
O
N
R1
N
MeO
O
NH
R1
Tryp.
S
O
Tol
O
3A R1=Tryp., R2=H
3B R1=Bn, R2=4-Cl-C6H4
4A R1=Tryp. 5A R2=H
4B R1=Bn
3A-1
5B R2=4-Cl-C6H4
For 3A
1) NaBH4
2) BF3-OEt2
(two steps 74%)
3) Na(Hg) (68%)
For 3B
1) NaH then LAH
2) BF3-OEt2
(two steps 68%)
Cl
Cl
O
1) Na(Hg)
(88%)
Tol S
O
H
N
ref 27,31,36
ref 42,44
1
O
N
2
O
N
R
O
N
Bn
9
2) H2, Pd(OH)2
(80%)
10 R=H
11 R=Bn
8
Scheme 2. Formal synthesis of 1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine (1)
and homobaclofen (2)
According to related reports,51-53 the regioselective reduction of piperidine-2,6-dione with sodium
borohydride was influenced by the α-substituted group. In our case, chelation between sulfonyl and
2-carbonyl groups of glutarimide (3A) was induced by sodium borohydride to produce
2-hydroxypiperidinone. 2-Hydroxypiperidinone was treated with boron trifluoride etherate to produce
pyridinone. The ring-closure for C-ring followed sequentially under the same condition. Tetracyclic
piperidinone was obtained in 74% yield (two steps). Finally, the lactam (8) was obtained from pyridinone
by desulfonation with sodium amalgam in methanol. The conversion of lactam (8) to target (1) has been
reported.27,31,36
2.3. Formal synthesis of homobaclofen (2)
Cycloaddition reaction of compound (4B) with 5B is the key step in the synthesis of homobaclofen (2) as
shown in Scheme 2. Reaction of benzylamine with chloroacetyl chloride followed by substitution of
p-toluenesulfonic acid sodium salt gave N-benzyl α-sulfonylacetamide (4B) in 85% yield. Deprotonation

HETEROCYCLES, Vol. 60, No. 1, 2003
103
of acetamide (4B) generated the dianion using sodium hydride in THF at refluxed temperature. The
α-sulfonylacetamide dianion reacted with acrylate (5B) to produce cycloadduct (3B). Compound (3B)
and sodium hydride (1.2 equiv.) in THF was allowed to react at room temperature for 5 min, then, one
portion of lithium aluminum hydride (2.0 equiv.) was added and further stirred for 1 h. After normal
work-up, hydroxypiperidinone was obtained with the reduction occurring exclusively at C-6 position. To
confirm these results, hydroxypiperidinone was treated with boron trifluoride etherate; the corresponding
dehydrated product (9) was produced in 68% yield. Finally, the lactam (10)42,44 was obtained in two steps
by the desulfonation with sodium amalgam in methanol and hydrogenation with palladium hydroxide asa
catalyst in acetic acid. A small amount of benzyl lactam (11) was also isolated in 10% ratio to the desired
product.
3. CONCLUSION
In summary, the formal synthesis of compounds (1) and (2) has been accomplished through the
cycloaddition formation of α-sulfonylacetamide, and the regioselective reduction and dehydration of the
α-sulfonylglutarimide.
4. EXPERIMENTAL
General. THF was distilled prior to use from a deep-blue solution of sodium-benzophenone ketyl. All
other reagents and solvents were obtained from commercial sources and used without further purification.
Reactions were routinely carried out under an atmosphere of dry nitrogen with magnetic stirring. Extract
was dried with anhydrous magnesium sulfate before concentration in vacuo.Crude products were purified
using preparative TLC or column chromatography on silica gel. All reported temperatures were
uncorrected.
N-[2-(3-Indolyl)ethyl]-2-(4-methylphenylsulfonyl)acetamide (4A)
Chloroacetyl chloride (1.20 g, 10.6 mmol) in THF (20 mL) was added to a solution of tryptamine (1.6 g,

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HETEROCYCLES, Vol. 60, No. 1, 2003
10.0 mmol) and triethylamine (1.11 g,11.0 mmol) in THF (40 mL) and the mixture was stirred in ice bath
for 1 h. After stirring at rt for 4 h, the reaction mixture was concentrated under reduced pressure. Water
(10 mL) was added to the residue, and the mixture was extracted with ethyl acetate (3 x 50 mL). The
combined organic layers were washed with brine (2 x 10 mL), dried, filtered and evaporated.
Recrystallization from hexane and ethyl acetate (50 mL :20 mL) yielded 2.2 g(93%) of chloro compound:
o
mp 145-146 C; IR (CHCl3) 3019, 1667, 1214 cm-1; HRMS (EI, M+) calcd for C12H13N2OCl 236.0178,
found 236.0722; 1H NMR (300 MHz, CDCl3): δ 8.17 (br s, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 7.8
Hz, 1H), 7.22 (t, J = 6.9 Hz, 1H), 7.14 (td, J = 0.9, 6.9 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.68 (br s, 1H),
4.01 (s, 2H), 3.64 (dd, J = 6.6, 12.6 Hz, 2H), 3.02 (t, J = 6.6 Hz, 2H); 13C NMR (75 MHz, CDCl3):
δ 165.75, 136.35, 127.07, 122.24, 122.03, 119.50, 118.57, 112.43, 111.24, 42.68, 39.99, 25.10; Anal.
Calcd for C12H13N2OCl: C, 60.89; H, 5.54. Found: C, 60.62; H, 5.52. A stirred solution of
chlorocompound (2.0 g, 8.46 mmol) and p-toluenesulfonic acid sodium salt (TolSO2Na-2H2O, 3.21 g,
15.0 mmol) was refluxed in dioxane (50 mL) and water (30 mL) for 10 h. The mixture was concentrated
under reduced pressure and the residue was extracted with ethyl acetate (3 x 50 mL). The combined
organic layers were washed with brine (2 x 20 mL), dried, filtered and evaporated. Recrystallization from
hexane and ethyl acetate (50 mL : 30 mL) yielded 2.83 g (94%) of 4A: mp 157-159 oC; IR (CHCl3) 3042,
1660 cm-1; HRMS (EI, M+) calcd for C19H20N2O3S 356.1196, found 356.1185; 1H NMR (300 MHz,
CDCl3): δ 8.42 (br s, 1H), 7.55-7.50 (m, 3H), 7.29 (d, J = 7.8 Hz, 1H), 7.19-7.07 (m, 4H), 7.02 (s, 1H),
6.79 (t, J = 5.4 Hz, 1H), 3.84 (s, 2H), 3.52 (dd, J = 6.6, 12.3 Hz, 2H), 2.92 (t, J = 6.6 Hz, 2H), 2.32 (s,
13
3H); C NMR (75 MHz, CDCl3): δ 160.60, 145.30, 136.32, 134.88, 129.79 (2x), 127.91 (2x), 126.94,
122.60,121.91, 119.18, 118.44, 111.82, 111.36, 61.83, 39.99, 24.68, 21.52; Anal.Calcd for C19H20N2O3S:
C, 64.02; H, 5.66. Found: C, 63.96; H, 5.64.
N-Benzyl-2-(4-methylphenylsulfonyl)acetamide (4B)
Chloroacetyl chloride (5.99 g, 53.0 mmol) in THF (40 mL) was added to a solution of benzylamine (5.35
g, 50.0 mmol) and triethylamine (5.57 g, 55.0 mmol) in THF (100 mL) and stirred in an ice bath for 1 h,

HETEROCYCLES, Vol. 60, No. 1, 2003
105
then stirred at rt for 4 h. The mixture was concentrated under reduced pressure. Water (30 mL) was added
to the crude product and the mixture was extracted with ethyl acetate (3 x 100 mL). The combined
organic layers were washed with brine (2 x 50 mL), dried, filtered and evaporated. Without purification,
the crude product and p-toluenesulfonic acid sodium salt (TolSO2Na-2H2O, 16.05 g, 75.0 mmol) were
refluxed in dioxane (150 mL) and water (150 mL) for 10 h. The mixture was concentrated under reduced
pressure and the residue was extracted with ethyl acetate (3 x 150 mL).The combined organic layers were
washed with brine (2 x 50 mL), dried, filtered and evaporated. Recrystallization from hexane (150 mL)
and ethyl acetate (100 mL) yielded 12.88 g(85%, two steps) of 4B as a solid: mp 157-159 oC; IR (CHCl3)
2361, 1664, 1528, 1290, 1147 cm-1; ESI-MS: C16H18NO3S m/z (%) = 91 (100),154 (65), 304 (M++1, 85);
1
HRMS (ESI, M++1) calcd for C16H18NO3S 304.1008, found 304.1009; H NMR (400 MHz, CDCl3)
δ 7.65 (d, J = 8.2 Hz, 2H), 7.33-7.24 (m, 7H), 7.06 (br s, 1H), 4.42 (d, J = 5.9 Hz, 2H), 3.99 (s, 2H), 2.42
13
(s, 3H); C NMR (100 MHz, CDCl3): δ 160.64, 145.58, 137.35, 135.12, 130.04, 128.74, 128.16 (4x),
127.97 (2x), 127.70, 62.01, 44.02, 21.70; Anal. Calcd for C16H17NO3S: C, 63.34; H, 5.65. Found: C,
63.14; H, 5.44.
N-[2-(3-Indolyl)ethyl]-3-(4-methylphenylsulfonyl)piperidine-2,6-dione (3A) and Methyl
5-[2-(3-indolylethyl)ethylcarbamoyl]-2-hydroxy-5-(4-methylphenylsulfonyl)-1-cyclohexene-1-carbo-
xylate (3A-1)
A solution of acetamide (4A) (1.07 g, 3.0 mmol) in THF (30 mL) was added to a rapidly stirred
suspension of sodium hydride (264 mg, 6.6 mmol, 60%) in THF (40 mL). After stirring at rt for 15 min,a
solution of methyl acrylate (5A) (335 mg, 3.9 mmol) in THF (33.5 mL) was added. The resulting mixture
was stirred at rt for ca. 11 h,quenched with saturated ammonium chloride solution (2 mL)in ice bath, and
concentrated under reduced pressure. Water (10 mL) was added to the residue, and the mixture was
extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (2 x 20
mL), dried, filtered and evaporated. Purification on silica gel (hexane/ethyl acetate = 2/1) afforded 873
mg (71%) of 3A as a solid and 134 mg (9%) of 3A-1 as a viscous oil. Compound (3A): mp 177-179 oC;

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HETEROCYCLES, Vol. 60, No. 1, 2003
IR (CHCl3) 3025, 1667 cm-1; HRMS (EI, M+) calcd for C22H22N2O4S 410.1300, found 410.1305; 1H
NMR (300 MHz, CDCl3): δ 8.07 (br s, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 6.3 Hz, 1H), 7.36 (d, J
= 8.4 Hz, 2H), 7.33 (d, J = 7.8 Hz, 1H), 7.18-7.11 (m, 2H), 7.02 (d, J = 2.4 Hz, 1H), 4.11-4.02 (m, 3H),
3.28-3.15 (m, 1H), 2.98 (t, J = 7.8 Hz, 2H), 2.75-2.60 (m, 2H), 2.45 (s, 3H), 2.23-2.15 (m, 1H); 13C NMR
(75 MHz, CDCl3): δ 170.64, 164.77, 145.73, 136.05, 134.84, 129.84 (2x), 128.97 (2x), 127.46, 122.33,
121.93, 119.33, 118.87, 112.28, 111.06, 65.64, 40.95, 29.25, 23.31, 21.77, 17.55; Anal. Calcd for
C22H22N2O4S: C, 64.37; H, 5.40. Found: C, 64.62; H, 5.56. Compound (3A-1): IR (CHCl3) 3452, 1652
cm-1; HRMS (EI, M+) calcd for C26H28N2O6S 496.1668, found 496.1678; 1H NMR (300 MHz, CDCl3): δ
12.08 (s, 1H), 8.25 (br s, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.1 Hz, 1H),
7.25-7.11 (m, 4H), 7.04 (d, J = 6.6 Hz, 1H), 6.78 (t, J = 8.1 Hz, 1H), 3.66 (s, 3H), 3.63-3.55 (m, 2H), 3.02
(t, J = 6.6 Hz, 2H), 2.90 (d, J = 15.9 Hz, 1H), 2.78 (d, J = 15.9 Hz, 1H), 2.37 (s, 3H), 2.36-2.28 (m, 3H),
2.15-2.09 (m, 1H); 13C NMR (75 MHz, CDCl3): δ 171.63, 170.05, 164.98, 145.59, 136.42, 131.48,
129.69 (2x), 129.66 (2x), 126.92, 122.45, 122.09, 119.37, 118.50, 112.05, 111.34, 94.20, 70.12, 51.65,
40.48, 26.13, 25.23, 24.69, 24.53, 21.64; Anal. Calcd for C26H28N2O6S: C, 62.89; H, 5.68. Found: C,
62.71; H, 5.71.
1,2,3,4,6,7,12,12b-Octahydroindolo[2,3-a]quinolizin-4-one (8)27,31,36
A solution of compound (3A) (615 mg, 1.5 mmol) in co-solvent of THF (10 mL) and methanol (5 mL)
o
was stirred at 4-7 C, and sodium borohydride (150 mg, 4.0 mmol) was added. The mixture was stirred
for 2 h at this temperature. Saturated sodium bicarbonate solution (1 mL) was added to the mixture and
the mixture was concentrated under reduced pressure. Water (5 mL) was added to the residue, and the
mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed
with brine (2 x 10 mL),dried,filtered and evaporated.Without further purification,the crude hydroxylactam
was dissolved in dichloromethane (10 mL) and a catalytic amount of boron trifluoride etherate (0.1 mL)
was added. The mixture was stirred for 15 h at rt. Saturated sodium bicarbonate solution (5 mL) was
added to the resulting mixture and the mixture was concentrated under reduced pressure. Water (5 mL)

HETEROCYCLES, Vol. 60, No. 1, 2003
107
was added to the residue, and the mixture was extracted with dichloromethane (3 x 10 mL). The
combined organic layers were washed with brine (2 x 10 mL), dried, filtered and evaporated. Purification
on silica gel (hexane/ethyl acetate = 1/1) afforded 437 mg (two steps 74%) of cyclized product: mp
258-260 oC; IR (CHCl3) 3240, 1610 cm-1; ESI-MS: C22H23N2O3S m/z (%) = 58 (48), 136 (50), 149 (88),
238 (72), 391 (57), 395 (M++1, 100); HRMS (ESI, M++1) calcd for C22H23N2O3S 395.1431, found
395.1436; 1H NMR (400 MHz, CDCl3) δ 9.75 (br s, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 7.8 Hz,
1H), 7.44 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H),
5.39 (d, J = 8.3 Hz, 1H), 4.95 (dd, J = 4.8, 13.2 Hz, 1H), 3.67-3.62 (m, 1H), 3.03-2.90 (m, 2H), 2.75-2.70
(m, 1H), 2.57 (dt, J = 4.5, 17.2 Hz, 1H), 2.49 (s, 3H), 2.20-2.12 (m, 1H),2.07-1.97 (m, 1H),1.95-1.88 (m,
1H);13C NMR (100 MHz, CDCl3) δ 169.32, 146.44, 136.11, 132.46, 131.49, 130.46 (2x),129.29, 129.12,
126.47, 122.61, 119.85, 118.45, 111.65, 111.03, 64.32, 52.18, 42.75, 30.08, 22.10, 21.78, 20.56; Anal.
Calcd for C22H22N2O3S: C, 66.98; H, 5.62. Found: C, 66.72; H, 5.66. A solution of sulfonyl compound
(394 mg, 1.0 mmol) and sodium phosphate (355 mg, 2.5 mmol) in methanol (15 mL) was stirred, and 6%
sodium amalgam (Na/Hg, 1.5 g) was added. The mixture was vigorously stirred for 2 h at rt. The residue
was filtered and washed with methanol (2 x 10 mL). The combined organic layers were concentrated to
the crude desulfonyl compound. Purification on silica gel (hexane/ethyl acetate = 1/1) afforded 163 mg
o
(68%) of 8: mp 140-141 C; IR (CHCl3) 3230, 1607 cm-1; HRMS (ESI, M++1) calcd for C15H17N2O
241.1342, found 241.1339; 1H NMR (400 MHz, CDCl3) δ 7.85 (br s, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.34
(d, J = 8.2 Hz, 1H), 7.18 (ddd, J = 1.1, 7.1, 8.0 Hz, 1H), 7.12 (td, J = 0.9, 7.8 Hz, 1H), 5.18-5.11 (m, 1H),
4.81 (m, 1H), 2.94-2.65 (m, 4H), 2.50-2.42 (m, 2H), 2.01-1.72 (m, 3H); 13C NMR (100 MHz, CDCl3) δ
171.06, 136.27, 132.50, 126.77, 122.46,120.06, 118.50, 110.97, 109.60, 54.60, 40.92,31.55,28.84, 20.91,
18.83.
N-Benzyl-3-(4-chlorophenyl)-5-(4-methylphenylsulfonyl)piperidine-2,6-dione (3B)
A solution of acetamide (4B) (0.9 g,3.0 mmol) in THF (30 mL) was added to a rapidly stirred suspension
of sodium hydride (264 mg, 6.6 mmol, 60%) in THF (20 mL). After the reaction mixture was stirred at rt

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HETEROCYCLES, Vol. 60, No. 1, 2003
for 15 min, a solution of methyl acrylate (5B) (590 mg, 3.0 mmol) in THF (10 mL) was added. The
resulting mixture was stirred at reflux temperature for 30 min, quenched with saturated ammonium
chloride solution (2 mL) in ice bath, and concentrated under reduced pressure. Water (10 mL) was added
to the residue, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic
layers were washed with brine (2 x 20 mL), dried, filtered and evaporated. Purification on silica gel
o
(hexane/ethyl acetate = 3/1) afforded 1.08 g (77%) of 3B as a solid: mp 192-194 C; IR (CHCl3) 1733,
1669 cm-1; ESI-MS: C25H23NO4ClS m/z (%) = 91 (26), 136 (61), 154 (100), 307 (32), 468 (M++1, 19);
1
HRMS (ESI, M++1) calcd for C25H23NO4ClS 468.1036, found 468.1033; H NMR (400 MHz, CDCl3) δ
7.85 (d, J = 8.3 Hz, 2/3H), 7.54 (d, J = 8.3 Hz, 4/3H), 7.36-7.24 (m, 9H), 7.12-7.07 (m, 2H), 5.07 (d, J =
13.9 Hz, 2/3H),4.94 (d, J = 13.9 Hz, 2/3H), 4.92 (d, J = 13.9 Hz, 1/3H), 4.87 (d, J = 13.9 Hz, 1/3H), 4.52
(dd, J = 5.7, 12.8 Hz, 2/3H), 4.32 (dd, J = 5.5, 12.9 Hz, 1/3H), 4.14 (dd, J = 2.8, 5.8 Hz, 2/3H), 3.68 (dd,
J = 4.7, 13.9 Hz, 1/3 H), 3.04 (ddd, J = 2.8, 5.8, 14.9 Hz, 1H), 2.81 (td, J = 5.2,13.4 Hz, 1/3H), 2.63-2.47
(m, 2/3H), 2.46 (s, 1H), 2.44 (s, 2H); Anal. Calcd for C25H22NO4ClS: C, 64.16; H, 4.74. Found: C, 64.28;
H, 4.81.
N-Benzyl-3-[(4-methylphenyl)sulfonyl]-5-(4-chlorophenyl)-3,4-dihydro-2(1H)-pyridinone (9)
A solution of 3B (468 mg, 1.0 mmol) in THF (10 mL) was added to a rapidly stirred suspension of
sodium hydride (48 mg, 1.2 mmol, 60%). After the reaction mixture was stirred at rt for 5 min, lithium
aluminum hydride (76 mg, 2.0 mmol) was added and the resulting reaction mixture was stirred for 1.0 h,
then quenched with a saturated ammonium chloride solution (1 mL) and extracted with ethyl acetate (3 x
20 mL). The organic layers were washed with brine (2 x 10 mL), dried, filtered and evaporated. Without
purification, the crude hydroxylactam was treated with boron trifluoride etherate (0.1 mL) in
dichloromethane (20 mL) for 10 h, water (20 mL) was then added. After extraction with dichloromethane
(2 x 20 mL), the organic layers were washed with brine (2×10 mL), dried, filtered and evaporated.
Purification on silica gel (hexane/ethyl acetate = 3/1) afforded 306 mg (68%) of 9 as a solid: mp 153-155
oC; IR (CHCl3) 1668 cm-1; ESI-MS: C25H23NO3ClS m/z (%) = 91 (100),136 (30), 154 (46), 295 (31), 452

HETEROCYCLES, Vol. 60, No. 1, 2003
109
(M++1, 70);HRMS (ESI, M++1) calcd for C25H23NO3ClS 452.1087, found 452.1087; 1H NMR(400 MHz,
CDCl3) δ 7.68 (d, J = 8.3 Hz, 2H), 7.36-7.14 (m, 11H), 6.20 (d, J = 2.5 Hz, 1H), 4.70 (s, 2H), 4.17 (dd, J
= 3.1, 7.9 Hz, 1H), 3.52 (dd, J = 3.1, 18.2 Hz, 1H), 3.19 (ddd, J = 2.5, 7.9, 18.2 Hz, 1H), 2.40 (s, 3H);13C
NMR (100 MHz, CDCl3): δ 160.58, 145.30, 135.88, 135.59, 135.49, 133.02, 129.60 (3x), 129.10 (3x),
128.87 (2x), 128.83, 127.97 (2x),126.17 (2x), 125.51, 115.17, 65.70, 50.32, 24.87, 21.74; Anal.Calcd for
C25H22NO3ClS: C, 66.44; H, 4.91. Found: C, 66.59; H, 4.86.
5-(4-Chlorophenyl)piperidin-2-one (10)42,44 and N-Benzyl-5-(4-chlorophenyl)piperidin-2-one (11)
A solution of compound (9) (450 mg, 1.0 mmol) and sodium phosphate (355 mg, 2.5 mmol) in methanol
(15 mL) was stirred, and 6% sodium amalgam (Na/Hg, 1.5 g) was added. The mixture was vigorously
stirred for 2 h at rt. The residue was filtered and washed with methanol (2 x 10 mL). The combined
organic layers were concentrated to leave the crude desulfonyl compound. Purification on silica gel
(hexane/ethyl acetate = 1/1) afforded 260 mg (88%) of desulfonyl compound: mp 80-82 oC; IR (CHCl3)
1651 cm-1; EI-MS: C18H16NOCl m/z (%) = 91 (100), 154 (33), 297 (M+, 81); HRMS (EI, M+) calcd for
C18H16NOCl 297.0920, found 297.0924; 1H NMR (400 MHz, CDCl3) δ 7.34-7.15 (m, 9H), 6.41 (s, 1H),
4.76 (s, 2H), 2.72 (s, 4H); 13C NMR (100 MHz, CDCl3): δ 168.74, 136.98, 136.75, 132.31, 128.79,
128.70 (4x), 127.66 (2x), 127.62, 126.43, 125.57, 117.69, 49.42, 31.13, 23.65; Anal. Calcd for
C18H16NOCl: C, 72.60; H, 5.42. Found: C, 72.44; H, 5.69. Palladium hydroxide on activated carbon as
catalyst (100 mg) was added to a solution of olefin (200 mg, 0.67 mmol) in acetic acid (10 mL).
Hydrogen was bubbled into the mixture for 10 min, and the mixture was stirred at rt for 18 h. Filtration
through a short plug of Celite and washing with ethyl acetate (3 x 10 mL) resulted in the crude products.
Purification on silica gel (hexane/ethyl acetate = 1/1~1/2) produced 112 mg (80%) of compound (10) as a
1
solid and 16 mg (8%) of compound (11) as a gum. H NMR data spectrum of 10 were the same with
reference 42. Compound (11): IR (CHCl3) 1656 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.33-7.14 (m, 9H),
4.69 (d, J = 14.6 Hz, 1H), 4.54 (d, J = 14.6 Hz, 1H), 3.35-3.33 (m, 1H), 3.28-3.23 (m, 1H), 3.06-3.01 (m,
1H), 2.69-2.52 (m, 2H), 2.09-2.02 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 169.44, 141.69, 136.98,

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HETEROCYCLES, Vol. 60, No. 1, 2003
128.71 (2x), 128.64 (2x), 128.23, 127.47, 127.15, 126.96 (2x), 116.32, 53.68, 50.34, 40.28, 32.06, 28.04;
Anal. Calcd for C18H18NOCl: C, 72.11; H, 6.05. Found: C, 72.50; H, 5.63.
5. ACKNOWLEDGEMENT
We thank the National Science Council of the Republic of China for its financial support. We are grateful
to John Y. Lin for his contributions to the manuscript.
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