New approach to N-substituted-1,2,3,6-tetrahydro-pyridine-4-carbaldehyde, a precursor for synthesizing Aricept, isoguvacine, and deethylibophyllidine

Article abstract of DOI:10.1002/jccs.200400092

A new route towards the synthesis of N-substituted-4-formylpiperidine using N-benzyl or tryptaminylsulfonylacetamide and α,β-unsaturated ester as starting materials is described. Formal synthesis of Aricept, deethylibophyllidine, and isoguvacine, which have potential biological activities, were synthesized via this strategy.

Full text of DOI:10.1002/jccs.200400092

Journal of the Chinese Chemical Society, 2004, 51, 613-617
613
New Approach to N-substituted-1,2,3,6-tetrahydro-pyridine-4-
®
carbaldehyde, a Precursor for Synthesizing Aricept , Isoguvacine, and
Deethylibophyllidine
a
a
Min-Ruei Tsai (
), Pei-Pei Sun (
),
b
a,
Meng-Yang Chang (
Department of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, R.O.C.
) and Nein-Chen Changa *(
)
a
b
Department of Applied Chemistry, National University of Kaohsiung 811, Taiwan, R.O.C.
A new route towards the synthesis of N-substituted-4-formylpiperidine using N-benzyl or tryptaminyl-
®
sulfonylacetamide and a,b-unsaturated ester as starting materials is described. Formal synthesis of Aricept ,
deethylibophyllidine, and isoguvacine, which have potential biological activities, were synthesized via this
strategy.
Keywords: Stepwise [3+3] annulation; Alane reduction; Dehydrosulfonated; N-substituted-4-formyl
piperidine.
INTRODUCTION
ward synthetic entry to 5a and 5b (Fig. 1).
Recently, the preparation of N-substituted 4-formyl
piperidine has become an attractive course for organic chem-
RESULTS AND DISCUSSION
1
ists. It processes an important and potential intermediate for
2
3
synthesizing various drugs, such as Donepezil, Eliprodill,
Herein, we describe a three-step practical approach to 1
on a multi-gram scale starting from glutarimide 3, which was
easily prepared via stepwise [3+3] annulation of N-benzyl
a-sulfonylacetamide with a,b-unsaturated ester as we previ-
4
5
Ifenprodil, and MDL-11,939. All these drugs have been
used successfully in clinics for the treatment of different can-
cers and tumors. To date, the reported approaches to 1 either
use expensive starting material or require tedious procedures.
Therefore, there is a continuing need for other methodology
to synthesize the desired N-substituted-4-formyl piperidine.
In this paper, we provide an efficient route to 1 from hydroge-
nation of 5a.
9
a-d
ously described.
The synthesis of 1 is illustrated in
/AlCl ) of 3a yielded
Scheme I. Alane reduction (LiAlH
4
3
piperidine 4a in 90% yield. Treatment of 4a with 10% HCl
furnished hydrolysis, then a dehydrosulfonated product 5a in
95% yield. We also have converted compound 5a to iso-
®
9
Donepezil hydrochloride (Aricept ) inaugurated a new
guvacine. Finally reduction of 5 with H
2
in the presence of
class of acetylcholinesterase (AChE) inhibitors with longer
and more selective action with manageable adverse effects
and is a promising agent for the treatment of mild to moderate
Pd/C gave 1 in 95% yield. The spectral data of 1 was highly
CHO
CO2Me
CO2H
H
N
2
dementia of the Alzheimer’s type. This drug has been ap-
proved in more than 67 countries. Donepezil hydrochloride is
synthesized through the Aldol condensation of 5,6-dimeth-
oxy-1-indanone and 1 followed by reduction and hydro-
N
N
Cl
H
H
R
N
Deethylibophyllidine
Isoguvacine
5a R=Bn
Hydrochloride
5b R=Tryp
6
chlorination.
CHO
5
Isoguvacine is a potent and selective g-Abu agonist
O
MeO
MeO
Cl
N
H
that interacts specifically with the g-Abu receptor and shows
considerable pharmacological potential. Surveying the prep-
aration of Isoguvacine, 5a is an important precursor. When
the N-alkyl group is tryptopheyl, it can be applied in synthe-
N
Bn
1
Donepezil Hydrochloride
Fig. 1.
7
sizing Deethylibophyllidine. Hence, we report a straightfor-

6
14 J. Chin. Chem. Soc., Vol. 51, No. 3, 2004
Tsai et al.
Scheme I Formal synthesis of Aricept, Isogavacine and Deethylibophyllidine
O
O
O
O
TolO S
2
TolO S
NaH
2
AlCl -LAH
3
+
O
NH
R
THF, rt
THF, rt
O
N
R
O
EtO
O
2
2
a, R=Bn
b, R=Tryp
3
3
a, R=Bn (95%)
b, R=Tryp (90%)
O
O
CHO
CHO
TolO S
10%HCl(aq)
(ref 9d)
2
TolO S
2
isoguvacine
4
a,R=Bn
N
R
acetone,
reflux
N
N
R
Bn
4
a,R=Bn
b,R=Tryp
5
a
4
(
95%)
H2/Pd-C rt,
CHO
8
0%HOAc(aq) 4b,R=Tryp,
reflux,
CHO
4b,R=Tryp
CHO
H
N
N
H
N
N
N
Bn
1
6
5b
(90%)
(
95%)
(
50%)
ref 8
ref 5
Deethylibophyllidine
Aricept
1
d
agreed with those of literature reports. Formal synthesis of
loids is currently underway in our laboratory.
®
Aricept was synthesized by this strategy. Following the
same procedures as described in Scheme I, 4b was synthe-
sized from 3b in 90% yield. Compound 4b can be trans-
formed into 5b with 10% aqueous hydrogen chloride. In 80%
EXPERIMENTAL
General
1
0,11
aqueous acetic acid,
compound 4b will undergo cycliza-
tion into 6. The spectral data of 5b and 6 agreed with those of
Tetrahydrofuran was distilled prior to use. All other re-
agents and solvents were obtained from commercial sources
and used without further purification. Reactions were rou-
tinely carried out under an atmosphere of dry nitrogen with
magnetic stirring. Products in organic solvents were dried
with anhydrous magnesium sulfate before concentration un-
der vacuum. All reported melting temperatures were uncor-
rected.
1
0
the literature reports. Since 6 has been converted into
8
Deethylibophyllidine, this work constitutes a formal total
synthesis of Deethylibophyllidine.
CONCLUSION
In conclusion, we have developed a facile [3+3] annu-
lation route to 4-formylpiperidine as the key intermediate for
Procedure of stepwise [3+3] annulation reaction9
®
the synthesis of Aricept . Most of the procedures proceeded
A solution of acetamide 2 (10.0 g, 33.0 mmol) in
tetrahydrofuran (100 mL) was added to a rapidly stirred sus-
pension of sodium hydride (3.9 g, 99.0 mmol, 60%) in tetra-
hydrofuran (300 mL). After the reaction mixture was stirred
at room temperature and in high yield. Furthermore, a formal
synthesis of Deethylibophyllidine has been successfully per-
formed. The application of this result in the synthesis of alka-

Synthesis of N-substituted-4-formylpiperidine
J. Chin. Chem. Soc., Vol. 51, No. 3, 2004 615
at room temperature for 15 min, a solution of a,b-unsaturated
ethyl ester (38.0 mmol) in tetrahydrofuran (10 mL) was
added. The resulting mixture was refluxed for 5 h, quenched
with saturated ammonium chloride solution (10 mL) in an ice
bath, and concentrated under reduced pressure. The residue
was diluted with water (100 mL) and extracted with ethyl ac-
etate (3 ´ 100 mL). The combined organic layers were
washed with brine (2 ´ 20 mL), dried, filtered and evapo-
rated. Purification on silica gel (hexane/ethyl acetate =
carefully, after 5 min compounds 3 (11.0 mmol) were added
as rapidly as possible. The mixture was stirred for 3 h at rt,
and quenched with water under cooling. The solution was fil-
tered and concentrated. The residue was diluted with water
(15 mL) and extracted with ethyl acetate (3 ´ 70 mL). The or-
ganic layer was washed with brine and water, dried, filtered
and concentrated to produce crude compounds 4. Purification
on silica gel (hexane/ethyl acetate = 4/1~2/1) produced 4a-b
in 90% yield.
3
/1~1/1) produced the products.
N-benzyl-4-(dimethoxymethyl)-3-[toluene-4-sulfonyl]
1
-Benzyl-4-dimethoxymethyl-3-(toluene-4-sulfonyl)-
piperidine (4a)
-
1
piperidine-2,6-dione (3a)
Yield 90%; Oil; IR (CHCl
ESI-MS: C22
3
) 1294, 2824, 2946 cm ;
+
Yield 95%; Yellow solid, mp = 152-154 °C; IR (CHCl
3
)
H
29NO
4
+
S m/z (%) = 91 (100), 326 (4), 403 (M ,
-
1
1
264, 1677, 2838, 3055 cm ; ESI-MS: C22
H
25NO
6
+
S m/z (%)
1); HRMS (ESI, M +1) calcd for C22
H
29NO
4
S 403.1812,
+
1
=
91 (100), 276 (4), 431 (M , 6); HRMS (ESI, M +1) calcd
found 403.1821; H NMR (500 MHz, CDCl
3
) d 7.68 (d, J =
1
for C22
H
25NO
6
S 431.1397, found 431.1403; H NMR (500
) d 7.56 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz,
H), 7.33-7.27 (m, 5H), 5.00 (d, J = 14.0 Hz, 1H), 4.86 (d, J =
8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.26-7.15 (m, 5H), 4.92
(d, J = 3.5 Hz, 1H), 3.44 (s, 3H), 3.40 (s, 3H), 3.39-3.35 (m,
3H), 2.66 (dt, J = 15.0, 4.0 Hz, 1H), 2.59 (dd, J = 12.5, 4.0 Hz,
1H), 2.42 (s, 3H), 2.25-2.18 (m, 2H), 2.07-1.91 (m, 2H),
MHz, CDCl
3
2
1
3
4.0 Hz, 1H), 4.24 (s, 1H), 4.19 (d, J = 8.0 Hz, 1H), 3.29 (s,
H), 3.22 (d, J = 7.5 Hz, 2H), 3.15 (s, 3H), 2.76 (d, J = 17.5
1
3
3
1.68-1.61(m, 1H); C NMR (125 MHz, CDCl ) d 144.51,
1
3
Hz, 1H), 2.43 (s, 3H); C NMR (125 MHz, CDCl
3
) d 170.33,
64.34, 145.58, 136.54, 134.20, 129.71 (2X), 128.93 (2X),
28.86 (2X), 128.04, 127.19, 106.57, 65.65, 56.30, 55.88,
3.21, 31.87, 30.45, 21.69; Anal. Calcd for C22 S: C,
137.52, 135.25, 129.60 (2X), 128.87 (2X), 128.07 (2X),
126.95, 104.56, 62.59, 61.64, 56.60, 55.60, 52.53, 51.65,
37.93, 22.07, 21.55.
1
1
4
7
H
25NO
6
6.67; H, 8.39; N, 6.88. Found: C, 76.81; H, 8.43; N, 6.89.
3-{2-[4-Dimethoxymethyl-3-(toluene-4-sulfonyl)-
piperidin-1-yl]-ethyl}-1H-indole (4b)
-
1
4
4
-Dimethoxymethyl-1-[2-(1H-indol-3-yl)-ethyl]-3-(toluene-
-sulfonyl)-piperidine-2,6-dione (3b)
Yield 90%; Oil; IR (CHCl
3
) 1294, 2824, 2946 cm ;
+
ESI-MS: C25
H
31
N
2
O
5
+
S m/z (%) = 91 (100), 326 (4), 470 (M ,
Yield 90%; Yellow solid, mp = 173-175 °C; IR (CHCl
3
)
1); HRMS (ESI, M +1) calcd for C25
H
31
N
2
O
5
S 470.1870
-
1
1
1
618, 2937, 3430 cm ; ESI-MS: C25
H
28
N
2
O
6
S m/z (%) = 75
found 470.1867; H NMR (500 MHz, CDCl
3
) d 7.97 (br s,
+
+
(
100), 237 (30), 484 (M , 2); HRMS (ESI, M +1) calcd for
1H), 7.74 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.34 (d,
J = 8.0 Hz, 2H), 7.19 (t, J = 6.0 Hz, 1H), 7.10 (t, J = 6.0 Hz,
1H), 7.01 (d, J = 1.5 Hz, 1H), 4.95 (d, J = 3.5 Hz, 1H), 3.44 (s,
3H), 3.43 (s, 3H), 2.84-2.72 (m, 4H), 2.57 (t, J = 6.0 Hz, 2H),
1
C
25
H
28
N
2
O
6
S 484.1664, found 484.1660; H NMR (500
MHz, CDCl
d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0
Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 7.02
s, 1H), 4.30-3.97 (m, 1H), 3.37 (s, 3H), 3.32 (s, 3H), 3.30-
.22 (m, 2H), 2.91 (t, J = 8.0 Hz, 2H), 2.77 (d, J = 17.5 Hz,
3
) d 8.08 (br s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.71
(
1
3
2.44 (s, 3H), 2.37-2.01 (m, 6H), 1.74-1.68 (m, 1H); C NMR
(125 MHz, CDCl ) d 144.83, 136.15 (2X), 135.27, 129.80
(
3
3
1
1
1
1
2
(2X), 128.58 (3X), 127.26, 121.98, 119.24, 118.60 (2X),
111.16, 104.53, 56.75 (2X), 51.67, 48.90, 46.11, 38.12,
22.92, 21.63, 20.88.
1
3
3
H), 2.45 (s, 3H); C NMR (125 MHz, CDCl ) d 170.35,
64.42, 145.73, 136.14, 134.55, 129.85 (2X), 128.95 (2X),
27.40, 122.13, 121.93, 119.32, 119.11, 112.57, 111.00,
06.47, 65.76, 56.32, 55.86, 40.71, 32.14, 30.55, 23.10,
1.73.
Preparation of N-substituted-4-formylpiperidine 5a and
5b
Compound 4a (1.0 g, 2.0 mmol) was dissolved in ace-
tone (150 mL) and aqueous 10% hydrogen chloride (5 mL)
was added and stirred under reflux temperature, and after 24
h concentrated under reduce pressure. The residue was di-
luted with water (20 mL) and potassium carbonate, and then
Reduction of glutaimides 3a and 3b
A solution of aluminum trichloride (1.4 g, 11.0 mmol)
in tetrahydrofuran (350 mL) was stirred at room temperature.
Lithium aluminum hydride (1.2 g, 33.0 mmol) was added

6
16 J. Chin. Chem. Soc., Vol. 51, No. 3, 2004
Tsai et al.
extracted with ethyl acetate (3 ´ 50 mL). The combined or-
ganic layers were washed with brine (2 ´ 20 mL), dried over
anhydrous magnesium sulfate, filtered and evaporated. Puri-
fication on silica gel (hexane/ethyl acetate = 4/1~2/1) pro-
duced 5a in 75% and 95% yield.
6.88. Found: C, 76.81; H, 8.43; N, 6.89.
Synthesis of 1,2,3,4,6,7,12,12b-Octahydro-indolo[2,3-a]-
quinolizine-2-carbaldehyde (6)
A solution of compound 4b (500 mg, 1.6 mmol) in 20%
aqueous acetic acid (20 mL) was heated at reflux overnight
and then concentrated. The residue was dissolved with di-
chloromethane, and the mixture was basified with 2 N aque-
ous sodium hydroxide in an ice bath. The organic layer was
separated off, and the aqueous layer was extracted with di-
chloromethane. The combined organic layers were washed
with brine, dried, and evaporated to give crude product 6 as
brown oil.
1
-Benzyl-1,2,3,6-tetrahydro-4-pyridinecarbaldehyde (5a)
-
1
Yield 90%; Oil; IR (CHCl
3
) 1474, 2253, 3160 cm ;
+
ESI-MS: C13
H
15NO m/z (%) = 91 (100), 201 (M , 1); HRMS
15NO 201.1154, found 201.1160;
) d 9.47 (s, 1H), 7.35-7.27 (m,
H), 6.72 (dt, J = 3.0, 2.0 Hz, 1H), 3.67 (s, 2H), 3.28 (s, 2H),
+
(
1
ESI, M +1) calcd for C13
H
H NMR (500 MHz, CDCl
3
5
2
1
3
.64 (t, J = 5.0 Hz, 2H), 2.37 (t, J = 5.0 Hz, 2H); C NMR
) d 192.82, 139.54, 129.10 (2X), 128.42
3X), 127.41, 76.7, 62.24, 52.86, 48.69, 22.33.
-
1
(
(
125 MHz, CDCl
3
Yield 50%; Oil; IR (CHCl
ESI-MS: C16
CDCl
1H), 7.32 (d, J = 7.5 Hz, 1H), 7.18 (td, J = 8.5, 1.5 Hz, 1H),
3
) 1294, 2824, 3410 cm ;
1
H
18
N
2
O m/z (%) = 254; H NMR (300 MHz,
3
) d 9.67 (s, 1H), 7.93 (br s, 1H), 7.48 (d, J = 7.5 Hz,
1
-[2-(1H-Indol-3-yl)-ethyl]-1,2,3,6-tetrahydro-pyridine-4-
carbaldehyde (5b)
Yield 90%; Oil; IR (CHCl
1
3
3
7.11 (td, J = 8.5 Hz, 1H); C NMR (75 MHz, CDCl ) d
-
1
3
) 1455, 1700, 2950 cm ;
O m/z (%) = 124 (100), 144 (33), 254 (1)
) d 9.47 (s, 1H), 8.43 (br s, 1H),
.60 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.18 (t, d, J
8.5, 1.5 Hz, 1H), 7.11 (t, d, J = 8.5 Hz, 1H), 7.02 (s, 1H),
202.87, 136.09, 133.90, 127.25, 121.58, 119.49, 118.17,
110.92, 108.57, 58.86, 54.49, 53.06, 48.54, 29.52, 25.50,
21.68.
ESI-MS: C16
H
18
N
2
1
H NMR (500 MHz, CDCl
3
7
=
Supplementary Material
6
7
2
1
1
.76 (t, J = 3.0 Hz, 1H), 3.40 (q, J = 3.0 Hz, 2H), 3.02 (t, J =
.5 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H), 2.72 (t, J = 5.5 Hz, 2H),
Additional spectroscopic data for 1, 4a, 4b, 5a, 5b and
1
6 ( H NMR in CDCl
3
).
1
3
3
.41 (t, J = 5.5 Hz, 2H); C NMR (125 MHz, CDCl ) d
92.99, 147.15, 139.39 (2X), 127.21, 121.81, 121.48, 119.07,
18.53, 113.78, 111.17, 58.47, 52.92, 48.85, 22.91, 22.21.
ACKNOWLEDGMENTS
Synthesis of N-benzyl-4-formylpiperidine 1
0% Palladium on activated carbon (30 mg) was added
The authors would like to thank the National Science
Council of the Republic of China for financial support.
1
to the solution of compound 5a (500 mg, 2.48 mmol) in meth-
anol (100 mL). Then hydrogen was bubbled into the mixture
for 30 min, and the reaction mixture was stirred for 3 h at
room temperature. The catalyst was filtered through a short
plug of Celite and washed with ethyl acetate (2 ´ 5 mL), and
the filtrate was concentrated to produce product 1 as colorless
oil.
Received September 20, 2003.
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-
1
Yield 90%; Oil; IR (CHCl
3
) 1294, 2824, 2946 cm ;
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H
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+
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2
7
2
2
); HRMS (ESI, M +1) calcd for C13
H
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2
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Synthesis of N-substituted-4-formylpiperidine
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