Novel and efficient method to synthesize N-benzyl-4-formyl-piperidine

Article abstract of DOI:10.1081/SCC-200030987

A novel and efficient method was developed to synthesize N-benzyl-4-formyl-piperidine, a key intermediate of Donepezil (Aricept). N-Benzyl-4-piperidone was reacted with dimethyloxosulfonium methylide to get epoxide, followed by rearrangement in the presence of magnesium bromide etherate to give target compound in high yield.

Full text of DOI:10.1081/SCC-200030987

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Novel and Efficient
Method to Synthesize
N‐Benzyl‐4‐Formyl‐Piperidine
a
a
Rong Sheng & Yongzhou Hu
a
Zhejiang University, Department of Medicinal
Chemistry, School of Pharmaceutical Science ,
Hangzhou, 310031, P. R. China
Published online: 10 Jan 2011.
To cite this article: Rong Sheng & Yongzhou Hu (2004) Novel and Efficient Method
to Synthesize N‐Benzyl‐4‐Formyl‐Piperidine, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry,
34:19, 3529-3533, DOI: 10.1081/SCC-200030987
To link to this article: http://dx.doi.org/10.1081/SCC-200030987
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w
SYNTHETIC COMMUNICATIONS
Vol. 34, No. 19, pp. 3529–3533, 2004
Novel and Efficient Method to Synthesize
N-Benzyl-4-Formyl-Piperidine
*
Rong Sheng and Yongzhou Hu
Zhejiang University, Department of Medicinal Chemistry, School
of Pharmaceutical Science, Hangzhou 310031, P. R. China
ABSTRACT
A novel and efficient method was developed to synthesize N-benzyl-4-
formyl-piperidine,
w
a key intermediate of Donepezil (Aricept ).
N-Benzyl-4-piperidone was reacted with dimethyloxosulfonium methyl-
ide to get epoxide, followed by rearrangement in the presence
of magnesium bromide etherate to give target compound in high yield.
Key Words: N-Benzyl-4-formyl-piperidine; Epoxidation; Rearrangement.
*
Correspondence: Yongzhou Hu, Zhejiang University, Department of Medicinal
Chemistry, School of Pharmaceutical Science, Hangzhou 310031, P. R. China;
E-mail: huyz@zjuem.zju.edu.cn.
3
529
DOI: 10.1081/SCC-200030987
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3
530
Sheng and Hu
INTRODUCTION
w
Donepezil hydrochloride (Aricept ) is the most promising agent in the
[
1]
treatment of Alzheimer’s diseases. It was synthesized through the Aldol
condensation of 5,6-dimethoxy-1-indanone and N-benzyl-4-formyl-piper-
[2]
idine, following double-bond reduction and hydrochlorination. N-Benzyl-
-formyl-piperidine is the key intermediate of Donepeziln, and as reported
4
in the literature, there are many approaches to its synthesis. Route A utilizes
the Wittig reaction of (methoxymethyl) triphenylphosphonium chloride with
[2]
N-benzyl-4-piperidone, followed by hydrolysis of the enol ether
to get
the target compound. Similarly, in route B, trimethylsilyldiazomethane is con-
densed with N-benzyl-4-piperidone to get enamine, followed by hydrolysis to
[
3]
give the final product. Route C is based on the partial reduction of N-benzyl-
-ethoxycarbonylpiperidine with sodium bis(2-methoxyethoxy) aluminum
4
hydride (SMEAH) in the presence of N-methyl piperazine or pyrrolidine.
[4]
[5]
All these methods commonly require expensive reagents, low temperature,
and tedious procedures, thus we set out to find a more economical and efficient
method.
There are many reports about the synthesis of aliphatic aldehyde via
[
epoxide rearrangement catalyzed by mineral acid or Lewis acid, such as
6]
[
7]
[8]
boron trifluroride etherate,
magnesium bromide etherate,
lithium
[9]
bromide, and so on. Our literature survey showed there was no reference
about the rearrangement of aza-cycle epoxide. So we tried the following
new route to synthesize N-benzyl-4-formyl-piperidine (Sch. 1). The epoxide
(
methylide
2) was prepared from N-benzyl-4-piperidone (1) and dimethyloxosulfonium
in high yield. Through wide scrutinization of catalysts in the
[10]
rearrangement reaction of (2), magnesium bromide etherate was picked out
as the best one, and other factors affecting results of the reaction
were carefully investigated. Results showed the title compound can be
prepared economically and efficiently through this new route.
Scheme 1.

N-Benzyl-4-Formyl-Piperidine Synthesis
RESULTS AND DISCUSSION
3531
In the course of our research, we found that catalysts played a crucial role
in the rearrangement reaction of (2). Two mineral acids (dilute sulfate acid,
perchlorate acid) and several Lewis acids (boron trifluroride etherate, zinc
chloride, aluminum chloride, lithium bromide, and magnesium bromide ether-
ate) were tested in the course of the experiments. When diluted sulfate acid,
perchlorate acid, or boron trifluroride etherate was used, no target compound
was produced. The yields of the target compound were very poor (19%, 25%,
and 27%, respectively) when zinc chloride, aluminum chloride, or lithium
bromide was used as the catalyst, while magnesium bromide etherate
showed promising results in a similar reaction condition. Three additional
factors (catalyst/substrate ratio, solvent, and reaction temperature) affecting
the results of the reaction were carefully investigated, as shown in Table 1.
The results in Table 1 show that changing solvents and temperature remark-
ably affected the yields of reactions. This was probably related to the solubility
of magnesium bromide etherate in different solvents and temperature; it cannot
be well dissolved in THF or Et O even under reflux, while in benzene, toluene,
2
and chloroform, magnesium bromide etherate can be completely dissolved at
about 408C. When temperature rose to 508C or higher, magnesium bromide
etherate would partly decompose to lose diethyl ether and cause the reduction
of yields. So we chose entry 8 as the optimum reaction condition.
a
Table 1. The selection of the reaction conditions.
Cat/sub
(mol/mol)
Temp
(8C)
Yield
(%)
Entry
Solvent
Et
THF
1
2
3
4
4
5
6
7
8
9
2
O
2/1
2/1
1/1
2/1
2/1
2/1
1/1
2/1
2/1
3/1
4/1
2/1
2/1
20
40
40
40
20
40
20
20
40
40
40
60
80
38
45
46
82
56
83
53
65
86
82
81
65
58
CHCl3
CHCl
3
Toluene
Toluene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
1
1
1
0
1
2
a
Magnesium bromide etherate was used as the catalyst.

3
532
Sheng and Hu
EXPERIMENTAL
1
HNMR spectra were recorded on a Brucker ADVANCE-400 MHz spec-
trometer using CDCl as solvent and SiMe as internal standard. Infrared
3
4
spectra were recorded on a Bruck Vector 200 spectrometer. ESIMS were
measured on an ESQUIRE-LC-00075 spectrometer.
GENERAL PROCEDURE
At room temperature, to a well-stirred mixture of N-benzyl-4-piperi-
þ
2
done (1) (18.9 g, 0.1 mol), (CH ) S OI (24.2 g, 0.11 mol), and tetrabuty-
3
3
lammonium bromide (0.5 g, 1.5 mmol) in 200 mL toluene, was added
dropwise a solution of NaOH (6.0 g, 0.15 mol) in 60 mL of water. The result-
ing mixture was warmed to 808C and stirred for 4 h. The organic phase was
separated and the water phase was extracted with toluene. The combined
organic phase was washed with water and brine, dried over anhydrous
Na SO , filtered, and concentrated under reduced pressure to give epoxide
2
4
(
without further purification. Infrared (IR) (KBr, cm ): 3028, 2919, 2799,
2) (19.2 g, 94.6% yield), which could be directly used in the next reaction
2
1
1
1
598, 1495, 1452, 1129, 739. H-NMR: d 1.49 (2 H, m, C-CH ), 1.76
2
(
2 H, m, C-CH ), 2.50 (6 H, m, 2N-CH , O-CH ), 3.53 (2 H, s, N-CH -Ph),
2
2
2
2
7
.20 (5 H, m, Ph).
Freshly prepared magnesium bromide etherate (0.2 mol) was dissolved in
200 mL anhydrous benzene, warmed to 408C, and a solution of epoxide (2)
(20.3g 0.1mol) in 20mL anhydrous benzene was added in one portion. The
mixture was stirred for 20 min, quenched by 50 mL of water, and extracted
with ethyl acetate. The extracts were washed with brine and dried over anhydrous
Na SO . The solvent was removed under reduced pressure to give crude product,
2
4
and then purified by reduced pressure distillation [boiling point (bp) 126–1288C/
.12kpa, (5) 130–1348C/1 mmHg] to get colorless oil 17.5 g (86.2% yield). IR
0
2
1
1
KBr, cm ): 3027, 2922, 2804, 2760, 1723, 1601, 1452, 738. HNMR: d 1.71
(
(
2 H, m, C-CH ), 1.90 (2 H, m, C-CH ), 2.12 (2 H, m, N-CH ), 2.28 (1 H, m,
2
2
2
CH), 2.83 ꢀ 2.87 (2 H, m, N-CH ), 3.54 (2 H, s, N-CH -Ph), 7.28 (5 H, m,
2
2
Ph), 9.68 (1 H, d, J ¼ 1.2 Hz, H-C 55 O). MS (ESI): m/z 204 (M þ H).
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N-Benzyl-4-Formyl-Piperidine Synthesis
3533
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Received in Japan April 22, 2004