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Improved Procedure for the Preparation of 1-(2-Phenethyl)-4-

piperidone

Article  in  Organic Preparations and Procedures International · June 2008

DOI: 10.1080/00304940809458092

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OPPI BRIEFS Volume 40, No. 2 (2008)

IMPROVED PROCEDURE FOR THE PREPARATION

OF 1-(2-PHENETHYL)-4-PIPERIDONE

Submitted by H. Fakhraian* and M. Babaei Panbeh Riseh

(11/01/07)
Department of Chemistry, Imam Hossein University, Tehran, IRAN
e-mail: [email protected]

1-(2-Phenethyl)-4-piperidone (4) is a key intermediate for the preparation of fentanyl

(analgesic),1-5 its analogues6 and other medicaments.7,8 The most widely-used method for the
synthesis of 4-piperidones is the Dieckmann cyclization of aminodicarboxylate esters which is a
multi-steps procedure that occurs under equilibrium condition and is influenced by multiple para-
meters.9 The general method of McElvain for the preparation of 4-piperidones consisting in the
condensation of appropriate primary amine with two equivalents of methyl (or ethyl) acrylate,
the cyclization of the resulting bis-ester (Dieckmann reaction) followed by hydrolysis and decar-
boxylation of the resulting cyclic product, is a well-known method (Scheme 1).10

Na
CO2Me CO2Me
Ph Ph CH Na
N N

1 2
CO2Me CO2Me

Na or NaOMe
CO2Me
Ph
Ph
N O

4
N O

3 Scheme 1
The first step of the Dieckmann condensation involves the base-catalyzed generation of
the ester enolate anion (2). The rate determining-step is the ring-closure, the subsequent loss of
the alkoxide being rapid.9 The reversibility of the process means that cyclic 2-alkoxycarbonyl
ketones such as 3 are liable to cleavage by alkoxide (retro-Dieckmann reaction), a process of
synthetic significance. Thus careful control of non-equilibrium conditions and high dilution tech-
niques (to prevent the dimerization of bis-ester) are often required. The work-up of the Dieck-
mann reaction must be performed very carefully.11 The sodium salt of 3 generated during the
reaction can be separated from the organic phase by slow filtration after addition of a filter aid or
by dissolution in water. The addition of water and mild acidification of the aqueous phase (to
regenerate 3) are exothermic and the temperature must be controlled to prevent the retro-Dieck-
mann reaction. In the synthesis of 4 from 1, varying final yields have been reported.3-5,12,13 In a
recent paper on the synthesis of fentanyl analogues,6 product 4 was obtained after several steps
producing intermediates which had to be separated prior to the next steps; in some cases, the
procedure was further complicated by the formation of the diethyl ketal hydrochloride salt of 4

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Volume 40, No. 2 (2008) OPPI BRIEFS

before the final acidification step for the preparation of the target product.12 Thus, in spite of the
inexpensive starting materials (phenethylamine and methyl acrylate for the quantitative prepara-
tion of 114), commercial 4 is expensive, not very pure, and available only in gram quantities
(98%, $ 50/g). In this contribution, we have reinvestigated different parameters such as reaction
time, temperature, nature of the base, the rate of bis-ester addition, the amount and type of
solvent that influence the yield of 4 through the Dieckmann condensation of N,N-bis-
(carbomethoxyethyl)phenethylamine (1).
After the first step (formation of ester enolate), cyclization occurred followed by depro-
tonation of another acidic proton at the α-position of other carboxylic group, leading to the
sodium salt of 3. This explains the necessity of two-fold excess of base in the first step. In the
second step, the sodium salt of 3 was dissolved in water and was thus separated from the unre-
acted and side-products left in the organic phase. If sodium is used as the base (in the form of
fine shot), it is necessary to separate unreacted excess sodium before addition of water. The addi-
tion of water must be carried out at 2-3 ºC to prevent a rise in temperature and the retro-Dieck-
mann reaction. Acidification of the aqueous phase to pH 3-4 by carefully controlled addition of
37% aqueous HCl led to the separation of 3 as an upper oily layer. Hydrolysis and decarboxyla-
tion of 3 were performed by addition of excess concentrated HCl and refluxing the mixture.
Finally, addition of an excess of sodium hydroxide provided the target product as an upper oily
layer which was extracted with xylene, evaporated to afford pure crystals of 4 (98%).
The first step is critical in the determination of the yield of the Dieckmann reaction.
Thus, using sodium as base in a dilute solution, rapid addition of 1 to mixture at 50 ºC, and
continuing the reaction at RT for 24h, has afforded pure 4 (98%) in 72% yield. Recrystalization
from xylene or n-heptane by slow partial evaporation of solvent afforded very pure (>99%) 4 as
yellow crystals. The inconvenience and danger of the use of sodium in large scale preparations
led us to perform the first step with other bases such as NaH, NaOtBu and NaOMe which
afforded 4 with yields of 64, 61 and 40% respectively.
Cyclization of the ester enolate was time consuming. Thus performing the first step at
RT using sodium as base for 6, 12, 24 and 72 h afforded 19, 44, 57 and 20% yield. After 24 h,
the yield decreased perhaps due to the side-reaction of the product in the reaction mixture.
Performing the first step at reflux temperature (or even an initial temperature of 50 ºC for several
minutes) decreased the yield.
Dilution had a remarkable effect on the yield and a three-fold increase of the solvent led
to an approximately two-fold increase in the yield. Under the optimized conditions, a twelve-fold
excess of solvent was necessary. The type of solvent also plays an important role on the yield:
xylene, toluene and benzene gave yields of 72, 24 and 13% respectively. It appears that solvent
with low boiling point do not favor intramolecular cyclization.
In summary, we have developed optimized conditions to obtain high yields of pure 4.

209
OPPI BRIEFS Volume 40, No. 2 (2008)

EXPERIMENTAL SECTION

NMR spectra were obtained on a Bruker DPX-250 instrument (250 MHz for 1H and 62.5 MHz
for 13C), in CDCl3. Chemical shifts are reported in δ from TMS. Electronic ionization GC-MS
spectra were recorded on a Varian (SATURN 4D) spectrometer with capillary column (DB-
5MS, 0.1 m, 30 m x 0.250 mm). Only m/z values of intensities of more than 5% are given and
retention times are reported for Tcol of 200 ºC and He flow rate of 10 mL/min. IR spectra were
determined on a Perkin-Elmer 783 instrument as KBr pellets. Melting point was obtained on a
Mettler FP61 apparatus. The solvents were previously dried on metallic sodium.

Preparation of 4.- Compound 1 (2.9 g, 0.01 mol), xylene (30 mL) and sodium t-butoxide (1.9 g,
0.02 mol) were placed in to a 100 mL, double-necked flask equipped with a magnetic stirrer, a
condenser, a drying column and an addition funnel. The mixture was stirred for 24 h at room
temperature. Then water (12 mL) was added dropwise at 2-3 ºC. The aqueous phase (lower
layer) was separated and acidified to pH 3-4 with 37% aqueous HCl. An oily liquid and some
precipitate appeared and the aqueous phase was separated. Excess 20% aqueous HCl (12 mL)
was added to the oily product and the mixture was refluxed for 2 h. By addition of 20% aqueous
NaOH (15 mL), an oily layer reappeared. Removal of the aqueous phase followed by extraction
of the oily layer with xylene (2 x 10 mL) afforded after drying (CaCl2 (5 g)) and evaporation of
solvent, 1.2 g (61%) of product containing 98% 1-(2-phenethyl)-4-piperidone (4) as yellow-
orange crystals, mp 62-63 ºC (lit.12 60.5-61.5 ºC, Merck product 98%, 56.5 ºC). Following the
same procedure with other bases such as Na, NaH and NaOMe led to 4 with yield of 72, 64 and
40% respectively.
1
H NMR (CDCl3): d 2.48 (t, JH-H = 6.25, 4H, CH2), 2.69-2.88 (m, 4H, CH2), 2.81 (t, JH-H = 6.25,
4H, CH2), 7.21-7.34 (m, 5H, C6H6).13C NMR (CDCl3): d 34.1, 41.2, 53.0, 59.3, 126.2, 128.4,
128.6, 139.9, 208.9. GC-MS: retention time: 4.3 min; m/z (intensity (%)): 42 (33), 112 (100),
113 (9), 204 (22). IR : 703(s),712(s), 753(s), 765(s), 1133(s), 1133(s), 1226(s), 1353(s), 1368(s),
1703(vs), 2765(s), 2796(s), 3933(s), 3958(s).

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