Oxidation and aromatization of the enantiopure piperidine derived from (R)-(-)-2-phenylglycinol to (1′R)-(-)-1-(2′-hydroxy-1′- phenylethyl)-1H-pyridin-2-one

Article abstract of DOI:10.3987/COM-13-12911

An efficient oxidation of enantiopure piperidine 1 with bromine in acetic acid to generate the corresponding enantiopure (R)-3,3-dibromo-1- (2′-hydroxy-1′-phenylethyl)piperidin-2-one 2 is described. Then, aromatization of compound 2 to give enantiopure py

Full text of DOI:10.3987/COM-13-12911

HETEROCYCLES, Vol. 89, No. 3, 2014
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HETEROCYCLES, Vol. 89, No. 3, 2014, pp. 725 - 729. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 13th December, 2013, Accepted, 24th January, 2014, Published online, 4th February, 2014
DOI: 10.3987/COM-13-12911
OXIDATION AND AROMATIZATION OF THE ENANTIOPURE
PIPERIDINE DERIVED FROM (R)-(-)-2-PHENYLGLYCINOL TO
(1’R)-(-)-1-(2’-HYDROXY-1’-PHENYLETHYL)-1H-PYRIDIN-2-ONE
Alejandro Castro,2 Oscar Romero,2 Joel L. Terán,1 Dino Gnecco,1 Laura
Orea,1 Angel Mendoza,1 and Jorge R. Juárez1*
1Centro de Química, Instituto de Ciencias, Benemérita Universidad Autónoma de
Puebla, Edif. 103H, Complejo de Ciencias, C.U., 72570 Puebla, Pue., México.
2Universidad Politécnica de Tlaxcala, Av. Universidad Politécnica 1, San Pedro
Xalcaltzinco,
90180
Tepeyanco,
Tlax.,
México;
E-mail:
jorge.juarez@correo.buap.mx
Abstract – An efficient oxidation of enantiopure piperidine 1 with bromine in
acetic acid to generate the corresponding enantiopure (R)-3,3-dibromo-1-
(2’-hydroxy-1’-phenylethyl)piperidin-2-one 2 is described. Then, aromatization of
compound 2 to give enantiopure pyridin-2-one 3 in 71% overall yield is presented.
In general, pyridin-2-ones and dihydropyridin-2-ones are versatile synthetic building blocks, which are
used as starting materials to carry out the synthesis of interesting and diversely functionalized nitrogen
heterocycles.1 In this context, we previously reported a practical procedure to carry out the oxidation of
enantiopure pyridinium salts Ia-c to the corresponding pyridin-2-ones IIa-c. This procedure involves the
treatment of the pyridinium salts Ia-c with a mixture of potassium ferricyanide and potassium hydroxide
to give the products IIa-c with yield of ca. 90%.2 However, it is remarkable mentioning that the
pyridinium salts are obtained from the reaction of Zincke’s salts with (R)-(-)-2-phenylglycinol with
average yields of 85%3 (Scheme 1).
R
R
NH2
80%
R
Cl
OH
Cl
1. K3Fe(CN)6, H2O, 5 ºC
N
Ph
N
N
O
NO2
OH
2. KOH, H2O, toluene, 40 ºC
90%
OH
Ph
Ph
enantiopure
pyridinium salts
Ia-c
enantiopure
pyridin-2-ones
IIa-c
NO2
R = H, Me, Et
Zincke's salt
Scheme 1

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HETEROCYCLES, Vol. 89, No. 3, 2014
Herein, we report the oxidation of enantiopure piperidine 14 with bromine in the presence of acetic acid
afforded 3,3-dibromopiperidin-2-one 2 in 80% yield.5 Then, the aromatization of compound 2 under basic
conditions gave access quantitatively to the corresponding enantiopure pyridin-2-one 3 (Scheme 2).
Scheme 2
The oxidation of piperidine 1 into 3,3-dibromopiperidin-2-one 2 was achieved using 10.0 eq. of bromine
in acetic acid (80%) and refluxing the solution for 1 h. Then, basic aqueous workup allowed to obtain the
product 2 in 80% yield, after purification by flash chromatography (Scheme 3).
Scheme 3
Compound 2 was crystallized and submitted to X-ray analysis.6 The ORTEP view of product 2 is shown
in the Figure 1.
Figure 1. ORTEP of piperidin-2-one 2

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727
The aromatization of compound 2 was carried out with 2.0 eq. of DBU in refluxing THF for 1 h. Thus,
pyridin-2-one 3 was obtained in quantitative yield (Scheme 4).
Scheme 4
The spectroscopic data of compound 3 are in good agreement with the data reported in the literature for
the (R) enantiomer.2
The aromatization process can be explained by
a
first dehydrobromination to give
5,6-dihydropyridin-2-one 4 which reacts through an aza-Michael reaction with DBU7 to afford the
corresponding salt 5. Then, elimination of DBU, followed by a secondly dehydrobromination gave access
to pyridin-2-one 3 (Scheme 5).
Scheme 5
It is worth mentioning that in a previous work we reported the oxidation of enantiopure piperidine 1 with
bromine in acetic acid to achieve the corresponding enantiopure piperidin-2-one III in 96% yield8
(Scheme 6).

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HETEROCYCLES, Vol. 89, No. 3, 2014
Scheme 6
Accordingly, starting from enantiopure piperidine 1, we can access to both compounds either
pyridin-2-one 3 or piperidin-2-one III in good yields, through two different oxidation process (Scheme
7).
Scheme 7
An efficient method for the preparation of pyridin-2-one 3 in good yield has been developed. Additionally,
two different oxidation processes have been proven, which give access to either piperidin-2-ones or
pyridin-2-ones. Further use of these oxidation processes for the oxidation of 2- or 3-alkylpiperidines is
currently under investigation.
EXPERIMENTAL
1
13
General. The H and C NMR spectra were determined in CDCl3 using TMS as an internal reference
with a Varian VX400 FT NMR spectrometer operating at 400 and 100 MHz respectively. IR spectra were
obtained with a Nicolet FTIR Magna 750 spectrometer. Optical rotations were determined at room
temperature with a Perkin-Elmer 341 polarimeter, using a 1dm cell with a total volume of 1 mL and are
referenced to the D-line of sodium. Mass spectra were recorded with a JEOL JEM-AX505HA instrument
at a voltage of 70 eV.
Oxidation of compound 1.
To a solution of 1 (0.205 g, 1.0 mmol) in acetic acid (1.0 mL, 80%) at 0 °C was added dropwise a solution
of bromine (10.0 mmol, 0.51 mL) in acetic acid (2.0 mL, 80%) and water (3.0 mL). The resulting solution
was stirred at room temperature for 2 h and, then, was heated at reflux for 1 h. After cooling to 0 ºC, the
resulting solution was basified by dropwise addition of aqueous K2CO3 (0.50 M). The aqueous layer was

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extracted with CH2Cl2 (3 × 50 mL), and the combined organic extracts were washed with saturated
aqueous Na2S2O3 (25 mL), dried and concentrated to give a yellow solid. Purification by flash
chromatography (SiO2, gradient from AcOEt to 95:5 AcOEt–MeOH) afforded pure lactam 2 in 80%
yield.
Aromatization of compound 2.
To a solution of 2 (0.190 g, 0.50 mmol) in THF (5 mL) was added dropwise DBU (0.170 g, 1.1 mmol)
and the mixture was heated at reflux for 1 h. Then, the reaction was quenched with saturated aqueous
NH4Cl (3 mL) and extracted with AcOEt (3 x 10 mL). The combined organic layers were successively
washed with 5% aqueous HCl, 5% aqueous NaHCO3, and brine, then dried, filtered, and concentrated to
give pyridin-2-one 3 in quantitative yield.
ACKNOWLEDGEMENTS
We thank VIEP-BUAP, PROMEP, and CONACYT CB-2009-01/128747, and INFR-2011-3-173585.
REFERENCES
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