HETEROCYCLES

Short Paper | Regular issue | Vol. 89, No. 3, 2014, pp. 725-729
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, Oscar Romero, Joel L. Terán, Dino Gnecco, Laura Orea, Angel Mendoza, and Jorge R. Juárez*

Centro de Química, Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Edif. 103G, 103H, 72570, Mexico

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).

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).

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).

Compound 2 was crystallized and submitted to X-ray analysis.6 The ORTEP view of product 2 is shown in the Figure 1.

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).

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).

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).

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).

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
General. The 1H and 13C 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 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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