Oxidative nuclear bromination of substituted 4-pyridones using pyridinium bromochromate

Article abstract of DOI:10.1080/00397911.2013.834363

An alternative convenient approach for the bromination of various poly-substituted 4-pyridones has been developed via an oxidative nuclear bromination in the presence of sole pyridinium bromochromate (PBC). The PBC performs the dual role of oxidant and so

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Oxidative Nuclear Bromination of
Substituted 4-Pyridones Using Pyridinium
Bromochromate
Zhiguo Zhang a , Jingjing Qian a , Qing Tian a , Tongxin Liu a ,
Qingfeng Liu a & Guisheng Zhang a
a Key Laboratory of Green Chemical Media and Reactions, Ministry
of Education, School of Chemistry and Chemical Engineering, Henan
Normal University , Xinxiang , Henan , China
Accepted author version posted online: 28 Oct 2013.Published
online: 27 Dec 2013.
To cite this article: Zhiguo Zhang , Jingjing Qian , Qing Tian , Tongxin Liu , Qingfeng Liu &
Guisheng Zhang (2014) Oxidative Nuclear Bromination of Substituted 4-Pyridones Using Pyridinium
Bromochromate, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 44:5, 674-681, DOI: 10.1080/00397911.2013.834363
To link to this article: http://dx.doi.org/10.1080/00397911.2013.834363
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Synthetic Communications1, 44: 674–681, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.834363
OXIDATIVE NUCLEAR BROMINATION OF
SUBSTITUTED 4-PYRIDONES USING PYRIDINIUM
BROMOCHROMATE
Zhiguo Zhang, Jingjing Qian, Qing Tian, Tongxin Liu,
Qingfeng Liu, and Guisheng Zhang
Key Laboratory of Green Chemical Media and Reactions, Ministry of
Education, School of Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang, Henan, China
GRAPHICAL ABSTRACT
Abstract An alternative convenient approach for the bromination of various poly-substituted
4-pyridones has been developed via an oxidative nuclear bromination in the presence of sole
pyridinium bromochromate (PBC). The PBC performs the dual role of oxidant and source
of Brþ during the process.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Bromopyridone; oxidative bromination; oxidative nuclear bromination
(ONB); pyridinium bromochromate (PBC); 4-pyridone
INTRODUCTION
Oxidative nuclear halogenation (ONH), essentially subordinate to electrophilic
halogenation,[1] is an effective tool to introduce the source of halogens into a variety
of organic molecules and thence to many useful halogenated chemical products.
Generally, the ONH should be carried out in the presence of oxidant and halogenated
Received April 14, 2013.
Address correspondence to Zhiguo Zhang or Guisheng Zhang, Key Laboratory of Green Chemical
Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan
Normal University, Xinxiang, Henan 453007, China. E-mail: zhangzhiguo3030@yahoo.com.cn;
zgs6668@yahoo.com
674

OXIDATIVE NUCLEAR BROMINATION
675
reagents, and in the process, the halogen cation is generated in situ from halide
anions in the presence of oxidant.[2] Oxidative nuclear bromination (ONB), the most
commonly used oxidative halogenation, has drawn much attention to the oxidative
bromination of aromatic molecules. To date, various methods have been developed
using metal bromide salts or an acid in combination with oxidizing agents, including
KBr–H2O2–(NH4)6Mo7O24 ꢀ 4H2O,[3] KBr–NaBO3 ꢀ 4H2O,[4] tBuOBr–zeolite,[5]
KBr=LiBr–(NH4)2Ce(NO3)6,[6]
NaBr–oxone,[7]
and
HBr–H2O2=tBuOOH.[8]
However, the ONB using single bromo reagents, such as PBC, as both the source
of Brþ and an oxidant is relatively rare.[9] A few examples have so far focused on
the ONB[3,4,6b,7,10] in the presence of PBC,[11] especially the NBO of aromatic mole-
cules. In 2003, Patwari et al. reported the use of PBC as a ortho-selective brominating
agent for the phenol compounds.[11a] Yazdanbakhsh and coworkers also successfully
achieved c-picolinium bromochromate (c-PBC) as a mild, efficient, and highly para-
selective oxidative mono-brominating reagent for the bromination of substituted
aromatic compounds in 2003.[11b] In their cases, the hydroxy or amino group was
a necessary part of the aromatic molecules. Using PBC as the brominating reagent
was done by Sarrafi’s group in 2009. They found that PBC was a highly efficient
and selective brominating reagent for the a-monobromination of 1,3-diketones
and b-keto-esters in the absence of base, Lewis acid, or other catalysts. In short
reaction times, the products could be isolated in good to excellent yields under mild
reaction conditions.[11c] Herein, we report our recent efforts on a new and efficient
ONB of multiple-substituted 4-pyrindones in the presence of only PBC.
RESULTS AND DISCUSSION
At present, a number of reports[12] and patents[13] reported the bromination of
4-pyridones because they have been identified to have antimalarial activity[12a] and
anti-inflammatory activity.[12b] Besides, they are also important intermediates in
the synthesis of pharmaceutical molecules (Fig. 1).[12c–e] Commonly, the bromopyr-
idones could be obtained by treating the pyridones with a bromine-containing agent
Figure 1. Representative pharmaceutically active molecules partially can be synthesized by bromopyri-
dones. (Figure is provided in color online.)

676
Z. ZHANG ET AL.
such as bromine or NBS. Some of these protocols suffered from some poignant
drawbacks, such as harsh reaction conditions (high temperature, corrosive, toxic,
strong acidity, or basic conditions), unpredictable yields, and poor regioselectivity.
Very recently, combined with our research on acetoacetamides in recent years,[14]
we successfully achieved a convenient one-pot process for the synthesis of a variety
of biologically potent polysubstituted 4-pyridones via a self-condensation of acetoa-
cetamides in the presence of only Na2S2O8.[15] We are interested in their bromination
at the 5-position because of its importance in the synthesis of some useful drugs
(Fig. 1).[16,17] We used ethyl 4-(1-(4-(ethoxycarbonyl)phenyl)-2,6-dimethyl-4-oxo-
1,4-dihydropyridine-3-carboxamido)benzoate 1a as a model for the bromination.
After many attempts, we found that ethyl 4-(5-bromo-1-(4-(ethoxycarbonyl)phenyl)-
2,6-dimethyl-4-oxo-1,4-dihydropyridine-3-carboxamido)benzoate 2a could be finally
obtained up to 94% by treating 1a (0.2 mmol) with PBC (1.1 equiv.) in AcOH
(1.0 mL) at 50 ꢁC after 3.0 h. If the reaction was performed at a lower temperature
(such as room temperature), the reactant could not be completely consumed, even
if we prolonged the reaction times, and the same situation occurred in the absence
of acetate in CH2Cl2 at reflux.
Consequently, we tested the universality of the bromination of 4-pyrindones
(Table 1). Notably a variety of substituted 4-pyridones 1a–1p could be easily con-
verted into the corresponding bromopyridones 2a–2p in the yield of 11–94% in
6.0 h. Various electron-withdrawing groups (EWG) (Cl, COOEt; compounds
2a–2f) and electron-donating groups (EDG) (Me, OMe, OEt; Table 1, compounds
2g–2k) on the aryl group were tolerated in the current transformation. For EDG,
the position of the substituents on the aryl group (para-, meta-, and ortho- position)
affected the reaction dramatically. N-(4-Methylphenyl)pyridine derivative 1i gave the
desired product 2i in the yield of 76%. When 1j was used, under the optimization
conditions, the reaction was fully disordered and gave 0% 2j, 76% N-(4-bromo-3-
methylphenyl)-2,6-dimethyl-4-oxo-1-(m-tolyl)-1,4-dihydropyridine-3-carboxamide
3j, and 14% 5-bromo-N-(4-bromo-3-methylphenyl)-2,6-dimethyl-4-oxo-1-(m-tolyl)-
1,4-dihydropyridine-3-carboxamide 4j respectively. When the reaction was carried
out with 1k, the mono-brominated product 2k was obtained in the yield of only
11% along with 47% 3k, 23% 4k, and 12% 1k.[3,6b,7b] Even if the reaction was
performed at ꢂ10 ꢁC in 1.0 mL CH2Cl2, it gave the sole product 3k in 52% and
45% 1k was recovered. These results suggested that the reactivity of the phenyl group
with EDG on the meta- or ortho- position in the amide moiety is a little higher than the
4-pyridone ring. A convincing proof for the dibromination occurring on the phenyl of
amide moiety rather than on the phenyl of the benzene-pyridone was that we got
the only product 5-bromo-2,6-dimethyl-4-oxo-1-(m-tolyl)-1,4-dihydropyridine-3-
carboxylic acid 5j via acidic hydrolysis of 4j. Additionally, 1m and 1n were also
accepted, thus leading to 2m and 2n in the yields of 60% and 91%. While some unidenti-
fied complex mixture was generated simultaneously, this made the yield of 2m slightly
less than 2n and the reaction times also were extended to 6.0 h. For 1o and 1p, it showed
satisfied efficiency because the bromopyridones 2o and 2p were obtained in good yields
(83% and 76%, respectively). It is noteworthy that in all tested cases, except 1j and 1k
where gave the by-products of brominated-4-pyridones 3 and 4, we did not get any
other side-chain ortho- or meta-brominated by-products,[6b,7b,10a,11a,18] which indicates
a strong regioselectivity for the current bromination.

OXIDATIVE NUCLEAR BROMINATION
677
Table 1. ONB of 4-pyridones 1a,b
aAll reactions were carried out with 1(0.2 mmol) and PBC (1.1equiv.) in AcOH (1.0 mL) at 50 ꢁCinanoilbath.
bIsolated yield.
c76% 3j and 14% 4j were obtained, and 10% 1j was recovered.
d47% 3k and 23% 4k were obtained, and 12% 1k was recovered.
EXPERIMENTAL
All reagents were purchased from commercial sources and used without further
treatment, unless otherwise indicated. 1H NMR and 13C NMR spectra were

678
Z. ZHANG ET AL.
13
recorded on a Bruker Avance 400 (1H: 400 MHz, C: 100 MHz at 25 ꢁC) and
tetramethylsilane (TMS) was internal standard. Data are represented as follows:
chemical shift, integration, multiplicity (br ¼ broad, s ¼ singlet, d ¼ doublet,
dd ¼ double doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet), with coupling constants
in hertz (Hz). All high-resolution mass spectras (HRMS) were measured on a Bruker
MicroTOF mass spectrometer (ESI-oa-TOF). Melting points were measured on a
YuHua X-5 apparatus.
Typical Experimental Procedure for the Synthesis of
Bromopyridones 2
Multiple-substituted 4-pyrindone derivatives 1 (0.2 mmol), PBC (1.1 equiv.)
and AcOH (1.0 mL) were added to a round-bottom flask (25 mL) and then the
mixture was well stirred at 50 ꢁC in oil bath. After cooling off, the reaction mixture
was poured into 0 ꢁC water (100 mL) and stirred vigorously for 3.0 h when thin-layer
chromatography (TLC) monitor 1 was completely consumed or the color of the
reaction turned from brown to light green. This suspension was filtered and washed
with water (5.0 mL ꢃ 3), and then the filter cake was dried under reduced pressure at
40 ꢁC to afford the final product bromopyridones 2.
Selected Data for 2a
White solid. mp: 212–215 ꢁC; 1H NMR (400 MHz, CDCl3) d 12.62 (s, 1H), 8.31
(d, J ¼ 8.0 Hz, 2H), 8.01 (d, J ¼ 8.4 Hz, 2H), 7.78 (d, J ¼ 8.4 Hz, 2H), 7.34 (d,
J ¼ 8.4 Hz, 2H), 4.46 (q, J ¼ 7.2 Hz, 2H), 4.35 (q, J ¼ 7.2 Hz, 2H), 2.49 (s, 3H),
2.26 (s, 3H), 1.44 (t, J ¼ 7.2 Hz, 3H), 1.39 (t, J ¼ 7.2 Hz, 3H). 13C NMR
(100 MHz, DMSO-d6) d 169.30, 165.29, 164.70, 164.29, 147.74, 146.96, 143.33,
143.20, 131.30, 131.09, 130.24, 128.93, 124.48, 123.09, 118.71, 116.24, 61.31, 60.48,
22.44, 19.07, 14.22, 14.11. HRMS (ESI) m=z calcd. for C26H25BrN2O6 ([M þ Na]þ):
563.0788, found: 563.0796.
CONCLUSION
In conclusion, an alternative convenient approach for the ONB of poly-
substituted 4-pyridone derivatives was successfully achieved with sole PBC in AcOH.
The PBC acted as the dual role of oxidant and source of Brþ during the process. The
absence of side-chain brominated products in the vast majority of instances in the
reactions suggested the essential effectiveness of the current bromination. All pro-
ducts were constructed efficiently from the readily available 4-pyridones.[15] Further-
more, the synthesized series of bromopyridones 2 could be used as versatile building
blocks to construct more useful pharmaceutically active molecules.[12c,12e]
SUPPORTING INFORMATION
1
Full experimental detail, H and 13C NMR spectra, and HRMS can be found
via the Supplementary Content section of this article’s Web page.

OXIDATIVE NUCLEAR BROMINATION
679
ACKNOWLEDGMENTS
We thank the NSFC (21002051, 21172056, and 21272057), PCSIRT (IRT1061),
China Postdoctoral Science Foundation (2012M521397), and the Foundation and
Frontier Technology Research Program of Henan Province (112300410312) for
financial support of this research.
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