Magnesium methoxide-assisted synthesis of 2,4,6-triaryl pyridines

Article abstract of DOI:10.1080/00397911.2012.696303

A new three-component reaction of chalcones, ketones, and ammonia assisted by magnesium methoxide is described. The corresponding 2,4,6-triaryl pyridines (Kroehnke pyridines) are formed in fair to good yields (34-76%) within 3 h. The method also provides a facile way to synthesize 2(6)-difluoromethyl pyridines via an interesting mechanism. Copyright

Full text of DOI:10.1080/00397911.2012.696303

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Magnesium Methoxide-Assisted Synthesis
of 2,4,6-Triaryl Pyridines
Chandan Kumar Banerjee a , Jayant D. Umarye a & Pranab R. Kanjilal
a
a Syngenta Research and Technology Centre , Corlim Ilhas , Goa ,
India
Accepted author version posted online: 05 Mar 2013.Published
online: 03 Jun 2013.
To cite this article: Chandan Kumar Banerjee , Jayant D. Umarye & Pranab R. Kanjilal (2013)
Magnesium Methoxide-Assisted Synthesis of 2,4,6-Triaryl Pyridines, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:16, 2208-2216,
DOI: 10.1080/00397911.2012.696303
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Synthetic Communications1, 43: 2208–2216, 2013
Copyright # Syngenta Research and Technology Centre
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.696303
MAGNESIUM METHOXIDE–ASSISTED SYNTHESIS
OF 2,4,6-TRIARYL PYRIDINES
Chandan Kumar Banerjee, Jayant D. Umarye, and
Pranab R. Kanjilal
Syngenta Research and Technology Centre, Corlim Ilhas, Goa, India
GRAPHICAL ABSTRACT
Abstract A new three-component reaction of chalcones, ketones, and ammonia assisted by
magnesium methoxide is described. The corresponding 2,4,6-triaryl pyridines (Kro¨hnke
pyridines) are formed in fair to good yields (34–76%) within 3 h. The method also provides
a facile way to synthesize 2(6)-difluoromethyl pyridines via an interesting mechanism.
Keywords Condensation; heterocycle; multicomponent reaction; pyridine
INTRODUCTION
Nitrogen heterocycles are significant in the living world. Among them, pyridine is
one of the most important ring systems because it is at the core of many biologically
active compounds. It is widely used in medicinal chemistry as an antimalarial, anaes-
thetic, anticonvulsant, and antitumor agent and also in agrochemicals as fungicide,
insecticide, and herbicide.[1] Aryl-substituted pyridines are particularly fascinating
because of their biological activities and their application in material science.[2] Since
Kro¨hnke’s first report have of the synthesis of 2,4,6-triarylpyridines,[3] many other
reports have appeared in literature over the years on the synthesis of arylsubstituted
pyridines.[4,5] The previously reported methods involve the condensation of 1,5-diketones
with ammonia[5a] or the activation of methyl ketone as N-phenacylpyridinium salts,[5d,e]
a-ketoketenedithioacetal,[5f] N-phosphinylethanimines,[5g] lithiated b-enaminophospho-
nates.[5h] These multistep processes suffered from various drawbacks such as harsh
Received March 15, 2012.
Address correspondence to Jayant D. Umarye, Syngenta Research and Technology Centre, Corlim
Ilhas, Goa 403 110, India. E-mail: Jayant.umarye@syngenta.com
2208

SYNTHESIS OF 2,4,6-TRIARYL PYRIDINES
2209
reaction conditions, tedious workup procedure, long reaction time, and poor yield with
occurrence of side products. Besides the procedures discussed previously, some other
methods,[6] though quite simple, also suffered from various other shortcomings, including
giving rise to only symmetrically substituted pyridines, requiring microwave condition, or
being limited to synthesis of only aryl-substituted pyridines. As a result, a short, simple,
and versatile route for the synthesis of substituted pyridinesis still a topic of research.[7].
From our literature search we did not find any simple method of preparing Kro¨hnke pyr-
idines using an enone and a ketone.
To overcome the limitations mentioned, we were looking for some simple reac-
tion condition for the synthesis of 2,4,6-trisubstituted pyridines from an enone and a
ketone in presence of ammonia. Kumar et al.[8] used bismuth(III) nitrate-alumina as
catalyst in their solid-phase synthesis of 2,4,6-triarylpyridines from benzylidene
acetophenones. The limitations of that method were that it resulted in either symme-
trically substituted pyridines or a mixture of products and required a high tempera-
ture. Recently, use of nanoparticles of magnesium oxide was reported,[9] in a reaction
of malononitrile, aryl aldehydes, and thiols to synthesize highly substituted pyri-
dines. Ley et al.[10] demonstrated the use of magnesium nitride (Mg3N2), a commer-
cially available reagent, as a surrogate for ammonia when used in protic media. Their
work inspired us to explore this reagent for the synthesis of Kro¨hnke pyridines. We
were curious to see the effect of this in situ–generated magnesium salt in the course of
a reaction between a chalcone and a ketone.
RESULTS AND DISCUSSION
Herein, we report a magnesium methoxide–assisted one-pot synthesis of 2,4,6-
trisubstituted, mainly triaryl pyridines by the reaction of an enone, a ketone, and
ammonia in methanol (Scheme 1).
We studied the effect of various enones[11] and ketones in the synthesis of sub-
stituted pyridines. The results are summarized in Table 1. The reaction worked well
with various aryl or heteroaryl substituents on the chalcone. We also cited examples
when R1 was t-butyl or trifluoromethyl or benzylidene group. Generally, reaction
with all types of ketone (acyclic, cyclic, aryl, or heteroaryl) worked satisfactorily.
In the case when R1 was an alkyl group, the reaction ended up with a tarry mass
from which nothing could be isolated, and when R2 was an aliphatic substituent,
we recovered the corresponding starting enone.
For this reaction the presence of magnesium ion was essential. When reaction
was carried out without any magnesium salt, we isolated only a 1:1 mixture [based
Scheme 1. Synthesis of 2,4,6-trisubstituted pyridines.

2210
C. K. BANERJEE, J. D. UMARYE, AND P. R. KANJILAL
Table 1. Magnesium methoxide–assisted three-component reaction of chalcones, ketones, and ammonia
Enone
Entry R1
R2
Ketone
Product Yield %
Mp (ꢀC)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
Pyridin-3-yl
2-Furyl
1-(4-Pyridyl)ethanone
Cyclohexanone
3a
3ba
3ca
3d
3ea
3f
3ga
3h
3i
64
60
38
34
50
60
50
50
76
45
48
60
57
45
50
53
68
140–142
64–65
1,2-diPhenylethanone
1-Cyclopropylethanone
Cyclohexanone
164–165
67–69
82–83
1-(Pyridin-40-yl)ethanone
132–134
65–67
2-Furyl
Cyclohexanone
Pyridin-3-yl 1-(Pyridin-40-yl)ethanone
202–204
Gummy mass
Gummy mass
118–120
109–110
125–126
180–181
73–74
Pyridin-3-yl
Phenyl
Cyclopentanone
Cyclopentanone
1-(Pyridin-40-yl)ethanone
Cyclopentanone
10
11
12
13
14
15
16
17
Benzylidinyl
2-Thenyl
3j
2-Thienyl
3-BrC6H4
3-Thienyl
3-Thienyl
Ph
3k
3l
Thiazol-2-yl
Pyridin-3-yl
Pyridin-3-yl
tBu
1-(Furan-20-yl)ethanone
1-(Pyridin-40-yl)ethanone
Cyclopentanone
3m
3n
3o
3p
3q
2-ClC6H4
4-OMeC6H4
3-Thienyl
2-Thienyl
1-(Pyridin-40-yl)ethanone
119–120
106–107
Cyclopentanone
aInitial isolated product contained ꢁ1:1 mixture of pyridine and dihydropyridine derivative (LCMS).
The dihydropyridine derivative could never be isolated in pure form, but on keeping in air for 4–5 h, it
underwent oxidation to yield the pyridine derivative only.
on liquid chromatography–mass spectrometry (LCMS) analysis] of the starting
enone and the corresponding enamine of the ketone. The same reaction mixture
afforded the desired pyridine when magnesium methoxide was added externally,
so we assumed that the reaction was initiated by polarization of the carbonyl group
of the enone assisted by magnesium ion, which was also perhaps simultaneously
bound to the nitrogen atom of the enamine,[12] making it more nucleophilic. Thus
the Michael reaction at the first step was facilitated by the two components in close
proximity to each other (Scheme 2). Subsequent ring cyclization=dehydration=
aromatization gave rise to the desired pyridine. Though the magnesium ion was initi-
ating the Michael addition, it was required in more than the stoichiometric amount;
otherwise the reaction was incomplete. Use of other metal salts such as magnesium
bromide, magnesium hydroxide, and ferric chloride also produced the desired
product, but in poor yields (10–20%), and magnesium methoxide was found to be
the best. Like some of the reported methods,[2a,4e,5b] we did not require any activat-
ing group at the a-position of the ketone for facilitating the initial Michael attack.
Generally we used dry methanol (from commercial source), but when the reaction

SYNTHESIS OF 2,4,6-TRIARYL PYRIDINES
2211
Scheme 2. Plausible mechanism for the magnesium methoxide–assisted synthesis of 2,4,6-trisubstituted
pyridines.
was carried out using moist (1% moisture) methanol, the yield dropped by ꢁ5–10%.
Thus by this method varieties of 2,4,6-trisubstituted pyridines could be synthesized
conveniently.
When R1 was atrifluoromethyl group, instead of isolating the expected 2(6)-
trifluoromethyl pyridine derivative, we isolated the corresponding difluoromethyl
derivative as the exclusive or the major product. As reported by Shen et al.,[13]
and in our case also, under the basic condition dehydrofluorination took place from
the dihydropyridine intermediate (Scheme 3) and finally gave rise to the difluoro-
methyl derivative as the product. [In some cases the ring aromatization competed
with the dehydrofluorination and resulted in some amount of trifluoro derivatives
(Table 2)]. This was a very important observation, as this process also provided a
facile method of synthesis of difluoromethyl substituted pyridines, which are not
easy to prepare and are well known for their biological activities.[14] However, the
same reaction did not work when the trifluoromethyl group was at R2 or R3 position.
In those cases we recovered the starting enones. The advantages of our procedure
over that reported by Shen et al. was that dehydrofluorination took place in the same
pot without using any additional base and it was more flexible for synthesizing 2(6)-
difluoromethyl-substituted pyridines of choice. The results are summarized in
Table 2.
However, magnesium nitride is known for its hazardous properties.[10,15] We
carried out all experiments safely using 1.3 mmol of the reagent, and for safety

2212
C. K. BANERJEE, J. D. UMARYE, AND P. R. KANJILAL
Scheme 3. Plausible mechanism for the formation of 2(6)-difluoromethyl pyridines.
reason any reaction using this reagent in the laboratory should not be scaled up
beyond the scale mentioned in the experimental section. We also developed an alter-
native method B to avoid the use of magnesium nitride. In the alternative method the
different components of the reaction were mixed together, in the same proportions as
described in method A, in a reaction vial under the same reaction condition. The
desired products were obtained in comparable yield.
In summary, we have developed a new, simple, and one pot synthesis of 2,4,6-
triaryl pyridines, assisted by magnesium methoxide, from enones, ketones, and
ammonia. This process also provided a facile way of synthesizing 2(6)-difluoromethyl
substituted pyridines starting from corresponding trifluoromethyl substituted enones
in single pot, without using any additional base.
Table 2. Magnesium methoxide–assisted synthesis of 2(6)-difluoromethyl pyridines
Entry Enone R Product Yield % Melting point (ꢀC) Product Yield % Melting point (ꢀC)
1
2
3
4
2- Thienyl
3-Pyridyl
2-Furyl
Ph
6a
6b
6c
6d
55
40
45
55
114–115
143–144
93–94
–
0
0
—
—
7b
7c
7d
10
10
124–125
109–110
113–114

SYNTHESIS OF 2,4,6-TRIARYL PYRIDINES
2213
EXPERIMENTAL
Unless otherwise mentioned, all chemicals and solvents were procured from
commercial sources and were used directly without any purification. Magnesium
nitride of 99.9% purity was procured from M=S Aldrich Chemicals. All reactions were
carried out using magnesium nitride safely and without any incident in the scale men-
tioned in method A. All yields reported are isolated yields. The products were char-
acterized by their melting points and spectral and analytical data. Melting points were
recorded in an Opti Melt machine from Stanford Research System in open capillaries
and are uncorrected. NMR spectra were taken in CDCl3 solution [in one case (3a) in
dimethylsulfoxide, DMSO-d6] at ambient temperature in a 400-MHz multinuclear
Bruker machine, and the chemical shift values are mentioned in d. Purities of all
the products were ꢂ96% and were checked by high-performance liquid chromato-
graphy (HPLC) in an Agilent-1200 series machine. They were also cross-checked
by LC-MS on a Surveyor HPLC with MSQ on a Thermo machine and by high-
resolution mass spectrometry (HRMS) on Agilent 6520 Q-TOF and on LTQ Orbi-
trap Velos (Thermo Scientific) instruments respectively. All experiments were carried
out using ꢁ0.5 and ꢁ2.5 mmol of the chalcones in methods A and B respectively
unless otherwise mentioned.
Typical Experimental Procedure (Preparation of Compound 3i)
Method A (Using Magnesium Nitride)
Magnesium nitride (0.131 g, 1.3 mmol) was added to a stirred solution of
1-phenyl-3-(pyridin-30-yl)propenone (0.110 g, 0.53 mmol) and cyclopentanone
(0.044 g, 0.52 mmol) in dry methanol (3 mL) at 0 ꢀC in a 2–5 mL microwave reaction
vial in a single portion. The vial was sealed immediately, kept in ice bath under stirring
for 1 h, and then allowed to warm at room temperature slowly in a water bath during
another 1 h. The reaction mixture was then placed in a preheated oil bath at 80 ꢀC
under stirring for 3 h. After allowing the reaction mixture to cool to room tempera-
ture, the vial was opened carefully. The content was diluted with ethyl acetate
(15 mL) and water (15 mL), and the layers were separated. The aqueous layer was neu-
tralized with 3 N hydrochloric acid and extracted with ethyl acetate (3 ꢃ 15 mL). The
combined organic extracts were dried (Na2SO4) and concentrated under reduced
pressure. The crude product was purified by a filtration column with mixture of
ethylacetate:hexane (3:7) to give rise to the product (0.109 g, brown gummy mass)
in 76% yield.1H NMR (400 MHz, CDCl3) d 2.12–2.19 (m, 2H), 3.02–3.06 (m, 2H),
3.14–3.18 (m, 2 H), 7.25–7.51 (m, 5H), 7.81–7.86 (m, 1H), 7.99 (d, 2H, J¼ 1.2 Hz), 8.65
(dd, 1H, J ¼ 4.8, 1.2 Hz), 8.79 (d, 1H, J¼ 2.0 Hz). 13C NMR (100 MHz, CDCl3) d 21.5,
28.5, 32.8, 115.9, 121.6, 125.1, 126.7, 126.8, 131.3, 132.8, 133.5, 137.7, 140.5, 147.1,
147.4, 154.9, 165.1. HRMS: (M þ H)þ, cal. for C19H17N2 273.1386; found 273.1387.
Method B (Using Freshly Prepared Magnesium Methoxide)
Freshly prepared magnesium methoxide (0.498 g, 5.8 mmol) was added to a
stirred solution of 1-phenyl-3-(pyridin-30-yl)propenone (0.500 g, 2.4 mmol) and
cyclopentanone (0.193 g, 2.3 mmol) in methanol (12 mL), saturated with ammonia

2214
C. K. BANERJEE, J. D. UMARYE, AND P. R. KANJILAL
gas, in a 10–20 mL microwave vial. The vial was sealed immediately and was placed in
a preheated oil bath at 80 ꢀC for 3 h. After allowing the reaction mixture to cool at
room temperature, the vial was opened carefully. The content was diluted with ethyl
acetate (50 mL) and water (30 mL), and the layers were separated. The aqueous layer
was neutralized with 3 N hydrochloric acid, and extracted with ethyl acetate
(3 ꢃ 50 mL). The combined organic extracts were dried (Na2SO4) and concentrated
under reduced pressure. The crude product was purified by passing through a fil-
tration column (ethylacetate:hexane) to give rise to the product 3i (0.487 g, brown
gummy mass) in 74.94% yield.
ACKNOWLEDGMENTS
We gratefully acknowledge the management of Syngenta for their support and
encouragement for this work. We thank Ravindra Sonawane for some valuable
technical discussions and Sudhindra Deshpande, Saikat Banerjee, and An Gea for
recording the spectral and analytical data.
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