Synthesis of 2,4,6-triarylpyridines using ZrOCl2 under solvent-free conditions

Article abstract of DOI:10.1055/s-0033-1340088

An efficient procedure for the synthesis of 2,4,6-triarylpyridines (Kr?hnke pyridines) by the one-pot multicomponent condensation of aldehydes (1 equiv) with acetophenones (2 equiv) and ammonium acetate (1.2 equiv) in the presence of catalytic amounts of

Full text of DOI:10.1055/s-0033-1340088

LETTER
▌193
lSetyternthesis of 2,4,6-Triarylpyridines Using ZrOCl2 under Solvent-Free Condi-
tions
Synthesis of 2,4,6-Triarylpyridines Using ZrOCl2
Ahmad Reza Moosavi-Zare,*a Mohammad Ali Zolfigol,*b Shohreh Farahmand,b Abdolkarim Zare,c Ali Reza Pourali,d
Roya Ayazi-Nasrabadib
a
University of Sayyed Jamaleddin Asadabadi, Asadabad, 6541835583, Iran
Fax +98(811)8257407; E-mail: moosavizare@yahoo.com
b
Faculty of Chemistry, Bu-Ali Sina University, Hamedan, 6517838683, Iran
E-mail: mzolfigol@yahoo.com
c
Department of Chemistry, Payame Noor University, Iran
d
School of Chemistry, Damghan University, Damghan, Iran
Received: 03.08.2013; Accepted after revision: 06.10.2013
agrochemical arena, pyridine-containing compounds
Abstract: An efficient procedure for the synthesis of 2,4,6-triaryl-
demonstrate biological activities including vasodilatory,
pyridines (Kröhnke pyridines) by the one-pot multicomponent con-
anticonvulsant, antimalarial, antiepileptic, anaesthetic,
densation of aldehydes (1 equiv) with acetophenones (2 equiv) and
ammonium acetate (1.2 equiv) in the presence of catalytic amounts
fungicidal, pesticidal and herbicidal effects.8–12
of oxozirconium(IV) chloride (ZrOCl2) under solvent-free condi-
tions is described. In this work, four products have been reported for
tion of pyridines, including reaction of α-keto ketene di-
the first time. Easy work-up, simple methodology, clean reaction
A range of methods have been introduced for the prepara-
thioacetals with methyl ketones in the presence of
and reusability of the catalyst are some advantages of this work.
NH4OAc,13 reaction of N-phopshinylethanamines with al-
Key words: pyridine, multicomponent reactions, zirconium,
Kröhnke pyridine, solvent-free
dehydes,14 addition of lithiated β-enaminophosphonates
to chalcones,15 reaction between acetophenones, benzal-
dehydes, and NH4OAc using sodium hydroxide,16 one-pot
reaction of acetophenones, benzaldehydes, and NH4OAc
Multicomponent reactions (MCRs) play a significant role
under microwave irradiation,17 and reaction between chal-
in combinatorial chemistry due to the potential use of this
cones and ammonium acetate in the presence of AcOH.18
approach to prepare target compounds with more efficien-
However, the reported methods are associated with one or
cy and atomic economy by reaction of three or more com-
more drawbacks including laborious and complex work-
pounds together in a single step. Moreover, MCRs
up and purification, production of significant amounts of
generally increase the simplicity and synthetic efficiency
waste, the need for harsh reaction conditions with conse-
of reactions compared to conventional sequential organic
quent occurrence of side reactions and poor yields, or the
transformations.1–5
use of expensive catalysts.
Pyridines are of importance because their saturated and
In this work, we report an efficient procedure for the prep-
partially saturated derivatives are present in biologically
aration of 2,4,6-triarylpyridines through a one-pot, multi-
active compounds and natural products such as NAD nu-
component reaction between a range of aromatic
cleotides, pyridoxol (vitamin B6) and pyridine alkaloids.6
aldehydes, acetophenones and NH4OAc in the presence of
Due to their π-stacking ability, pyridines are also used in
catalytic amounts of oxozirconium(IV) chloride (ZrOCl2)
supramolecular chemistry.7 In the pharmaceutical and
under solvent-free conditions (Scheme 1).
R1
R1
H
O
ZrOCl2 (15 mol%)
solvent-free, 100 °C
+
O
O
N
R2
R2
R2
R2
NH4OAc
1–10
Scheme 1 The preparation of 2,4,6-triarylpyridines catalyzed by ZrOCl2
SYNLETT 2014, 25, 0193–0196
Advanced online publication: 13.11.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340088; Art ID: ST-2013-D0705-L
© Georg Thieme Verlag Stuttgart · New York

194
A. R. Moosavi-Zare et al.
LETTER
To optimize the reaction conditions in terms of nature and Subsequently, to explore the efficacy of ZrOCl2 in the
quantity of catalyst, temperature, and duration of reaction, preparation of 2,4,6-triarylpyridines, various aromatic al-
we studied the condensation of 4-chlorobenzaldehyde (1 dehydes (including aldehydes with electron-releasing
mmol) with 4-methoxyacetophenone (2 mmol) and am- substituents, electron-withdrawing substituents and halo-
monium acetate (1.2 mmol) as a model reaction under dif- gen) were reacted with a range of acetophenones and am-
ferent conditions. Initially, we studied this model system monium acetate to furnish the corresponding products in
in the presence of 15 mol% of various zirconium com- high yields and in short reaction times (Figure 1).
pounds such as ZrCl2, ZrCl4, Zr(NO3)5·5H2O,
To demonstrate the applicability of our method on a larger
Zr(NO3)5·2H2O, ZrO2, ZrOCl2, Zr(NO3)4, ZrCoCl2·8H2O
scale, 4-chlorobenzaldehyde (20 mmol) was reacted with
and Zr(HSO4)4 under solvent-free conditions at 100 °C.
4-methoxyacetophenone (40 mmol) and ammonium ace-
As indicated in Table 1, the highest yield and shortest re-
tate (24 mmol) in the presence of ZrOCl2 (15 mol%) as
action time were obtained in the presence of ZrOCl2.
catalyst to obtain the product without a significant drop in
yield.
Table 1 Screening the Reaction with Zirconium Compoundsa
In a further study, the recyclability of the catalyst was ex-
Entry
Catalyst
Time (h)
Yield (%)b
amined with the model system. After completion of the
first reaction, the reaction mixture was extracted with
warm ethyl acetate, centrifuged for 10 minutes, and the
catalyst was separated and employed for subsequent reac-
tion. We observed that the catalytic activity of the catalyst
was restored within the limits of the experimental errors
for four successive runs (Table 3).
1
2
3
4
5
6
7
8
9
ZrCl2
9
6
66
85
66
67
62
91
65
72
60
ZrCl4
Zr(NO3)5·5H2O
Zr(NO3)5·2H2O
ZrO2
11
11
8
Table 3 Recycling the Catalysta
ZrOCl2
4
Run
Time (min)
Yield (%)b
Zr(NO3)4
ZrCoCl2·8H2O
Zr(HSO4)4
10
9
1
2
3
4
240
240
250
255
91
90
90
88
13
a Reaction conditions: 4-chlorobenzaldehyde (1 mmol), 4-methoxy-
acetophenone (2 mmol), NH4OAc (1.2 mmol), zirconium compound
(15 mol%), 100 °C.
a Reaction conditions: 4-chlorobenzaldehyde (1 mmol), 4-methoxy-
acetophenone (2 mmol), NH4OAc (1.2 mmol), (reused) ZrOCl2 (15
mol%), solvent-free conditions, 100 °C.
b Isolated yield.
b Isolated yield.
To optimize the amount of catalyst and temperature, the
model reaction was examined in the presence of different
amounts of ZrOCl2 in the range 50–120 °C under solvent-
free conditions and found that the reaction was, in fact,
most efficiently performed by using our original condi-
tions of 15 mol% catalyst at 100 °C (Table 2, entry 3).
In summary, we have reported a one-pot, multi-compo-
nent synthesis of 2,4,6-triarylpyridines by using oxozirco-
nium(IV) chloride (ZrOCl2) as catalyst under solvent-free
conditions.19 The advantages of this protocol over other
procedures are higher yields, cleaner reaction profile, and
methodological simplicity, making it an attractive process
for the synthesis of Kröhnke pyridines.
Table 2 Screening of the Reaction Conditionsa
Entry
ZrOCl2 (mol%) Temp (°C)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
5
10
15
20
15
15
15
100
100
100
100
50
9
8
65
75
91
91
52
79
90
Acknowledgment
The authors gratefully acknowledge partial support of this work by
the Research Affairs Office of Bu-Ali Sina University (Grant num-
ber 32-1716 entitled development of chemical methods, reagents
and molecules), and the Center of Excellence in Development of
Chemical Methods (CEDCM), Hamedan, I. R. Iran.
4
4
11
7
80
References and Notes
120
4
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(2) Hasaninejad, A.; Zare, A.; Shekouhi, M.; Ameri Rad, J.
J. Comb. Chem. 2010, 12, 844.
a Reaction conditions: 4-chlorobenzaldehyde (1 mmol), 4-methoxy-
acetophenone (2 mmol), NH4OAc (1.2 mmol), solvent-free condi-
tions.
b Isolated yield.
Synlett 2014, 25, 193–196
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2,4,6-Triarylpyridines Using ZrOCl2
195
Cl
Cl
Me
Cl
N
N
N
N
MeO
OMe
Me
Me
2
1
3
4
[time: 210 min; yielda: 87%]
mp: 121–124 °C [122–124 °C]20
[time: 240 min; yielda: 90%]
mp: 136–140 °C [200–202 °C]19
[time: 240 min; yielda: 92%]
mp: 133–136 °C
[time: 230 min; yielda: 92%]
mp: 118–121 °C [118 °C]20
Cl
Cl
Me
OMe
N
N
N
N
O2N
NO2
Cl
Cl
Me
Me
Me
Me
6
7
8
5
[time: 170 min; yielda: 89%]
mp: 149–151 °C
[time: 190 min; yielda: 91%]
mp: 170–172 °C [176-177 °C]20
[time: 210 min; yielda: 85%]
mp: 147–149 °C [155–157 °C]19
[time; 170 min; yielda: 93%]
mp: 158–161 °C
Cl
NO2
N
N
MeO
OMe
Cl
Cl
9
10
[time: 180 min; yielda: 92%]
mp: 189–192 °C
[time: 240 min; yielda: 91%]
mp: 110–113 °C [115–116 °C]19
Figure 1 The preparation of 2,4,6-triarylpyridines using oxozirconium(IV) chloride (ZrOCl2) at 100 °C under solvent-free conditions. a Iso-
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© Georg Thieme Verlag Stuttgart · New York
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130.2, 127.7, 127.0, 124.7, 113.9, 55.4. IR (KBr): 3081,
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(19) Synthesis of 2,4,6-Triarylpyridines with ZrOCl2;
General Procedure: A mixture of aldehyde (1 mmol),
acetophenone (2 mmol), NH4OAc (1.2 mmol) and ZrOCl2
(15 mol%) was stirred in an oil-bath (100 °C) for the
appropriate time (Figure 1). After completion of the reaction
(progress monitored by TLC), hot ethyl acetate was added to
the mixture, which was then centrifuged for 10 min and the
insoluble catalyst was filtered off. The filtrate was
evaporated, and the residue was purified by preparative plate
chromatography on silica (n-hexane–EtOAc, 5:1) to give the
pure product.
2962, 1594, 1519, 1346, 855 cm–1. MS: m/z = 401 [M]+.
4-(4-Chlorophenyl)-2,6-bis(4-nitrophenyl)pyridine (5):
1H NMR (400 MHz, CDCl3): δ = 7.41 (s, 4 H), 7.28 (s, 4 H),
6.98–7.06 (m, 2 H), 6.85 (s, 1 H), 6.80 (s, 1 H), 6.58 (d,
J = 10 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ = 150.3,
148.8, 144.5, 142.6, 136.0, 133.8, 131.3, 130.0, 129.4,
128.1, 124.3, 122.9. IR (KBr): 3055, 1664, 1606, 1587,
1492, 716 cm–1. MS: m/z = 431 [M]+.
2,4,6-Tris(4-chlorophenyl)pyridine (6): 1H NMR (400
MHz, CDCl3): δ = 7.14–7.23 (m, 4 H), 6.96–7.03 (m, 3 H),
6.80 (s, 1 H), 6.75 (s, 1 H), 6.58–6.69 (m, 3 H), 6.56 (d,
J = 9.6 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 150.3,
148.8, 144.5, 142.6, 136.0, 133.8, 131.3, 130.4, 130.0,
129.4, 128.1, 124.3, 122.9. IR (KBr): 3087, 1656, 1603,
1488, 742 cm–1. MS: m/z = 410 [M]+.
2,6-Bis(4-chlorophenyl)-4-(4-nitrophenyl)pyridine (10):
1H NMR (400 MHz, CDCl3): δ = 8.39–8.41 (m, 1 H), 8.38
(d, J = 2.4 Hz, 1 H), 8.14–8.15 (m, 2 H), 8.11–8.13 (m, 2 H),
7.87–7.90 (m, 2 H), 7.85 (s, 2 H), 7.50–7.51 (m, 2 H), 7.48–
7.49 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 156.8,
148.2, 135.7, 129.7, 129.5, 129.0, 128.4, 128.3, 128.2,
127.9, 124.4, 124.0, 117.0. IR (KBr): 3069, 1596, 1548,
1428, 1347, 827 cm–1. MS: m/z = 421 [M]+ .
Analytical data for novel compounds:
4-(2-Chlorophenyl)-2,6-bis(4-methoxyphenyl)pyridine
(1): 1H NMR (400 MHz, CDCl3): δ = 8.18 (s, 1 H), 8.13 (s,
1 H), 8.03 (d, J = 8.8 Hz, 4 H), 7.52 (s, 1 H), 7.30–7.46 (m,
3 H), 6.98 (d, J = 8.7 Hz, 4 H), 3.88 (s, 6 H). 13C NMR (100
MHz, CDCl3): δ = 163.8, 140.1, 135.3, 133.4, 130.9, 130.8,
Synlett 2014, 25, 193–196
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