An efficient improve for the kroehnke reaction: One-pot synthesis of 2,4,6-triarylpyridines using raw materials under microwave irradiation

Article abstract of DOI:10.1246/cl.2005.732

A series of 2,4,6-triarylpyridines have been prepared by the one-pot reaction of aldehydes with aromatic ketones in the presence of ammonium acetate under microwave irradiation without catalyst. This method has the advantage of easier workup, shorter reaction time, higher yield, and environment-friendly. Copyright

Full text of DOI:10.1246/cl.2005.732

732
Chemistry Letters Vol.34, No.5 (2005)
¨
An Efficient Improve for the Krohnke Reaction: One-pot Synthesis of 2,4,6-Triarylpyridines
Using Raw Materials under Microwave Irradiation
Shujiang Tu,ꢀ Tuanjie Li, Feng Shi, Fang Fang, Songlei Zhu, Xianyong Wei,y and Zhimin Zongy
Department of Chemisty, Xuzhou Normal University, Key Laboratory of Biotechnology for Medicinal Plant,
Xuzhou, Jiangsu, 221116, P. R. China
ySchool of Chemical Engineering, China University of Mining and Technology, Xuzhou, Jiangsu, 221008, P. R. China
(Received February 21, 2005; CL-050227)
A series of 2,4,6-triarylpyridines have been prepared by the
one-pot reaction of aldehydes with aromatic ketones in the pres-
Ar
ence of ammonium acetate under microwave irradiation without
catalyst. This method has the advantage of easier workup, short-
er reaction time, higher yield, and environment-friendly.
NH4OAc
+
ArCHO
RCOCH3
MWI
R
N
R
1
Krohnke type pyridines1 and substituted phenylpyridines2,3
¨
Scheme 1.
are useful intermediates in the synthesis of drugs, agrochemicals,
herbicides, insecticides, desiccants, surfactant agents, and antiin-
flammartory agents.4,5 They are widely used as ligands in coor-
dination complex preparation. Triarylpyridines are prominent
building blockers in supramolecular chemistry with their ꢀ-
stacking ability, directional H-bonding and coordination. Hence,
their synthesis has received much attention.
dehydes and aromatic or heteroaromatic ketones can take part in
this reaction. This method is simple and easy work up.
1
All these products were characterized by IR and H NMR
analysis, and their melting points were identical to those of the
known compounds reported in the literature. Meanwhile, the
structure of the compound 1s was established on the basis of
spectroscopic data and conformed by X-ray diffraction study
Traditionally, triarylpyridines are synthesized using the
Krohnke approach1 by the reaction of pyridium salts with an un-
¨
Table 1. The synthesis of triarylpyridine 1
saturated ketone, which started from the preparation of pyridium
salts and involved the release of pyridium halide in the last step.
And many articles adopting the method to synthesize 2,4,6-tri-
arylpyridines have been described.6–12 However, these methods
coupled with the fact that the pyridinium halide and ꢁ,ꢂ-unsat-
urated ketone often have to be synthesized first. So it was an ex-
pensive, time consumming protocol and did harm to the enviro-
ment. Since then, some new methods for the synthesis of 2,4,6-
triarylpyridines have also been reported. One employed the reac-
tion of ꢂ-enaminophosphonates with chalcones in tetrahydrofur-
an catalized by butyllithium.13 Gareth reported the synthesis of
triarylpyridines in the presence of sodium hydroxide using a
multistep solid-phase reaction.14
Green chemistry is an environmental, health, and safe strat-
egy that emphasizes pollution prevention and application of
chemical process to reduce or eliminate the use and generation
of hazardous substance.
We investigated that microwave irradiation could assist this
reaction, and streamlined the usual multistep procedure to a sin-
gle step, cut it use of poisonous catalyst and eliminated the gen-
eration of poisonous pyridium halide. In our previous paper, we
have reported the synthesis of heterocyclic compounds under
microwave irradiation.15 In this paper, we would like to report
the one-pot synthesis of 2,4,6-triarylpyridines using raw materi-
als under microwave irradiation without catalyst.
Entry
Ar
R
Yield/% Mp (ꢁC).Lit.
1a
1b
1c
1d
1e
1f
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4 4-CH3OC6H4
4-ClC6H4 2,4-Cl2C6H3
3-O2NC6H4
4-CH3C6H4
2-ClC6H4
4-FC6H4
92
90
91
92
91
95
90
91
89
285.6–286.6
200.6–202
155.8–156
209.4–210.1
113.8–115.0
176.4–177.0
143.1–144.7
>300
161.0–161.8
156.8–157.9
(156–157.5)18
136–137 (135)19
146.5–147.3
201.2–201.6
177.9–178.2
163.9–165
1g 4-O2NC6H4 4-CH3OC6H4
1h 3-O2NC6H4 3-O2NC6H4
1i 4-CH3OC6H4 2,4-Cl2C6H3
1j 4-CH3OC6H4 4-CH3C6H4
92
1k 4-CH3OC6H4 4-CH3OC6H4
92
89
89
92
92
88
91
90
89
84
1l
1m
1n
1o
1p
2-ClC6H4
2-ClC6H4
4-BrC6H4
4-BrC6H4 4-CH3OC6H4
C6H5 2,4-Cl2C6H3
2-ClC6H4
2,4-Cl2C6H3
2,4-Cl2C6H3
160.1–161
1q 2,4-Cl2C6H3 2,4-Cl2C6H3
1r 3,4-Cl2C6H3 2,4-Cl2C6H3
1s 3-indole
1t 2,4-Cl2C6H3
203.9–204.8
152.9–154.8
232.0–233.0
158.4–159.3
167–168
(171–172)20
154–156
(158–160)20
166–167
4-CH3OC6H4
2-pyridyl
1u 4-CH3OC6H4 2-pyridyl
81
89
80
80
Under microwave irradiation, the reaction of an aldehyde
with an aromatic ketone in the presence of ammonium acetate
completed within 6 min and yielded 1a–1x in 80–96% yields
(Scheme 1).16 While in traditional heating mode (110 ꢁC), the re-
action time is 2 h and the yields are 70–78%, which indicates this
reaction can be promoted by microwave irradiation.
1v
1w 4-CH3C6H4
1x C6H5
4-BrC6H4
2-pyridyl
2-pyridyl
2-pyridyl
(166–167)20
210.8–211.6
(206–207)20
The results (Table 1) show that a wide range of aromatic al-
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.5 (2005)
733
any hazardous products. In summary, this procedure is simple,
environment-friendly.
We thank the Natural Science Foundation of the China
(No. 20372057), the Key Laboratory of Biotechnology for
Medicinal Plants of Jiangsu Province (No. 01AXL 14), the
Open-end Fund of the Key Experiments of Organic Synthesis,
Jiangsu Province (S8109111) for finanical support.
References and Notes
1
2
3
F. Krohnke, Synthesis, 1976, 1.
¨
F. Neve, A. Grispini, and S. Campagna, Inorg. Chem., 36, 6150 (1997).
B. Olenyuk, J. A. Whiteford, A. Frechtenkotter, and P. J. Stang, Nature,
398, 796 (1999).
¨
4
5
S. Shimizu, N. Abe, N. Goto, T. Niwa, and A. Iguchi, Jpn. Patent,
JP 01261367A (1998).
S. Peter, H. Gerhard, H. Elisabeth, K. Ralf, K. Hartmann, H. Albercht,
G. Norbert, W. Helmut, W. Karl-Otto, and M. Uif, U. S. Patent, US 5
733850 (1998).
Figure 1. X-ray structures of 1s.
(Figure 1).17
6
7
8
R. S. Tewari and N. K. Mishra, Croat. Chem. Acta, 54, 241 (1981).
R. S. Tewari and A. K. Dubey, J. Chem. Eng. Data, 25, 91 (1980).
N. K. Mishra, K. S. Mishra, and H. C. Srivastara, Indian J. Agric. Chem.,
21, 91 (1988).
R. K. Singhal and N. K. Mishra, Indian J. Chem., Sect. B, 24B, 1079
(1985).
However, when using aldehyde and two different ketones as
the starting material, we obtained mixture including two differ-
ent chalcone, which are primary products, and a little amount of
unsymmetrical triarylpyridine.
9
10 T. Kobayashi and M. Nitta, Chem. Lett., 1986, 1549.
11 S. Sukhwal and B. L. Verma, Indian J. Heterocycl. Chem., 31, 287
(1994).
12 A. S. Kiselyor, Tetrahedron Lett., 36, 9297 (1995).
13 P. Francisco, M. Ana, R. Ochoa, and O. Julen, Tetrahedron Lett., 37,
4577 (1996).
14 W. V. C. Gareth and L. R. Collin, Chem. Commun., 2000, 2199.
15 S. Tu, C. Miao, F. Fang, F. Youjian, T. Li, Q. Zhuang, X. Zhang, S. Zhu,
and D. Shi, Bioorg. Med. Chem. Lett., 14, 1533 (2004).
This method is applied to aromatic and heteroaromatic
ketones. Furthermore, this versatile method is also suitable for
the synthesis of 1-indenone and ꢁ-tetralone. 11-aryl-10H,12H-
diindeno[1,2-b:20,10-e]pyridine 2 and 7-aryl-5,6,8,9-tetrahydro-
dibenzo[c,h]acridine 3 were obtained with good yields (Scheme
2). The results are listed in Table 2.
Here, we disclose a facile method to synthesize a wide range
of symmetrical triarylpyridines. This methodology is superior to
the reported methods from the view of green chemistry. The sig-
nificance of our approach relates to the elimination of toxic start-
ing materials, as well as its simplicity and avoiding the release of
16 A Typical procedure for triarylpyridine: A dry flask (25 mL) was charg-
ed with a solution of the appropriate aldehyde (2 mmol), aromatic ketone
(4 mmol), NH4OAc (2 mmol) in a microwave oven. The flask was then
connected with refluxing equipment. After irradiation for 5–9 min (irra-
diation sequences were interrupted with a cooling perios in between), the
reaction mixture was cooled and the crude solid precipitated from the so-
lution was filtered and washed with 95% ethanol to afford the products.
Analytical data of compound 1j: IR (neat): 3038, 1609, 1598, 1580,
Ar
O
( )n
( )n
1543, 820 cmꢂ1 1H NMR (400 MHz, DMSO-d6): ꢃ 2.39 (6H, s, 2
.
NH4OAc
MWI
CH3), 3.85 (3H, s, OCH3), 7.11 (2H, d, J ¼ 8:0 Hz, ArH), 7.35 (2H,
d, J ¼ 8:0 Hz, ArH), 8.01 (2H, d, J ¼ 8:0 Hz, ArH), 8.08 (2H, s, Pyri-
dine–CH), 8.21 (2H, d, J ¼ 8:0 Hz, ArH). compound 1s: IR (neat):
3135, 3105, 3061, 3008, 2829, 1599, 1512, 1458, 1421, 1342, 1299,
+
ArCHO
N
( )n
2: n = 1, 3:n = 2
1244, 1171, 1103, 1033, 880, 801, 753 cmꢂ1 1H NMR (400 MHz,
.
DMSO-d6): ꢃ 3.86 (6H, s, 2OCH3), 7.10–7.12 (4H, m, ArH), 7.22–
7.24 (2H, m, ArH), 7.51–7.58 (2H, m, ArH), 8.08 (2H, s, Pyridine–
CH), 8.08–8.11 (1H, m, Indole–CH), 8.24–8.27 (4H, m, Indole–CH),
11.75 (1H, s, Indole–NH). Compound 2f: IR (neat): 3041, 1612, 1560,
Scheme 2.
Table 2. The synthesis of 2, 3
1517, 858, 831, 749 cmꢂ1 1H NMR (400 MHz, DMSO-d6): ꢃ 3.88
.
Entry
Ar
Yield/%
Mp (ꢁC).Lit.
(3H, s, OCH3), 3.96 (4H, s, 2CH2), 7.14 (2H, d, J ¼ 8:0 Hz, ArH),
7.42–7.52 (4H, m, ArH), 7.63 (2H, d, J ¼ 7:2 Hz, ArH), 7.76 (2H, d,
J ¼ 8:0 Hz, ArH), 8.11 (2H, d, J ¼ 7:2 Hz, ArH). Compound 3a: IR
2a
2b
2c
2d
2e
2f
2g
2h
3a
3b
3c
3d
3e
3f
C6H5
4-OH-3-CH3OC6H3
4-ClC6H4
3,4-OCH2OC6H3
4-BrC6H4
93
92
95
93
96
93
94
90
91
90
90
92
93
95
95
>300 (298)1
>300
>300
>300
>300
251.8–252.2
>300
>300
292.0–292.8
147.6–148.9
167.5–168.9
183.6–184.4
193.0–195.6
260.0–262.0
279.6–280.0
(neat): 3446, 3028, 1594, 1542, 1511, 766, 750, 736 cmꢂ1 1H NMR
.
(400 MHz, DMSO-d6) ꢃ 2.60–2.87 (8H, m, 4CH2), 3.81 (3H, s, OCH3),
6.68 (1H, d, J ¼ 8:4 Hz, ArH), 6.84 (s, 1H, ArH), 6.92 (1H, d,
J ¼ 8:4 Hz, ArH), 7.27–7.42 (6H, m, ArH), 8.42 (2H, d, ArH), 9.17
(1H, s, OH).
4-CH3OC6H4
3,4-Cl2C6H3
3-indole
17 Crystal data for 1s: Empirical formula C27H22N2O2, Mr ¼ 406:47,
ꢀ
ꢁ
T ¼ 193ð2Þ K, Triclinic, space group P1, a ¼ 8:7438ð13Þ A, b ¼
16:341ð2Þ A, c ¼ 16:460ð2Þ A, ꢁ ¼ 68:442ð11Þꢁ, ꢂ ¼ 76:059ð12Þꢁ,
ꢁ
ꢁ
ꢄ ¼ 75:827ð12Þ , V ¼ 2090:7ð5Þ A , Z ¼ 4, Dcalcd ¼ 1:291 Mg/cm3,
ꢁ
ꢁ 3
4-OH-3-CH3OC6H3
3,4-Cl2C6H3
C6H5
4-CH3OC6H4
3,4-OCH2OC6H3
4-ClC6H4
ꢂ1
ꢁ
ꢅðMo KꢁÞ ¼ 0:71073 A, ꢆ ¼ 0:082 mm
,
Fð000Þ ¼ 856, 3:05ꢁ
<
ꢇ < 27:48ꢁ, R ¼ 0:0741, wR ¼ 0:1445, S ¼ 1:160, Largest diff. Peak
ꢁ 3
and hole: 0.248 and ꢂ0:207 e/A .
18 R. Lombard and J. P. Stephan, Bull. Soc. Chim. Fr., 1958, 1458.
19 G. N. Dorofeenko, E. P. Olekhnovich, and L. I. Laukhina, Zh. Org.
Khim., 7, 1296 (1971).
20 T. Mutai, J. D. Cheon, S. Arita, and K. Araki, J. Chem. Soc., Perkin
Trans. 2, 2001, 1045.
3g
4-BrC6H4
Published on the web (Advance View) April 22, 2005; DOI 10.1246/cl.2005.732