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Green Chemistry
Page 4 of 6
ARTICLE
Based on the above results and previous reports,14,19
Journal Name
a
DOI: 10.1039/C6GC03137D
plausible mechanism for the Fe-catalyzed cyclization could be vacuo. The residue was purified by column chromatography on
proposed as shown in Scheme 4. Initially, benzoyl radical
formed from benzaldehyde by a single-electron transfer (SET) hexane/ethyl acetate as the eluent.
process with Fe3+.19b Subsequently, the reductive cleavage of
the N-O bond of ketoxime acetate
by a Fe2+ species via a
two-step SET process forms the Fe3+ imine anion complex B 14
Tautomerization of affords , which combines with a benzoyl
radical Through a SET process,
to produce radical D 19
intermediate leads to the production of intermediate upon
releasing Fe2+. Then, the condensation of intermediate
with a
second molecular of ketoxime acetate forms intermediate
F 5,14
Next, tautomerization of produces complex and
intramolecular cyclization of intermediate
forms intermediate . The latter species
A is silicagel to afford the corresponding pyridines 3 with
2
1
Acknowledgements
.
B
C
This work was supported by generous grants from the National
Natural Science Foundation of China (21272183, 21472147 and
216222203).
A
.
D
E
E
1
.
F
G
Notes and references
G
, assisted by FeCl3
H then undergoes a
1
2
(a) A. Y. Sukhorukov and S. L. Ioffe, Chem. Rev., 2011, 111,
H
5004; (b) L. Ran, H. Liang and Z.-H. Guan, Chin. J. Org. Chem.,
2013, 33, 66; (c) J. C. Walton, Acc. Chem. Res., 2014, 47, 1406.
(a) H. Huang, X. Ji, W. Wu and H. Jiang, Chem. Soc. Rev., 2015,
44,1155; (b) S. Liu and L. S. Liebeskind, J. Am. Chem. Soc.,
2008, 130, 6918; (c) A. Faulkner, N. J. Race, J. S. Scott and J. F.
dehydration step promoted by FeCl3 to provide pyridine 3.
Ph
NH2
O
NOAc
FeCl3 (20 mol%)
+
Bower, Chem. Sci., 2014, 5, 2416.
toluene, 140 oC, Ar
Ph
Ph
Ph
Ph
N
Ph
3
4
(a) K. Narasaka and M. Kitamura, Eur. J. Org. Chem., 2005,
4505; (b) K. Narasaka, Pure Appl. Chem., 2002, 74, 143.
E'
1a
3ab, 35%
(a) S. Zaman, K. Mitsuru and A. D. Abell, Org. Lett., 2005, 7,
Scheme 5 Investigation of the reaction mechanism.
609; (b) T. Gerfaud, L. Neuville and J. Zhu, Angew. Chem., Int.
Ed., 2009, 48, 572; (c) Y. Tan and J. F. Hartwig, J. Am. Chem.
Soc., 2010, 132, 3676; (d) A. Faulkner and J. F. Bower, Angew.
Chem., Int. Ed., 2012, 51, 1675.
To further gain insights into the reaction mechanism, 3-
amino-1,3-diphenylprop-2-en-1-one E’ was synthesized to
undergo cycloaddition reaction with acetophenone oxime
acetate 1a under the standard conditions. The desired
symmetrical pyridine 3ab were obtained in morderate yields
(Scheme 5). These results further confirm the proposed
reaction mechanism.
5
6
(a) L. Ran, Z.-H. Ren, Y.-Y. Wang and Z.-H. Guan, Green Chem.,
2014, 16, 112. (b) W. Du, M.-N. Zhao, Z.-H. Ren, Y.-Y. Wang
and Z.-H. Guan, Chem. Commun., 2014, 50, 7437. (c) H. Liang,
Z.-H. Ren, Y.-Y. Wang and Z.-H. Guan, Chem. Eur. J., 2013, 19
,
9789. (d) Z.-H. Ren, Z.-Y. Zhang, B.-Q. Yang, Y.-Y. Wang and
Z.-H. Guan, Org. Lett., 2011, 13, 5394. (e) Z.-H. Guan, Z.-Y.
Zhang, Z.-H. Ren, Y.-Y. Wang and X. Zhang, J. Org. Chem.,
2011, 76, 339.
For selected examples, see: (a) S.-P. Jiang, Y.-T. Su, K.-Q. Liu,
Q.-H. Wu and G.-W. Wang, Chem. Commun., 2015, 51, 6548;
(b) Y. Fu, P. Wang, X. Guo, P. Wu, X. Meng, and B. Chen, J.
Org. Chem., 2016, 81, 11671; (c) H. Jiang, J. Yang, X. Tang, J.
Li and W. Wu, J. Org. Chem., 2015, 80, 8763; (d) J. Ke, Y. Tang,
H. Yi, Y. Li, Y. Cheng, C. Liu and A. Lei, Angew. Chem., Int. Ed.,
2015, 54, 6604; (e) Z. Cai, X. Lu, S. Wang and S. Ji, Acta Chim.
Sinica, 2014, 72, 914; (f) X. Tang, L. Huang, Y. Xu, J. Yang, W.
Wu and H. Jiang, Angew. Chem., Int. Ed., 2014, 53, 4205; (g)
Y. Wei and N. Yoshikai, J. Am. Chem. Soc., 2013, 135, 3756.
M.-N. Zhao, R.-R. Hui, Z.-H. Ren, Y.-Y. Wang and Z.-H. Guan,
Org. Lett., 2014, 16, 3082.
Conclusions
In summary, we have developed a facile, efficient and green
iron-catalyzed cyclization of ketoxime acetates and aldehydes
for the synthesis of diverse 2,4,6-triaryl substituted pyridines.
In comparation with our previous pyridine synthesis, the
current reaction proceeded smoothly under redox-neutral
t
conditions to produce H2O instesd of Ph(RCH2)NH and BuOH
as the byproducts. The reaction tolerates a wide range of
functional groups and provides a simple protocol for the rapid
synthesis of valuable 2,4,6-trisubstituted symmetrical
pyridines. In addition, grams-scale reaction was performed to
demonstratethe scaled-up applicability of this synthetic
method. Further scope and mechanistic studies of the reaction
are underway in our laboratory.
7
8
(a) B. Sun, T. Yoshino, M. Kanai and S. Matsunaga, Angew.
Chem., Int. Ed., 2015, 54, 12968; (b) H. Wang, J. Koeller, W.
Liu and L. Ackermann, Chem. Eur. J., 2015, 21, 15525.
9
(a) P. C. Too, Y.-F. Wang and S. Chiba, Org. Lett., 2010, 12,
5688; (b) J. M. Neely and T. Rovis, J. Am. Chem. Soc., 2013,
135, 66; (c) J. M. Neely and T. Rovis, J. Am. Chem. Soc., 2014,
136, 2735; (d) H. Chu, S. Sun, J.-T. Yu and J. Cheng, Chem.
Commun., 2015, 51, 13327.
10 H. Huang, J. Cai, L. Tang, Z. Wang, F. Li and G.-J. Deng, J. Org.
Chem., 2016, 81, 1499.
Experimental
Procedure for the Synthesis of Pyridines
11 For selected examples, see: (a) C. Bolm, J. Legros, J. Le Paih
and L. Zani, Chem. Rev., 2004, 104, 6217; (b) A. Correa, O. G.
Mancheño and C. Bolm, Chem. Soc. Rev., 2008, 37, 1108; (c)
A. A. O. Sarhan and C. Bolm, Chem. Soc. Rev., 2009, 38, 2730;
(d) S. Enthaler, K. Junge and M. Beller, Angew. Chem. Int. Ed.,
2008, 47, 3317; (e) C.-L. Sun, B.-J. Li and Z.-J. Shi, Chem. Rev.,
2011, 111, 1293; (f) Y. Song, X. Tang, X. Hou and Y. Bai, Chin.
J. Org. Chem., 2013, 33, 76; (g) F. Jia and Z. Li, Org. Chem.
In a 10 mL round bottom flask, the ketoxime acetates
mmol), aldehydes (0.2 mmol) and FeCl3 (20 mol%, 6.5 mg)
was stirred in toluene (2.0 mL) under Ar at 140 C. When the
reaction was completed (detected by TLC), the mixture was
cooled to room temperature, extracted with EtOAc (2 × 10 mL)
and washed with brine (10 mL). The combined organic layers
1 (0.6
2
o
4 | J. Name., 2012, 00, 1-3
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