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ChemComm
Page 4 of 4
DOI: 10.1039/C6CC09582H
COMMUNICATION
Journal Name
NR3R4
Notes and references
1 (a) E. Kleinman and C. H. Heathcock, Tetrahedron Lett., 1979, 20, 4125-4128; (b)
C. H. Heathcock, E. F. Kleinman and E. S. Binkley, J. Am. Chem. Soc., 1982, 104,
2
R3
R4
Ar
N
I
Ar
NR3R4
R4R3N
N
N
8
+
N
N
1
I
1054-1068; (c) C. Tsukano, L. Zhao, Y. Takemoto and M. Hirama, Eur. J. Org.
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Siegel, J. Org. Chem., 2013, 78, 5647-5668; (g) L. Zhao, C. Tsukano, E. Kwon, Y.
Takemoto and M. Hirama, Angew. Chem. Int. Ed., 2013, 52, 1722-1725; (h) C.
Yuan, C.-T. Chang, A. Axelrod and D. Siegel, J. Am. Chem. Soc., 2010, 132, 5924-
5925; (i) M. Uosis-Martin, G. D. Pantoş, M. F. Mahon and S. E. Lewis, J. Org. Chem.,
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R1
R2
R1
R2
9
NR3R4
Ar
NR3R4
Ar
NR3R4
Ar
H
9
2
R4R3N
R4R3NH
N
N
I
N
R4R3N
N
N
I
9
N
R1
R2
R1
R2
R1
R2
10
12
11
NR3R4
Zn, HOAc
R1 = acyl, sulfonyl
R2, R3, R4 = alkyl
Ar = aryl, H
Yoshino, T. Katoh and S. Terashima, Heterocycles, 1997, 46
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, 27-30; (p) C.
Ar
,
5
3
N
Scheme 5. Plausible reaction mechanism
2
2253; (u) R. Ding, B. F. Sun and G. Q. Lin, Org. Lett., 2012, 14, 4446-4449; (v) J. D.
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performed at room temperature (Scheme 4). These facts indicated
that morpholine added to 1g at the less hindered C6 position and
the Mannich type reaction took place at the bromined carbon para
to the morpholinyl group of 5. The bromine atom was presumably
displaced by abundant morpholine presented in the mixture10
followed by expelling morpholine activator to yield 7’ (path b,
Scheme 4). Intermediate 6 leading to product 7 was precluded
considering the steric hindrance (path a, Scheme 4).
15,
Rotenberg, Expert Rev Neurother, 2016, 16
51-85; (c) U. Damar, R. Gersner, J. T. Johnstone, S. Schachter and A.
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4 (a) C. S. Giam and J. L. Stout, J. Chem. Soc. D, 1970, 1970, 478-478; (b) C. S. Giam
Thus, a plausible reaction mechanism of this regio-selective
umpolung functionalization of 1-amidopyridin-1-ium salt was
proposed based on our experimental observations (Scheme 5).
Aminal 2 decomposes reversibly upon the treatment with 1-
amidopyridin-1-ium salt 1 to form iminium salt 9 and nucleophilic 1-
amido-2-amino-1,2-dihydropyridine 8,8e which traps 9 at the more
nucleophilic and less steric C5 position (para to the amino group) to
form iminium intermediate 10. Intermediate 10 tautomerizes to
dienamine 11 with the aid of excessive aminal 2, and then 11
partially rearomatizes by extruding one molecule of secondary
and S. D. Abbott, J. Am. Chem. Soc., 1971, 93
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Tsuge, S. Kanemasa, T. Naritomi and J. Tanaka, Bull. Chem. Soc. Jpn., 1987, 60
1497-1504; (e) J. M. Bakke and I. Hegbom, J. Chem. Soc., Perk. Trans. 2, 1995,
1995, 1211-1215; (f) J. M. Bakke and E. Ranes, Synthesis, 1997, 1997, 281-283; (g)
H. Suzuki, M. Iwaya and T. Mori, Tetrahedron Lett., 1997, 38, 5647-5650; (h) A.
, 1294-1296; (c) O. Tsuge, S.
,
Klapars and E. Vedejs, Chem. Heterocycl. Compd., 2004, 40, 759-766; (i) S.
Wübbolt and M. Oestreich, Angew. Chem. Int. Ed., 2015, 54, 15876-15879; (j) M.
Ye, G.-L. Gao, A. J. F. Edmunds, P. A. Worthington, J. A. Morris and J.-Q. Yu, J. Am.
Chem. Soc., 2011, 133, 19090-19093; (k) M. Ye, G.-L. Gao and J.-Q. Yu, J. Am.
Chem. Soc., 2011, 133, 6964-6967; (l) B.-J. Li and Z.-J. Shi, Chem Sci, 2011, 2, 488-
493; (m) F. Dai, Q. Gui, J. Liu, Z. Yang, X. Chen, R. Guo and Z. Tan, Chem. Commun.,
2013, 49, 4634-4636.
amine in the presence of
9 to deliver C3-functionalized 1-
5 For reviews on pyridine functionalization, see: (a) Y. Nakao, Synthesis, 2011, 2011
3209-3219; (b) J. A. Bull, J. J. Mousseau, G. Pelletier and A. B. Charette, Chem.
Rev., 2012, 112, 2642-2713; (c) D. E. Stephens and O. V. Larionov, Tetrahedron,
2015, 71, 8683-8716.
6 (a) T. Zincke, G. Heuser and W. Möller, Justus Liebigs Ann. Chem., 1904, 333, 296-
345; (b) T. Zincke, Justus Liebigs Ann. Chem., 1904, 330, 361-374; (c) T. Zincke and
W. Würker, Justus Liebigs Ann. Chem., 1904, 338, 107-141; (d) T. Zincke and G.
Weißpfenning, Justus Liebigs Ann. Chem., 1913, 396, 103-131; (e) N. C. de Lucas, J.
C. Netto-Ferreira, J. Andraos and J. C. Scaiano, J. Org. Chem., 2001, 66, 5016-5021;
(f) T. Kanzian, T. A. Nigst, A. Maier, S. Pichl and H. Mayr, Eur. J. Org. Chem., 2009,
2009, 6379-6385.
,
amidopyridin-1-ium salt 12. Finally, reductive cleavage of the N-N
bond of 12 in acidic condition forces the rearomatization of 11 to
completion and converts them to functionalized pyridine 3.
In summary, we have developed a natural product inspired
method transforming 1-amidopyridin-1-ium salt to 3-
(aminomethyl)pyridine and/or 3,5-bis(aminomethyl)pyridine by a
one-pot traceless umpolung and Mannich type reaction followed by
N-N bond reductive cleavage sequence.
A plausible reaction
7 (a) W.-C. Cheng and M. J. Kurth, Org. Prep. Proced. Int., 2002, 34, 585-608; (b) A.
M. Kearney and C. D. Vanderwal, Angew. Chem. Int. Ed., 2006, 45, 7803-7806.
mechanism is analysed according to isolated key intermediates in
designed experiments. This novel method allows rapid access of C3-
functionalized pyridine in mild condition via metal free C-C bond
formation. Total synthetic study toward lycodine and complanadine
A exploiting this reaction is underway in our laboratory, and will be
reported in due course.
8 (a) Y. Xie, J. Hu, Y. Wang, C. Xia and H. Huang, J. Am. Chem. Soc., 2012, 134
,
20613-20616; (b) Y. Xie, J. Hu, P. Xie, B. Qian and H. Huang, J. Am. Chem. Soc.,
2013, 135, 18327-18330; (c) Y. Liu, Y. Xie, H. Wang and H. Huang, J. Am. Chem.
Soc., 2016, 138, 4314-4317; (d) J. Hu, Y. Xie and H. Huang, Angew. Chem. Int. Ed.,
2014, 53, 7272-7276; (e) J. Li, G. Qin and H. Huang, Org Biomol Chem, 2016, 14
10572-10575; (f) B. Hatano, K. Nagahashi and T. Kijima, J. Org. Chem., 2008, 73
,
,
9188-9191; (g) M. F. Sansone, T. Koyanagi, D. E. Przybyla and R. W. Nagorski,
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9 R. R. Castillo, M. Córdoba, M. L. Izquierdo and J. Alvarez-Builla, Tetrahedron, 2009,
65, 9782-9790.
10 The rare α-debromination of iminium species was observed in the presence of
different types of nucleophiles: (a) J.-M. Poirier, Bull. Soc. Chim. Fr., 1982, 2, 17-
22; (b) D. Donati, S. Fusi, M. A. Macripò and F. Ponticelli, J. Heterocycl. Chem.,
1987, 24, 481-483.
We are grateful for financial support from The Hundred Talent
Program of the Chinese Academy of Sciences; National Natural
Science Foundation of China (NSFC) (21402182); Science and
Technology
Development
Project
of
Jilin
Province
(20150414043GH).
4 | Chem. Commun., 2016, 00, 1-3
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