Simple Br?nsted acid catalyzed C-H functionalization: Efficient access to poly-substituted pyridines

Article abstract of DOI:10.1016/j.tetlet.2016.05.061

An exceptionally simple and environmentally friendly methodology has been developed for directly functionalizing the benzylic C-H bond of the poly-substituted pyridines with aromatic imines. Simple Br?nsted acid catalysts including salicylic acid and TsOH were successfully employed. Different types of poly-substituted pyridines could be efficiently obtained with moderate yields. Traditional ways to such types of pyridines involved the aromatization of the corresponding Hantzsch 1,4-dihydropyridines, while this method greatly simplified the synthetic procedures.

Full text of DOI:10.1016/j.tetlet.2016.05.061

Accepted Manuscript
Simple Brønsted Acid Catalysed C-H Functionalization: Efficient Access to
poly-substituted pyridines
Shujun Lai, Xuwen Ren, Jinzhong Zhao, Zhuo Tang, Guangxun Li
PII:
S0040-4039(16)30584-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.061
TETL 47680
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 February 2016
14 May 2016
17 May 2016
Please cite this article as: Lai, S., Ren, X., Zhao, J., Tang, Z., Li, G., Simple Brønsted Acid Catalysed C-H
Functionalization: Efficient Access to poly-substituted pyridines, Tetrahedron Letters (2016), doi: http://dx.doi.org/
10.1016/j.tetlet.2016.05.061
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Simple Brønsted Acid Catalysed C-H Functionalization: Efficient Access to
poly-substituted pyridines
Shujun Lai,a Xuwen Ren, a Jinzhong Zhao,a* Zhuo Tangb* and Guangxun Lib*
aCollege of Art and Sciences, Shanxi Agricultural University Taigu, Shanxi 030800(China) E-mail: zhaojz@sxau.edu.cn
bNatural Products Research Center, Chengdu Institution of Biology, Chinese Academy of Science, Chengdu, Sichuan 610041(China)
E-mail: ligx@cib.ac.cn; E-mail: tangzhuo@cib.ac.cn
Abstract: An exceptionally simple and environmentally friend methodology has been developed for directly
functionalizing the benzylic C−H bond of the poly-substituted pyridines with aromatic imines. Simple Brønsted
acids catalysts including salicylic acid and TsOH were successfully employed. Different type of poly-substituted
pyridines could be efficiently obtained with moderate yields. Traditional ways to such type of pyridines involved
the aromatization of the corresponding Hantzsch 1,4-dihydropyridines, while this method greatly simplified the
synthetic procedures.
Keywords: Hantzsch 1,4-dihydropyridine; C-H functionalization; imine; poly-substituted pyridine
Introduction
The poly-substituted pyridines with the skeleton
A were pharmaceutically useful with anti-hypoxic,
anti-ischemic, acaricidal, insecticidal, bacterial and herbicidal activities, (Figure 1). 1 The existing methods
for obtaining such types of skeleton depended on the aromatization of the corresponding Hantzsch
1,4-diydropyridines,2 which could be obtained through Hantzsch reaction.3 However, the asymmetric
Hantzsch 1,4-dihydropyridines were difficult to obtain, which were involves with the preformed enamines.
4
Therefore, the direct functionalization of the methyl group of the poly-substituted pyridine was
interesting and significant. In addition, the obtained poly-substituted pyridines could be reduced to the
corresponding Hantzsch 1,4-dihydropyridines, which were pharmaceutically important.5
Figure 1 the numerous applications of poly-substituted pyridines

Scheme 1 Benzylic C–H functionalization of azaarenes
Recently, the direct benzylic C−H bond functionalization of azaarenes has stimulated tremendous
research interest. Traditionally ways of the benzylic transformation involved the process of
deprotonation-nucleophilic substitution/addition with a strong base such as n-BuLi or LDA.6 However,
recent research revealed that a suitable Lewis acid6b,7 or Brønsted acid7k,8 could efficiently catalyse this
transformation via transforming the alkyl azaarene to its enamine counterpart. This strategy has been
successively applied to various nucleophilic additions of benzylic C−H bond of azaarenes for the C−C,
C=C, and C-N bond formations. However, in the additions to imines, the substrates employed were mainly
N-tosylimines7b,7h,9 or N-Boc imines,10 under metal catalyst, (Scheme 1a, 1b). However, the ordinary
phenyl imines could not work due to the slightly lower reactivity. We herein report a useful method for
direct functionalizing the benzylic C-H of the poly-substituted pyridines with simple N-aryl imines under
mild reaction conditions, (Scheme 1c).
Result and discussion
Our initial study began with the reaction between the poly-substituted pyridine (1a) and aromatic
imine (2a), (Table 1). The result revealed that the reaction could easily occur to produce the corresponding
product 3a with 36% yield in chloroform with TsOH as catalyst at ambient temperature, (Entry 1). Then
we began to optimize the reaction conditions through screening of different solvent, (Entries 2-7).
Acetonitrile was the optimal reaction solvent considering the reaction yield. Then we turned to optimize

the reaction by screening different types of Lewis acid such as AlCl3, FeCl3, ZnCl2, InCl3, etc. and
different types of Brønsted acid such as acetic acid, TFA and salicylic acid (SA), etc. Interestingly, SA was
chosen as the better catalyst in this reaction than other Brønsted acid, and Lewis acid, (Entries 8-16). As
we known, SA was a commonly useful Brønsted acid catalyst.11 Therefore we screened the reaction
solvent again with SA as catalyst, which demonstrated that THF was the optimal reaction solvent, (Entries
17-22). Meanwhile, the reaction temperature was investigated, which demonstrated that 30
℃
was
optimal, and the side product 3ab was found after the raise of the temperature to 40
℃ (Entries 23-25).
Finally, the reaction yield was improved to 80% after 1.2 eq. of imine was used.
Table 1. Optimization of Reaction Conditions for 3aa
Entry
1
2
3
4
5
6
7
8
Solvent
CHCl3
DMF
DMSO
DME
Catalyst
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
AlCl3
FeCl3
ZrCl4
SnCl2
InCl3
T (℃)
30
30
30
30
30
30
30
30
Yield (%)b
Entry
14
15
16
17
18
19
20
21
Solvent
MeCN
MeCN
MeCN
THF
CHCl3
DMF
DME
DMSO
MeOH
THF
Catalyst
SA
AcOH
TFA
SA
SA
SA
SA
SA
T (℃)
30
Yield (%)b
36
17
23
-
76
48
55
54
57
48
38
47
<5
60
-
53
75
50
45
<5
48
30
30
30
30
30
30
30
30
20
40
50
30
MeCN
THF
MeOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
9
30
30
30
30
22
23
24c
25c
26d
SA
SA
SA
SA
20
65
55(10)
47(15)
80
10
11
12
13
THF
THF
ZnCl2
30
THF
SA
a The reaction was run with 0.2 mmol of 1a and 0.2 mmol of 2a with 10 mol% of catalyst for 48 h; b The reaction yield was calculated
based on purification with fast silicon colum; c the yield of 3ab in the parenthesis; d 1.2 eq. of the imine was used.
Under the optimized reaction conditions, the scopes of the reaction were investigated. As shown in
Table 2, various N-aryl aldimine
aldimines obtained from p-anisidine and different aldehydes were easily used to afford the corresponding
poly-substituted pyridines with moderate yields, (Table 2, 3b 3l). Meanwhile, imines with heterocylic
rings such as furan and thiophene, imines with naphthalene, were also efficiently used to afford the
corresponding product, (3j 3l). The imines obtained from different types of aromatic amines (with electron
2 were employed in this reaction. Generally, the results demonstrated that
2
3
-
-

withdrawing groups, without substituent or with hydroxyl group) were also investigated, which
demonstrated that the corresponding product could be obtained with moderate yield, (3 -3 ). However,
m
o
when imine obtained from alkyl aldehyde or imine formed with alkyl amine was used as substrate, the
resulting products were not obtained, (3o and 3p). In addition, we tried to screen all sorts of BINOL
derived phosphoric as catalyst, (Table S2, see supporting information). However, the resulted products
were racemic, (Table 2, 3a).
Table 2. Substrate scopes of various N-aryl aldimines a
a Reaction conditions: 1a (0.2 mmol) , 2 (1.2 eq. 0.24 mmol), and SA (10 mol%) in THF (2 mL) were reacted for 2 d. b Isolated yields
after fast silicon column chromatography. b Used BINOL derived TRIP phosphoric acid as catalyst.
The efficiency of the reaction prompted us to extend the reaction to different types of poly-substituted
pyridines, which could be easily obtained by aromatization of the corresponding Hantzsch

1,4-dihydropyridines. However, the reaction were inefficient under the above optimized reaction
conditions. The corresponding product 3n was obtained with low yield, (< 5%). We therefore re-screened
the reaction conditions and finally increased the reaction yield to 45% under such reaction condition as
following: TsOH 10 mol% in acetonitrile at room temperature for 48 h, (Table S1, see supporting
information).
Table 3. Substrates scope of various 4-substituted pyridine derivatives
a Reaction conditions: 1 (0.2 mmol) , 2 (1.2 eq. 0.24 mmol), and TsOH (10 mmol%) in MeCN (2 mL) were reacted for 2 d . b Isolated
yields after column chromatography.
Then we screened the substrates under the optimized reaction conditions. The results revealed that the
poly-substituted pyridines with different types of phenyl ring substituted at the C-4 of the pyridine ring,
could efficiently transformed to the corresponding products, (Table 3, 3q-3y). Both electron-withdrawing

and electron-donating groups had no obvious effect on the reaction yields. In addition, hetero aromatic
substituted pyridine derivatives could be utilized in this protocol to afford the corresponding product with
moderate yield (3x, 3y).
Scheme 2 Proposed reasonable reaction mechanisms.
Based on the above reaction results and the related references for direct benzylic C−H bond
functionalization of azaarenes, the reaction mechanisms were proposed, (Scheme 2). We proposed two
reaction mechanisms according to the reaction results. For poly-substituted pyridine without substituent at
C-4 of the pyridine ring, the reaction was catalysed efficiently with SA, and the transition state for the
activation of the benzylic C-H was TsA. However, the activation of the benzylic C-H of poly-substituted
pyridine with different aromatic ring substituted at C-4, SA were used inefficient which might be ascribed
to the slightly lower acidity. Instead, TsOH were efficient due to the higher acidity. And the transition state
of the activation of the benzylic C-H bond was TsB. Generally, the two catalysts activated the benzylic
C-H bond with both the Brønsted acid and Brønsted base functions. The formation of enamine
important, which could nucleophilically attack the imine substrate to afford the final product.
A or B was
Conclusion
In summary, we have developed an efficient, convenient, and environmentally benign protocol for
preparation of various poly-substituted pyridines under mild reaction conditions. Traditional ways

depended on the synthesis of the corresponding asymmetric Hantzsch 1, 4-dihydropyridine and the
following aromatization step, while this way simplified the process and greatly improved the synthetic
efficiency. The investigations of the Pharmaceutical activity of the obtained product are still under way in
our lab.
Acknowledgements
This work was supported financially by the Natural Science Foundation of China (21402188) and the Key
Scientific Research Projects of Coal Fund in Shanxi (FT201402-01).
Supplementary data
Supplementary data (detailed experimental procedure and spectroscopic data) associated with this article
can be found, in the online version.
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Graphical abstract
An exceptionally simple and environmentally friend methodology has been developed for the synthesis of
Poly-substituted pyridines with easily accessible substrates
.

Highlights
Benzylic C-H bond of pyridines were functionalized with ordinary aromatic imines.
Simple Brønsted acids efficiently catalyzed the reactions.
Poly-substituted pyridines were obtained from accessible aromatic Hantzsch esters.