B(C6F5)3-catalyzed oxidative deamination/cyclization cascade reaction of benzylamines and ketones for the synthesis of 2,4,6-triarylpyridines

Article abstract of DOI:10.1016/j.tetlet.2018.08.060

The B(C₆F₅)₃-catalyzed oxidative deamination/cyclization cascade reaction of benzylamines and ketones for the construction of 2,4,6-triarylpyridines under metal-/solvent-free conditions has been successfully achieved. The advantages of this strategy include good functional group tolerance, low catalyst loading and high yields.

Full text of DOI:10.1016/j.tetlet.2018.08.060

Accepted Manuscript
B(C F ) -Catalyzed Oxidative Deamination/Cyclization Cascade Reaction of
6
5 3
Benzylamines and Ketones for the Synthesis of 2,4,6-Triarylpyridines
Fei Ling, Leixin Shen, Zhentao Pan, Lu Fang, Dingguo Song, Zhen Xie, Weihui
Zhong
PII:
S0040-4039(18)31068-2
https://doi.org/10.1016/j.tetlet.2018.08.060
TETL 50235
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
8 July 2018
23 August 2018
29 August 2018
Please cite this article as: Ling, F., Shen, L., Pan, Z., Fang, L., Song, D., Xie, Z., Zhong, W., B(C F ) -Catalyzed
6
5 3
Oxidative Deamination/Cyclization Cascade Reaction of Benzylamines and Ketones for the Synthesis of 2,4,6-
Triarylpyridines, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.08.060
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B(C
6
F
5
)
3
-Catalyzed Oxidative
Leave this area blank for abstract info.
Deamination/Cyclization Cascade Reaction
of Benzylamines and Ketones for the
Synthesis of 2,4,6-Triarylpyridines
Fei Ling, Leixin Shen, Zhentao Pan, Lu Fang, Dingguo Song, Zhen Xie and Weihui Zhong

1
Tetrahedron Letters
journal homepage: www.els evier.com
B(C
6
F ) -Catalyzed Oxidative Deamination/Cyclization Cascade Reaction of
5
3
Benzylamines and Ketones for the Synthesis of 2,4,6-Triarylpyridines
Fei Ling, Leixin Shen, Zhentao Pan, Lu Fang, Dingguo Song, Zhen Xie and Weihui Zhong*
a
Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang
University of Technology, Hangzhou 310014, People’s Republic of China. e-mail: weihuizhong@zjut.edu.cn
ARTICLE INFO
ABSTRACT
Article history:
Received
6 5 3
The B(C F ) -catalyzed oxidative deamination/cyclization cascade reaction of benzylamines and
ketones for the construction of 2,4,6-triarylpyridines under metal-/solvent-free conditions has
been successfully achieved. The advantages of this strategy include good functional group
tolerance, low catalyst loading and high yields.
Received in revised form
Accepted
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
B(C
6 5 3
F )
2
,4,6-Triarylpyridines
Oxidative
Deamination
N-heterocycles
1
0-13
1
The construction of N-heterocycles is one of the most
significant areas of research in organic synthesis. Symmetrical
reagents. Hence, it is imperative to develop practical
synthetic methods to gain easy access to 2,4,6-triarylpyridines.
2
pyridines are widely present in various pharmaceuticals and
3
natural products, and represent versatile building blocks for the
Recently, boron Lewis acids have been received attention as
14
powerful catalysts for various synthetic transformations.
4
preparation of chemical fibres and fluorescent materials.
5
6
Typically, 2,4,6-triarylpyridines (Kröhnke pyridines) are
extensively used as essential cores in national defence and
6 5 3
Significantly, tris(pentafluorophenyl)-borane[B(C F ) ], a key
component of Frustrated Lewis Pairs (FLP), shows powerful
capability for the hydrogenation of ketones, imines and N-
7
military industries. For example, PBAPP serves as a key
intermediate in the synthesis of aramid fiber (Fig. 1). Moreover,
1
5
heterocycles. Various other transformations catalyzed by
B(C have been discovered, including the Friedel-Crafts
reaction, Michael addition reaction and Meinwald
rearrangement. However, few efforts have been devoted to
B(C -catalyzed oxidation reactions. In 2016, Paradies and co-
workers reported that the B(C -catalyzed dehydrogenative
oxidation of indolines produced indoles along with the release of
8
compound 1A has been used for the preparation of luminescent
materials.
6 5 3
F )
16
6 5 3
F )
6 5 3
F )
17
hydrogen. Recently, Babu and co-workers reported an efficient
one-pot oxidative esterification and amidation of aldehydes using
B(C
6
F
5
)
3
as the catalyst and TBHP as the oxidant, affording
O as by-
-catalyzed oxidative
various carboxylic esters and amides with i-PrOH and H
2
18
6 5 3
products. Herein, we describe a B(C F )
deamination/cyclization cascade reaction of benzylamines and
aryl ketones for the construction of 2,4,6-triarylpyridines under
solvent-free conditions. This process employs molecular oxygen
Figure 1. Structures of PBAPP and 1A
Recently, a number of approaches have been developed for the
9
synthesis of 2,4,6-triarylpyridines. Among them, the oxidation-
as the oxidant and a low loading of B(C
mol%), and produces H O as the only by-products. Moreover,
6 5 3
F ) as the catalyst (0.5
2
condensation-cyclization reaction of aryl ketones and
benzylamines represents one of the most straightforward and
efficient methods to access these skeletons. Various catalysts are
this protocol features a wide substrate scope and good functional
tolerance, thereby providing an easy access to PBAPP.
10
11
12
used in this reaction, such as Cu(OTf)
1
2
, HOTf , I
2
and eosin-
Y . However, the majority of these reactions required harsh
3
1
conditions, for example, metal catalysts, high temperatures,
0
12
10,11,13
high catalyst loading,
and various environmental-unfriendly

2
Tetrahedron Letters
products were obtained in good to excellent yields. Moreover,
3
’,4’-(methylenedioxy) acetophenone reacted with 2a to give the
corresponding product 3h in 93% yield. Interestingly,
heteroaromatic ketones, such as 1-(pyridin-2-yl)ethanone, were
good substrates for this reaction, giving the desired product 3i in
5
6% yield. Notably, when meta- and ortho-bromo substituted
acetophenones were employed as substrates, the reactions were
less efficient, producing 3j and 3k in relatively low yields.
Interestingly, 2-acetylfluorene successfully underwent the
oxidation-condensation-cyclization reaction, affording 3m in
5
7% yield.
a
Table 2. Substrate scope of the acetophenone 1
6 5 3
Scheme 1. Various B(C F ) -catalyzed oxidation reactions
Optimization of the reaction conditions was carried out using
’-methoxy-acetophenone 1a and benzylamine 2a as the model
4
substrates (Table 1). Pleasingly, the desired product 3a was
obtained in 69% yield with 0.5 mol% of B(C as the catalyst
at 120 C for 12 h (Entry 1). Next, a
6 5 3
F )
o
in xylene under 1 atm of O
2
set of solvents were examined; toluene, DMF and DMSO gave
lower yields than xylene, while only trace amounts of 3a was
obtained using CH CN or 1,4-dioxane (Entries 2‒6).
3
Interestingly, a significant increase in yield was observed when
the reaction was conducted under solvent free conditions, giving
3
a in 82% yield (Entry 7).Changing the reaction temperature did
not improve the yield. (Entries 7‒10). A lower yield was
observed when the reaction was carried out under an air
atmosphere (Entry 11) and no product formation was observed
under a nitrogen atmosphere (Entry 12). It was noteworthy that
extending the reaction time from 12 h to 18 h resulted in a
relatively lower yield (Entry 14). Furthermore, the reaction was
a
6 5 3
Reagents and conditions: 1 (2.0 mmol), 2a (1.6 mmol), B(C F ) (0.5 mol%),
b
20 °C, 12 h. Isolated yield based on compound 1.
1
Next, the substrate scope with respect to benzylamine 2 was
examined (Table 3). Benzylamines bearing electron-donating
groups on the benzene rings (3n, 3o, 3u, 3v) gave slightly lower
yields than those with electron-withdrawing groups (3p‒3r, 3w).
As expected, piperonylamine was compatible with this reaction,
giving 3s in 66% yield. Moreover, a naphthyl group was also
tolerated to afford the 3t in 65% yield. It was noteworthy that a
steric effect was observed, where meta- and ortho-substituted
benzylamines gave lower yields than para-substituted substrates.
6 5 3
less effective using 0.1 mol% of B(C F ) , while no product was
6 5 3
formed in the absence of B(C F ) (Entries 15 and 16).
Table 1. Optimization of the reaction conditionsa
Table 3. Substrate scope of the benzylamines 2a
o
b
Entry
Solvent
Xylene
Toluene
DMF
Time (h)
12
T ( C)
120
120
120
120
120
120
120
80
Yield 3a (%)
1
2
3
4
5
6
7
8
9
69
67
12
12
43
DMSO
12
61
CH
3
CN
12
Trace
Trace
82
1,4-Dioxane
12
-
-
-
-
-
-
-
-
-
-
12
12
33
12
100
140
120
120
120
120
120
120
69
1
0
12
78
c
1
1
2
12
66
d
1
12
0
1
3
6
63
1
4
18
81
e
1
5
12
61
f
1
6
12
0
a
a
Reagents and conditions: 1a (2.0 mmol), 2a (1.6 mmol), B(C
b
mol%), 120 °C, 12 h. Isolated yield based on 1a.
6
F
5
)
3
(0.5
Reagents and conditions: 4’-methoxyacetophenone 1a (2.0 mmol),
benzylamine 2a (1.6 mmol), B(C
sealed tube after sparging with O
6
F
5 3
) (0.01 mmol), solvent (0.5 mL), in a
b c
2
.
(0.1 mol%). In the absence of B(C
Isolated yield based on 1a. Under air.
f
d
e
atmosphere. B(C
Under a N
2
6
F
5
)
3
6
F
5
)
3
.
In order to gain insight into the reaction mechanism, several
1
1
control experiments were conducted (Scheme 2). Initially,
benzylamines 2a were converted into benzaldehyde 4a in 92%
yield under the standard conditions. Additionally, benzaldehyde
With the optimal catalytic system in hand, the substrate scope
with respect to aryl ketone 1 was explored (Table 2). Various
substituted aryl ketone were well tolerated and the corresponding
4
a reacted with 4’-methoxyacetophenone 1a and ammonium

3
acetate under the standard conditions, affording the desired
product 3a in 56% yield. These results suggested that 4a might
be involved in this transformation. The reaction of 5a
hydrazine hydrate as the reducing reagent, 3g was reduced to
2
PBAPP in 85% yield (1.58 g).
0
(
condensation product of 1a and 4a) and 1a in the presence of
ammonium acetate under identical conditions also gave the
desired product 3a in 67% yield. Thus, we proposed that
chalcone derivatives might also be intermediates for this reaction.
Scheme 4. Preparation of PBAPP
Conclusion
In summary, we have developed a mild and efficient one-pot
metal-/solvent-free approach for the preparation of 2,4,6-triaryl
pyridines from acetophenone and benzylamine via a B(C F )
Scheme 2. Control experiments
6
5 3
promoted oxidative deamination/cyclization cascade reaction. A
wide range of aryl ketones and benzylamines were well tolerated
in this catalytic system. Further investigations regarding the
application of this methodology for the preparation of other N-
heterocycles are underway in our lab.
1
9
Based on the above control experiments and previous reports,
a plausible reaction mechanism was proposed, using 3a as a
representative example (Scheme 3). Initially, benzylamine 2a is
oxidized to benzaldehyde 4a in the presence of B(C
catalyst, with the release of ammonia-boron complex B.
Subsequently, benzaldehyde 4a reacts with 4’-
6 5 3
F ) as the
Acknowledgements
methoxyacetophenone 1a via a condensation reaction to produce
chalcone 5a. At the same time, 4’-methoxyacetophenone 1a
reacts with the ammonia-boron complex B to give intermediate
We thank the National Natural Science Foundation of China
Nos.21276238 and 21706234) for financial support.
(
6
6 5 3 2
a, with the release of B(C F ) •H O complex C. Then, the
References and notes
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nitroacetophenone 1g with benzylamine 2a afforded 2,6-bis(4-
nitrophenyl)-4-phenylpyridine 3g in 78% yield (2.0 g).
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Graphical Abstract
To create your abstract, type over the instructions in the
template box below.
Fonts or abstract dimensions should not be changed or altered.
B(C
6
F
5
)
3
-Catalyzed Oxidative
Leave this area blank for abstract info.
Deamination/Cyclization Cascade Reaction
of Benzylamines and Ketones for the
Synthesis of 2,4,6-Triarylpyridines
Fei Ling, Leixin Shen, Zhentao Pan, Lu Fang, Dingguo Song, Zhen Xie and Weihui Zhong
Highlights
1
) 0.5 mol% of B(C
deamination/cyclization cascade reaction
) Constructing 2,4,6-triarylpyridines under metal-
free and solvent-free condition
6 5 3
F ) promoting oxidative
2
3
) Easy access to PBAPP, a key intermediate of
aramid fiber