Acylation of 2-benzylpyridine N-oxides and subsequent in situ [3,3]-sigamatropic rearrangement reaction

Article abstract of DOI:10.1016/j.tetlet.2020.152401

An effective method for the acylation of 2-benzylpyridine N-oxides and their fast in situ [3,3]-sigmatropic rearrangement was reported. This transformation has a wide substrate scope under mild conditions, giving moderate to excellent yields. The application for the synthesis of chiral phenyl-2-pyridylmethanol products was briefly explored. Furthermore, an interesting example of tandem substitution and in situ [3,3]-sigamatropic rearrangement of 2-benzylpyridine N-oxide with benzenecarboximidoyl chloride was reported.

Full text of DOI:10.1016/j.tetlet.2020.152401

Tetrahedron Letters 61 (2020) 152401
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Acylation of 2-benzylpyridine N-oxides and subsequent in situ
[3,3]-sigamatropic rearrangement reaction
⇑
⇑
Hua-qing Jing, Hong-liang Li , Jon C. Antilla
Institute for Molecular Design and Synthesis, School of Pharmaceutical Science and Technology, Nankai District, Tianjin 300072, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An effective method for the acylation of 2-benzylpyridine N-oxides and their fast in situ [3,3]-sigmatropic
rearrangement was reported. This transformation has a wide substrate scope under mild conditions, giv-
ing moderate to excellent yields. The application for the synthesis of chiral phenyl-2-pyridylmethanol
products was briefly explored. Furthermore, an interesting example of tandem substitution and in situ
[3,3]-sigamatropic rearrangement of 2-benzylpyridine N-oxide with benzenecarboximidoyl chloride
was reported.
Received 18 June 2020
Revised 13 August 2020
Accepted 24 August 2020
Available online 31 August 2020
Keywords:
Acylation
Ó 2020 Elsevier Ltd. All rights reserved.
[3,3]-Sigamatropic rearrangement
2-Benzylpyridine N-oxides
Acyl chloride
Boekelheide rearrangement
Introduction
focused on the derivation and application of this rearrangement
reaction [11]. As a result, the Boekeheide-like rearrangement reac-
Pyridine derivatives are important moieties in many bioactive
compounds as well as in organic materials and ligands [1]. Among
of them, 2-benzylpyridine and their analogues are the most poten-
tial derivatives, which have recently attracted strong attention in
the field of medicinal chemistry because of their unique pharmaco-
logical and biological properties [2] (e.g., Carbinoxamine maleate
[3], Bepotastine [4], PGI2 agonist [5], 2-APB analogue [6] etc.
Fig. 1). Therefore, it is of particular significance to develop or
improve the synthetic methods for the 2-benzylpyridine
derivatives.
tion of aromatic heterocycles N-oxides with alkyl substituents
have been extensively explored, which is very important for syn-
thesizing various complex compounds. However, the research on
aromatic heterocycles N-oxides with benzyl substituents is still
limited.
In 2009, Oshima’s group developed the Boekeheide-like rear-
rangement reaction of 2-benzylpyridine N-oxides refluxing with
acetic anhydride, while the reaction showed narrow substrate
Pyridine N-oxide, first made by Meisenheimer in 1926, provides
a new process for the synthesis of various pyridine derivatives due
to their unique chemical properties and reactivity [7]. In 1947,
Katada reported the first rearrangement reaction of pyridine N-
oxide with acetic anhydride, after hydrolysis, to 2-pyridone [8].
Later, Ochiai and his collaborators further applied this rearrange-
ment to the N-oxides of quinine, dihydroquinine and benzoquino-
line to give the corresponding
a-pyridones [9]. In 1954, as an
excellent research work, Boekelheide demonstrated the rearrange-
ment reaction of 2-alkyl substituted pyridine N-oxides with acetic
anhydride. Surprisingly, the corresponding pyridyl carbinol deriva-
tives were obtained, which is now known as the Boekelheide rear-
rangement (entry 1, Scheme 1) [10]. After that, many researchers
⇑
Corresponding authors.
E-mail addresses: lhl522508@126.com (H.-l. Li), jantilla@tju.edu.cn (J.C. Antilla).
Fig. 1. Examples of the 2-benzylpyridine moiety in drugs and bioactive compounds.
https://doi.org/10.1016/j.tetlet.2020.152401
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

H.-q. Jing et al.
Tetrahedron Letters 61 (2020) 152401
[3,3]-sigmatropic rearrangement reaction of 2-benzylpyridine N-
oxides with acyl chloride.
We started the reaction by identified different acylation
reagents (entries 1–4, Table 1). Treatment of 2-benzylpyridine N-
oxide (1a) and different acylation reagents (2a) at 110 °C give pro-
duct 3a in 70% and 81% yield respectively (entries 2, 4, Table 1). We
then investigated different bases (entries 5–9, Table 1) and found
that pyridine performed most efficiently giving 80% isolated yield
even at room temperature. After that, a variety of solvents (entries
9–13, Table 1) were investigated, and DCM was the best, which
could improve the yield to 92% (entry 10, Table 1).
With the optimized conditions in hand (entry 10, Table 1), we
studied the substrates scope of this reaction (Scheme 2). A series
of substituted 2-benzylpyridine N-oxides reacted with acetyl chlo-
ride 2a giving acylation products (3b–3n) in 55% to 94% yield.
Introducing electron-donating groups, such as methyl and meth-
oxy at ortho-, meta-, and para-position of benzene ring afforded
the desired products in excellent yield (3b–3d, 3g–3h). The slightly
lower yield was obtained by introducing weak electron-withdraw-
ing group (such as –COOMe and -F) on substrates (3e, 3f, 3i, 3j).
Substrates with strong electron-withdrawing group as trifluo-
romethyl and cyano group gave moderate yields in 55% to 68%.
These results indicated that electron-withdrawing groups on the
benzene ring diminished the reactivity of this reaction. We specu-
lated that substrates with electron-donating substituents could
form more stable conjugated transition intermediates.
Subsequently, substrates with different substituents on the pyr-
idine ring were also investigated. Methyl substitution at the 3-, 4-,
5-, 6-positions of the pyridine ring (3o-s) also worked very well,
and giving desired products in excellent yields. Substrate 3q gave
a slightly diminished yield, possibly due to its steric effect. Gratify-
ingly, when we tried to change the pyridine ring to a quinoline
ring, the desired product 3s was obtained in a high yield of 86%.
Furthermore, we also investigated different acyl chlorides as acyla-
tion reagents (Scheme 3). Under the standard condition, several
acyl chlorides (propionyl chloride, butyryl chloride, pivaloyl chlo-
ride and benzoyl chloride) reacted with 1a to afford the desired
products 3t–w in excellent yields of 92–96%. It is worth mention-
ing that the benzoyl chloride gave the best result, the product 3w
was obtained in an excellent yield of 96%.
Scheme 1. The Boekelheide-like rearrangement for the preparation of 2-benzyla-
cyloxy pyridine derivatives.
scope (entry 2, Scheme 1) [11c]. Recently, Sukhorukov and his co-
workers reported the acylation of nitronates and their fast in situ
[3,3]-sigmatropic
rearrangement
in
the
presence
of
triethylamine, which undergoes
a
similar process as the
Boekelheide-like rearrangement (entry 3, Scheme 1) [12]. Inspired
by this work, we assumed that the 2-benzylpyridine N-oxide with
acyl chloride could also proceed with the similar process in the
presence of a base (entry 4, Scheme 1). Herein, we report an effec-
tive and practical method for the tandem acylation and in situ
Table 1
Optimization of the reaction conditions.a
Entry
RCOX
Temp/℃
Time/h
Base
solvent
Yield /%b
1
2
3
4
5
6
7
8
Ac2O
Ac2O
AcCl
AcCl
AcCl
AcCl
AcCl
AcCl
AcCl
AcCl
AcCl
AcCl
AcCl
rt
110
rt
110
rt
rt
rt
rt
rt
rt
48
12
48
12
2
2
2
2
2
2
2
2
2
–
–
–
–
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCM
20
70
28
81
62
68
35
40
80
92
64
53
30
DBU
DMAP
Et3N
DIPEA
Py
Py
Py
Py
Py
9
10
11
12
13
rt
rt
rt
THF
Et2O
CH3CN
a
Reaction conditions: 1a (0.16 mmol), RCOX (0.24 mmol, 1.5 equiv), base (0.32 mmol, 2.0 equiv), solvent (1.0 mL). bIsolated yield.
2

H.-q. Jing et al.
Tetrahedron Letters 61 (2020) 152401
Scheme 2. Substrate scope of 2-benzylpyridine N-oxides 1a–s.a,b aReaction conditions: 1a–s (0.16 mmol), 2a (0.24 mmol, 1.5 equiv), pyridine (0.32 mmol, 2.0 equiv), DCM
(1.0 mL). bIsolated yields of compounds 3a–s.
Scheme 4. Gram-scale reaction and application. aReaction conditions: 1a
(6.4 mmol), 2a (9.6 mmol), pyridine (12.8 mmol), DCM (20 mL). bReaction
conditions: 3a, LiOH in THF and H2O, 70 ℃, 8 h.
Scheme 3. Substrate scope of acyl chloride 2b–e.a,b aReaction conditions: 1o-s
.
(0.16 mmol), 2a (0.24 mmol, 1.5 equiv), pyridine (0.32 mmol, 2.0 equiv), DCM
(1.0 mL). bIsolated yields of compounds 3o-s.
Results and discussion
We then conducted this reaction in gram scale. Treatment of
1.20 g of 2-benzylpyridine N-oxide 1a with acyl chloride under
optimized conditions gave 1.24 g acylated product 3a in yield of
85% (step 1, Scheme 4). And the application of this reaction was
further demonstrated through hydrolysis of 3a giving phenyl-2-
pyridylmethanol 4 (step 2, Scheme 4) [13], which can be used as
various biological compounds and analogues [14]. Envisioned by
Andreotti’s work on the stereoselective Boekelheide-like rear-
rangement using chiral Mosher’s acyl chloride as an activator in
2010 [11d], we also tried to achieve enantioselectivity of this
Scheme 5. Reaction of 2-benzylpyridine N-oxide with (R)-Mosher’s acid chloride
and hydrolysis reaction. aReaction conditions: 1a (0.48 mmol), (R)-Mosher’s acyl
chloride (0.96 mmol), Et3N (1.44 mmol), 2-Propanol (5 mL), À78 ℃, 18 h. bReaction
conditions: 5 (138 mg, 0.34 mmol), LiOH in THF (5 mL) and H2O (3 mL), 70 ℃, 8 h.
3

H.-q. Jing et al.
Tetrahedron Letters 61 (2020) 152401
Scheme 6. The new derivative reaction of 2-benzylpyridine N-oxide with benzenecarboximidoyl chloride.a aReaction conditions: 1a (30 mg, 0.16 mmol), 6 (48 mg,
0.19 mmol, 1.2 equiv), CH3COOAg (26.7 mg, 0.16 mmol, 1.0 equiv), DCM (20 mL), r.t., 8 h.
reaction by using 2-benzylpyridine N-oxide and (R)-mosher’s acyl
chloride obtained the phenyl-2-pyridylmethanol in 70% yield
with an enantiomeric ratio of 91:9 (Scheme 5), and efforts on
further improving enantioselectivity is underway in our lab.
Finally, based on the research of aminoarylation of 2- and 4-
picoline l-oxides [15], we also successfully developed a novel reac-
tion of 2-benzylpyridine N-oxide with benzenecarboximidoyl chlo-
ride giving amide derivatives in yield of 23%, through a tandem
process of substitution and in situ [3,3]-sigamatropic rearrange-
ment (Scheme 6).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152401.
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Declaration of Competing Interest
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Acknowledgments
We are thankful for the financial support from the National
1000 Talent Plan of China and the 64th China Postdoctoral Science
Foundation Grant (No. 2018M641642).
4