Multicatalytic Beckmann rearrangement of 2-hydroxylarylketone oxime: Switchable synthesis of benzo[d]oxazoles and N-(2-hydroxylaryl)amides

Article abstract of DOI:10.1016/j.tetlet.2018.09.043

A switchable synthesis route is developed for benzo[d]oxazole derivatives and (2-hydroxylaryl)benzamide from 2-hydroxylbenzeneketoxime using organomolecules (BOP-Cl, and CNC) and Lewis acid cocatalyzed Beckmann rearrangement (BR) reaction. Further, this reaction is switched using different organocatalysts.

Full text of DOI:10.1016/j.tetlet.2018.09.043

Accepted Manuscript
Multicatalytic Beckmann Rearrangement of 2-Hydroxylarylketone Oxime:
Switchable Synthesis of Benzo[d]oxazoles and N-(2-Hydroxylaryl)amides
Zhen Li, Chengtao Fang, Yannan Zheng, Guanyinsheng Qiu, Xiaofang Li,
Hongwei Zhou
PII:
S0040-4039(18)31133-X
https://doi.org/10.1016/j.tetlet.2018.09.043
TETL 50282
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 July 2018
12 September 2018
17 September 2018
Please cite this article as: Li, Z., Fang, C., Zheng, Y., Qiu, G., Li, X., Zhou, H., Multicatalytic Beckmann
Rearrangement of 2-Hydroxylarylketone Oxime: Switchable Synthesis of Benzo[d]oxazoles and N-(2-
Hydroxylaryl)amides, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.09.043
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Tetrahedron Letters
Multicatalytic Beckmann Rearrangement of 2-Hydroxylarylketone Oxime:
Switchable Synthesis of Benzo[d]oxazoles and N-(2-Hydroxylaryl)amides
,a
Zhen Li,a Chengtao Fang, a Yannan Zheng,a Guanyinsheng Qiu , Xiaofang Li,b and Hongwei Zhou*,a
a College of Biological, Chemical Science and Engineering, Jiaxing University, 118 Jiahang Road, Jiaxing 314001, China.
b School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Hunan 411201, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A
switchable synthesis route is developed for benzo[d]oxazole derivatives and (2-
hydroxylaryl)benzamide from 2-hydroxylbenzeneketoxime using organomolecules (BOP-Cl,
and CNC) and Lewis acid cocatalyzed Beckmann rearrangement (BR) reaction. Further, this
reaction is switched using different organocatalysts.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Beckmann Rearrangement
Switchable Synthesis
Benzo[d]oxazoles
Multicatalysis
2-Hydroxylarylketone Oxime
As a well-known name reaction, Beckmann rearrangement
(BR) represents an important route to synthesize substituted-
amides.1 Compared to other synthetic reactions towards amide-
containing compounds, the BR reaction is featured with high
atom efficiency, thus received significant attention by the
synthetic chemists. The initial endeavour focused intensively on
exploiting strong acid-mediated BR transformations.2 The
established achievements suggested that a series of inorganic
acids enabled the BR reaction. It has been reported that acid-
assisted removal of hydroxyl group produces nitrene as an
intermediate;2f in addition, the removal of hydroxyl group and
migration of group at ortho-site was in a stepwise manner.2g
Acid-mediated BR reaction produced a mixture of amide with
high efficiency, which probably resulted from isomerisation of
Z/E oxime in the presence of acid; though it suffered by using
acid-resistant reaction equipments. To achieve functional group
migration selectivity under mild reaction conditions, it is highly
desirable for the BR reaction to design a synthetic route without
using strong acids.
Recent advances in BR reaction indicated that an array of
organocatalysts were engaged in BR reaction.3-10 As shown in
Scheme 1, TsCl,3 BOP-Cl,4 CNC,5 TAPC,6 CPI-Cl,7 BAC,8 and
DCID9 etc. served as efficient catalysts to promote BR reaction
(Scheme 1, eq 1a). Distinctively, the acid-mediated BR reaction
was enabled by generating the nitrene as an intermediate, while a
self-propagating mechanism11 was postulated mainly for the use
of organomolecules promoted BR reaction. More importantly,
Scheme
1 Proposed synthesis route for benzo[d]oxazole
derivatives via organocatalytic Beckmann rearrangement
reaction.
 G. Qiu, Tel.: +86-0573-83642057; fax: +86-0573-83642057; e-mail: 11110220028@fudan.edu.cn

2
Tetrahedron Letters
functional group migration in the organocatalytic BR
and provided the desired product 2a in 81% yield (entry 1, Table
4). It is important mentioned here that the use of CNC catalyst
did not give the desired product 2a, instead, surprisingly resulted
the product of N-(2-hydroxylphenyl)benzamide 3a in 70% yield
(entry 1, Table 3). This interesting outcome probably provided
the possibility that switchable synthesis of benzo[d]oxazole 2a
and amide 3a could be reached by adopting different
organocatalysts and Lewis acid additives. Inferior results were
observed when either FeCl3 or AlCl3 was used (entries 5-6, Table
1). Reduction of reaction temperature was not favourable for the
BR reaction, but it resulted in the product 2a in 67% yield (entry
7, Table 1). In addition, change of reaction solvent was also not
favourable for BR reaction. For instance, the use of DMF and
MeCN as solvent, resulted low product yields (entries 8-9, Table
1). A blank experiment was conducted without MgSO4 and
displayed the yield of desired product 2a to be 44%, suggesting
that the importance of MgSO4 in BR reaction (entry 10, Table 1).
Based on the above facts, we optimized the reaction conditions as
follows: BOP-Cl (10 mol%), ZnCl2 (10 mol%), MgSO4 (2.0
equiv), toluene, and reflux.
reaction was specific, proceeding in an anti fashion. It is believed
that the development of organocatalytic BR reaction represents a
huge advance in amide synthesis.
Based on progress of organocatalytic BR reaction, numerous
useful functional architectures were achieved.12 For example, Wu
and co-workers reported the synthesis of indole from 2-
alkynylarylketoxime through a tandem CNC/InCl3-promoted BR
reaction and palladium-catalyzed 5-endo aza-cyclization.12a In
light of this finding, our continuous interests in the development
of synthetic methodology for organocatalytic BR reaction with
privileged structures,13 we design an alternative synthetic route
toward benzo[d]oxazole core 2 from 2-hydroxylarylketoxime 1.
Particularly, the reaction proceeded through an organocatalytic
self-propagating pathway to produce a 2-hydroxylphenylimine
cation
A (Scheme 1, eq1b). It was expected that the
benzo[d]oxazole core was formed via an intramolecular
annulation. Sardarian and co-workers reported that the
stoichiometric loading of diethyl chlorophosphate ((EtO)2POCl)
enabled the synthesis of benzo[d]oxazole core.14 Considering
potential usage of benzo[d]oxazole core in many functional
molecules15, it is of highly synthetic significance to develop a
catalytic version on organomolecular-promoted BR reaction for
the synthesis of benzo[d]oxazole core.
Table 2 Synthesis of benzo[d]oxazole derivatives using BOP-
Cl/ZnCl2-catalyst in Beckmann rearrangement reaction a
Table
1
Optimization of organocatalytic Beckmann
rearrangement for the synthesis of benzo[d]oxazole derivatives a
yield of
entr
y
organo
catalyst
additive
-
solvent
Temp (oC)
2a
(%)a,b
110
110
110
110
110
110
80
`1
2c
3c
4c
5c
6c
7c
8c
9c
10e
TsCl
toluene
toluene
toluene
trace
TsCl
ZnCl2
ZnCl2
20
traced
81
CNC
BOP-Cl
BOP-Cl
BOP-Cl
BOP-Cl
BOP-Cl
BOP-Cl
BOP-Cl
ZnCl2 toluene
FeCl3
AlCl3
ZnCl2
ZnCl2
ZnCl2
ZnCl2
toluene
toluene
toluene
MeCN
DMF
53
34.
67
110
110
110
52
39
toluene
44
a Isolated yield based on 2-hydroxylketone oxime 1.
a
Reaction conditions: 1a (0.2 mmol ), organocatalyst (0.1 equiv),
b
additive (0.1 equiv),
8
h.
Isolated yield based on 2-
hydroxylbenzoketoxime 1a. c 2.0 equiv MgSO4. d Amide 3a was observed
With the optimized reaction conditions, (entry 4, Table 1), we
then examined the yield of benzo[d]oxazole derivatives and
obtained results as illustrated in Table 2. The substituent R1 could
be replaced by aryl and alkyl functional groups. For example,
under optimized conditions the reaction of 1-(2-
hydroxyphenyl)propan-1-one oxime 1b offered benzo[d]oxazole
2b in 87% yield. Next, the substituent R2 functional group
tolerance was also highly favourable in BR reaction. For instance,
the reaction of 1-(1-hydroxynaphthalen-2-yl)ethan-1-one oxime
1c under optimized conditions delivered a corresponding product
2c in 67% yield. Methyl-, methoxyl-, chloro-, bromo-, and
fluoro-substituted substrates were also compatible in BR reaction.
Particularly, substrates (2e and 2f) with sensitive hydroxyl group
were also merely suitable for BR reaction. For example, the
reaction of 1-(2,5-dihydroxyphenyl)ethan-1-one oxime 1e
provided the desired product of 2e in 75% yield, while that of 1-
(2,4-dihydroxyphenyl)ethan-1-one oxime 1f produced the
in 70% yield. e no MgSO4 was added.
Based on this ideal strategy, various organocatalysts are
initially evaluated and optimized for BR reaction. Tosylating
reagent, p-methylbenzenesulfonyl chloride (TsCl) was readily
available and employed as an organocatalyst to commence the
reaction condition optimization. The results obtained from the
model reaction of 2-hydroxylbenzeneketoxime 1a, inspired us to
reconsider the reaction (entry 1, Table 1). Enlightened by
Yamamoto’s findings,5a we used ZnCl2 as an additional additive
when TsCl was selected as an organocatalyst (entry 2, Table 1).
To reduce hydrolysis of the starting material 1a, 2.0 equivalent
amount of MgSO4 was also added. To our delight, a desired
benzo[d]oxazole 2a was achieved as expected in a 20% isolated
yield (entry 1, Table 2). With aid of this promising result, other
organocatalysts for BR reaction were also screened. Based on the
obtained results, BOP-Cl was found to be the best organocatalyst,

targeted molecule 2f in 73% yield. As we know, hydroxyl and
bromo groups in benzo[d]oxazole core were highly useful for
structural elaboration via substitution and transition metal-
catalyzed cross-coupling reactions.
the organocatalyst B was proposed as a key intermediate in BR
reaction.
In summary, we have developed a switchable route for
organocatalytic
hydroxylbenzeneketoxime using BOP-Cl/ZnCl2 and CNC/ZnCl2.
series of benzo[d]oxazole derivatives and N-(2-
hydroxylaryl)amides were also synthesized with high reaction
efficiency and offered a broad scope in synthetic organic
chemistry. It is believed that, the hydroxyl group in final products
is useful for structural elaboration through substitution and
transition metal-catalyzed cross-coupling reactions.
Beckmann
rearrangement
of
2-
Table 3 Synthesis of N-(2-hydroxylaryl)amide derivatives using
A
CNC/ZnCl2-catalyst in Beckmann rearrangement reaction a
Acknowledgments
Financial supports from the Natural Science Foundation of
China (Nos: 21502069 and 21772067) is gratefully
acknowledged. Authors also gratefully thank Dr. Kannan
Palanisamy (Jiaxing University, China) for English editing of this
manuscript.
a Isolated yield based on 1.
As mentioned above, the amide product 3a was produced
when CNC/ZnCl2 was used as organocatalyst/additive in BR
reaction. Recently, Yamamoto and co-workers developed
CNC/ZnCl2-promoted BR reaction for the synthesis of amides.5b
In particular, the CNC/ZnCl2 system exhibited an excellent
reaction efficiency for alkyl ketoxime-based Beckmann
rearrangement. However, they5b did not exploit the compatibility
of 2-hydroxylbenzeneketoxime derivatives 1 under optimized
condition. Therefore, we would like to disclose Yamamoto’s
References and notes
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results using 2-hydroxylbenzeneketoxime derivatives
1 as
starting materials. The reaction optimization was already
presented in entry 3, Table 1 indicated by using 10 mol%
CNC/ZnCl2 in toluene and the amide 3a was afforded in 70%
yield. Changing solvent from toluene to MeCN at a refluxing
temperature (80C), resulted in a drastic improvement of reaction
efficiency, leading to the desired amide 3a in a yield of 90%.
Consequently, we then explored the reaction tolerance for
producing various amides 3 under optimized conditions indicated
as follows: CNC (10 mol%), ZnCl2 (10 mol%), MgSO4 (2.0
equiv), MeCN, reflux.
As illustrated in Table 3, various 2-hydroxylbenzeneketoxime
1 were compatible for the amide-forming reaction under
optimized conditions, and the desired amides 3 were achieved in
good yields. Replenishing the results from Yamamoto, the
combination of CNC and ZnCl2 also enabled BR reaction of 2-
3.
4.
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hydroxylbenzeneketoxime
1
and it produced N-(2-
hydroxyphenyl)benzamide
3
when the concentration of
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Scheme 2 Control experiments
To gain insight into the mechanism, two control experiments
were further carried out (Scheme 2). As illustrated in Scheme 2,

4
Tetrahedron Letters
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Supplementary Material
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Multicatalytic Beckmann Rearrangement
of
2-Hydroxylarylketone
Oxime:
of
Switchable
Benzo[d]oxazoles
Synthesis
and
N-(2-
Hydroxylaryl)amides
a
Zhen Li,a Chengtao Fang, Yannan Zheng,a
a
Guanyinsheng Qiu , Xiaofang Li,b and Hongwei
Zhou*a
College of Biological, Chemical Science and Engineering, Jiaxing
University, 118 Jiahang Road, Jiaxing 314001, China.
School of Chemistry and Chemical Engineering, Hunan University of
Science and Technology, Hunan 411201, China
 G. Qiu, Tel.: +86-0573-83642057; fax: +86-0573-83642057; e-
mail: 11110220028@fudan.edu.cn

6
Tetrahedron Letters
Research Highlights:
1) A BOP-Cl catalyzed Beckmann rearrangement is
described toward benzo[d]oxazole.
2) By using CNC as catalyst, N-(2-hydroxylaryl)amides
is afforded as well.
3) A switchable synthesis is reached by the use of
different organocatalysts.