A Simple Transformation of 1-(Isoxazol-3-yl)ureas to 5-(2-oxoalkyl)-2,4-dihydro-3H-1,2,4-triazol-3-ones through Base-Promoted Boulton-Katritzky Rearrangement

Article abstract of DOI:10.1002/adsc.201801357

2,4-Dihydro-3H-1,2,4-triazol-3-ones are a class of biologically important heterocycles. A novel and simple synthesis of such structures is developed. The method is through a base-promoted Boulton-Katritzky-type rearrangement of 1-(isoxazol-3-yl)ureas and is highly efficient for the formation of 2,4-dihydro-3H-1,2,4-triazol-3-ones. (Figure presented.).

Full text of DOI:10.1002/adsc.201801357

Title: A Simple Transformation of 1-(Isoxazol-3-yl)ureas to 5-(2-
oxoalkyl)-2,4-dihydro-3H-1,2,4-triazol-3-ones through Base-
Promoted Boulton-Katritzky Rearrangement
Authors: Jisheng Liu, Chen Chen, Rajendraprasad Kotagiri, wenqiang
Yang, and Qian Cai
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801357
Link to VoR: http://dx.doi.org/10.1002/adsc.201801357

10.1002/adsc.201801357
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
A Simple Transformation of 1-(Isoxazol-3-yl)ureas to 5-(2-
oxoalkyl)-2,4-dihydro-3H-1,2,4-triazol-3-ones through Base-
Promoted Boulton-Katritzky Rearrangement
Jisheng Liua,b, Chen, Chena,b, Rajendraprasad Kotagiria, Wenqiang Yangc and Qian
Caia,b*
a
College of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou, 510632, China
Guangzhou City Key Laboratory of Precision Chemical Drug Development
College of Pharmacy, Linyi University, Shuangling Road, Linyi, 276000, China.
b
c
caiqian@jnu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
The ring-transformation reactions have attracted
great interests in synthetic community and many
excellent methods and strategies have been developed
for the formation of different heterocycles due to their
importance.[9] The Boulton-Katritzky rearrangement
between two five-membered heterocycles is one of the
most investigated methods for ring-transformation and
has been extensively applied in the synthesis of
heterocyclic compounds.[10,11] Generally, such
rearrangements typically occurred in heterocycles
with N-O bond, such as in isoxazoles and 1,2,4-
oxadiazoles, in which the N atom is electrophilic and
could be attacked by nucleophilic side chains.[12, 13] In
this way, a new five-membered skeleton is formed by
accompanied with the cleavage of N-O bond in the
isoxazole or 1,2,4-oxadiazole five-membered ring
(Scheme 1).[14]
Abstract. 2,4-Dihydro-3H-1,2,4-triazol-3-ones are a
class of biologically important heterocycles. A novel
and simple synthesis of such structures is developed.
The method is through a base-promoted Boulton-
Katritzky-type rearrangement of 1-(isoxazol-3-
yl)ureas and is highly efficient for the formation of
2,4-dihydro-3H-1,2,4-triazol-3-ones.
Keywords:
Boulton-Katritzky
Rearrangement;
Heterocycles; Ring-Transformation; (1-isoxazol-3-
yl)urea; 2,4-dihydro-3H-1,2,4-triazol-3-one.
Heterocyclic compounds have been widely found as
core structures in natural products[1] and utilized as key
motif in pharmaceuticals and other function
molecules.[2] 2,4-Dihydro-3H-1,2,4-triazol-3-ones and
derivatives are a class of five-membered heterocycles
showing broad bioactivities (Figure 1), such as
anticonvulsant,[3]
anticancer,[4]
antiretroviral,[5]
antifungal[6] and other else.[7] The preparation and
derivation of such structures have also been
extensively explored in synthetic community.[8]
Scheme 1. General Boulton-Katritzky rearrangement of N-
O containing heterocycles.
A variety of three-atom side chains have been
explored as nucleophilic groups to form new
heterocyclic compounds.[12-15] However, it is still
highly desirable to explore different side chains for
efficient formation of novel heterocyclic skeletons.
Herein, we’d like to disclose our research in the
formation of 5-(2-oxoalkyl)-2,4-dihydro-3H-1,2,4-
triazol-3-ones from (1-isoxazol-3-yl)ureas via the
Boulton-Katritzky rearrangement with a urea motif as
the nucleophilic group.
Our research was initiated with the
transformation of 1-(5-(tert-butyl)isoxazol-3-yl)-3-
phenylurea (1a) to 5-(3,3-dimethyl-2-oxobutyl)-2-
phenyl-2,4-dihydro-3H-1,2,4-triazol-3-one (2a) as a
Figure 1. Examples for bioactive 2,4-Dihydro-3H-1,2,4-
triazol-3-ones and derivatives
1
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10.1002/adsc.201801357
Advanced Synthesis & Catalysis
With the optimized conditions in hand, we then
explored the reaction scope with a variety of substrates.
The results were shown in Scheme 2. All the reactions
of 1-(isoxazol-3-yl)-3-arylureas 1a-k proceeded well
and were completed in 0.5-1.5 hours in most cases.
Both the electron-withdrawing and donating
substituents on the aryl urea parts were well tolerated
and the corresponding products were afforded in
excellent yields. Alkyl or aryl substituents on the
isoxazole ring were also well tolerated and the
rearrangement products were obtained in high yields.
One exception was the conversion of compound 1m
with two methyl groups on the isoxazole ring. The
reaction of 1m was much slower by comparing with
other substrates and only 50% yield was obtained in 5
hours. However, no rearrangement for N-alkyl ureas
1n and 1o was observed under the same condition and
all the starting materials were recovered.
model case. Compound 1a was prepared by reacting
the corresponding amine with phenyl isocyanate in
toluene. With 1a as the substrate, the rearrangement
reaction was first explored under air in different
solvent with NaOH as the base. As shown in Table 1,
A variety of solvents such as DMSO, DMF,
acetonitrile, 1,4-dioxane, toluene, THF and DCM,
were screened with 2 equivalents of NaOH as the base
in 80 oC. It revealed that in 1 hour, only the reactions
in DMSO and DMF afforded the corresponding
product in 88% and 45% yield (Table 1, entries 1-2),
respectively. No transformation was observed in other
solvents (Table 1, entries 3-6). Inferior result (about
20% yield) was obtained by reducing the amount of
NaOH to 1 equivalent (Table 1, entry 7). Then,
different bases were explored in DMSO. It showed that
organic bases such as Et3N and DIPEA didn’t work
(Table 1, entries 8 and 9), while strong base t-BuOK
and inorganic bases such as K3PO4, K2CO3, Cs2CO3
could promote the transformation (Table 1, entries 10-
13). Among them, Cs2CO3 showed the best result and
afforded the desired product in excellent yield in 1 h
(Table 1, entry 13).The structure of compound 2a was
confirmed through X-ray experiment (Figure 2).[16]
Table 1. Reaction Condition Screeninga
Entry
base
solvent
yield of 2a
(%)b
1
2
3
4
5
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
Et3N
DMSO
DMF
MeCN
88
45
-
-
-
-
20
-
1,4-dioxane
toluene
CH2Cl2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
6
7c
8
9
iPr2NEt
tBuOK
K2CO3
K3PO4
Cs2CO3
-
10
11
12
13
53
30
51
93
Scheme 2. Substrate Scope for the Rearrangement
a)
Reagents and conditions, 1a (1 mmol), base (2
mmols), solvent (2 mL), 80 oC, 1 h. b) Isolated yields. c)
NaOH (1mmol).
Noteworthy is that oxidized side products could
be formed with prolonged time in these reactions. This
is very similar to the observations by Piccionello and
co-workers in the rearrangement of isoxazole to
imidazoles.[12c-d] For example, the reaction of 1d
afforded 2d in 89% yield within 1 h. However, after
18 h, only 68% of 2d was isolated, together with 2d‘ in
25% yield, which was formed through the oxidation of
t-butylacyl side chain of 2d (Scheme 3). The structure
of 2d‘ was confirmed through X-ray experiment
(Figure 3).[17]
Figure 2. X-ray structure of compound 2a.
2
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10.1002/adsc.201801357
Advanced Synthesis & Catalysis
completion. Afterwards, H2O (5 mL) and EtOAc (10 mL)
were added into the mixture. The organic phase was
separated and washed with brine, dried over Na2SO4. The
solvent was removed under reduced pressure. The crude
product was purified by flash column chromatography
(ethyl acetate/petroleum ether = 1/8) to afford product 2a as
a white solid.
Scheme 3. the rearrangement-oxidation cascade
General Procedure for the One-Pot Reactions: The mixture
of compound 3a (1 mmol) and tolyl isocyanate (1.2 mmol)
o
was heated at 80 C for 0.5 hour in toluene (1 mL). Then,
Cs2CO3 (3.0 mmol) and DMSO (2 mL) were added and the
o
mixture was heated in 80 C for another hour. Afterwards,
H2O (5 mL) and EtOAc (10 mL) were added into the
mixture. The organic phase was separated and washed with
brine, dried over Na2SO4. The solvent was removed under
reduced pressure. The crude product was purified by flash
column chromatography (ethyl acetate/petroleum ether =
1/8) to afford product 2b as a white solid.
Figure 3. X-ray structure of compound 2d’.
To further simplify the reaction process, we then
investigated the reactions of isoxazol-3-amine 3a with
aryl isocyanates in one-pot manner without isolating
the corresponding urea intermediates. After heating
the reactions of isoxazol-3-amines with aryl
isocyanates at 80 oC for 0.5 h in toluene, Cs2CO3 and
DMSO were directly added into the mixture and
heated for another 0.5-4 hours. In this way, the desired
rearrangement products could be directly prepared and
purified as final products. As shown in Scheme 4,
several examples were tested and all afforded the
desired products in good to excellent yields, which are
comparable to that shown in Scheme 2.
Acknowledgements
The authors are grateful to the National Natural Science
Foundation (Grants 21772066, 21572229, 21602095) and the
Fundamental Research Funds for the Central Universities for their
financial support.
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3
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10.1002/adsc.201801357
Advanced Synthesis & Catalysis
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4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801357
Advanced Synthesis & Catalysis
COMMUNICATION
A Simple Transformation of 1-(Isoxazol-3-yl)ureas
to 5-(2-oxoalkyl)-2,4-dihydro-3H-1,2,4-triazol-3-
ones through Base-Promoted Boulton-Katrizky
Rearrangement
Adv. Synth. Catal. Year, Volume, Page – Page
Jisheng Liu, Chen, Chen, Rajendraprasad Kotagiri,
Wenqiang Yang and Qian Cai*
5
This article is protected by copyright. All rights reserved.