Stereospecific Synthesis of (E)-5-Tetrasubstituted-ylidene-3,5-dihydro-4 H-imidazol-4-ones

Article abstract of DOI:10.1021/acs.orglett.9b01063

A stereospecific synthesis of (E)-5-tetrasubstituted-ylidene-3,5-dihydro-4H-imidazol-4-one derivatives is demonstrated through a cascade process by combination of a Michael addition and Boulton-Katritzky rearrangement. The method provides a simple and eff

Full text of DOI:10.1021/acs.orglett.9b01063

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereospecific Synthesis of (E)‑5-Tetrasubstituted-ylidene-3,5-
dihydro‑4H‑imidazol-4-ones
Rajendraprasad Kotagiri, Zhuoji Deng, Wei Xu,* and Qian Cai*
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of
Chinese Ministry of Education, College of Pharmacy, Jinan University, No 601 Huangpu Avenue West, Guangzhou 510632, China
S
* Supporting Information
ABSTRACT: A stereospecific synthesis of (E)-5-tetrasubstituted-
ylidene-3,5-dihydro-4H-imidazol-4-one derivatives is demonstrated
through a cascade process by combination of a Michael addition and
Boulton−Katritzky rearrangement. The method provides a simple and
efficient approach for the synthesis of (E)-5-tetrasubstituted-ylidene-
3,5-dihydro-4H-imidazol-4-ones from the reactions of N-(isoxazol-3-
yl)-propiolamides or N-(1,2,4-oxadiazo-3-yl) propiolamides with N or C nucleophiles.
Scheme 1. Cascade Reaction by Combination of a Michael
Addition and Boulton−Katritzky Rearrangement
3,5-Dihydro-5-methylidene-4H-imidazol-4-one (MIO) is a key
active site for some important aminomutases in the
biosynthetic pathways of biologically active compounds in
plants and microorganisms.1 Such a structure has also been
found extensively in many bioactive natural products and
represents an attractive motif in the development of new drugs
and function molecules (Figure 1).2−4
atom was attacked by nucleophilic side chains and led to the
cleavage of the N−O bond and the rearrangement for the
formation of more stable five-membered rings.10 A variety of
three-atom side chains have been explored for such rearrange-
ments. However, in most cases, the three-atom side chains
need to be preinstalled in the substrates, and normally, N or O
was chosen as the nucleophilic group. Only sporadic examples
with a C nucleophilic group have been explored.11
Figure 1. Some examples of bioactive 5-ylidene-3,5-dihydro-4H-
imidazol-4-one derivatives.
Our group is interested in the development of novel
synthetic methods for the efficient formation of bioactive
heterocycles. Recently, we have developed a base-promoted
Boulton−Katritzky rearrangement of 1-(isoxazole-3-yl)ureas to
5-(2-oxoalkyl)-2,4-dihydro-3H-1,2,4-triazol-3-ones.12 For a
further study, in this work, we would like to disclose our
research in combination of a Michael addition and Boulton−
Katritzky rearrangement for stereospecific synthesis of (E)-5-
ylidene-3,5-dihydro-4H-imidazol-4-one derivatives (Scheme
1b). In this reaction, a nucleophilic carbon was involved in
the rearrangement process.
5-Ylidene-3,5-dihydro-4H-imidazol-4-ones were generally
synthesized through the condensation of corresponding
imidazolones with aldehydes or ketones or through different
multicomponent reactions from simple substrates.5 However,
the formation of fully substituted double bonds at the 5-
position is difficult, and the control of the stereoconfiguration
of the double bond is a great challenge in such reactions. Thus,
it is extremely desirable to develop novel methods for the
highly stereoselective formation of imidazolones with fully
substituted 5-position double bonds.
The Boulton−Katritzky rearrangement between two five-
membered heterocycles is one of the most investigated ring-
transformation reactions and has been extensively applied in
the synthesis of a variety of heterocyclic compounds (Scheme
1a).6,7 Such reactions typically occurred in heterocycles such as
isoxazoles8 and 1,2,4-oxadiazoles,9 in which the electrophilic N
The reaction of N-(5-(tert-butyl)isoxazol-3-yl)-N-methyl-3-
phenylpropiolamide 1a and TsNH2 2a was initiated as a model
case. As shown in Table 1, with 1.0 equiv of Cs2CO3 as the
Received: March 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01063
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
3aa′ was also confirmed through X-ray experiment (Figure 2).
Similar side reactions have been found in our previous
research12 and are also reported in other groups’ work.8c,d
With the optimized conditions in hand, we then explored
the reaction scope with a variety of N-(isoxazole-3-yl)
propiolamides and sulfonamide substrates. As shown in
Scheme 2, different substituent groups, such as methyl,
Table 1. Reaction Condition Screening
b
entry
base (equiv)
solvent
temp (°C) time (min) yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Cs2CO3 (1.0)
K3PO4 (1.0)
K2CO3 (1.0)
KOtBu (1.0)
NaOEt (1.0)
NaOH (1.0)
DMAP (1.0)
Et3N (1.0)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
120
120
120
120
120
120
120
120
120
120
100
100
120
70
30
30
45
30
30
45
60
60
60
45
30
75
75
75
67
46
72
46
12
n.d.
n.d.
81
80
76
63
57
51
65
Scheme 2. Substrate Scope of N-(Isoxazo-3-
yl)propiolamides with Sulfonamides
c
c
DABCO
K2CO3 (0.5)
Cs2CO3 (1.0)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
45
THF
dioxane
MeCN
24 h
24 h
8 h
100
85
a
Reagents and conditions: 1a (0.5 mmol), 2a (0.5 mmol), solvent 2
b
c
mL. Isolated yield. Not detected.
base, the reaction proceeded smoothly at 120 °C in DMSO to
afford the corresponding product 3aa in 75% yield in 30 min
(Table 1, entry 1). The structure of 3aa was confirmed through
X-ray experiment (Figure 2). The stereoconfiguration of a fully
Figure 2. X-ray structures of compounds 3aa and 3aa′.
substituted double bond at the 5-position of the 3,5-dihydro-
4H-imidazol-4-one ring was determined as E, which is due to
the formation of a hydrogen bond between the oxygen atom of
the carbonyl group and NHTs. The double bond of enol was
determined as Z due to the formation of a hydrogen bond
between −OH and the nitrogen atom of the imidazolone. The
formations of these two double bonds are very characteristic
and made the product structure very attractive. Other bases
such as K3PO4, K2CO3, KOtBu, NaOEt, and NaOH were also
screened, and all delivered the desired product in moderate
yield (Table 1, entries 2−6). While organic bases such as
DMAP, Et3N, and DABCO showed poor efficiency (Table 1,
entries 7−9), only low yield was obtained with DMAP. Thus,
we then took the cheapest K2CO3 for further exploration. It
revealed that 0.5 equiv of K2CO3 is enough to promote the
reaction at 120 °C in DMSO, which afforded the product in
81% yield (Table 1, entry 10). A similar result was obtained
with 0.5 equiv of Cs2CO3 at 100 °C (Table 1, entry 11). Other
solvents such as DMF, 1,4-dioxane, THF, or MeCN were also
screened at 120 °C or under refluxing, and all the results are
inferior to that in DMSO (Table 1, entries 13−16).
Noteworthy is that an oxidized diketone side product 3aa′
was detected under prolonged reaction time. The structure of
methoxy, trifluoromethyl, trifluoromethoxy, and amine, on
the aryl rings of aryl sulfonamides were well tolerated, and all
delivered the corresponding products in moderate to good
results (3aa−3ag). Heteroaryl sulfonamides such as pyridine-
3-sulfonamide and thiophene-2-sulfonamide were also tested
and afforded the desired products in high yields (3ah and 3ai).
While alkyl-substituted sulfonamides such as methanesulfona-
mide and cyclopropanesulfonamide were used, the reaction
also proceeded well, and the corresponding products 3aj and
3ak were obtained in moderate yields. Different substituents of
N-(isoxazole-3-yl) propiolamides were also well tolerated, and
the corresponding products (3ba−3ga) were delivered in
moderate yields.
Further, two N-(1,2,4-oxadiazo-3-yl) propiolamides 4a/b
and typical sulfonamides were explored in our reactions. As
shown in Scheme 3, the reactions proceeded smoothly with
Cs2CO3 as the base at 100 °C, and all afforded the desired
products in good yields. The structure of product 5ba was
determined through X-ray experiment (Figure 3). The
characteristic formations of two hydrogen bonds between the
oxygen atom of imidazolone with NHTs and the oxygen atom
of the side chain with the nitrogen atom of the imidazolone
were clearly observed in the structure.
B
DOI: 10.1021/acs.orglett.9b01063
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Organic Letters
Letter
Scheme 3. Substrate Scope of N-(1,2,4-Oxadiazo-3-
Scheme 5. Proposed Mechanism
yl)propiolamides with Sulfonamides
and (Z)-configurations. Intermediate B could form an
equilibrium with tautomerized intermediates C and D under
basic conditions. Intermediate D acted as the nucleophilic
intermediate to attack the N atom and undergo the Boulton−
Katritzky rearrangement to afford the desired product. The
rotation of the single bond during the process and the
formation of the hydrogen bond between the oxygen atom of
the carbonyl group and NHTs are the key factors accounting
for the stereospecificity of the 5-position double bond, while
the formation of enol and the stereoconfiguration of the enol
double bond are governed by the hydrogen bond between enol
OH and the nitrogen atom of the imidazolone.
Figure 3. X-ray structures of 5ba and 7ea.
To further explore the reaction scope, we chose diethyl
malonate 6a and ethyl 2-cyanoacetate as C-nucleophiles for the
cascade reactions. As shown in Scheme 4, the reactions of N-
To confirm the mechanism, a control experiment was
performed and shown in Scheme 6. As observed, the reaction
Scheme 4. Exploring a C-Nucleophile for the Cascade
Reactions
Scheme 6. Control Experiment
of 1a with N-4-dimethylbenzenesulfonamide 9 afforded the
Michael addition products 10a/10a′, which are mixtures of Z
and E products. No Boulton−Katritzky rearrangement product
was detected. It means that the alkenyl carbanion A preferred
protonation rather than attacking the electrophilic nitrogen
atom to undergo Boulton−Katritzky rearrangement. Since
there is no free proton on the nitrogen in 10a/10a′, the
following deprotonation and rearrangement could not occur.
Thus, the reaction stopped at the Michael addition step. The
structure of product (Z)-10a was confirmed through X-ray
experiment, and the (E)-product was deduced through NMR
data. The control experiment proved that the mechanism
through path b is more reasonable for our reactions.
In summary, a stereospecific synthesis of (E)-5-tetrasub-
stituted-ylidene-3,5-dihydro-4H-imidazol-4-ones is developed.
The method is through a tandem reaction of N-(isoxazole-3-
yl) or N-(1,2,4-oxadiazol-3-yl) propiolamides with sulfona-
mides or diethyl malonate by combination of a Michael
addition and Boulton−Katritzky rearrangement. Further
development and applications of this method are ongoing in
our laboratory.
(isoxazole-3-yl) and N-(1,2,4-oxadiazo-3-yl)propiolamides
with 6a or 6b also worked well and afforded the desired
products in good yields. The structure of product 7ea was
confirmed through X-ray experiment (Figure 3).
Two pathways may be possible for the reactions of
compound 1a and TsNH2 as shown in Scheme 5. One is
through Michael addition to produce an alkenyl carbanion A.
The alkenyl carbanion A acted as a nucleophilic intermediate
to attack the electrophilic N atom of the isoxazoles directly and
undergo a Boulton−Katritzky rearrangement to afford the
product 3aa with both (Z) and (E)-configurations (path a),
which may finally convert into thermally more stabilized (E)-
3aa under the basic conditions. Another reasonable pathway
(path b) was also proposed. The protonation of intermediate A
would lead to the formation of intermediate B with both (E)
C
DOI: 10.1021/acs.orglett.9b01063
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01063.
■
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xwnail2003@163.com.
*E-mail: caiqian@jnu.edu.cn.
ORCID
Qian Cai: 0000-0002-5700-3275
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the National Natural Science
Foundation (Grants 21772066, 21572229) and Guangdong
Special Support Program (2017TX04R059) for their financial
support.
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DOI: 10.1021/acs.orglett.9b01063
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