Synthesis of 2-unsubstituted imidazolones from bisamides via a one-pot, domino dehydration/base promoted cyclisation process

Article abstract of DOI:10.1016/j.tetlet.2018.01.074

A one-pot, domino process was developed as an alternative approach for the preparation of 2-unsubstituted imidazolones. The methodology utilizes readily accessible bisamides, which upon a dehydration/cyclisation sequence produced imidazolones in good yields. The transformation relies on the compatibility of the dehydrating agent and base, and the reaction conditions tolerate various functional groups.

Full text of DOI:10.1016/j.tetlet.2018.01.074

Tetrahedron Letters xxx (2018) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 2-unsubstituted imidazolones from bisamides via a one-pot,
domino dehydration/base promoted cyclisation process
⇑
⇑
Dimitrije Djukanovic, Milos Petkovic , Milena Simic, Predrag Jovanovic, Gordana Tasic, Vladimir Savic
University of Belgrade, Faculty of Pharmacy, Department of Organic Chemistry, Vojvode Stepe 450, 11221 Belgrade, Serbia
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot, domino process was developed as an alternative approach for the preparation of 2-unsubsti-
tuted imidazolones. The methodology utilizes readily accessible bisamides, which upon a dehydration/-
cyclisation sequence produced imidazolones in good yields. The transformation relies on the
compatibility of the dehydrating agent and base, and the reaction conditions tolerate various functional
groups.
Received 20 November 2017
Revised 10 January 2018
Accepted 23 January 2018
Available online xxxx
Ó 2018 Elsevier Ltd. All rights reserved.
Keywords:
Imidazolones
Bisamides
One-pot cyclisation
Imidazolones are an important class of nitrogen containing,
non-aromatic heterocycles that exhibit a variety of interesting bio-
logical and chemical properties. This motif forms the cores of fluo-
rescent probes related to fluorescent proteins (Fig. 1A)1–5 and also
structural fragments of compounds with activity against obesity-
related disorders and hypertension (irbesartan, Fig. 1B).6–9
inhibitors,21 and calcitonin gene-related peptide (CGRP) receptor
antagonists.22,23
Regarding the synthesis of 2-unsubstituted imidazolones, Mus-
seli and co-workers reported the dehydrative cyclization of dia-
mide compounds obtained from the Ugi reaction, using
bistrimethylsilylacetamide (BSA) at an elevated temperature.24
Two additional metal-based processes, the Pd-promoted transfor-
Furthermore, imidazolones are useful intermediates for the syn-
thesis of naturally occurring alkaloids, e.g. axinellamine A and
massadine (Fig. 1C).10 They have also found application in agro-
chemistry as herbicides, most of which are used to control weeds
in legume, cereal crops, and peanuts (imazapyr, Fig. 1D).11,12
Several methodologies have been reported for the preparation
of imidazolone derivatives. The Erlenmayer synthesis of azlactones
has proved useful since these compounds can be efficiently trans-
formed into imidazolone derivatives via an amidation/ring closure
mation of isonitriles with
a
-amino acid esters25 and the Ag-cat-
sequence.1 The cyclisation of
a-bisamides under acidic, basic, or
microwave conditions represents another widely used methodol-
ogy.13–17
Although various methods are available for imidazolone syn-
thesis, few provide access to the corresponding C(2)-unsubstituted
derivatives. These compounds are useful precursors for the prepa-
ration of N-heterocyclic carbene-type ligands.18 Their chemistry is
further enriched by the recently developed Pd-catalyzed C(2)-H
functionalisation reaction with aryl or alkenyl halides.19,5 This
makes them valuable building blocks for the synthesis of pincer
type ligands for palladium,20 fatty acid synthetase (FAS)
⇑
Corresponding author.
E-mail addresses: milosp@pharmacy.bg.ac.rs (M. Petkovic), vladimir.savic@
pharmacy.bg.ac.rs (V. Savic).
Fig. 1. Selected imidazolone derivatives.
https://doi.org/10.1016/j.tetlet.2018.01.074
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Djukanovic D., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.01.074

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D. Djukanovic et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Table 1
i) ref. 23
ii) ref. 24
H
R1
O
R1
O
Reaction optimization (1 ? 2, Scheme 1).
NH
BSA
N
H
N
Entrya
Solvent
Base
pKad
Yield 2 (%)b
N
O
pyridine
100 oC, 12 h
R2
R2
R2 R2
1 h
20 h
H
R1, R2 = alkyl
1
2
3
4
5
6
7
8
9
10
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
Benzene d6
DMSO d6
Methanol d4
DABCO
Et3N
8.8
10.6
10.8
9.2
5.2
6.7
12
–
–
–
–
10
9
4
DIPEA
DMAP
Pyridine
2,6-Lutidine
DBU
DBU
DBU
DBU
R2
4
4
66
57
–
H
H2N
COOEt
R1
O
54
R2 = alkyl
N
PdCl2
88 (73)c
N
+
benzene
12
12
12
–
–
–
–
–
–
80 oC, 7 h
R1NC
R2
R1= t-Bu
a
Reagents and conditions: 1 (0.03 mmol), base (0.21 mmol), PPh3 (0.09 mmol),
iii) ref. 25
CBr4 (0.12 mmol) CDCl3 (0.5 mL), 40 °C, 1 h.
H
MeOOC
NC
R1 R2
b
R3
Yield calculated from NMR data using 1,4-dioxane as an internal standard.
Isolated yield.
AgNO3 (10 mol%)
c
N
N
d
+
Conjugate acid.
toluene
R2
R3NH2
O
60 oC, 12 h
R1
R1, R2, R3 = alkyl, aryl
drating reagent with the expectation that it would be compatible
with the weak bases necessary for cyclisation (Scheme 1).30,31
Initially, we examined the envisaged process in an NMR tube
employing substrate 1, PPh3/CBr4, and various bases in CDCl3 as a
solvent. After 1 h at 40 °C, with 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) as a base, product 2 was formed in 88% yield (Table 1,
entry 7). Other bases such as 1,4-diazabicyclo[2.2.2]octane
iv) ref. 26, 27
R1
O
H
R1
O
R1
O
NH
NH
n-BuLi
H
N
POCl3
NEt3
N
R2
O
N
NC
THF
R2
R2 R2
-60-0 oC
H
R2 R2
-10-0 oC, 2 h
R1 = alkyl, aryl; R2 = alkyl
(DABCO),
triethylamine
(Et3N),
N,N-diisopropylethylamine
this work:
R1
(DIPEA), 4-dimethylaminopyridine (DMAP) were inefficient
(Table 1, entries 1–4). On the other hand, the reactions with pyri-
dine and 2,6-lutidine (Table 1, entries 5, 6) also afforded product 2,
albeit in lower yields than the reaction with DBU even with pro-
longed reaction times. It is evident that the nature of the base is
essential for the success of this reaction, but that the base strength
is not the only controlling factor. The exact role of the base is pre-
sently not clear and remains to be studied in more detail. Conduct-
ing the reaction in benzene d6, DMSO d6 and methanol d4 (Table 1,
entries 8–10) did not lead to the desired product.
H
R1
O
NH
H
DBU, PPh3, CBr4
N
N
N
O
O
R2
CH2Cl2
R2
R2 R2
40 oC, 1 h
H
R1 = alkyl, aryl
R2 = alkyl
Fig. 2. Selected methodologies for the synthesis of 2H-5-imidazolones.
All reactions were carried out with excess dehydrating agent
and base; all attempts to decrease their amount or to perform
alyzed reaction of methyl
a,a-disubstituted a-isocyanoacetates
with primary amines have also been reported (Fig. 2).26 The most
the reaction at
transformation.
a lower temperature resulted in incomplete
common reaction conditions involve the n-BuLi promoted
intramolecular cyclization of
diamide compounds using POCl3 as
a
-isocyanoamides prepared from
dehydrating reagent
As shown in Table 2, all reactions proceeded smoothly in CH2Cl2
at reflux to give the corresponding imidazolones in good to high
yields (56–89%) in less than one hour. Diamides obtained via the
Ugi reaction of aniline derivatives bearing functional groups which
are potentially incompatible with n-BuLi (carbonyl or aryl-halide)
gave the expected products 4a–d in 56–77% yield (Table 2, entries
1–4). When the aniline moieties of amide 3 were substituted with
more nucleophilic aliphatic amines (Table 2, entries 5–8), the cor-
responding products were formed in slightly higher yields (80–
88%). The reaction was also efficient with amino acid derivatives
(Table 2, entries 9–14) affording the desired products in good
yields. As anticipated, the imidazolones were isolated as racemates
(confirmed by HPLC analysis). This is most likely the result of the
Ugi reaction which is known to cause the isomerisation of
aminoacids.32 Notably, glycine derived imidazolone 4i could
potentially be a useful intermediate in the synthesis of CGRP recep-
tor antagonists as developed by Merck & Co.22
In summary, a simple and efficient one-pot method involving a
domino dehydration/cyclisation process leading to 2-unsubsti-
tuted-5-imidazolones has been developed. The readily accessible
bisamides and reagents, relatively mild conditions which tolerate
a number of functional groups, and short reaction times make this
procedure an attractive alternative to previously reported
methodologies.
a
(Fig. 2).27,28 The main drawback of this methodology is the incom-
patibility of POCl3 and n-BuLi with numerous functional groups.29
In our hands, the attempted use of n-BuLi in the cyclisation step
towards the synthesis of polyfunctionalised C(2)-unsubstituted
imidazolones failed, most likely due to the presence of sensitive
functional groups. As a result, alternative conditions with a focus
on weaker bases were explored.
We hypothesized that the direct synthesis of 2-unsubstituted
imidazolones could be achieved under mildly basic conditions in
a
one-pot dehydration/cyclisation reaction using formamides
accessible via the Ugi reaction. PPh3/CBr4 was selected as a dehy-
COOMe
COOMe
N
COOMe
base
PPh3
CBr4
NH
N
NH4+HCOO-
H
N
N
O
C
O
+
O
O
MeOH
70 oC
16 h
CDCl3
40 oC
time
H
1
2
Scheme 1. Synthesis of 2H-imidazolones.
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D. Djukanovic et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
Table 2
Reaction scope.
R1
O
R1
O
NH
N
DBU, PPh3, CBr4
R1 = alkyl, aryl
R2, R3 = alkyl
H
N
N
R3
O
CH2Cl2, 40 o
56-89%
C
R2
R2 R3
3
H
4
Entrya
1
4
Yieldb (%)
77
Entrya
8
4
Yieldb (%)
84
N
N
MeOOC
N
N
Ph
O
O
2
3
56
57
9
73
78
N
N
I
N
N
MeOOC
O
O
10
N
N
I
N
N
MeOOC
Ph
O
O
4
5
6
56
80
88
11
12
13
77
73
89
N
N
N
N
EtOOC
Ph
Br
O
N
O
N
N
N
N
Ph
Ph
MeOOC
Ph
O
O
N
N
N
MeOOC
O
O
7
81
14
78
N
N
MeOOC
N
Ph
O
O
a
Reagents and conditions: 1 (0.3 mmol), base (2.1 mmol), PPh3 (0.9 mmol), CBr4 (1.2 mmol), CH2Cl2 (5 mL), 40 °C.
Isolated yield after column chromatography.
b
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Acknowledgments
Financial support from the Serbian Ministry of Education,
Science and Technological Development (grant no. 172009) is
greatly appreciated. We also thank the Faculty of Pharmacy for
support.
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