Synthesis of Imidazolidinone, Imidazolone, and Benzimidazolone Derivatives through Oxidation Using Copper and Air

Article abstract of DOI:10.1021/acs.orglett.9b00973

A new synthetic method of urea derivatives using copper and air was developed. These mild conditions provided moderate to very good yields for 15 examples (53-93%), while low yields were obtained with sterically hindered substrates (3 examples). The reaction was found to go through an in situ generated copper-N-heterocyclic carbene, which was then oxidized into cyclic urea derivatives possessing alkyl, benzyl, aryl, hydroxy, Boc-protected, and tertiary amine groups.

Full text of DOI:10.1021/acs.orglett.9b00973

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Imidazolidinone, Imidazolone, and Benzimidazolone
Derivatives through Oxidation Using Copper and Air
Dazhi Li and Thierry Ollevier*
́
́
́
́
Departement de chimie, Universite Laval, 1045 avenue de la Medecine, Quebec, QC, G1V 0A6, Canada
S
* Supporting Information
ABSTRACT: A new synthetic method of urea derivatives using copper and air was
developed. These mild conditions provided moderate to very good yields for 15
examples (53−93%), while low yields were obtained with sterically hindered
substrates (3 examples). The reaction was found to go through an in situ generated
copper−N-heterocyclic carbene, which was then oxidized into cyclic urea
derivatives possessing alkyl, benzyl, aryl, hydroxy, Boc-protected, and tertiary
amine groups.
rea derivatives play an important role in medicinal
chemistry,1,2 as they show many biological and
Scheme 1. Synthesis of Urea Derivatives by Oxidation
U
pharmacological activities, e.g., cofactor biotin,3 kealiiquinone
from the Micronesian sponge,4 antagonist naamidine A,5 and
cytotoxin agelastatin A (Figure 1).6 Among urea derivatives,
oxidants is their incompatibility with oxidant-sensitive function-
alities, thus hindering the substrate scope. Here, we report mild,
easy, and practical conditions using copper metal and air for the
oxidation of imidazolium, imidazolinium, and benzimidazolium
substrates to obtain the corresponding urea derivatives. The
conditions are applicable to substrates bearing alkyl, benzyl, aryl,
primary hydroxy, acid-sensitive tert-butyloxycarbonyl group
(−Boc), and tertiary amine groups.
While investigating reported procedures that describe the
synthesis of related Cu−NHC under air in the presence of Cu2O
or Cu,21,22 it was found that for the chiral substrates targeted
here the corresponding imidazolidinones and benzimidazolones
were isolated instead (Scheme 2). The conditions using Cu2O
under reflux (Scheme 2, eq a) led to urea 2a in 39% yield, while
the conditions using Cu powder at room temperature (Scheme
2, eq b) afforded the corresponding imidazolidinones and
benzimidazolones in yields up to 85% (2b) and 45% (2c),
respectively. These mild conditions using copper metal and air
as oxidant were compatible with the hydroxyl group (2c). An
iodo-substituted product 2cc was also obtained in 10% yield
Figure 1. Structures of selected biologically active urea derivatives.
imidazolidinones and benzimidazolones are two important
categories, e.g., antiviral agent DBPR1037 and RSV inhibitor
BMS-433771 (Figure 1).8−10 For this reason, new approaches
for the synthesis of urea derivatives remain of interest.2,11 In the
course of our studies toward the synthesis of various copper−N-
heterocyclic carbene complexes (Cu−NHC) from imidazoli-
nium and benzimidazolium derivatives, the corresponding urea
derivatives were advantageously isolated instead of the expected
Cu−NHCs. We disclose herein a new synthetic method to
prepare these ureas.
Among the previously described synthetic methods, the
oxidation of imidazolium, imidazolinium, and benzimidazolium
substrates into urea derivatives has been disclosed, using strong
oxidants, such as PhI(OAc)2,12 NaOCl,13−15 di-tert-butyl
peroxide,16 H2O2,17,18 and m-chloroperoxybenzoic acid (m-
CPBA) (Scheme 1).19,20 A major disadvantage of using strong
Received: March 19, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00973
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
were used (entries 7−9). When a catalytic quantity of Cu was
used (25 mol %, entry 10), 2d was afforded in only 16% yield.
Thus, the conditions involving stoichiometric Cu in CH2Cl2
were chosen for further study.
Scheme 2. Synthesis of Chiral Imidazolidinones and
Benzimidazolones: Initial Attempts
After the optimization of reaction conditions, the substrate
scope was studied (Scheme 3). The reaction conditions were
Scheme 3. Synthesis of Imidazolidinones, Imidazolones, and
a b
,
Benzimidazolones
(a proposed mechanism is available in the Supporting
Information). Seeing that these conditions (eq b) were mild
enough to tolerate an oxidant-sensitive functionality, further
studies were pursued, including the effect of solvents and
substrate scope.
Our first focus was to use the model substrate 1d to optimize
the reaction conditions (Table 1). The reactions run in CH2Cl2
afforded the best yield in imidazolone 2d (83%, entry 1), while
in other solvents, such as THF (low solubility of 2d and longer
time), CH3CN, EtOH, acetone, and MeOH, lower yields of 2d
were obtained (entries 2−6). The reaction was also run on a
gram scale, and a 67% yield of 2d was obtained (entry 1). The
starting materials remained intact when Cu2O, CuO, and Fe
Table 1. Oxidation of 1d: Optimization of the Reaction
a
Conditions
a
Reaction conditions: imidazolium halide (0.30 mmol) and Cu (0.33
mmol) in CH2Cl2 (1 mL) under air (relative humidity 10−20%).
b
c
Isolated yields. CH2Cl2/EtOH (10:1) was used due to low
d
solubility of imidazolium and 72 h of reaction time. 3.0 equiv of
Cu used. Yields determined by H NMR. CH2Cl2/MeOH (10:1)
e
f
1
was used, and the product was obtained as a mixture of rotamers.
g
The tertiary amino groups in the starting materials were present as
b
entry
metal/catalyst
Cu
Cu
solvent
yield 2d (%)
h
ammonium salt of HCl and 72 h of reaction time. 4.0 equiv of Cu
used in CH2Cl2/MeOH (10:1).
c
1
2
CH2Cl2
THF
83 (67)
d
70
3
4
5
6
7
8
9
10
Cu
Cu
Cu
Cu
Cu2O
CuO
Fe
CH3CN
EtOH
42
33
29
24
suitable for the synthesis of urea derivatives bearing saturated
(2e, 2h, 2i, 2l, and 2m), unsaturated (2g, 2j), and aromatic
backbones (2f, 2n−r). Except for the sterically hindered
substrates (2i−k), the reactions proceeded to give moderate
to very good yields (53−93%). 1H NMR analysis of the crude
reaction mixtures obtained from 1j and 1k indicated that the
major products were the corresponding Cu−NHCs. For 1j, the
crude reaction mixture contained 70% of Cu−NHC, 22% of
urea 2j, and 8% of imidazolinium, while for 1k, the crude
reaction mixture contained 71% of Cu−NHC along with 29% of
remaining imidazolium and no detection of urea derivative. This
was attributed to the combination of steric and electronic factors
of the Cu−NHCs, exhibiting trends similar to those of their Ni−
acetone
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
e
0
e
0
e
0
Cu (0.25 equiv)
16
a
Reaction conditions: imidazolium bromide 1d (0.30 mmol) and
metal (0.33 mmol) in solvent (1 mL) under air (relative humidity
10−20%). Isolated yields. 1 g scale of substrate 1d. 72 h of
reaction time due to low solubility of the starting material. Starting
b
c
d
e
material intact.
B
DOI: 10.1021/acs.orglett.9b00973
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
NHCs analogues,23 i.e., being stable toward any oxidation into
ureas or decomposition into imidazoliums. Actually, these two
Cu−NHCs from 1j and 1k could be isolated as pure compounds
in air.21 The current conditions are suitable for substrates
containing different N-substituents, including benzyl (2e−g),
aryl (2h, 2i, 2m, 2p), −Boc group (2l, acid-sensitive), alkyl (2m,
2n), and the substituents tethered to tertiary amino groups
(2o−r). The case of 2g showed that the oxidation was
chemoselective toward the imidazolium, while the hydroxy
group remained intact. Subsequently, the synthesis of DBPR103
(Figure 1) was attempted. Unfortunately, due to the
unsuccessful synthesis of the corresponding N-pyridylimidazo-
linium (see the Supporting Information), the oxidation using the
current conditions could not be carried out. Hence, an N-phenyl
analogue of DBPR103, which may also show bioactivities,24,25
was synthesized from simple starting materials. The oxidation of
N-phenyl imidazolinium 1s gave the DBPR103 analogue 2s in
87% yield.
To further support this reaction pathway, three other Cu−
NHC solutions (Scheme 5) were exposed to air and monitored
a
Scheme 5. Oxidation of Cu−NHCs under Air
Originally, the imidazolium was thought to be oxidized by
Cu2O or CuO, which was previously formed through Cu
oxidation under air. However, the fact that the use of Cu2O or
CuO at room temperature did not lead to any desired products
(Table 1, entries 8 and 9) ruled out this hypothesis. In fact, the
reaction of imidazolium with Cu2O (under reflux) was believed
to first generate Cu−NHC according to the findings by Cazin.22
However, the present study demonstrated that the urea
derivatives were generated through the oxidation of correspond-
ing Cu−NHCs, which was confirmed by high resolution mass
a
1
Reactions were monitored by H NMR and HRMS. Because the
solutions were not agitated in the NMR tube, longer times were
needed.
1
spectrometry (HRMS, see the Figures S1−S3) and H NMR
(see the Supporting Information). The reaction pathway was
presented below using 1d as a model substrate (Scheme 4).
by H and 13C NMR (see Figures S4−S7). More information
1
Scheme 4. Proposed Reaction Pathway of the Formation of
about the decomposition of Cu−NHC and the proposed
mechanism for the oxidation of Cu−NHC by air and for the
formation of iodo-substituted product 2cc is also available in the
SI. As expected, the Cu−NHCs were oxidized smoothly to give
the corresponding urea derivatives. The new 13C NMR signals at
150−160 ppm clearly showed the formation of urea structures.
It is important to mention that the urea synthesis using the
current method relies on the instability of Cu−NHCs. The
reaction time increased with the robustness of the Cu−NHCs
(3e vs 3n vs 3t, Scheme 5). The low yields of 2i, 2j, and 2k
(Scheme 3) indicated that the current method is not suitable for
the substrates possessing large steric hindrance at the urea core.
In fact, the preparation of such sterically hindered ureas requires
strong oxidizing conditions from free carbenes instead of from
imidazoliums.26−29 In addition, the results obtained in this study
also shed light on the low yields obtained with some Cu−NHCs
in the literature,21 which have not been rationalized before.
In conclusion, a new synthetic method of imidazolidinone,
imidazolone, and benzimidazolone derivatives using copper and
air as oxidant was developed, which provided moderate to very
good yields for sterically unhindered substrates. The mild
oxidation conditions are suitable for the synthesis of urea
derivatives possessing alkyl, benzyl, aryl, primary hydroxy, acid-
sensitive tert-butyloxycarbonyl group (−Boc), and tertiary
amine groups. The formation of the urea derivatives was
confirmed to occur through the oxidation of the corresponding
Cu−NHCs, even though the sometimes tedious preparation of
Cu−NHC complexes is avoided in our method. Further
applications in the synthesis of potent compounds will be
disclosed in due course.
Urea through Oxidation of Cu−NHCs
When the reaction was run under argon atmosphere, Cu−NHC
3d was indeed obtained. After the reaction mixture was exposed
to air, the Cu−NHC decomposed quickly to give the oxidation
product 2d and the corresponding hydrolysis product. For the
decomposition of Cu−NHCs bearing saturated backbones with
N-aryl substituents, ring-opening products were also detected in
addition to imidazoliniums (Scheme 4).
C
DOI: 10.1021/acs.orglett.9b00973
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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.orglett.9b00973.
■
S
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Details of the synthetic procedures of the urea derivatives,
imidazoliums, imidazoliniums, and benzimidazoliums
1
and copies of H, 13C, and 19F NMR spectra for 1a−t
and 2a−t (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: thierry.ollevier@chm.ulaval.ca.
ORCID
Dazhi Li: 0000-0002-2907-7795
Thierry Ollevier: 0000-0002-6084-7954
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the Natural Sciences and Engineering
Research Council of Canada (NSERC) and the Centre in Green
Chemistry and Catalysis (CGCC) for financial support of our
program. D.L. thanks the China Scholarship Council (CSC) for
(19) Mooijman, M.; Bon, R. S.; Sprenkels, N. E.; van Oosterhout, H.
N.; de Kanter, F. J. J.; Groen, M. B.; Ruijter, E.; Orru, R. V. A. Synthesis
of Imidazolidine-2-(thi)ones via C2-Selective Oxidation and Thiona-
tion of 2-Imidazolinium Halides. Synlett 2012, 2012, 80.
́
(20) Bon, R. S.; Sprenkels, N. E.; Koningstein, M. M.; Schmitz, R. F.;
a doctoral scholarship. We thank Nour Tanbouza (Departement
̈
de Kanter, F. J. J.; Domling, A.; Groen, M. B.; Orru, R. V. A. Efficient C2
́
de chimie, Universite Laval) for proofreading the manuscript.
functionalisation of 2H-2-imidazolines. Org. Biomol. Chem. 2008, 6,
130.
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