Tetrasubstituted 2-imidazolones via ag(I)-catalyzed cycloisomerization of propargylic ureas

Article abstract of DOI:10.1021/jo200789t

A one-pot protocol based on a Ag(I)-catalyzed cycloisomerization of propargylic ureas, derived from secondary propargylamines and isocyanates, was developed for the generation of the 2-imidazolone core.

Full text of DOI:10.1021/jo200789t

NOTE
pubs.acs.org/joc
Tetrasubstituted 2-Imidazolones via Ag(I)-Catalyzed
Cycloisomerization of Propargylic Ureas
Vsevolod A. Peshkov,† Olga P. Pereshivko,† Sweta Sharma,†,‡ Thirumal Meganathan,‡
Virinder S. Parmar,‡ Denis S. Ermolat’ev,*,† and Erik V. Van der Eycken*,†
†Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, Katholieke Universiteit Leuven,
Celestijnenlaan 200F, B-3001 Leuven, Belgium
‡Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi-110 007, India
S Supporting Information
b
ABSTRACT: A one-pot protocol based on a Ag(I)-catalyzed cycloisomerization of
propargylic ureas, derived from secondary propargylamines and isocyanates, was
developed for the generation of the 2-imidazolone core.
he role of silver catalysis rapidly grows, providing novel
Table 1. Optimization of the One-Pot Formation of
2-Imidazolone 4a Starting from Methylpropargylamine (1a)
T
methodologies for CꢀC and CꢀX (X = O, N) bond
formation to address a wide range of synthetic targets.1 Ag(I)
salts are found to be efficient promoters for decarboxylative
transformations,2 modulators of the decomposition of diazo
compounds,3 and CꢀH activators of terminal alkynes.4 Of
particular interest are the Ag(I)-catalyzed heterocyclizations
involving the activation of the triple bond.5,6 These transforma-
tions allow to obtain a diverse set of O- and N-heterocycles
starting from readily available precursors.
entry
catalyst
conditions
yielda
1
2
3
4
5
6
7
MeCN, rt, 2 h
ꢀ (81)b
ꢀ (82)b
94
10 mol % AgOTf
10 mol % AgOTf
10 mol % AgOOCCF3
10 mol % AgSbF6
10 mol % AgNO3
10 mol % Cu(OTf)2
MeCN, rt, 2 h
We have recently described a rapid and diversity-oriented
Ag(I)-mediated synthesis of 2-iminoimidazolines via guanylation
of secondary propargylamines followed by 5-exo-dig cyclization.7
2-Iminoimidazolines possess a strong structural resemblance
with 2-imidazolones, which are widespread among pharmaceu-
tically interesting compounds such as human dopamine D4
receptor antagonists,8 MurB enzyme inhibitors,9 potential anti-
tumor agents,10 and antioxidants.11
MeCN, 80 °C, 2 h
MeCN, 80 °C, 2 h
MeCN, 80 °C, 2 h
MeCN, 80 °C, 2 h
MeCN, 80 °C, 2 h
86
89
76
8 (85)b
a Isolated yields are reported. b Isolated yield for the propargylic urea 3a
is given in parentheses.
Herein we wish to disclose the synthesis of 2-imidazolones
from secondary propargylamines and isocyanates via a one-pot
acylation, Ag(I)-catalyzed cycloisomerization procedure. To the
best of our knowledge, there is only one reported example
regarding the transition-metal-catalyzed ring closure of pro-
pargylic urea.12 In this process the 2-imidazolone core results
from a primary propargylamine and a tosyl isocyanate via
sequential acylation and Au(I)-catalyzed 5-exo-dig cyclization
followed by pTsOH-promoted double-bond migration.
We have started our study with the investigation of the
condensation between methylpropargylamine (1a) and phenyl
isocyanate (2a) in acetonitrile at 0ꢀ5 °C. This reaction appeared
to be very fast, delivering the propargylic urea 3a in a mere 5 min.
However, running the reaction for an additional 2 h at room
temperature did not provide the cycloisomerization product 4a,
but the propargylic urea 3a was obtained in 81% yield (Table 1,
entry 1). Also addition of Ag(I) catalyst at room temperature did
not result in the formation of 2-imidazolone 4a, and the
corresponding urea 3a was again isolated as the sole reaction
product (Table 1, entry 2). Gratifyingly, the desired 2-imidazo-
lone 4a was formed in high yields when the temperature was
increased to 80 °C employing 10 mol % of various Ag(I) catalysts
(Table 1, entries 3ꢀ6). The best result was obtained with AgOTf
(Table 1, entry 3). Performing the reaction with 10 mol % of
Cu(OTf)2 at 80 °C for the 2 h, the desired 2-imidazolone 4a was
isolated in a very low yield of 8% next to the 85% of the
uncyclized urea 3a (Table 1, entry 7). This is remarkable as
Received: April 18, 2011
Published: June 03, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
NOTE
Table 2. Isocyanate Substrate Scope for the One-Pot
Formation of 2-Imidazolones 4
Table 3. Adaption of the Protocol for the Synthesis of
Tetrasubstituted 2-Imidazolones
yielda
entry
conditions
time (h)
yielda
entry
R (isocyanate)
temp (°C)
product
1
2
3
4
5
MeCN, 80 °C
MeCN, 110 °C
DCE, 110 °C
toluene, 110 °C
toluene, 110 °C
2
2
2
2
4
tr, (81)b
18
1
2
3
4
5
6
7
8
9
Ph (2a)
80
80
4a
4b
4c
4d
4e
4f
94
93
p-Tol (2b)
PMP (2c)
p-FC6H4 (2d)
m-ClC6H4 (2e)
Hex (2f)
35
80
91
72
80
82
57
110
80
91
a Isolated yields are reported. b Isolated yield for the propargylic urea 3i is
34
given in parentheses.
Hex (2f)
110
80
4f
29
32 (42)b
Bn (2g)
4g
4h
1b,c,f bearing both an unbranched aliphatic R2-substituent and
an aromatic R3-substituent, provided good yields of the target
2-imidazolones 4iꢀm,rꢀt ranging from 50% to 72%. However
when propargylamine 1d was used, a significant drop of the yield
was observed. The corresponding 2-imidazolones 4n and 4o
were obtained in low yields of 33% and 32%, respectively,
probably due to the bulkiness of the branched R2-substituent.
When propargylamine 1e was used, the corresponding 2-imida-
zolones 4p and 4q were also obtained in low yields of 25% and
21%, respectively. This might be ascribed to the lower electro-
philicity of the triple bond bearing an aliphatic R3-substituent.
A plausible mechanism for the one-pot formation of the
2-imidazolones 4 is presented in Scheme 1. Propargylic urea 3,
derived from the corresponding propargylamine and isocyanate,
undergoes 5-exo-dig cyclization through transition state A. Sub-
sequent proton transfer in intermediate B provides the 2-imida-
zolone 40 bearing an exocyclic double bond. Finally, double-bond
migration results in the formation of the 2-imidazolone 4. We
presume that this migration process occurs very fast as the
formation of the intermediate 2-imidazolones 40 could not be
observed under the applied reaction conditions.16 However,
when reaction with methyl propargylamine (1a) and tosyl
isocyanate (2h) was performed in wet acetonitrile, both 40h
and 4h have been isolated in 52% and 20% yield, respectively
(Scheme 1). In order to verify the role of the Ag(I) catalyst in the
double-bond migration process, we set up two experiments
(Scheme 1). Heating a mixture of 40h with 10 mol % of AgOTf
in dry acetonitrile for 4 h at 80 °C resulted in full conversion into
4h. Running the same reaction in the absence of AgOTf resulted
in 90% conversion as was determined by 1H NMR. This indicates
that the Ag(I) catalyst might participate in the double-bond
migration process.
Ts (2h)
80
66
a Isolated yields are reported. b Isolated yield for the propargylic urea 3g
is given in parentheses.
Cu(OTf)2 is known to be an efficient triple bond activator for
ring-closure reactions with nitrogen nucleophiles.13
Having the optimized conditions at hand (Table 1, entry 3) we
evaluated the scope and limitations of our procedure, applying
various isocyanates 2 (Table 2). With aromatic isocyanates 2aꢀe
the corresponding 2-imidazolones 4aꢀe were obtained in high
yields ranging from 82% to 94% (Table 2, entries 1ꢀ5). For the
m-chlorophenyl isocyanate (2e) a higher temperature of 110 °C
was required to reach full conversion of the propagylic urea 3e into
the final 2-imidazolone 4e (Table 2, entry 5). The use of aliphatic
hexyl and benzyl isocyanates 2f,g resulted in low conversions of
intermediate ureas 3f,g into the corresponding 2-imidazolones 4f,
g, which were obtained in low yields of 34% and 32% respectively
(Table 2, entries 6 and 8). An attempt to improve the yield of 4f by
increasing the reaction temperature to 110 °C met with failure
(Table 2, entry 7). The reaction of methyl propargylamine (1a)
with tosyl isocyanate (2h) resulted in the formation of the
2-imidazolone 4h in a moderate yield of 66%.
Then we decided to adapt our protocol for the synthesis of
tetrasubstituted 2-imidazolones 4.14 We chose the reaction
between N-benzyl-1-phenylhex-1-yn-3-amine (1b) and phenyl
isocyanate (2a) as a model. The formation of the propargylic
urea 3i in acetonitrile occurred at 80 °C within 1 h. However,
after silver triflate addition and 2 h of further heating at the same
temperature, only traces of 2-imidazolone 4i could be observed
(Table 3, entry 1). Increasing the reaction temperature to 110 °C
resulted in the formation of 4i in a meager yield of 18% (Table 3,
entry 2). When the solvent was switched to DCE, an improved
yield of 35% was obtained (Table 3, entry 3). Gratifyingly,
reaction in toluene resulted in the isolation of the desired
2-imidazolone 4i in a good yield of 72% (Table 3, entry 4). A
further attempt to improve the conversion of urea 3i into 4i by
increasing the reaction time to 4 h resulted in a decreased yield of
57% (Table 3, entry 5).
In summary, we have elaborated an efficient one-pot protocol
for theconstruction of the 2-imidazolonecorestarting fromreadily
available secondary propargylamines. The key step of the process
is a Ag(I)-catalyzed cycloisomerization of an in situ formed
propargylic urea. The method allows the introduction of four
points of diversity in a concise way and can be potentially useful for
the synthesis of biologically active 2-imidazolone derivatives.
Next we applied this modified protocol for the generation of a
small library of tetrasubstituted 2-imidazolones. An array of
aromatic isocyanates and variously substituted propargylamines,
which are readily available via our recently reported A3-coupling
protocol,15 was successfully explored (Table 4). Propargylamines
’ EXPERIMENTAL SECTION
1H spectra and 13C NMR were recorded with 300 and 75 MHz
respectively unless otherwise noted. The 1H and 13C chemical shifts are
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The Journal of Organic Chemistry
NOTE
Table 4. Scope and Limitations of the Protocol for the Synthesis of Tetrasubstituted 2-Imidazolones
reported in parts per million relative to tetramethylsilane using the
residual solvent signal as the internal reference. High-resolution EI-
mass spectra were recorded with a resolution of 10 000. The ion
source temperature was 150ꢀ250 °C, as required. All microwave
irradiation experiments were carried out in a dedicated CEM-Dis-
cover monomode microwave apparatus, operating at a frequency of
2.45 GHz with continuous irradiation power from 0 to 300 W with
utilization of the standard absorbance level of 300 W maximum
power. The reactions were carried out in 10-mL glass tubes, sealed
with Teflon septum and placed in the microwave cavity. The reaction
was irradiated at a required ceiling temperature using maximum
power for the stipulated time. Then it was cooled to ambient
temperature with air jet cooling.
3.94 (d, J = 12.6 Hz, 1H), 3.79 (s, 3H), 3.73 (d, J = 12.6 Hz, 1H),
3.40ꢀ3.25 (m, 1H), 2.30ꢀ2.10 (m, 2H), 1.65ꢀ1.40 (m, 6H), 1.01 (t, J =
7.3 Hz, 3H), 0.91 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
δ 158.6, 132.5, 129.6, 113.7, 83.7, 81.7, 55.2, 50.8, 49.3, 38.6, 22.5,
20.8, 19.4, 13.9, 13.5; MS (ESI+) calcd for C17H25ON 259.2, found
260.7 [M + H]+.
N-Benzyl-1-phenyltridec-12-en-1-yn-3-amine (1f). Benzylamine
(214 mg, 2.0 mmol), undec-10-enal (337 mg, 2.0 mmol), phenyl
acetylene (409 mg, 4.0 mmol), copper bromide (76 mg, 0.4 mmol),
and toluene (2.0 mL) were loaded to a microwave vial equipped with
a magnetic stirring bar. The mixture was degassed and flushed with
argon. The reaction vessel was sealed and irradiated in the cavity of a
CEM-Discover microwave reactor for 25 min at a ceiling tempera-
ture of 100 °C and a maximum power of 80 W. The resulting reaction
mixture was cooled to ambient temperature and subjected to the
column chromatography with (EtOAc/hepthane, 1:4) to afford
Synthesis of Starting Propargylamines 1bꢀf. Propargyla-
mines 1b,d were synthesized following known procedure.15
General Procedure for the Synthesis of Propargylamines
1c,e. Amine (2.0 mmol), aldehyde (2.0 mmol), acetylene (4.0 mmol),
copper bromide (76 mg, 0.4 mmol) and toluene (2.0 mL) were loaded
to a glass tube with a screw cap. The mixture was degassed and flushed
with argon. The reaction vessel was conventionally heated with stirring
for 4 h at 100 °C. The resulting reaction mixture was cooled to ambient
temperature and subjected to the column chromatography with
(EtOAc-hepthane, 1:4) to afford the product.
1
propargylamine 2d (364 mg, 51%). H NMR (CDCl3, 300 MHz)
δ 7.50ꢀ7.16 (m, 10H), 5.90ꢀ5.67 (m, 1H), 5.06ꢀ4.82 (m, 2H),
4.08 (d, J = 12.8 Hz, 1H), 3.88 (d, J = 12.8 Hz, 1H), 3.66ꢀ3.43 (m,
1H), 2.10ꢀ1.93 (m, 2H), 1.80ꢀ1.61 (m, 2H), 1.59ꢀ1.21 (m, 12H);
13C NMR (CDCl3, 75 MHz) δ 140.2, 139.2, 131.7, 128.4, 128.3,
127.9, 127.0, 123.5, 114.2, 91.2, 84.0, 51.6, 50.1, 36.2, 33.9, 29.6,
29.5, 29.2, 29.0, 26.2; HRMS (EI) calcd for C26H33N 359.2613,
found 359.2602.
General Procedure for the Synthesis of the Imidazol-2-
ones 4aꢀh via One-Pot Acylation, Ag(I)-Catalyzed Cycloi-
somerization. To a solution of methylpropargylamine (1a) (69 mg,
1 mmol) in dry MeCN (2.5 mL) was added the appropriate isocyanate
2aꢀh (1.1 mmol) at 0ꢀ5 °C. The glass tube with reaction mixture was
degassed and flushed with argon. After 5 min of stirring, silver triflate
(26 mg, 0.1 mmol) was added, and the reaction mixture was sealed and
stirred for 2 h at 80 °C. Upon completion of reaction MeCN was
removed under reduced pressure. The crude product was loaded onto a
N-(4-Methoxybenzyl)-1-(thiophen-3-yl)pent-1-yn-3-amine (1c).
Yield 30%; 1H NMR (CDCl3, 300 MHz) δ 7.46ꢀ7.35 (m, 1H),
7.34ꢀ7.18 (m, 3H), 7.16ꢀ7.03 (m, 1H), 6.86 (d, J = 8.5 Hz, 2H),
4.00 (d, J = 12.7 Hz, 1H), 3.87ꢀ3.70 (m, 4H), 3.55ꢀ3.40 (m, 1H),
1.85ꢀ1.60 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 75
MHz) δ 158.7, 132.2, 130.1, 129.6, 128.2, 125.2, 122.4, 113.8, 90.5, 79.0,
55.3, 51.4, 51.0, 29.2, 10.6; HRMS (EI) calcd for C17H19ONS 285.1187,
found 285.1172.
N-(4-Methoxybenzyl)non-5-yn-4-amine (1e). Yield 24%; 1H NMR
(CDCl3, 300 MHz) δ 7.27 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H),
5869
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NOTE
Scheme 1. Plausible Mechanism for the One-Pot Formation
of the 2-Imidazolones 4a
3-(3-Chlorophenyl)-1,4-dimethyl-1H-imidazol-2(3H)-one (4e). Re-
action was run at 100 °C; yield 91%; H NMR (CDCl3, 300 MHz)
δ 7.45ꢀ7.27 (m, 3H), 7.25ꢀ7.15 (m, 1H), 6.09ꢀ5.99 (m, 1H), 3.26
(s, 3H), 1.93 (d, J = 1.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 152.9,
136.4, 134.6, 130.1, 127.8, 127.6, 125.6, 118.3, 109.2, 30.2, 11.1; HRMS
(EI) calcd for C11H11ClON2 222.0560, found 222.0558.
1
3-Hexyl-1,4-dimethyl-1H-imidazol-2(3H)-one (4f). Yield 34%; 1H
NMR (CDCl3, 300 MHz) δ 5.90ꢀ5.84 (m, 1H), 3.57 (t, J = 7.5 Hz,
2H), 3.20 (s, 3H), 2.06ꢀ2.00 (m, 3H), 1.68ꢀ1.52 (m, 2H), 1.36ꢀ1.22
(m, 6H), 0.88 (t, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 153.4,
118.2, 107.3, 41.1, 31.4, 29.9, 29.6, 26.4, 22.5, 14.0, 10.2; HRMS (EI)
calcd for C11H20ON2 196.1576, found 196.1569.
3-Benzyl-1,4-dimethyl-1H-imidazol-2(3H)-one (4g). Yield 32%; 1H
NMR (CDCl3, 300 MHz) δ 7.40ꢀ7.10 (m, 5H), 5.95ꢀ5.84 (m, 1H),
4.83 (s, 2H), 3.25 (s, 3H), 1.94ꢀ1.85 (m, 3H); 13C NMR (CDCl3, 75
MHz) δ 153.8, 137.7, 128.6, 127.3, 127.0, 118.6, 107.7, 44.5, 30.2, 10.4;
HRMS (EI) calcd for C12H14ON2 202.1106, found 202.1107.
1
1,4-Dimethyl-3-tosyl-1H-imidazol-2(3H)-one (4h). Yield 66%; H
NMR (CDCl3, 400 MHz) δ 7.95 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz,
2H), 5.92ꢀ5.86 (m, 1H), 3.05 (s, 3H), 2.41 (s, 3H), 2.30ꢀ2.24 (m,
3H); 13C NMR (CDCl3, 75 MHz) δ 151.0, 145.3, 135.5, 129.7, 128.0,
118.4, 111.8, 29.9, 21.7, 13.1; HRMS (EI) calcd for C12H14O3N2S
266.0725, found 266.0728.
General Procedure for the Synthesis of the Tetrasubsti-
tuted Imidazol-2-ones 4iꢀt via One-Pot Acylation, Ag(I)-
Catalyzed Cycloisomerization. To a solution of propargylamine
1bꢀf (0.33 mmol) in dry toluene (2.5 mL) was added the appropriate
isocyanate 2aꢀd (0.4 mmol). The glass tube with reaction mixture was
degassed and flushed with argon. After 1 h of heating at 110 °C, silver
triflate (17 mg, 0.07 mmol) was added, and the reaction mixture was
sealed and stirred for 2 h at 110 °C. The resulting reaction mixture was
cooled to ambient temperature and subjected to the column chroma-
tography with (EtOAc-/hepthane, 1:1) to afford imidazol-2-one 4iꢀt.
1,4-Dibenzyl-3-phenyl-5-propyl-1H-imidazol-2(3H)-one (4i). Yield
72%; 1H NMR (CDCl3, 300 MHz) δ 7.40ꢀ7.20 (m, 8H), 7.18ꢀ7.05
(m, 5H), 6.90ꢀ6.78 (m, 2H), 4.95 (s, 2H), 3.67 (s, 2H), 2.31 (t, J = 7.8
Hz, 2H), 1.46ꢀ1.29 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) δ 153.6, 138.3, 138.0, 135.3, 128.9, 128.7, 128.3,
128.0, 127.9, 127.6, 127.4, 127.0, 126.3, 120.6, 117.0, 44.8, 29.4, 25.6,
23.1, 13.9; HRMS (EI) calcd for C26H26ON2 382.2045, found 382.2049.
1,4-Dibenzyl-3-(4-methoxyphenyl)-5-propyl-1H-imidazol-2(3H)-
a Notes: (a) Yield was determined by 1H NMR due to contamination by
tosylamide, which was formed in wet acetonitrile as a byproduct. (b)
Isolated yield. (c) Determined by 1H NMR.
silica gel column for chromatography. The impurities were removed by
elution with EtOAc/hepthane, 1:1 followed by elution with DCM/
MeOH, 9:1 to provide the target imidazol-2-one 4aꢀh.
1
1,4-Dimethyl-3-phenyl-1H-imidazol-2(3H)-one (4a). Yield 94%; 1H
NMR (CDCl3, 300 MHz) δ 7.48ꢀ7.38 (m, 2H), 7.37ꢀ7.24 (m, 3H),
6.06ꢀ5.98 (m, 1H), 3.25 (s, 3H), 1.90 (d, J = 1.2 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) δ 153.1, 135.2, 129.1, 127.6, 127.4, 118.6, 108.7, 30.1,
11.0; HRMS (EI) calcd for C11H12ON2 188.0950, found 188.0957.
1,4-Dimethyl-3-p-tolyl-1H-imidazol-2(3H)-one (4b). Yield 93%; 1H
NMR (CDCl3, 300 MHz) δ 7.24 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 8.2 Hz,
2H), 6.04ꢀ5.94 (m, 1H), 3.26 (s, 3H), 2.37 (s, 3H), 1.94ꢀ1.82 (m,
3H); 13C NMR (CDCl3, 75 MHz) δ 153.3, 137.5, 132.6, 129.8, 127.3,
118.8, 108.4, 30.2, 21.1, 11.0; HRMS (EI) calcd for C12H14ON2
202.1106, found 202.1103.
one (4j). Yield 53%; H NMR (CDCl3, 300 MHz) δ 7.39ꢀ7.24 (m,
5H), 7.21ꢀ7.11 (m, 3H), 7.00 (d, J = 8.9 Hz, 2H), 6.91ꢀ6.84 (m, 2H),
6.80 (d, J = 8.9 Hz, 2H), 4.96 (s, 2H), 3.78 (s, 3H), 3.65 (s, 2H), 2.31 (t,
J = 7.9 Hz, 2H), 1.47ꢀ1.30 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 158.9, 153.8, 138.4, 138.1, 129.3, 128.7, 128.3,
128.1, 127.9, 127.3, 127.0, 126.3, 120.2, 117.4, 114.2, 55.5, 44.8, 29.4,
25.6, 23.1, 13.9; HRMS (EI) calcd for C27H28O2N2 412.2151, found
412.2157.
1,4-Dibenzyl-3-(4-fluorophenyl)-5-propyl-1H-imidazol-2(3H)-one
(4k). Yield 71%; 1H NMR (CDCl3, 300 MHz) δ 7.40ꢀ7.22 (m, 5H),
7.20ꢀ7.08 (m, 3H), 7.07ꢀ6.89 (m, 4H), 6.88ꢀ6.79 (m, 2H), 6.80 (d,
J = 8.9 Hz, 2H), 4.95 (s, 2H), 3.65 (s, 2H), 2.32 (t, J = 7.8 Hz, 2H),
1.48ꢀ1.31 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3, 75
MHz) δ 163.4, 160.2, 153.6, 138.0, 137.8, 131.3, 131.2, 129.9, 129.8,
128.7, 128.4, 127.8, 127.5, 126.9, 126.4, 120.7, 117.0, 116.0, 115.7, 44.9,
29.4, 25.6, 23.2, 13.9; HRMS (EI) calcd for C26H25ON2F 400.1951,
found 400.1953.
3-(4-Methoxyphenyl)-1,4-dimethyl-1H-imidazol-2(3H)-one (4c).
1
Yield 91%; H NMR (CDCl3, 300 MHz) δ 7.19 (d, J = 8.9 Hz, 2H),
6.95 (d, J = 8.9 Hz, 2H), 6.06ꢀ5.96 (m, 1H), 3.80 (s, 3H), 3.24 (s, 3H),
1.87 (d, J = 1.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 158.9, 153.3,
128.7, 127.9, 118.9, 114.4, 108.2, 55.4, 30.1, 10.8; HRMS (EI) calcd for
C12H14O2N2 218.1055, found 218.1073.
3-(4-Fluorophenyl)-1,4-dimethyl-1H-imidazol-2(3H)-one (4d). Yield
4-Ethyl-3-(4-methoxybenzyl)-1-phenyl-5-(thiophen-3-ylmethyl)-
1H-imidazol-2(3H)-one (4l). Yield 50%; 1H NMR (CDCl3, 400 MHz)
δ 7.39ꢀ7.24 (m, 5H), 7.19ꢀ7.13 (m, 3H), 6.90 (d, J = 8.6 Hz, 2H),
6.68ꢀ6.64 (m, 1H), 6.61ꢀ6.57 (m, 1H), 4.91 (s, 2H), 3.82 (s, 3H), 3.67
(s, 2H), 2.43 (q, J = 7.5 Hz, 2H), 1.05 (t, J = 7.5 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) δ 158.9, 153.4, 138.9, 135.3, 130.1, 128.9, 128.5,
1
82%; H NMR (CDCl3, 300 MHz) δ 7.32ꢀ7.20 (m, 2H), 7.19ꢀ7.05
(m, 2H), 6.05ꢀ5.97 (m, 1H), 3.26 (s, 3H), 1.92ꢀ1.88 (m, 3H); 13C NMR
(CDCl3, 75 MHz) δ 163.4, 160.2, 153.2, 131.21, 131.17, 129.3, 129.2,
118.6, 116.3, 116.0, 108.7, 30.2, 10.9; HRMS (EI) calcd for C11H11FON2
206.0855, found 206.0869.
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NOTE
127.8, 127.6, 127.5, 125.6, 121.4, 121.1, 116.4, 114.0, 55.3, 44.2, 24.3,
16.8, 14.5; HRMS (EI) calcd for C24H24O2N2S 404.1558, found
404.1574.
1,4-Dibenzyl-5-(dec-9-enyl)-3-(4-methoxyphenyl)-1H-imidazol-
2(3H)-one (4t). Yield 52%; 1H NMR (CDCl3, 400 MHz) δ 7.42ꢀ7.29
(m, 5H), 7.24ꢀ7.13 (m, 3H), 7.03 (d, J = 8.8 Hz, 2H), 6.95ꢀ6.88 (m,
2H), 6.83 (d, J = 8.8 Hz, 2H), 5.84 (ddt, J = 17.0, 10.3, 6.6 Hz, 1H),
5.08ꢀ4.92 (m, 4H), 3.80 (s, 3H), 3.66 (s, 2H), 2.34 (t, J = 7.8 Hz, 2H),
2.14ꢀ2.01 (m, 2H), 1.43ꢀ1.17 (m, 12H); 13C NMR (CDCl3, 100
MHz) δ 158.9, 153.8, 139.1, 138.5, 138.1, 129.3, 128.7, 128.3, 128.1,
127.9, 127.4, 127.0, 126.3, 120.4, 117.2, 114.2, 55.5, 44.8, 33.8, 29.8, 29.4,
29.3, 29.2, 29.0, 28.9, 23.7; HRMS (EI) calcd for C34H40O2N2 508.3090,
found 508.3091.
Spectral Data for Isolated Propargylic Ureas 3a,g,i. 1-
Methyl-3-phenyl-1-(prop-2-ynyl)urea (3a). Mixture of rotamers
∼9:1; 1H NMR (CDCl3, 300 MHz) δ 7.42ꢀ7.31 (m, 2H),
7.30ꢀ7.19 (m, 2H), 7.07ꢀ6.96 (m, 1H), 6.74 (bs, 1H), 4.14 (d, J =
2.1 Hz, 2H), 3.02 (s, 3H), 2.29 (t, J = 2.1 Hz, 0.9H), 2.03 (bs, 0.1H); 13C
NMR (CDCl3, 75 MHz) δ 155.4, 138.9, 128.8, 123.2, 120.3, 79.0, 72.5,
37.9, 34.2; MS (CI) calcd for C11H12ON2 188, found 189 [M + H]+.
3-Benzyl-1-methyl-1-(prop-2-ynyl)urea (3g). Mixture of rotamers
∼9:1; 1H NMR (CDCl3, 300 MHz) δ 7.37ꢀ7.17 (m, 5H), 5.09 (t, J =
5.6 Hz, 1H), 4.40 (d, J = 5.6 Hz, 2H), 4.10 (d, J = 2.4 Hz, 2H), 2.92 (s,
3H), 2.24 (t, J = 2.4 Hz, 0.9H), 2.15 (bs, 0.1H); 13C NMR (CDCl3, 75
MHz) δ 157.7, 139.5, 128.5, 127.6, 127.2, 79.3, 72.1, 44.9, 37.8, 33.7; MS
(CI) calcd for C12H14ON2 202, found 203 [M + H]+.
4-Ethyl-1-(4-fluorophenyl)-3-(4-methoxybenzyl)-5-(thiophen-3-
ylmethyl)-1H-imidazol-2(3H)-one (4m). Yield 58%; 1H NMR (CDCl3,
300 MHz) δ 7.24 (d, J = 8.5 Hz, 2H), 7.18ꢀ6.95 (m, 5H), 6.87 (d, J = 8.5
Hz, 2H), 6.67ꢀ6.61 (m, 1H), 6.60ꢀ6.53 (m, 1H), 4.88 (s, 2H), 3.79 (s,
3H), 3.61 (s, 2H), 2.41 (q, J = 7.5 Hz, 2H), 1.03 (t, J = 7.5 Hz, 3H); 13C
NMR (CDCl3, 75 MHz) δ 163.4, 160.1, 159.0, 153.5, 138.8, 131.30,
131.26, 130.0, 129.7, 129.6, 128.4, 127.4, 125.8, 121.5, 121.1, 116.3,
116.0, 115.7, 114.1, 55.3, 44.2, 24.3, 16.8, 14.5; HRMS (EI) calcd for
C24H23O2N2FS 422.1464, found 422.1468.
4-Benzyl-5-isobutyl-3-phenyl-1-propyl-1H-imidazol-2(3H)-one
(4n). Yield 33%; 1H NMR (CDCl3, 400 MHz) δ 7.31ꢀ7.23 (m, 3H),
7.19ꢀ7.11 (m, 3H), 7.10ꢀ7.04 (m, 2H), 6.90ꢀ6.82 (m, 2H), 3.71 (s,
2H), 3.66 (t, J = 7.6 Hz, 2H), 2.37 (d, J = 7.5 Hz, 2H), 1.93ꢀ1.74 (m,
3H), 1.04ꢀ0.95 (m, 9H); 13C NMR (CDCl3, 75 MHz) δ 153.1, 138.4,
135.4, 128.8, 128.2, 128.0, 127.8, 127.4, 126.2, 119.6, 117.1, 43.2, 32.5,
29.5, 28.8, 22.8, 22.4, 11.4; HRMS (EI) calcd for C23H28ON2 348.2202,
found 348.2195.
4-Benzyl-3-(4-fluorophenyl)-5-isobutyl-1-propyl-1H-imidazol-
2(3H)-one (4o). Yield 32%; 1H NMR (CDCl3, 400 MHz) δ 7.20ꢀ7.11
(m, 3H), 7.04ꢀ6.91 (m, 4H), 6.89ꢀ6.82 (m, 2H), 3.71ꢀ3.60 (m, 4H),
2.38 (d, J = 7.4 Hz, 2H), 1.94ꢀ1.73 (m, 3H), 1.05ꢀ0.94 (m, 9H); 13C
NMR (CDCl3, 75 MHz) δ 163.3, 160.1, 153.2, 138.1, 131.33, 131.29,
129.8, 129.7, 128.3, 127.8, 126.3, 119.7, 117.1, 115.8, 115.5, 43.2, 32.5,
29.5, 28.9, 22.8, 22.4, 11.3; HRMS (EI) calcd for C23H27ON2F
366.2107, found 366.2101.
1-Benzyl-3-phenyl-1-(1-phenylhex-1-yn-3-yl)urea (3i). 1H NMR
(CDCl3, 300 MHz) δ 7.61ꢀ7.06 (m, 14H), 7.05ꢀ6.90 (m, 1H), 6.45
(bs, 1H), 5.50 (t, J = 7.7 Hz, 1H), 4.85 (d, J = 17.1 Hz, 1H), 4.54 (d, J =
17.1 Hz, 1H), 1.95ꢀ1.75 (m, 2H), 1.72ꢀ1.42 (m, 2H), 1.00 (t, J = 7.3 Hz,
3H); 13CNMR(CDCl3, 75MHz) δ155.2, 138.9, 137.6, 131.5, 129.1, 128.7,
128.31, 128.26, 128.0, 126.9, 123.0, 122.6, 119.7, 87.9, 85.2, 48.7, 48.2, 36.9,
19.6, 13.7; MS (CI) calcd for C26H26ON2 382, found 383 [M + H]+.
4-Butyl-1-(4-methoxybenzyl)-5-propyl-3-p-tolyl-1H-imidazol-2(3H)-
1
one (4p). Yield 25%; H NMR (CDCl3, 400 MHz) δ 7.28ꢀ7.18 (m,
6H), 6.87 (d, J = 8.6 Hz, 2H), 4.85 (s, 2H), 3.81 (s, 3H), 2.40 (s, 3H),
2.35ꢀ2.25 (m, 4H), 1.47ꢀ1.36 (m, 2H), 1.18ꢀ1.08 (m, 4H), 0.92 (t, J =
7.3 Hz, 3H), 0.75 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
158.8, 153.6, 137.3, 133.2, 130.4, 129.7, 128.4, 127.5, 118.9, 118.6, 114.0,
55.3, 44.2, 31.1, 25.5, 23.2, 23.0, 22.1, 21.1, 13.9, 13.6; HRMS (EI) calcd
for C25H32O2N2 392.2464, found 392.2449.
’ ASSOCIATED CONTENT
1
Supporting Information. Copies of H and 13C NMR
S
b
spectra for compounds 4aꢀt and 3a,g,i. This material is available
free of charge via the Internet at http://pubs.acs.org.
4-Butyl-3-(4-fluorophenyl)-1-(4-methoxybenzyl)-5-propyl-1H-imi-
1
dazol-2(3H)-one (4q). Yield 21%; H NMR (CDCl3, 400 MHz) δ
’ AUTHOR INFORMATION
7.34ꢀ7.29 (m, 2H), 7.22 (d, J = 8.6 Hz, 2H), 7.18ꢀ7.12 (m, 2H), 6.87
(d, J = 8.6 Hz, 2H), 4.83 (s, 2H), 3.81 (s, 3H), 2.36ꢀ2.25 (m, 4H),
1.48ꢀ1.36 (m, 2H), 1.18ꢀ1.07 (m, 4H), 0.93 (t, J = 7.3 Hz, 3H), 0.75 (t,
J = 6.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 163.4, 160.1, 158.9,
153.5, 131.80, 131.76, 130.1, 129.5, 129.4, 128.4, 119.0, 118.7, 116.2,
115.9, 114.0, 55.3, 44.2, 31.1, 25.4, 23.2, 23.0, 22.1, 13.9, 13.6; HRMS
(EI) calcd for C24H29O2N2F 396.2213, found 396.2217.
Corresponding Author
*E-mail: denis.ermolatev@chem.kuleuven.be; erik.vandereycken@-
chem.kuleuven.be.
’ ACKNOWLEDGMENT
1,4-Dibenzyl-5-(dec-9-enyl)-3-phenyl-1H-imidazol-2(3H)-one (4r).
Yield 52%; 1H NMR (CDCl3, 400 MHz) δ 7.43ꢀ7.27 (m, 8H),
7.24ꢀ7.10 (m, 5H), 6.99ꢀ6.86 (m, 2H), 5.85 (ddt, J = 17.0, 10.3, 6.7
Hz, 1H), 5.10ꢀ4.90 (m, 4H), 3.71 (s, 2H), 2.36 (t, J = 7.8 Hz, 2H),
2.18ꢀ2.03 (m, 2H), 1.47ꢀ1.18 (m, 12H); 13C NMR (CDCl3, 75 MHz)
δ 153.5, 139.2, 138.4, 138.0, 135.3, 128.9, 128.7, 128.3, 128.0, 127.9,
127.6, 127.4, 127.0, 126.3, 120.8, 116.8, 114.2, 44.8, 33.8, 29.8, 29.4, 29.3,
29.2, 29.1, 28.9, 23.7; HRMS (EI) calcd for C33H38ON2 478.2984,
found 478.2981.
1,4-Dibenzyl-5-(dec-9-enyl)-3-(4-fluorophenyl)-1H-imidazol-2(3H)-
one (4s). Yield 54%; 1H NMR (CDCl3, 400 MHz) δ 7.43ꢀ7.29
(m, 5H), 7.24ꢀ7.14 (m, 3H), 7.10ꢀ6.95 (m, 4H), 6.94ꢀ6.84 (m,
2H), 5.84 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.12ꢀ4.90 (m, 4H), 3.67
(s, 2H), 2.36 (t, J = 7.8 Hz, 2H), 2.14ꢀ2.01 (m, 2H), 1.44ꢀ1.17 (m,
12H); 13C NMR (CDCl3, 75 MHz) δ 163.4, 160.1, 153.6, 139.1, 138.1,
137.9, 131.3, 131.2, 129.9, 129.8, 128.7, 128.4, 127.8, 127.5, 127.0, 126.4,
120.9, 116.8, 116.0, 115.6, 114.2, 44.9, 33.8, 29.8, 29.4, 29.3, 29.2,
29.0, 28.9, 23.6; HRMS (EI) calcd for C33H37ON2F 496.2890, found
496.2876.
Support was provided by the Fund for Scientific Research
(FWO)ꢀFlanders and by the Research Fund of the Katholieke
Universiteit Leuven. P.V.A. is grateful to the EMECW (Triple I)
for a doctoral scholarship.
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