Novel one-pot synthesis of imidazolinones from esters: A concise synthesis of GSK2137305

Article abstract of DOI:10.1039/c9ob02743b

A new copper-catalyzed one-pot reaction resulted in the practical synthesis of imidazolinones in moderate yields from esters. The use of inexpensive copper iodide as the catalyst, (NH₄)₂CO₃ as the nitrogen source and readi

Full text of DOI:10.1039/c9ob02743b

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Organic & Biomolecular Chemistry
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DOI: 10.1039/C9OB02743B
Novel one-pot synthesis of imidazolinones from ester: A
concise synthesis of GSK2137305
Naiguo Xing,[a] Jiangkun Huang,[a] Peng Wang,[a] Lan Luo,[a] Shilong Zheng[b] Ling He*[a]
a Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory
for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Department of Medicinal
Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041(P. R. China).b Department of
Chemistry and RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA
Supporting Information Placeholder
R1
O
two steps
R2
NH
One- Pot
N
N
Ar
MeO
N
CuI, MeOH
(NH4)2CO3
Ar
CF3
O
N
N
N
O
O
O
H
18 examples
R1
R2
GSK2137305
One-pot synthesis of imidazolinones
Protocol via C-H activation,C-N formation and condensation with ketone
18 samples,yields up to 85%
A concise approach to obtain GSK213705
ABSTRACT: A new copper-catalyzed one–pot reaction resulted in the practical synthesis of imidazolinones in moderate yield from
the ester. The use of inexpensive copper iodide as catalyst, (NH4)2CO3 as the nitrogen source and readily available starting
materials makes this process economically viable. Applying this protocol to the synthesis of GSK213705, a concise approach was
developed to obtain GSK213705 from the ester in only three steps with an overall yield of 26.9%.
Introduction
α-amination catalyzed by transition metal complexes,[13] which
is an attractive reaction for the synthesis of amine derivatives
and amino-functionalized heterocycles.
Imidazolinones are not only particularly relevant due to their
abundance in the chromophoric system of the green
fluorescent protein (GFP),[1] but also belong to a class of
herbicides.[2] Many natural and therapeutic products with other
biological activities also contain imidazolinone core,[3] such as
Kottamides A-D with antitumor activity,[4] SCH900822 with
hypoglycemic activity,[5] and GSK2137305, an effective and
selective glycine transporter type 1 (GlyT1) inhibitor for
R3
O
R1
HN
R4
N
HN
R2
H
N
O
Kottamides A-D
potential treatment of neuropsychiatric disorders.[6]
Some
N
Cl
Cl
O
N
imidazolinones and complexes of imidazolinones with
transition metals such as copper, rhodium, palladium and
ruthenium are excellent enantioselective catalysts for carbon-
carbon coupling reactions.[7,8] The importance of
imidazolinones led to the versatile methods for the formation
of imidazolinone core (Scheme 1).[1b,2,6,9]
N
NH
N
N
CF3
N
NH
O
O
N
O
N
N
N
H
In the past decade, metal-catalyzed C-H bond activation and
amination have been favored.[10-11] The activation energy of C-
H can be reduced by directly metal-catalyzed activation of the
C-H, which makes the reaction easier and simplifies the
synthetic process. We are interested in tandem metal-catalyzed
transformation for the heterocyclic synthesis,[12] especially the
GSK2137305
SCH900822
Figure 1. Structure of Bioactive Imidazolinones

Organic & Biomolecular Chemistry
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DOI: 10.1039/C9OB02743B
In this paper, we demonstrated that the phenylacetates,
initiated by a copper salt with inorganic (NH4)2CO3 as the
nitrogen source, form the divergent imidazolinones in one-pot
reaction. The approach provides a simple and rapid synthesis
of imidazolinones derivatives and has certain versatility. Thus,
it may provide a new convenient route to synthitic bioactive
imidazolinones.
for the reaction (Table 1, entry 3), however, if the amount of
CuI decreased from 10% to 5%, the reaction still maintain a
good yield (Table 1, entry 2 ).
The effect of reaction time on the reaction depends on the
structure of the substrate. It only takes 1 to 2 hours to get 3a
in 52% yield, prolonging the reaction time did not further
improve the yield significantly. However, the product 3n of
42% yield can be obtained by the reaction of 6 hours from
dichlorophenyl acetate 1n and a 12-hour reaction gave a yield
of 60% under the same other conditions.
Scheme 1 Versatile Methods for Imidazolinones Synthesis
Previous works
Table 1. Optimization of Reaction Conditions
O
O
R1
O
O
[O]
R2
R3
R1
NH2
N
HN
R2
H2N
N
NH
O
O
CuI
R3
+
O
O
(NH4)2CO3
O
3a
1a
2a
R1
R1
R3NH2
O
N R3
Amount of
CuI(%)
N
N
Entry
Solvent
Temperature(℃)
Yield(%)
R2
R2
R3
MeOH
MeOH
MeOH
THF
100
100
100
100
100
100
100
rt
10
5
52
1
O
O
O
50
2
Ph3P or Bu3P
R3
N
R1
N R2
0
NR
NR
NR
Trace
Trace
NR
Trace
26
3
N
N3 R2
R1
10
10
10
10
10
10
10
10
4
Toluene
DMSO
DMF
O
5
O
R1
+
[O]
NaCN, NH4
R2
R3
6
HN
R2
R1CHO
N
7
R3
MeOH
MeOH
MeOH
MeOH
8
This work
65
9
80
10
11
H
R
N
1 R2
N
N
O
120
45
CuI, (NH4)2CO3
O
N
Ar
NH
O
O
MeO
O
Mole ratio of methyl phenylacetate, acetone, catalyst, and (NH4)2CO3 was 1 : 1 : 0.1
: 20; NR: no product 3a was found; rt: room temperature.
Ar
F3C
R1
R2
N
N
GSK2137305
Next, maintaining other optimal reaction conditions not
changed, we investigate the effect of different metal catalysts
on the imidazolinone synthesis. Methyl 4-bromophenylacetate
1b was selected as substrate for the formation of
imidazolinone 3b which is the analogous of the key
intermediate 3c for the synthesis of GSK213705. The results
(Table 2) show that only copper catalysts are effective in this
one-pot reaction of methyl 4-bromophenylacetate and acetone
(Table 2, entries 2-7). Although dinitrato 1,10-phenanthrol-
ine copper (II) is a little better catalyst for the reaction, copper
iodide is still selected for the next step study due to its low
cost and environmental friendliness. As with 3a, 3b was not
found in the reaction without the catalyst (Table 1, entry 3；
Table 2, entry 1). The other metal catalysts, such as palladium,
ruthenium, and silver complexes, also failed to initiate the
reaction (Table 2, entries 8-11).
Results and discussion
Initially, we began to investigate the best reaction conditions by using
methyl phenylacetate 1a, acetone,CuI and (NH4)2CO3 under the
condition of heating (Table 1). The result (Table 1, entry 1)
shows that one-pot reaction of methyl phenylacetate and
acetone with (NH4)2CO3 nitrogen source was successfully
initiated by copper iodide to form the desired imidazolinone
3a. The structure of 3a was further confirmed by the X-ray
single crystal analysis (detailed crystal data is provided in the
Supporting Information).
In the meantime, we also studied the effects of solvent,
temperature, and the amount of catalyst CuI on the reaction
(Table 1). We replaced the methanol solvent with THF,
toluene, DMSO, and DMF. The results indicate that methanol
is only an effective solvent for the reaction, which may be
related the good solubility of ammonia in methanol. We could
not find any imidazolinone product 3a while we used THF or
toluene as solvent (Table 1, entries 4, 5). Similarly, there was
only trace amounts of the product to form in the reaction with
DMSO or DMF as solvent (Table 1, entries 6, 7). The effect of
reaction temperature displays that the optimal temperature was
100 oC and the yield declined at higher (120 oC, Table 1, entry
Table 2. Selection of Catalysts.
(NH4)2CO3
N
O
100oC,MeOH
NH
O
O
Catalyst (10%)
Br
O
Br
2a
1b
3b
Entry
1
Catalyst
--
Yield(%)
NR
o
11) or lower reaction temperatures (room temperature, 65 C,
and 80 oC, Table 1, entries 8-10). The catalyst CuI is necessary

Page 3 of 8
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DOI: 10.1039/C9OB02743B
CuI
85
84
83
72
82
GSK2137305, but the key imidazolinone intermediate has a
yield of only 33%, resulting in only 1.4% of overall yield for
the six-step synthesis approach.[15] Subsequently, we applied
our new imidazolinone synthesis to the synthesis of
GSK2137305 (Scheme 3).
2
3
4
5
6
CuCl2
[Cu(CH3CN)4]ClO4
Cu
CuBr
The synthesis of GSK2137305 was completed as shown in
Scheme 3. The key step in the three-step synthesis is the
formation of imidazolinone 3c, which was carried out from
commercially available methyl 4-bromophenylacetate 1b and
cyclopentanone with ammonium carbonate as nitrogen source
under copper iodide catalysis in 40% yield. Compared with
previous synthesis of 3c,[9b,14] the new synthesis of 3c avoided
the use of NaCN and greatly increased the yield. N-arylation
of 4-methylimidazole with 3c followed the reference
procedure,[14] however, the less expensive bis(dibenzylidene-
acetone)Pd catalyst not original Pd2(dba)3 was used to achieve
nearly similar yield (85% yield). Subsequent substitution
reaction of 4 easily formed GSK2137305 in DMF in 79%
yield. A total yield of 26.9% was obtained for the synthesis of
GSK2137305 in three steps from commercially available 1b.
87
N
Cu2+
(NO3)2
N
7
Pd(acac)2
NR
NR
NR
NR
8
Ru3(CO)12
AgCF3SO3
Yb(CF3SO3)3
9
10
11
NR: no product 3b was found
Furtherly, we explored the scope of the new imidazolinone
synthesis, eighteen imidazolinones were obtained from
different substrates under the optimized conditions in which
the reaction for the imidazolinone synthesis was carried out in
MeOH at 100 oC for 2~12h with mole ratio of methyl
phenylacetate, acetone, CuI, and (NH4)2CO3 of 1 : 1 : 0.1 :
20.We applied four different methyl phenylacetate compounds
and a variety of ketones as substrates to the cyclization
reaction.
Scheme 3. Synthesis of GSK2137305
H
N
O
N
NH
O
NH
N
CF3
O
N
O
N
O
O
c
a
b
Scheme 2 Formation of Divergent Imidazolinones from the
Ester
Br
N
N
Br
3c
R1
R2
N
1b
N
(NH4)2CO3
CuI (10%)
N
GSK2137305
NH
4
O
O
MeOH, 100oC
R
R
O
R1
R2
O
1
2
3
a. cyclopentanone, (NH4)2CO3, 10%CuI, MeOH, 40% yield. b. 4-methyl-1H-
imidazole,bis(dibenzylideneacetone)Pd, L1(0.2%), K3PO4(2.0 eq.), toluene-dioxane
（1：1）, 85% yield. c. 2-chloro-N-(3-(trifluoromethyl) phenyl) acetamide, NaH（
2.5 eq.), DMF, 79% yield.
Br
Br
Br
Br
N
N
N
N
N
NH
NH
3e 52%
NH
NH
40%
O
NH
O
O
O
O
3d 56%
During the imidazolinone synthesis reaction, we examined the
reaction mixture and detected the presence of the intermediate
F by LC-MS. Meanwhile, the effects of air and trace amount
water on the reaction were also investigated. In the absence of
air or water, only trace target product was obtained, indicating
that the oxygen was beneficial to this reaction. It may also
mean that α-oxidation is easier than α-amination. Therefore,
we speculed a possible pathway of imidazolinone synthesis, as
shown in Scheme 4. The novel imidazolinone synthesis
possibly occurred via α-imination of the ester by C-H
activation oxidation affording α-oxophenyl acetic ester in the
presence of copper salt[16], followed by a formation of imino
group due to the amine source, and aminolysis then a
following condensation reaction with ketone.
85%
3c
3b
3a 52%
Br
Br
Ph
Br
(CH2)5CH3
Br
Ph
N
N
N
N
N
NH
NH
NH
NH
O
O
3h 52%
O
O
CH2CH3
NH
O
3j 43%
Cl
41%
3i
3g
46%
55%
3f
Cl
Ph
N
N
N
N
Ph
N
Cl
Cl
NH
NH
NH
NH
NH
O
O
O
O
O
3k
53%
40%
3l
3m 43%
3o 46%
3n 60%
Cl
Cl
Br
O
O
Ph
N
(CH2)5CH3
CH2CH3
N
N
Cl
Cl
NH
NH
NH
O
O
O
3a
3q
3r 32%
51%
3p
41%
Scheme 4. Conjecture on the formation pathway of
Imidazolinone
The initial eight-step synthesis of GSK2137305 provided <5%
yield of crude product and must be further purified by
preparative HPLC to remove a regioisomeric impurity.[6] An
improved four-stage synthesis using a highly toxic reagent
NaCN has an overall yield of 12% for GSK2137305,[9b] which
was further optimized in its third step to increase overall yield
to 25.7%, but the use of NaCN could not be excluded.[14] Zhao,
et al developed
a new method for the synthesis of

Organic & Biomolecular Chemistry
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8.37 (m, 2H), 7.56-7.45 (m, 3H), 1.60D(Os,I: 610H.1)0.3193/CC9NOMB0R274(130B0
MHz, Chloroform-d) δ 165.2, 160.9, 131.8, 130.1, 128.5,
128.5, 80.3, 27.0. HRMS (ESI) m/z calcd for C11H13N2O
(M+H+): 189.1028, found: 189.1022.
(NH4)2CO3
NH3
OEt
O
[Cu(II)(NH3)n]2+
Cu(II)
Cu(II)
O2
O
OH
H+
5-(4-Bromophenyl)-2,2-dimethyl-2,3-dihydro-4H-imidazol-4-
N
NH2
one (3b)
Cu(I)
NH
O
Cu(II)(NH3)n
OEt
NH2
Prepared according to the general procedure. Methyl 4-
bromophenylacetate(85 mg, 0.37 mmol) and acetone(21 mg,
0.37 mmol) were employed to give 3b (84 mg, 85%) as a
O2
NH3
O
H2O
O
OEt
F
O
A
O
N
NH3
NH
O
1
white solid. H NMR (400 MHz, Chloroform-d) δ 9.12 (s,
H+
H2N
Cu(II)(NH3)n-1
OEt
1H), 8.29 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 1.60 (s,
6H). 13C NMR (100 MHz, Chloroform-d) δ 165.4, 160.1,
131.7, 129.9, 129.3, 126.4, 80.7, 26.9. HRMS (ESI) m/z calcd
for C11H12BrN2O (M+H+): 267.0133, found: 267.0126.
3-(4-Bromophenyl)-1,4-diazaspiro[4.4]non-3-en-2-one (3c)
Prepared according to the general procedure. Methyl 4-
bromophenylacetate(85 mg, 0.37 mmol) and cyclopentanone
(31 mg, 0.37 mmol. It is noted that the increase of the ratio of
cyclopentanone will reduce the yield.) were employed to give
3c (43 mg, 40%) as a taupe solid.1H NMR (400 MHz,
Chloroform-d) δ 8.70 (s, 1H), 8.29 (d, J = 8.1 Hz, 2H), 7.60
(d, J = 8.1Hz, 2H), 2.15-2.02 (m, 4H), 1.94 (m, 4H). 13C NMR
(100 MHz, Chloroform-d) δ 165.3, 159.4, 131.7, 129.7, 129.5,
126.3, 90.4, 37.5, 24.4. HRMS (ESI) m/z calcd for
C13H14BrN2O (M+H+): 293.0290, found: 293.0283.
Cu(I)(NH3)n-1
O
H2N
B
O
NH2
E
Cu(I)
Cu(III)(NH3)n-1
OEt
Cu(I)(NH3)n-1
H2N
H2N
NH3
O
O
OEt
C
D
Conclusion
In summary, we have developed a novel imidazolinone
synthesis process, which is carried out from commercially
available esters and ketones with inorganic ammonium
carbonate as nitrogen source under the catalysis of less
expensive copper iodide in moderate yield. This reaction is
environmentally friendly and easy to control. The method was
applied to the synthesis of GSK2137305 and a concise
preparation approach to GSK2137305 was developed with a
much higher overall yield from readily available starting
materials.
5-(4-Bromophenyl)-2-ethyl-2-methyl-2,3-dihydro-4H-
imidazol-4-one (3d)
Prepared according to the general procedure. Methyl 4-
bromophenylacetate(85 mg, 0.37 mmol) and 2-butanone (27
mg, 0.37 mmol) were employed to give 3d (58 mg, 56%) as a
yellowish solid.1H NMR (400 MHz, Chloroform-d) δ 8.71 (s,
1H), 8.29 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 1.94 (q,
J = 7.4 Hz, 2H), 1.57 (s, 3H), 0.86 (t, J = 7.4 Hz, 3H). 13C
NMR (100 MHz, Chloroform-d) δ 165.6, 160.5, 131.7, 129.9,
129.3, 126.4, 83.1, 32.6, 25.3, 7.9. HRMS (ESI) m/z calcd for
C12H14BrN2O (M+H+): 281.0290, found: 281.0283.
5-(4-Bromophenyl)-2-isobutyl-2-methyl-2,3-dihydro-4H-
imidazol-4-one (3e)
Prepared according to the general procedure. Methyl 4-
bromophenylacetate(85 mg, 0.37 mmol) and 4-methyl-2-
pentanone (37 mg, 0.37 mmol) were employed to give 3e (59
Experimental section
General Information. All reactions were carried out under air
atmosphere, unless otherwise mentioned. Commercially
available materials were used as received without further
purification. Reactions were monitored by thin-layer
chromatography (TLC) carried out on commercial silica gel
plates using UV light as a visualizing agent . Commercial
silica gel was used for column chromatography. H and 13C
1
NMR spectra were recorded on 400 MHz or 600 MHz
spectrometer. 1H NMR spectra were referenced to
Chloroform-d (7.26 ppm) or DMSO-d6 (2.50 ppm), and
reported as follows; chemical shift, multiplicity (s = singlet, d
= doublet, t = triplet, q = quartet, m = multiplet). Chemical
shifts of the 13C NMR spectra were measured relative to
Chloroform-d (77.23 ppm) or DMSO-d6(39.51 ppm). Mass
spectral data were obtained from Bruker Daltonics Data
analysis 3.2 mass spectrometer. X-Ray data were collected on
a Bruker APEX-II equipped with a CCD area detector using
Mo/Kα radiation. The structures were solved by direct method
using SHELXL-97.
mg, 52%) as
a
yellowish solid.1H NMR (400 MHz,
Chloroform-d) δ 9.01 (s, 1H), 8.29 (d, J = 8.6 Hz, 2H), 7.60
(d, J = 8.6 Hz, 2H), 1.88 -1.78 (m, 2H), 1.55 (s, 3H), 0.89 (m,
7H). 13C NMR (100 MHz, Chloroform-d) δ 165.7, 160.2,
131.8, 129.9, 129.5, 126.4, 83.2, 48.1, 26.4, 24.3, 24.2, 23.9.
HRMS (ESI) m/z calcd for C14H18BrN2O (M+H+): 309.0603,
found: 309.0595.
5-(4-Bromophenyl)-2-ethyl-2-hexyl-2,3-dihydro-4H-imidazol-
4-one (3f)
Prepared according to the general procedure. Methyl 4-
bromophenylacetate(85 mg, 0.37 mmol) and 3-nonanone (53
mg, 0.37 mmol) were employed to give 3f (60 mg, 46%) as a
yellow liquid.1H NMR (400 MHz, Chloroform-d) δ 8.96 (s,
1H), 8.28 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 2.00–
1.85 (m, 4H), 1.24 (m, 8H), 0.81 (m, 6H). 13C NMR (100
MHz, Chloroform-d) δ 166.0, 160.9, 131.7, 129.8, 129.3,
126.3, 85.4, 37.9, 31.5, 31.2, 29.2, 22.9, 22.5, 13.9, 7.5.
HRMS (ESI) m/z calcd for C17H24BrN2O (M+H+): 351.1072,
found: 351.1065.
5-(4-Bromophenyl)-2-methyl-2-phenethyl-2,3-dihydro-4H-
imidazol-4-one (3g)
Prepared according to the general procedure. Methyl 4-
bromophenylacetate(85 mg, 0.37 mmol) and benzylacetone
(55 mg, 0.37 mmol) were employed to give 3g (73 mg, 55%)
as a yellow solid. 1H NMR (400 MHz, Chloroform-d) δ 10.05
General procedures for imidazolinones 3
A 25ml sealed tube was charged with CuI (10 mmol %),
carboxylic ester (0.37 mmol), ketone (0.37 mmol), (NH4)2CO3
(7.4 mmol), and MeOH (2 mL), the mixture was stirred at
100℃ in an oil bath for 2-12h. After disappearance of the
reactant (monitored by TLC) , the reaction mixture was
filtered and the filtrate was concentrated under reduced
pressure.The crude residue was purified by silica gel
chromatography using petroleum ether/ ethyl acetate as eluent
to give pure product 3.
2,2-Dimethyl-5-phenyl-2,3-dihydro-4H-imidazol-4-one (3a)
Prepared according to the general procedure. Methyl
phenylacetate(55 mg, 0.37 mmol) and acetone(21 mg, 0.37
mmol) were employed to give 3a (36 mg, 52%) as a white
solid. 1H NMR (400 MHz, Chloroform-d) δ 8.79 (s, 1H), 8.42-

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DOI: 10.1039/C9OB02743B
(s, 1H), 8.28 (d, J = 6.9 Hz, 2H), 7.71 (d, J = 6.9 Hz, 2H), 7.24
(t, J = 7.5 Hz, 2H), 7.15 (m , 3H), 2.56-2.33 (m, 2H), 2.08 (m,
2H), 1.49 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 164.3,
160.4, 141.4, 131.8, 130.1, 129.9, 128.5, 128.3, 126.0, 125.6,
81.9, 40.9, 29.5, 25.9. HRMS (ESI) m/z calcd for
C18H18BrN2O (M+H+): 357.0603, found:357.0569.
0.37 mmol) were employed to give 3m (32 mg, 43%) as a
white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.29 (d, J =
7.9 Hz, 2H), 7.28 (d, J = 7.9 Hz, 2H), 2.41 (s, 3H), 1.59 (s,
6H). 13C NMR (100 MHz, Chloroform-d) δ 165.8, 160.8,
141.9, 129.2, 128.3, 127.8, 80.3, 27.0, 21.6. HRMS (ESI) m/z
calcd for C12H15N2O (M+H+): 203.1184, found: 203.1177.
5-(3,5-Dichlorophenyl)-2,2-dimethyl-2,3-dihydro-4H-imidaz-
ol-4-one (3n)
5-(4-Bromophenyl)-2-methyl-2-phenyl-2,3-dihydro-4H-
imidazol-4-one(3h)
Prepared according to the general procedure. Methyl 4-
bromophenylacetate(85 mg, 0.37 mmol) and acetophenone (45
mg, 0.37 mmol) were employed to give 3h (63 mg, 52%) as a
Prepared according to the general procedure. Methyl 2-(3,5-
dichlorophenyl)acetate (81 mg, 0.37 mmol) and acetone(21
mg, 0.37 mmol) were employed to give 3n (57 mg, 60%) as a
1
1
white solid. H NMR (400 MHz, Chloroform-d) δ 10.70 (s,
white solid. H NMR (400 MHz, Chloroform-d) δ 9.41 (s,
1H), 8.32 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.54
(d, J = 7.7 Hz, 2H), 7.35 (m, 3H), 1.77 (s, 3H). 13C NMR (100
MHz, DMSO-d6) δ 164.1, 159.6, 141.3, 137.6, 131.7, 130.0,
129.5, 128.5, 127.9, 125.6, 83.1, 28.6. HRMS (ESI) m/z calcd
for C16H14BrN2O (M+H+): 329.0290, found: 329.0283.
5-(4-Bromophenyl)-2-ethyl-2-(p-tolyl)-2,3-dihydro-4H-
imidazol-4-one(3i)
1H), 8.34 (d, J = 2.0 Hz, 2H), 7.50 (t, J = 2.0 Hz, 1H), 1.62 (s,
6H). 13C NMR (100 MHz, Chloroform-d) δ 164.8, 158.9,
135.2, 133.1, 131.3, 126.6, 81.1, 26.8. HRMS (ESI) m/z calcd
for C11H11Cl2N2O (M+H+): 257.0248, found: 257.0242.
5-(3,5-Dichlorophenyl)-2-ethyl-2-methyl-2,3-dihydro-4H-imi-
dazol-4-one (3o)
Prepared according to the general procedure. Methyl 2-(3,5-
dichlorophenyl)acetate (81 mg, 0.37 mmol) and 2-butanone
(27 mg, 0.37 mmol) were employed to give 3o (46 mg, 46%)
as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 9.05 (s,
1H), 8.33 (d, J = 1.9 Hz, 2H), 7.50 (t, J = 1.9 Hz, 1H), 1.96 (q,
J = 7.6 Hz, 2H), 1.59 (s, 3H), 0.87 (t, J = 7.6 Hz, 3H). 13C
NMR (100 MHz, Chloroform-d) δ 165.0, 159.3, 135.2, 133.0,
131.2, 126.6, 83.5, 32.5, 25.1, 7.85. HRMS (ESI) m/z calcd
for C12H13Cl2N2O (M+H+): 271.0405, found: 271.0399.
5-(3,5-Dichlorophenyl)-2-ethyl-2-hexyl-2,3-dihydro-4H-
imidazol-4-one (3p)
Prepared according to the general procedure. Methyl 2-(3,5-
dichlorophenyl)acetate (81 mg, 0.37 mmol) and 3-nonanone
(53 mg, 0.37 mmol) were employed to give 3p (52 mg, 41%)
as a yellow liquid.1H NMR (400 MHz, Chloroform-d) δ 8.90
(s, 1H), 8.34 (d, J = 1.9 Hz, 2H), 7.50 (d, J = 1.9 Hz, 1H),
2.00-1.88 (m, 4H), 1.25 (m, 8H), 0.82 (m, 6H). 13C NMR (100
MHz, Chloroform-d) δ 165.4, 159.6, 135.2, 133.0, 131.2,
126.6, 85.8, 37.9, 31.5, 31.1, 29.2, 23.0, 22.5, 13.9, 7.4.
HRMS (ESI) m/z calcd for C17H23Cl2N2O (M+H+): 341.1187,
found: 341.1179.
Prepared according to the general procedure. Methyl 4-
bromophenylacetate(85
mg,
0.37
mmol)
and
4-
methylpropiophenone (55 mg, 0.37 mmol) were employed to
1
give 3i (54 mg, 41%) as a yellow solid. H NMR (400 MHz,
Chloroform-d) δ 10.03 (s, 1H), 8.35 (d, J = 8.3 Hz, 2H), 7.59
(d, J = 8.3 Hz, 2H), 7.46 (d, J = 7.9 Hz, 2H), 7.17 (d, J = 7.9
Hz, 2H), 2.33 (s, 3H), 2.30–2.10 (m, 2H), 0.86 (t, J = 7.3 Hz,
3H). 13C NMR (100 MHz, Chloroform-d) δ 166.3, 160.0,
137.9, 137.2, 131.7, 130.0, 129.3, 129.2, 126.5, 125.9, 87.2,
34.7, 21.0, 8.1. HRMS (ESI) m/z calcd for C18H18BrN2O
(M+H+): 357.0603, found: 357.0596.
2-Ethyl-2-methyl-5-phenyl-2,3-dihydro-4H-imidazol-4-one
(3j)
Prepared according to the general procedure. Methyl
phenylacetate(55 mg, 0.37 mmol) and 2-butanone (27 mg,
0.37 mmol) were employed to give 3j (32 mg, 43%) as a white
1
solid. H NMR (400 MHz, Chloroform-d) δ 8.38 (d, J = 6.6
Hz, 2H), 8.02 (s, 1H), 7.56-7.43 (m, 3H), 1.95 (q, J = 7.5 Hz,
2H), 1.58 (s, 3H), 0.86 (t, J = 7.5Hz, 3H). 13C NMR (100
MHz, CDCL3) δ 166.1, 161.5, 131.4, 130.5, 128.5, 128.3,
82.9, 32.5, 25.3, 7.9. HRMS (ESI) m/z calcd for C12H15N2O
(M+H+): 203.1184, found: 203.1179.
5-(3,5-Dichlorophenyl)-2-methyl-2-phenethyl-2,3-dihydro-4H-
imidazol-4-one (3q)
Prepared according to the general procedure. Methyl 2-(3,5-
dichlorophenyl)acetate (81 mg, 0.37 mmol) and benzylacetone
(55 mg, 0.37 mmol) were employed to give 3q (65 mg, 51%)
as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.67 (s,
1H), 8.24 (d, J = 2.0 Hz, 2H), 7.43 (t, J = 2.0 Hz, 1H), 7.22-
7.13 (m, 2H), 7.13 -7.03 (m, 3H), 2.49 (m, 2H), 2.28– 2.09 (m,
2H), 1.56 (s, 3H). 13C NMR (150 MHz, Chloroform-d) δ
164.9, 159.5, 140.6, 135.3, 132.9, 131.4, 128.5, 128.2, 126.7,
126.2, 82.9, 40.8, 29.9, 25.8. HRMS (ESI) m/z calcd for
C18H17Cl2N2O (M+H+): 347.0718, found: 347.0709.
2-Methyl-2-phenethyl-5-phenyl-2,3-dihydro-4H-imidazol-4-
one (3k)
Prepared according to the general procedure. Methyl
phenylacetate(55 mg, 0.37 mmol) and benzylacetone (55 mg,
0.37 mmol) were employed to give 3k (55 mg, 53%) as a
yellow solid.1H NMR (400 MHz, Chloroform-d) δ 9.18 (s,
1H), 8.42 (d, J = 7.5 Hz, 2H), 7.51 (m, 3H), 7.24 (m, 2H), 7.15
(m, 3H), 2.59 (m, 2H), 2.28 (m, 2H), 1.65 (s, 3H). 13C NMR
(100 MHz, Chloroform-d) δ 166.0, 161.6, 140.9, 131.6, 130.4,
128.5, 128.4, 128.3, 128.2, 125.9, 82.5, 41.1, 29.8, 25.9.
HRMS (ESI) m/z calcd for C18H19N2O (M+H+): 279.1497,
found: 279.1490.
11-(4-Bromophenyl)-1,4-dioxa-9,12-diazadispiro[4.2.48.25]
tetradec-11-en-10-one (3r)
Prepared according to the general procedure. Methyl 4-
bromophenylacetate(85 mg, 0.37 mmol) and 1,4-
dioxaspiro[4.5]decan-8-one (58 mg, 0.37 mmol) were
employed to give 3r (43 mg, 32%) as a white solid.1H NMR
(400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.28 (d, J = 8.2 Hz,
2H), 7.71 (d, J = 8.2 Hz, 2H), 3.91 (s, 4H), 2.05- 1.50 (m,
8H).13C NMR (101 MHz, DMSO-d6) δ 164.1, 160.3, 131.8,
130.1, 130.0, 125.6, 107.4, 81.3, 64.0, 34.4, 31.5. HRMS
(ESI) m/z calcd for C16H18BrN2O3 (M+H+): 365.0501, found:
365.0493.
2-Methyl-2,5-diphenyl-2,3-dihydro-4H-imidazol-4-one (3l)
Prepared according to the general procedure. Methyl
phenylacetate(55 mg, 0.37 mmol) and acetophenone (45 mg,
0.37 mmol) were employed to give 3l (37 mg, 40%) as a white
solid. 1H NMR (400 MHz, Chloroform-d) δ 9.77 (s, 1H),
8.50–8.42 (m, 2H), 7.62-7.44 (m, 5H), 7.42-7.30 (m, 3H), 1.94
(s, 3H). 13C NMR (100 MHz, Chloroform-d) δ 166.1, 160.8,
140.7, 131.7, 130.4, 128.7, 128.6, 128.5, 128.2, 125.6, 83.8,
28.7. HRMS (ESI) m/z calcd for C16H15N2O (M+H+):
251.1184, found: 251.1177.
Synthetic procedures and spectra data of 3-(4-(4-methyl-1H-
imidazol-1-yl)phenyl)-1,4-diazaspiro[4.4]non-3-en-2-one. An
oven-dried vial was equipped with a magnetic stir bar and
2,2-Dimethyl-5-(p-tolyl)-2,3-dihydro-4H-imidazol-4-one (3m)
Prepared according to the general procedure. Methyl 4-
methylphenylacetate(61 mg, 0.37 mmol) and acetone(21 mg,

Organic & Biomolecular Chemistry
Page 6 of 8
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DOI: 10.1039/C9OB02743B
charged with Pd(dba)2 (0.3 mg, 0.0005 mmol) and L1 (0.5 mg,
Corresponding author
0.001 mmol). The vial was sealed with a screw-cap septum,
and then evacuated and backfilled with argon (this process
was repeated a total of 3 times). Then, toluene (0.5 mL) was
added via syringe. This dark purple mixture was stirred at 115
°C for 10 min. A second oven-dried vial which was equipped
with stir bar was charged with 1a (30 mg, 0.1 mmol), 4-
methylimidazole (17 mg, 0.2 mmol) and K3PO4 (42mg, 0.2
mmol). The vial was sealed with a screw-cap septum, and then
evacuated and backfilled with argon (this process was repeated
a total of 3 times). 0.2 mL of the premixed catalyst solution
was transferred to the second vial via syringe and then toluene
(0.4 mL) and dioxane (0.6 mL) were added to the second vial.
The reaction was heated at 115 °C for 12 h. The reaction
mixture was cooled to room temperature, diluted with EtOAc,
washed with brine, dried over MgSO4, concentrated in vacuo
and purified via silica gel chromatography (EtOAc) to provide
*heling2012@scu.edu.cn
(Word Style “FA_Corresponding_Author_Footnote”). Give
contact information for the author(s) to whom correspondence
should be addressed.
Present addresses
†If an author’s address is different than the one given in the
affiliation line, this information may be included here.
Author contributions
The manuscript was written through contributions of all authors. /
All authors have given approval to the final version of the
manuscript.
/ ‡These authors contributed equally. (match
statement to author names with a symbol)
Notes
Any additional relevant notes should be placed here.
1
the title compound as a white solid (26 mg, 85%), H NMR
(400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.42 (d, J = 8.4 Hz,
2H), 8.27 (s, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.55 (s, 1H), 2.17
(s, 3H), 1.97–1.81 (m, 8H).13C NMR (150 MHz, DMSO-d6)
δ 164.5, 159.2, 139.4, 139.3, 135.2, 129.9, 128.9, 119.7,
114.2, 90.1, 37.6, 24.3, 14.0.HRMS (ESI) m/z calcd for
C17H19N4O (M+H+): 295.1559, found: 295.1553
Acknowledgments
We gratefully acknowledge the financial support from the
National Science Foundation of China (No. 21072131) and
Sichuan University–Lu Zhou Strategic Cooperation Projects (No.
2017 CDLZ-S34).
Synthesis of GSK 2137305. An oven-dried vial was equipped
with a stir bar and charged with 3-(4-(4-Methyl-1H-imidazol-
1-yl)phenyl)-1,4-diazaspiro[4.4]non-3-en-2-one (20mg, 0.07
mmol).The vial was sealed with a screw-cap septum, and then
evacuated and backfilled with argon (this process was repeated
a total of 3 times). Then, NaH (4mg,0.17mmol) and DMF (1
mL) was added to the vial and stirred at room temperature for
10 min. 2-chloro-N-(3-(trifluoromethyl)phenyl) acetamide
(20mg, 0.084 mmol) was added and the reaction mixture was
stirred at room temperature for 12 h , then diluted with EtOAc,
washed with brine, dried over MgSO4, concentrated in vacuo
and purified via silica gel chromatography (n-hexane :
acetone=1:1 and 1:1.2) to provide the title compound as a
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