A sequential one-pot approach to 1,2,4,5-tetrasubstituted-2H-imidazole synthesis from disubstituted alkynes

Article abstract of DOI:10.1039/c5nj00959f

A sequential one-pot approach to the tetrasubstituted 2H-imidazole scaffolds has been developed from disubstituted alkynes and structurally diverse ketones. The reaction proceeds via a diketo intermediate generated from internal alkynes followed by the addition of ammonium acetate and a suitable ketone, affording a diverse range of 2H-imidazoles. Using air-moisture stable reaction conditions and inexpensive reagents, the transformation demonstrates a broad substrate scope and good functional group compatibility.

Full text of DOI:10.1039/c5nj00959f

NJC
View Article Online
View Journal
PAPER
A sequential one-pot approach to
1,2,4,5-tetrasubstituted-2H-imidazole
synthesis from disubstituted alkynes†
Cite this:DOI: 10.1039/c5nj00959f
Siva Senthil Kumar Boominathan, Chung-Yu Chen, Po-Jui Huang, Ruei-Jhih Hou
and Jeh-Jeng Wang*
Received (in Montpellier, France)
17th April 2015,
Accepted 29th June 2015
A sequential one-pot approach to the tetrasubstituted 2H-imidazole scaffolds has been developed from
disubstituted alkynes and structurally diverse ketones. The reaction proceeds via a diketo intermediate
generated from internal alkynes followed by the addition of ammonium acetate and a suitable ketone,
affording a diverse range of 2H-imidazoles. Using air-moisture stable reaction conditions and inexpensive
reagents, the transformation demonstrates a broad substrate scope and good functional group compatibility.
DOI: 10.1039/c5nj00959f
www.rsc.org/njc
Introduction
Imidazole derivatives are valuable synthetic targets because of
their uses in numerous natural products, pharmaceuticals and
materials science.1 In medicinal chemistry, these compounds are
well-known for their anti-cancer, anti-fungal and anti-bacterial
activities.2 Owing to their profound applications in chemistry and
biology, much interest has been focused on the synthesis of a
diverse range of imidazoles.
Although numerous reports have documented 1H-imidazole
derivatives, 2H-imidazoles have appeared less frequently in the
literature.3 In 1952, Weiss reported the first synthesis of 2,2,4,5-
tetrasubstituted-2H-imidazoles from benzils via condensation.4
Furthermore, a few other methods were also developed for
these compounds.5 Moreover, the diazaspiro derivatives of
2H-imidazole derivatives have proven to be useful precursors
in the preparation of racemic-(1R,2R and 1S,2S)-transdiphenyl-
ethylenediamines, which are useful ligands and chiral auxiliaries
for asymmetric synthesis.6 Thus, the development of simple and
efficient approaches to these compounds from commercially
available starting materials is desirable.
Recently, our group developed an ortho substituted amide-
directed oxidation of alkynes using CAN in the presence of
oxygen (Scheme 1, eqn (1)).7a Furthermore, we extended the
concept of oxidizing alkynes followed by reaction with various
nucleophiles to generate useful heterocycles such as quinoxalines
(Scheme 1, eqn (2))7b and 1H-imidazoles (eqn (3)).7c Based on our
Scheme 1 Our previous and present studies.
previous works and continuous interest in the development of
new synthesis methods,8 herein we report a sequential one-pot
approach to the construction of 2H-imidazoles from disubstituted
alkynes via oxidation followed by condensation (Scheme 1,
eqn (4)). Moreover, the one-pot strategies have gained significant
attention due to their several advantages such as successive
reactions in the same reactor, no purification, and savings on
cost, time and amounts of reagents and solvents.9
Results & discussion
We started our investigation using diphenylacetylene (1a) and
cyclohexanone (2a) as a model substrate; the results are pre-
sented in Table 1. First, compounds 1a, 2b, ammonium acetate
and trifluoroacetic acid (TFA) were added to DMSO at the same
time and heated to 100 1C for 8 h; the reaction failed to proceed
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University,
100, Shih-Chuan 1st Road, Kaohsiung, Taiwan. E-mail: jjwang@kmu.edu.tw
† Electronic supplementary information (ESI) available. CCDC 1404628 (3c). For
ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c5nj00959f
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2015
New J. Chem.

View Article Online
Paper
NJC
Table 1 Optimization of conditionsa
Table 2 Substrate scope of the 2H-imidazolesa
Entry
Acid
Temp. (1C)
Time (h)
Yieldb (%)
1c
2
3
4
5
6
7
8
9
TFA
TFA
100
100
100
100
100
100
100
120
80
8
Traces
76
82
75
86
38
40
81
76
4 + 4
4 + 4
4 + 4
4 + 4
4 + 4
4 + 4
4 + 4
4 + 4
4 + 4
4 + 4
4 + 4
TfOH
PivOH
AcOH
MsOH
TsOH
AcOH
AcOH
AcOH
AcOH
—
10
11d
12
100
100
100
60
53
—
a
Reaction conditions: step I: 1a (1 mmol), DMSO (4 ml) and acid (4 eq.)
heated to 100 1C for 4 hours under air; step II: 2a (1.3 mmol) and
b
c
NH4OAc (4 eq.) heated to 100 1C for 4 hours. Isolated yields. All the
reagents were added at one time and heated to 100 1C for 4 hours.
d
NH4OAC (2 eq.).
(Table 1, entry 1). Instead of adding all the reagents at the same
time, we planned the reaction with sequential additions of
compound 1a in acid/DMSO to oxidize into a diketo compound,
followed by compound 2a and ammonium acetate. Accordingly,
we attempted a reaction with compound 1a and TFA in DMSO,
and heated it to 100 1C for 4 hours to complete the oxidation
(monitored by TLC), followed by the addition of compound 2a
and ammonium acetate at 100 1C for another 4 hours. To our
delight, the expected 2H-imidazoles were obtained in 76% yield
(entry 2). Furthermore, we focused our studies on preparing
these scaffolds via a sequential one-pot approach. To improve
the reaction yield, various acids were screened, and acetic acid
provided the best yield among them (entries 3–7). Reducing the
equivalent of ammonium acetate affected the reaction yield
(entry 11). Deviating from our optimized temperature (100 1C) in
either direction decreased the reaction yield (entries 8 and 9). When
the reaction was performed in the absence of an acid source, the
reaction failed to proceed (entry 12). From this result, we confirm
that the acid source was necessary for both the steps. Finally, we
concluded entry 5 as an optimized reaction condition.
Having identified the suitable reaction conditions, the
applicability of the range of diversely substituted 2H-imidazoles
was investigated, as shown in Table 2. First, we examined the
scope of various aliphatic and aromatic ketones at R3 and R4
positions. Replacement of R3 and R4 with cyclic (3a–b) and acyclic
ketones (3c–d) was well tolerated and the desired products were
isolated in high yields. The feasibility of aromatic (3e–f) and
heterocyclic ketones (3g–h) was also studied: the reaction pro-
ceeded smoothly to give the expected products. Furthermore, the
R1 and R2 groups in phenyl acetylene were replaced with methyl
and trimethoxy groups and corresponding products (3h–o) were
isolated in good yields. It can be noted that the reaction was
suitable for other interesting heterocyclic derivatives such as fluorene
a
Reaction conditions: step A: 1 (1 mmol), AcOH (4 eq.), DMSO (4 ml)
heated to 100 1C for 4 hours; step B: 2 (1.3 mmol) and NH4OAc (4 eq.)
heated to 100 1C for 4 hours.
Fig. 1 X-ray structure of compound 3c.
moderate to good yields. Attempts to replace ketones (2) with
aldehydes failed. The probable reason could be that the geminal
diamine (20) intermediate of aldehydes is more reactive and may not
be stable under the reaction conditions. The structure of compound
3c was unambiguously confirmed by X-ray analysis (Fig. 1).‡
Based on these observations and previous literature,10,11 we
proposed a two reaction mechanism, as shown in Scheme 2
(Path A and B). In Path A, compound 1 oxidized in the presence
of DMSO and acid generates the diketo intermediate (10). Moreover,
the decomposition of ammonium acetate under the reaction
conditions generates ammonia, which subsequently reacts with
ketone (2), providing the diamine intermediate (20). Finally, the
condensation between 10 and 20 with the elimination of water gives
(3p) and isatins (3q–r), and the products were successfully isolated in ‡ CCDC 1404628 (3c).
New J. Chem.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2015

View Article Online
NJC
Paper
were obtained using a Varian (400 MHz) spectrometer. High
resolution mass spectra (HRMS) were obtained on a Micromass
Q-TOF spectrometer using EI (electron impact, 70 eV).
General experimental procedure for compound 1a
An oven dried round-bottom flask was charged with compound
1a (1 mmol) and acetic acid (4 equiv.) in DMSO (4 ml) and was
heated to 100 1C in air atmosphere for 4 hours. After the diketo
intermediate (1a0) was formed (monitored by TLC), the reaction
mixture was cooled to room temperature. Then, compound 2a
(1.3 mmol) and ammonium acetate (4 eq.) were added and the
mixture was heated to 100 1C for another four hours. After the
reaction was completed (monitored by TLC), the reaction mass
was poured into water and extracted with EtOAc. The combined
organic layer was washed with brine solution and dried and
evaporated to remove the solvent. The crude residue was passed
through flash column chromatography to afford the title compound
as a white solid (3a, 86%).
2,3-Diphenyl-1,4-diazaspiro[4.5]deca-1,3-diene (3a). Yield:
86%; white solid; m.p.: 104 1C; 1H NMR (400 MHz, CDCl3) d
7.51–7.48 (m, 4H), 7.45–7.41 (m, 2H), 7.37–7.33 (m, 4H), 1.99–
1.93 (m, 4H), 1.83–1.80 (m, 4H), 1.76–1.70 (m, 2H). 13C NMR
(CDCl3, 100 MHz): d 164.0, 133.0, 129.9, 128.8, 128.2, 114.4,
104.0, 34.6, 25.6, 24.0. HRMS-ESI (m/z): calcd for C20H20N2
[M + 1]+: 288.1626, found 289.1698.
Scheme 2 Proposed reaction mechanism.
the final product 3. In Path B,12 the diketo intermediate (10) and
ketone are converted into corresponding imines (A & B). The
nucleophilic addition of a-imino ketone (A) to imine (B) generates
intermediate C. Finally, the intramolecular condensation of inter-
mediate C produces the desired product 3.
Conclusion
In summary, a simple and convenient sequential one-pot
approach to tetrasubstituted 1H-imidazoles was successfully
synthesized. The course of the reaction proceeded through
the internal alkynes being oxidized into diketo intermediates
(10), which were captured with various ketones (2) and ammonium
acetate, giving the desired products. In particular, when cyclic
ketones such as cyclohexanone, isatins, and fluorenes were used,
the reactions provide interesting spirocyclic imidazole products.
Additional features of the study consist of a one-pot approach,
commercially available starting materials, inexpensive reagents,
operational simplicity and moderate to high reaction yields. These
advantages make this methodology a new alternative approach for
this rare class of 2H-imidazole derivatives and further biological
studies of the synthesized compounds are underway in our
laboratory.
2,3-Diphenyl-1,4-diazaspiro[4.4]nona-1,3-diene (3b). Yield:
1
81%; purple solid; m.p. 101 1C; H NMR (400 MHz, CDCl3) d
7.52–7.49 (m, 4H), 7.44–7.40 (m, 2H), 7.36–7.32 (m, 4H), 2.22–
2.13 (m, 8H). 13C NMR (CDCl3, 100 MHz): d 163.8, 132.6, 129.9,
128.7, 128.2, 111.4, 35.3, 26.1. HRMS-ESI (m/z): calcd for
C
19H18N2 [M + 1]+: 274.1470, found 275.1540.
2,2-Dimethyl-4,5-diphenyl-2H-imidazole (3c). Yield: 64%;
purple solid; m.p. 74 1C; 1H NMR (400 MHz, CDCl3) d 7.52–
7.49 (m, 4H), 7.46–7.41 (m, 2H), 7.37–7.33 (m, 4H), 1.66 (s, 6H).
13C NMR (CDCl3, 100 MHz): d 164.1, 132.5, 130.1, 128.7, 128.2,
101.5, 24.0. HRMS-ESI (m/z): calcd for C17H16N2 [M + 1]+:
248.1313, found 249.1387.
2-Ethyl-2-methyl-4,5-diphenyl-2H-imidazole (3d). Yield: 70%;
brown solid; m.p. 98 1C; 1H NMR (400 MHz, CDCl3) d 7.51–7.48
(m, 4H), 7.42–7.38 (m, 2H), 7.34–7.30 (m, 4H), 2.20 (q, J = 7.2 Hz,
2H), 1.64 (s, 3H), 0.76 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3,
100 MHz): d 164.5, 132.5, 129.9, 128.6, 128.1, 103.7, 30.7, 22.63,
8.05. HRMS-ESI (m/z): calcd for C17H16N2 [M + 1]+: 262.1470,
Experimental
Materials and methods
All chemicals were purchased as best grade commercially found 263.1542.
available and were used without further purification. All solvents
2-Methyl-2,4,5-triphenyl-2H-imidazole (3e). Yield: 74%;
were purchased as HPLC grade and were used without any brown sticky oil; 1H NMR (400 MHz, CDCl3) d 7.86–7.83 (m,
purification or distillation. Analytical thin layer chromatography 2H), 7.58–7.56 (m, 4H), 4.49–7.44 (m, 2H), 7.40–7.36 (m, 6H),
was performed on an aluminium plate coated with silica gel 7.33–7.26 (m, 1H), 1.96 (s, 3H). 13C NMR (CDCl3, 100 MHz): d
(Merck). Gravity column chromatography was performed using 164.5, 140.6, 132.2, 128.9, 128.27, 128.24, 127.5, 127.1, 27.5.
100–200 mesh silica gel, and mixtures of hexane-ethyl acetate HRMS-ESI (m/z): calcd for C22H18N2 [M + 1]+: 310.1470, found
were used for elution. Visualization was accomplished using 311.1540.
ultraviolet light (254 nm) and chemical staining with acidic
2-(4-Fluorophenyl)-2-methyl-4,5-diphenyl-2H-imidazole (3f).
1
potassium permanganate solution, ninhydrin and iodine. Melting Yield: 74%; pale-yellow solid; m.p. 108 1C; H NMR (400 MHz,
points were determined using ‘‘Mel-Temp’’ melting point apparatus CDCl3) d 7.80–7.76 (m, 2H), 7.56–7.53 (m, 4H), 7.49–7.44
and were uncorrected. Proton nuclear magnetic resonance (1H NMR) (m, 2H), 7.39–7.36 (m, 4H), 7.07–7.02 (m, 2H), 1.90 (s, 3H).
and carbon nuclear magnetic resonance (13C NMR) spectra 13C NMR (CDCl3, 100 MHz): d 164.7, 163.4, 160.9, 132.3, 130.4,
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2015
New J. Chem.

View Article Online
Paper
NJC
128.9, 128.9, 128.8, 128.3, 115.1, 114.9, 104.5, 27.6. HRMS-ESI 1H NMR (400 MHz, CDCl3) d 7.53–7.51 (m, 2H), 7.43–7.37
(m/z): calcd for C22H17FN2 [M + 1]+: 328.1376, found 329.1445. (m, 3H), 6.74 (s, 2H), 3.86 (s, 3H), 3.68 (s, 3H), 1.96–1.92
2-(Furan-2-yl)-2-methyl-4,5-diphenyl-2H-imidazole (3g). Yield: (m, 4H), 1.90–1.84 (m, 2H), 1.77–1.67 (m, 4H). 13C NMR (CDCl3,
71%; orange solid; m.p. 81 1C; 1H NMR (400 MHz, CDCl3) d 7.56– 100 MHz): d 164.3, 163.5, 153.1, 139.8, 133.7, 130.0, 129.1,
7.54 (m, 4H), 7.48–7.44 (m, 2H), 7.40–7.35 (m, 4H), 7.33–7.322 128.4, 128.1, 106.5, 104.1, 61.1, 56.1, 34.9, 25.8, 24.3. HRMS-ESI
(dd, J = 7.6, 1.2 Hz, 1H), 7.24–7.23 (dd, J = 5.2, 1.2 Hz, 1H), 7.01 (m/z): calcd for C23H26N2O3 [M + 1]+: 378.1943, found 379.2013.
(dd, J = 5.2, 3.6 Hz, 1H), 2.02 (s, 3H). 13C NMR (CDCl3, 100 MHz):
2-Ethyl-2-methyl-4-phenyl-5-(3,4,5-trimethoxyphenyl)-2H-imidazole
d 165.1, 141.6, 132.1, 130.4, 129.0, 128.9, 128.2, 126.6, 125.0, (3o). Yield: 72%; pale-yellow solid; m.p. 172 1C; 1H NMR
124.6, 103.0, 27.5. HRMS-ESI (m/z): calcd for C20H16FN2O (400 MHz, CDCl3) d 7.53–7.50 (m, 2H), 7.46–7.36 (m, 3H),
[M + 1]+: 300.1263, found 301.1278.
6.72 (s, 2H), 3.85 (s, 3H), 3.66 (s, 6H), 2.23–2.14 (m, 2H), 1.64
2-Methyl-4,5-diphenyl-2-(thiophen-2-yl)-2H-imidazole (3h). Yield: (s, 3H), 0.77 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3, 100 MHz): d
79%; orange solid; m.p. 89 1C; 1H NMR (400 MHz, CDCl3) d 7.58– 164.8, 164.0, 152.8, 139.6, 133.0, 129.9, 128.8, 128.2, 127.4,
7.55 (m, 3H), 7.49–7.44 (m, 2H), 7.41–7.37 (m, 4H), 6.37–6.32 106.2, 103.7, 60.8, 55.8, 30.8, 29.6, 22.7, 8.2. HRMS-ESI (m/z):
(m, 1H), 1.99 (s, 3H). 13C NMR (CDCl3, 100 MHz): d 166.1, 150.6, calcd for C21H24N2O3 [M + 1]+: 352.1787, found 353.1798.
142.6, 132.0, 130.5, 129.0, 128.2, 110.1, 106.4, 101.2, 23.0. HRMS-
40,50-Diphenylspiro[fluorene-9,20-imidazole] (3p). Yield: 68%;
ESI (m/z): calcd for C20H16N2S [M + 1]+: 316.1034, found 303.1853. white solid; m.p. 230 1C; 1H NMR (400 MHz, CDCl3) d 7.80 (d, J =
2-Phenyl-3-(p-tolyl)-1,4-diazaspiro[4.5]deca-1,3-diene (3i). Yield: 7.6 Hz, 2H), 7.71–7.68 (m, 4H), 7.53–7.49 (m, 2H), 7.44–7.40 (m,
85%; sticky yellow oil; 1H NMR (400 MHz, CDCl3) d 7.52–7.48 6H), 7.26–7.21 (m, 2H), 6.89 (d, J = 7.6 Hz, 2H). 13C NMR (CDCl3,
(m, 2H), 7.44–7.32 (m, 5H), 7.14 (d, J = 7.6 Hz, 2H), 2.36 (s, 3H), 100 MHz): d 168.5, 142.2, 138.7, 132.1, 130.7, 129.6, 129.1, 128.3,
1.98–1.92 (m, 4H), 1.81–1.80 (m, 4H), 1.75–1.70 (m, 2H). 13C NMR 127.8, 123.1, 120.8. HRMS-ESI (m/z): calcd for C27H18N2 [M + 1]+:
(CDCl3, 100 MHz): d 164.1, 163.8, 140.0, 133.1, 129.9, 129.8, 128.8, 370.1470, found 371.1541.
128.7, 128.1, 16, 128.12, 103.7, 34.5, 25.5, 23.9, 21.3. HRMS-ESI
10-Methyl-4,5-diphenylspiro[imidazole-2,30-indolin]-20-one (3q).
Yield: 62%; white solid; m.p. 232 1C; 1H NMR (400 MHz, CDCl3) d
(m/z): calcd for C21H22N2 [M + 1]+: 302.1783, found 303.1853.
2-Phenyl-3-(p-tolyl)-1,4-diazaspiro[4.4]nona-1,3-diene (3j). Yield: 8.58 (d, J = 6.8 Hz, 1H), 7.61–7.56 (m, 3H), 7.46–7.42 (m, 5H), 7.41–
82%; orange sticky oil; 1H NMR (400 MHz, CDCl3) d 7.52–7.49 7.38 (m, 1H), 7.33–7.31 (m, 1H), 7.25–7.20 (m, 3H), 3.68 (s, 3H). 13
C
(m, 2H), 7.45–7.33 (m, 5H), 7.15 (d, J = 8.0 Hz, 2H), 2.37 (s, 3H), NMR (CDCl3, 100 MHz): d 146.4, 142.6, 136.3, 131.1, 131.0, 130.8,
2.19–2.14 (m, 8H). 13C NMR (CDCl3, 100 MHz): d 164.0, 163.8, 128.5, 128.2, 128.0, 127.9, 127.5, 125.9, 124.5, 123.8, 30.7. HRMS-
140.2, 132.9, 129.9, 129.7, 129.1, 128.9, 128.8, 128.2, 128.2, 111.3, ESI (m/z): calcd for C23H17N3O [M + 1]+: 351.137, found 352.1441.
35.4, 29.6, 26.2, 21.4. HRMS-ESI (m/z): calcd for C20H20N2 [M + 1]+:
288.1626, found 289.1696.
10-Methyl-4-phenyl-5-(p-tolyl)spiro[imidazole-2,30-indolin]-20-
one (3r). Yield: 55%; pale-yellow solid; m.p. 185 1C; 1H NMR
2-Ethyl-2-methyl-4-phenyl-5-(p-tolyl)-2H-imidazole (3k). Yield: (400 MHz, CDCl3) d 8.54–8.52 (dd, J = 7.6, 1.2 Hz, 2H), 7.64–7.47
1
80%; sticky orange oil; H NMR (400 MHz, CDCl3) d 7.51–7.49 (m, 6H), 7.39–7.35 (m, 2H), 7.30–7.26 (m, 3H), 7.08 (d, J = 8.0 Hz,
(m, 2H), 7.45–7.32 (m, 5H), 7.15–7.13 (dd, J = 8.4, 0.4 Hz, 2H), 1H), 3.65 (s, 3H), 2.46–2.32 (d, J = 5.6 Hz, 3H). HRMS-ESI (m/z):
2.36 (s, 3H), 2.18 (q, J = 7.2 Hz, 2H), 1.64 (s, 3H), 0.757 (t, J = calcd for C24H19N3O [M + 1]+: 365.1528, found 366.1599.
7.6 Hz, 3H). 13C NMR (CDCl3, 100 MHz): d 164.8, 164.5, 140.2,
Benzil (1a0). Yield 92%; yellow solid; m.p. 92 1C; 1H NMR
132.7, 129.9, 129.6, 128.8, 128.7, 128.1, 103.6, 30.8, 22.7, 21.3, (400 MHz, CDCl3) d 7.99–7.96 (m, 4H), 7.68–7.64 (tt, J = 8.0,
8.0. HRMS-ESI (m/z): calcd for C19H20N2 [M + 1]+: 276.1626, 1.6 Hz, 2H), 7.54–7.49 (m, 4H). 13C NMR (CDCl3, 100 MHz):
found 277.1696.
d 194.5, 134.88, 129.8, 129.0.
2-Methyl-2,4-diphenyl-5-(p-tolyl)-2H-imidazole (3l). Yield:
1
76%; sticky orange oil; H NMR (400 MHz, CDCl3) d 7.85–7.82
Acknowledgements
(m, 2H), 7.59–7.56 (m, 2H), 7.48–7.44 (m, 3H), 7.40–7.35
(m, 4H), 7.32–7.28 (m, 1H), 7.18 (d, J = 8.0 Hz, 2H), 2.40
(s, 3H), 1.95 (s, 3H). 13C NMR (CDCl3, 100 MHz): d 164.7,
164.4, 140.7, 140.4, 132.6, 130.2, 130.1, 129.5, 128.9, 128.27,
128.24, 128.20, 127.5, 127.4, 127.1, 104.8, 27.5, 21.4. HRMS-ESI
(m/z): calcd for C23H20N2 [M + 1]+: 324.1626, found 325.1696.
2-(4-Fluorophenyl)-2-methyl-4-phenyl-5-(p-tolyl)-2H-imidazole
The authors gratefully acknowledge funding from the Ministry
of Science and Technology (MOST), Taiwan, and the Centre for
Research Resources and Development of Kaohsiung Medical
University for 400 MHz NMR analyses.
1
(3m). Yield: 77%; white solid; m.p. 116 1C; H NMR (400 MHz,
References
CDCl3) d 7.81–7.77 (m, 2H), 7.57–7.54 (m, 2H), 7.48–7.36 (m, 5H),
7.18 (d, J = 8.0 Hz, 2H), 7.07–7.02 (m, 2H), 2.39 (s, 3H), 1.90
(s, 3H). 13C NMR (CDCl3, 100 MHz): d 164.8, 164.5, 140.6, 136.5
( JF = 4.6 Hz), 132.5. 130.3, 129.4, 128.9, 128.9, 128.8, 128.7, 128.3,
128.2, 115.1, 114.9, 104.3, 27.6, 21.4. HRMS-ESI (m/z): calcd for
C23H19FN2 [M + 1]+: 342.1532, found 343.1602.
1 (a) B. Cui, B. L. Zheng, K. He and Q. Y. Zheng, J. Nat. Prod.,
2003, 66, 1101; (b) M. R. Grimmett, Imidazole and Benzimidazole
Synthesis, Academic Press, 1997; (c) S. Tsukamoto, T. Kawabata,
H. Kato, T. Ohta, H. Rotinsulu, R. E. P. Mangindaan, R. W. M.
Van Soest, K. Ukai, H. Kobayashi and M. Namikoshi, J. Nat.
Prod., 2007, 70, 1658; (d) A. Bhatnagar, P. K. Sharma and
N. Kumar, Int. J. PharmTech Res., 2011, 3, 268–282;
2-Phenyl-3-(3,4,5-trimethoxyphenyl)-1,4-diazaspiro[4.5]deca-
1,3-diene (3n). Yield: 74%; pale-yellow solid; m.p. 173 1C;
New J. Chem.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2015

View Article Online
NJC
(e) H. Konishi, T. Ueda, T. Muto and K. Manabe, Org. Lett.,
Paper
H. Guttmann, J. Org. Chem., 1975, 40, 2562; (c) B. Schmidt,
S. Krehl and S. Hauke, J. Org. Chem., 2013, 78, 5427.
6 (a) E. J. Corey, D.-H. Lee and S. Sarshar, Tetrahedron: Asymmetry,
1995, 6, 95; (b) Y. Zhou, A. Andreou, E. Biktagirov, J. Eames and
J. Wadhawan, Electrochem. Commun., 2010, 12, 1493.
7 (a) C.-F. Su, W.-P. Hu, J. K. Vandavasi, M.-I. Chung and
J.-J. Wang, Synlett, 2012, 2132; (b) C.-Y. Chen, W.-P. Hu, M.-C.
Liu, P.-C. Yan, J.-J. Wang and M.-I. Chung, Tetrahedron, 2013,
69, 9735–9741; (c) C.-Y. Chen, W.-P. Hu, P.-C. Yan, G. C.
Senadi and J.-J. wang, Org. Lett., 2013, 15, 6116.
8 (a) S. S. K. Boominathan, W.-P. Hu, G. C. Senadi, J. K.
Vandavasi and J.-J. Wang, Chem. Commun., 2014, 51, 6726;
(b) J. K. Vandavasi, W.-P. Hu, C.-T. Hsiao, G. C. Senadi and
J.-J. Wang, RSC Adv., 2014, 4, 57547; (c) G. C. Senadi, W.-P.
Hu, T.-Y. Lu, A. M. Garkhedkar, J. K. Vandavasi and J.-J.
Wang, Org. Lett., 2015, 17, 1521.
2012, 14, 4722; ( f ) Z. Wang, P. Lu, S. Chen, Z. Gao, F. Shen,
W. Zhang, Y. Xu, H. S. Kwok and Y. J. Ma, J. Mater. Chem.,
2011, 21, 5451; (g) L. Zhou and K. M. Nicholas, Inorg. Chem.,
2008, 47, 4356; (h) P. Abhishek, C. J. Kulkarni, A. B. Tonzola
and A. J. Samson, Chem. Mater., 2004, 16, 4556.
2 (a) S. N. Riduan and Y. Zhang, Chem. Soc. Rev., 2013, 42, 9055;
(b) N. Rani, A. Sharma, G. K. Gupta and R. Singh, Mini-Rev. Med.
Chem., 2013, 13, 1626; (c) E. M. Perchellet, J.-P. Perchellet and
P. W. Baures, J. Med. Chem., 2005, 48, 5955; (d) S. Khabnadideh,
Z. Rezaei, A. Khala-Nezhad, R. Bahrinaja, R. Mohamadia and
A. Farrokhroza, Bioorg. Med. Chem. Lett., 2003, 13, 2863.
3 (a) A. Chawla, A. Sharma and A. Sharma, Pharma Chem.,
2012, 4, 116; (b) G. Bratulescu, Synthesis, 2009, 2319–2320;
(c) M. Adib, S. Ansari, S. Feizi, J. A. Damavandi and
P. Mirzaei, Synlett, 2009, 3263; (d) S. A. Siddiqui, U. C.
Narkhede, S. S. Palimkar, T. Daniel, R. J. Lahoti and
K. V. Srinivasan, Tetrahedron, 2005, 61, 3539; (e) J. Li and
9 (a) D. B. Ramachary and S. Jain, Org. Biomol. Chem., 2011,
9, 1277; (b) M. O. Sydnes, Curr. Green Chem., 2015, 1, 216.
L. Neuville, Org. Lett., 2013, 15, 1752–1755; ( f ) Y. Wang, 10 (a) Z. Wan, C. D. Jones, D. Mitchell, J. Y. Pu and T. Y. Zhang,
H. Shen and Z. Xie, Synlett, 2011, 969; (g) B. Hu, Z. Wang,
N. Ai, J. Zheng, X.-H. Liu, S. Shan and Z. Wang, Org. Lett.,
2011, 13, 6362; (h) K. Rajaguru, R. Suresh, A. Mariappan,
S. Muthusubramanian and N. Bhuvanesh, Org. Lett., 2014,
16, 744.
J. Org. Chem., 2006, 71, 826–828; (b) C.-Y. Chen, W.-P. Hu,
M.-C. Liu, P.-C. Yan, J.-J. Wang and M.-I. Chung, Tetrahedron,
2013, 69, 9735; (c) B. Kiumars, M. K. Mohammad and
N. Akbar, Monatsh. Chem., 2011, 142, 159.
11 The diketo intermediate (1a0) was isolated and confirmed by
proton and carbon NMR (see ESI† for spectra).
4 M. Weiss, J. Am. Chem. Soc., 1952, 74, 5193.
5 (a) E. J. Corey, R. Imwinkelried, S. Pikul and Y. B. Xiang, J. Am. 12 J. Li, G. Hu, X. Li, B. Hu, N. Wang, P. Lu and Y. Wang, Eur.
Chem. Soc., 1989, 11, 5493; (b) J. H. M. Hill, T. R. Fogg and J. Org. Chem., 2013, 7320.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2015
New J. Chem.