Acid-Catalyzed 1,3-Dipolar Cycloaddition of 2 H-Azirines with Nitrones: An Unexpected Access to 1,2,4,5-Tetrasubstituted Imidazoles

Article abstract of DOI:10.1021/acs.joc.9b03288

The first 1,3-dipolar cycloaddition of 2H-azirines with nitrones, a straightforward approach toward the regioselective synthesis of 1,2,4,5-tetrasubstituted imidazoles, is reported. This trifluoroacetic acid-catalyzed protocol tolerates a broad range of aliphatic and aromatic substrates, offering an efficient access to highly diverse, multisubstituted imidazoles in isolated yields up to 83% under mild conditions.

Full text of DOI:10.1021/acs.joc.9b03288

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Article
Acid-Catalyzed 1,3-Dipolar Cycloaddition of 2H‑Azirines with
Nitrones: An Unexpected Access to 1,2,4,5-Tetrasubstituted
Imidazoles
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Aniko Angyal, Andras Demjen, Janos Wolfling, Laszlo G. Puskas, and Ivan Kanizsai*
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ABSTRACT: The first 1,3-dipolar cycloaddition of 2H-azirines with nitrones, a
straightforward approach toward the regioselective synthesis of 1,2,4,5-
tetrasubstituted imidazoles, is reported. This trifluoroacetic acid-catalyzed protocol
tolerates a broad range of aliphatic and aromatic substrates, offering an efficient
access to highly diverse, multisubstituted imidazoles in isolated yields up to 83%
under mild conditions.
Scheme 1. 2H-Azirines and Nitrones in 1,3-DC
INTRODUCTION
■
2H-Azirines have received significant attention because of their
wide applicability as building blocks in organic synthesis.1 In
addition to their ability to act as both nucleophiles and
electrophiles,2 2H-azirines can also operate as dienophiles,
dipolarophiles, and dipoles in cycloaddition reactions.3
Furthermore, they can undergo selective ring cleavage on
thermal or photochemical excitation to generate reactive vinyl
nitrene, imino carbene, and nitrile ylide species.4 By exploiting
this versatile reactivity, efforts have been made over the past
decades on the synthesis of N-heterocycles, such as pyrroles,5
pyrazoles,6 pyridines,7 pyrazines,8 and indoles,9 from 2H-
azirines.1 In contrast, the azirine-based assembly of imidazoles
has been less extensively explored.10
Looking at the 1,3-dipolar cycloaddition (1,3-DC) of 2H-
azirines as dipolarophiles, the dipole scope of the reaction is
almost exclusively limited to azomethine ylides (Scheme 1a).11
To the best of our knowledge, there is no precedent for the
utilization of nitrones in cycloaddition reactions involving
azirines. Inspired by this information and the well-known
dipolar cycloaddition reactions of the easily accessible
nitrones12 with alkenes,13 alkynes,14 and strained cyclo-
propenes15 toward the synthesis of isoxazolidine and isoxazo-
line scaffolds (Scheme 1b,c), we envisioned a 1,3-DC approach
for the construction of an unprecedented aziridine-fused
bicyclic framework (Scheme 1d). Unexpectedly, the reaction
between 2H-azirines and nitrones led to the discovery of a
novel access to 1,2,4,5-tetrasubstituted imidazoles (Scheme
1e), which have drawn considerable attention owing to their
wide range of biological and pharmacological properties
including, among others,16 p38α MAP kinase inhibitory,17
antiviral,18 antibacterial,19 and anticancer20 activities.
azirine-2-carboxylate (( )-2a) in anhydrous acetonitrile.
However, no conversion was observed. In order to increase
the reactivity of azirine ( )-2a, several Brønsted and Lewis
acid catalysts were tested at room and elevated temperatures
(60 °C) (Table 1, entries 2−31; see the Supporting
Information for conversions and yields in 8 and 24 h). The
Received: December 6, 2019
Published: February 5, 2020
RESULTS AND DISCUSSION
■
We initiated our study by investigating the 1,3-DC of C-
phenyl-N-methylnitrone 1a and racemic ethyl 3-methyl-2H-
https://dx.doi.org/10.1021/acs.joc.9b03288
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a
a
Table 1. Catalyst Screening
Table 2. Optimization of the Reaction Conditions
b
c
b
entry
catalyst
HCOOH
AcOH
TFA
MeSO3H
PTSA × H2O
HClO4 (70%)
H2SO4
yield (%)
yield (%)
entry
solvent
2a (equiv)
TFA (mol %)
yield (%)
1
2
3
4
5
6
7
8
0
36
0
0
42
17
50
42
44
48
41
30
39
49
43
41
1
1
2
3
4
5
6
7
8
MeCN
MeOH
EtOH
IPA
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.25
1.5
2.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
1
62
39
46
33
14
3
62
52
57
56
49
28
35
54
52
16
1
22
8
7
0
12
2
c
TFE
c
HFIP
CHCl3
CH2Cl2
Toluene
THF
dioxane
DMF
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
39
55
42
54
47
48
13
70
74
74
43
60
73
72
68
41
69
9
NaHSO4
B(OH)3
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
10
11
12
13
14
15
16
17
18
19
20
21
22
f
PTA
g
BINOL-phosphoric acid
de
,
silica gel
Amberlyst 15
d
d
montmorillonite K10
ZnCl2
Zn(OAc)2
ZnF2
22
22
9
22
21
20
35
31
20
13
16
2
23
37
39
42
39
2.5
5
15
20
40
5
InCl3
In(OAc)3
In(OTf)3
FeCl2 × 4H2O
FeCl3 × 6H2O
CuCl
39
4
7
2
3
d
23
24
d
e
10
78 (72)
a
CuCl2
Reaction conditions: nitrone 1a (0.10 mmol), 2H-azirine ( )-2a
(0.10−0.20 mmol), anhydrous solvent (0.3 mL), TFA (1−40 mol %),
Cu(OAc)2
Cu(OTf)2
Mg(OTf)2
Yb(OTf)3
Sc(OTf)3
Dy(OTf)3
2
b
c
12
56
57
56
59
rt, 24 h. Yields were determined by HPLC−MS analysis. Non-dried.
d e
60 °C, 6 h. Isolated yield. Nitrone 1a (1 mmol), 2H-azirine ( )-2a
(1.5 mmol), anhydrous MeCN (3 mL), TFA (10 mol %), 60 °C, 6 h.
none of the tested media proved superior to acetonitrile (62%
HPLC yield, Table 2, entry 1). In general, the formation of 3a
was slightly more favored in aprotic solvents, while fluorinated
alcohols (entries 5 and 6) and dimethyl sulfoxide (DMSO)
were not tolerated. To our delight, by employing 1.5-fold
excess of azirine 2a, further improvement in the yield of 3a
could be achieved (74% HPLC yield, Table 2, entry 15). On
the other hand, when lower or higher catalyst loadings in the
range of 1−40 mol % were applied, a trend of decreasing yields
was observed (Table 2, entries 17−22). Finally, the reaction
performed at 60 °C in the presence of 10 mol % of TFA
pleasingly furnished the product 3a in 78% HPLC yield and
72% isolated yield in 6 h (Table 2, entry 24). It is noteworthy
that HPLC−MS analysis of the crude reaction mixtures did not
indicate the formation of the cycloadduct or other isomeric
imidazoles.
To explore the scope of the reaction, a range of N-
methylnitrones (1a−r) were reacted with azirine 2a under
optimized conditions [2a (1.5 equiv), TFA (10 mol %),
anhydr. MeCN, 60 °C, 6 h] (Table 3, entries 1−13). The
developed method was found to be facile with nitrones bearing
both electron-donating (MeO) and electron-withdrawing (F,
NO2) substituents on the C-phenyl ring, affording 3b−d in
68−78% isolated yields (entries 2−4). Moreover, the reaction
could be readily extended to heteroaromatic N-methylnitrones,
as exemplified by the synthesis of pyridyl and furyl imidazoles
a
Reaction conditions: nitrone 1a (0.10 mmol), 2H-azirine ( )-2a
(0.10 mmol), anhydrous MeCN (0.3 mL), catalyst (10 mol %), 24 h.
b
Room temperature. Yields were determined by HPLC−MS analysis.
c
d
60 °C. Yields were determined by HPLC−MS analysis. 10 w/v %
e
f
g
was applied. 60 Å, 70−230 mesh. Phosphotungstic acid. 1,1′-
Binaphthyl-2,2′-diyl hydrogen phosphate.
reaction of 1a and 2a was readily promoted by most of the
applied catalysts. Surprisingly, however, the regioselective
formation of imidazole-4-carboxylate 3a was observed instead
of the expected cycloadduct. The best results were obtained
when trifluoroacetic acid (TFA) was utilized at room
temperature, affording 3a in 62% high-performance liquid
chromatography (HPLC) yield (Table 1, entry 4). Other
Brønsted acids such as HClO4 and p-toluenesulfonic acid
(PTSA) gave similar yields (Table 1, entries 6 and 7), whereas
AcOH and solid acids exhibited poor catalytic activity (Table
1, entries 3, 13−15). Among the tested Lewis acids, only
Mg(OTf)2, Yb(OTf)3, Sc(OTf)3, and Dy(OTf)3 showed
considerable efficiency (Table 1, entries 28−31), while zinc,
indium, iron, and copper salts proved to be ineffective (Table
1, entries 16−27).
To further optimize the reaction conditions, various solvents
were examined at room temperature in the presence of TFA
(10 mol %) as a catalyst (Table 2, entries 1−13). However,
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a
Table 3. Reactions of Various Nitrones 1 with 2H-Azirine
( )-2a
Table 4. Scope of 2H-Azirines
a
entry
1
R1
C6H5
R2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
i-Pr
Bn
Bn
3
yield (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
72
68
78
69
82
81
41
70
53
49
54
72
70
55
63
71
37
42
4-MeOC6H4
4-FC6H4
4-NO2C6H4
2-pyridyl
3-pyridyl
5-Me-2-furyl
Me
i-Pr
t-Bu
n-heptyl
c-Pr
c-Hex
9
10
11
12
13
14
15
16
17
18
i-Pr
C6H5
i-Pr
C6H5
c-Hex
4-FC6H4
C6H5
a
Reaction conditions: nitrone 1a−r (1 mmol), 2H-azirine ( )-2a
(1.5 mmol), anhydrous MeCN (3 mL), TFA (10 mol %), 60 °C, 6 h.
3e−g (82, 81, and 41%, entries 5−7). Gratifyingly, C-aliphatic
N-methylnitrones, including bulky substrate 1j (R1 = t-Bu),
also underwent smooth transformation to furnish multi-
substituted imidazoles 3h−m in moderate to good yields
(49−72%, entries 8−13). Subsequently, we examined the
influence of the N-substituents (R2) on the efficiency of the
reaction (entries 14−18). Interestingly, while N-isopropyl- and
N-benzylnitrones 1n−p were well-tolerated (3n−p, 55−71%,
entries 14−16), the corresponding N-cyclohexyl- and N-4-
(fluorophenyl)imidazoles 3q and 3r were obtained in lower
isolated yields (37 and 42%, entries 17 and 18).
a
Reaction conditions: nitrone 1a,i (1 mmol), azirine 2b−h (1.5
mmol), anhydrous MeCN (3 mL), TFA (10 mol %), 60 °C, 6 h.
a
Table 5. Scope of Nitrones with Aromatic 2H-Azirine 2c
Next, we focused on exploring the scope of the reaction with
respect to azirine, using both a C-aromatic and a C-aliphatic N-
methylnitrone (1a and 1i) for a more reliable comparison
(Table 4). As expected, transformations of azirine 2b
proceeded smoothly to give the corresponding imidazoles 4a
and 5a in yields (Table 4, 67 and 49%) similar to those of
ethoxycarbonyl analogue 2a (Table 3, 3a, 72% and 3i, 53%).
We were pleased to find that 2,3-diarylazirines 2c−f were fully
compatible with the reaction and could be efficiently converted
to products 4b−e and 5b−e in good yields, regardless of the
electronic nature of the azirine or the nitrone substrate (Table
4, 67−79%). Benzylazirine 2g was also well-tolerated, albeit it
provided lower isolated yields (4f, 45% and 5f, 57%).
Unfortunately, the application of monosubstituted azirine 2h
led to complex reaction mixtures and only trace amounts of the
desired products.
Finally, to give a comprehensive evaluation with respect to
the generality, we briefly surveyed the reactivity of aromatic
azirine 2c toward some of the nitrones applied previously
(Table 5). Pleasingly, both C-aromatic and C-aliphatic N-
methylnitrones could be subjected to the reaction, delivering
imidazoles 6a−f in moderate to good yields (Table 5, 50−
79%). It is notable that introducing the sterically demanding
a
Reaction conditions: nitrone 1 (1 mmol), azirine 2c (1.5 mmol),
anhydrous MeCN (3 mL), TFA (10 mol %), 60 °C, 6 h.
tert-butyl group as the R1 substituent resulted again in a lower
isolated yield (6d, 50%). On the other hand, nitrones
possessing more electron-donating isopropyl and cyclohexyl
substituents on the nitrogen (1n and 1q) were less tolerated
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and solvents were commercially available and used without further
purification.
(6g, 24% and 6h, 32%). In contrast, when N-benzylnitrone 1p
was employed, product 6i was isolated in a superior yield of
83%.
Although the detailed reaction mechanism remains to be
clarified, a plausible mechanism is proposed in Scheme 2.
General Procedure for the Synthesis of Imidazoles 3a−l,
4a−f, 5a−f, and 6a−i. To a solution of the corresponding nitrone 1
(1 mmol, 1.0 equiv) and 2H-azirine 2 (1.5 mmol, 1.5 equiv) in
anhydrous MeCN (3 mL, 0.33 M), TFA (7.7 μL, 0.1 mmol, 10 mol
%) was added at room temperature and stirred at 60 °C for 6 h on a
heating block-mounted hot plate magnetic stirrer. After the reaction
was complete (monitored by TLC), the solvent was removed under
reduced pressure to give the crude product, which was purified by
flash column chromatography on silica gel (eluent: hexane/EtOAc or
toluene/MeCN) to afford pure 3a−l, 4a−f, 5a−f, and 6a−i.
Ethyl 1,5-Dimethyl-2-phenyl-1H-imidazole-4-carboxylate (3a).
White solid, 175 mg, 72% yield, mp 84−85 °C. Silica gel TLC Rf =
0.20 (hexane/EtOAc = 1/1); 1H NMR (500 MHz, DMSO-d6): δ 7.64
(d, J = 7.1 Hz, 2H), 7.57−7.46 (m, 3H), 4.24 (q, J = 7.1 Hz, 2H),
3.60 (s, 3H), 2.54 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 13C{1H} NMR
(126 MHz, DMSO-d6): δ 163.8, 146.9, 138.1, 130.6, 129.4, 129.2,
129.0, 128.0, 59.7, 32.5, 14.9, 10.7. HRMS (ESI) m/z: [M + H]+
calcd for C14H17N2O2, 245.1285; found, 245.1284.
Scheme 2. Plausible Mechanism for the Formation of
Imidazoles
Ethyl 2-(4-Methoxyphenyl)-1,5-dimethyl-1H-imidazole-4-car-
boxylate (3b). White solid, 187 mg, 68% yield, mp 98−99 °C. Silica
1
Initially, 1,3-DC between nitrone 1 and activated 2H-azirine 2
might occur to form cycloadduct A, which immediately
rearranges to ketoamidine B in the presence of the acid
catalyst. Following the intramolecular cyclization of inter-
mediate B, the final product is achieved by the dehydration of
hydroxyimidazoline C.
gel TLC Rf = 0.11 (hexane/EtOAc = 1/1); H NMR (500 MHz,
chloroform-d): δ 7.52 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H),
4.39 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 3.56 (s, 3H), 2.61 (s, 3H), 1.40
(t, J = 7.1 Hz, 3H). 13C{1H} NMR (126 MHz, chloroform-d): δ
164.2, 160.2, 147.4, 137.0, 130.7, 128.4, 122.6, 113.9, 60.2, 55.4, 31.9,
14.6, 10.6. HRMS (ESI) m/z: [M + H]+ calcd for C15H19N2O3,
275.1391; found, 275.1390.
Ethyl 2-(4-Fluorophenyl)-1,5-dimethyl-1H-imidazole-4-carboxy-
late (3c). White solid, 204 mg, 78% yield, mp 98−100 °C. Silica gel
TLC Rf = 0.23 (hexane/EtOAc = 1/1); 1H NMR (500 MHz,
chloroform-d): δ 7.60−7.54 (m, 2H), 7.15 (t, J = 8.7 Hz, 2H), 4.40
(q, J = 7.1 Hz, 2H), 3.57 (s, 3H), 2.61 (s, 3H), 1.40 (t, J = 7.1 Hz,
3H). 13C{1H} NMR (126 MHz, chloroform-d): δ 164.2, 163.1 (d, J =
223.5 Hz), 146.5, 137.2, 131.2 (d, J = 8.3 Hz), 128.6, 126.3, 115.7 (d,
J = 22.0 Hz), 60.3, 31.9, 14.6, 10.5. 19F NMR (471 MHz, chloroform-
d): δ −114.7; HRMS (ESI) m/z: [M + H]+ calcd for C14H16FN2O2,
263.1191; found, 263.1191.
CONCLUSIONS
■
In summary, we have developed a novel procedure for the
regioselective synthesis of 1,2,4,5-tetrasubstituted imidazoles
through an unprecedented 1,3-DC of 2H-azirines with
nitrones. This TFA-catalyzed cascade reaction is compatible
with a variety of 2H-azirines and a wide range of C-aliphatic
and C-aromatic as well as N-aliphatic and N-arylnitrones,
offering a general and straightforward access to highly diverse
multisubstituted imidazoles in isolated yields up to 83% under
mild conditions.
Ethyl 1,5-Dimethyl-2-(4-nitrophenyl)-1H-imidazole-4-carboxy-
late (3d). Yellow solid, 200 mg, 69% yield, mp 145−146 °C. Silica
1
gel TLC Rf = 0.35 (hexane/EtOAc = 1/1); H NMR (500 MHz,
EXPERIMENTAL SECTION
chloroform-d): δ 8.31 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 8.8 Hz, 2H),
4.41 (q, J = 7.1 Hz, 2H), 3.66 (s, 3H), 2.64 (s, 3H), 1.41 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (126 MHz, chloroform-d): δ 163.7, 147.9,
145.0, 138.3, 136.2, 129.9, 129.6, 123.8, 60.6, 32.3, 14.54, 10.6.
HRMS (ESI) m/z: [M + H]+ calcd for C14H16N3O4, 290.1136; found,
290.1138.
■
General Information. The NMR spectra were recorded at 298 K
on a Bruker Ascend 500 with a 5 mm BBO Prodigy Probe in CDCl3-
d1 or DMSO-d6. The chemical shifts are reported in δ (ppm) relative
to the internal standard (tetramethylsilane) or the residual solvent
signal. In case of 19F NMR, hexafluorobenzene was used as the
reference compound. Data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, dd = doublet of doublet, dt = doublet of triplet, etc.),
coupling constants, and integration. Coupling constants (J) are given
in hertz (Hz). LC/MS analyses were carried out on an Agilent 1200
Series equipment with an Agilent G1946D MS detector (APCI,
operated in a positive mode) with a Kinetex C18 column (100 Å, 5
μm, 250 × 4.6 mm, Phenomenex). High-resolution mass spectra
(HRMS) were performed on a Thermo Scientific Q Exactive hybrid
quadrupole-Orbitrap mass spectrometer using an heated electrospray
ionisation (HESI) ion source. Samples (5 μL from 1 μg/mL solution)
were injected to the mass spectrometer using the flow injection
method (200 μL/min, water/MeCN 1:1, 0.1% TFA). Melting points
(mp) were recorded with a Digital Melting Point Apparatus
(Electrothermal, IA 9000 Series). Chromatographic purification of
the products was performed on Merck silica gel 60, particle size
0.063−0.200 mm. Thin-layer chromatography (TLC) was performed
on fluorescent-indicating plates (aluminum sheets precoated with
silica gel 60F254, 1.05554, Merck), and visualization was achieved using
UV light (254 nm) or by staining with basic potassium permanganate
solution. Nitrones 1a−r and racemic 2H-azirines 2a−h were
synthesized according to literature procedures.21 All other reagents
Ethyl 1,5-Dimethyl-2-(pyridin-2-yl)-1H-imidazole-4-carboxylate
(3e). Light yellow solid, 201 mg, 82% yield, mp 114−115 °C. Silica
1
gel TLC Rf = 0.13 (hexane/EtOAc = 1/1); H NMR (500 MHz,
chloroform-d): δ 8.61−8.56 (m, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.77
(dt, J = 7.8, 1.8 Hz, 1H), 7.26−7.22 (m, 1H), 4.41 (q, J = 7.1 Hz,
2H), 4.04 (s, 3H), 2.62 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (126 MHz, chloroform-d): δ 164.0, 150.2, 148.1, 144.7, 138.8,
136.7, 128.6, 124.0, 123.0, 60.4, 33.0, 14.6, 10.4. HRMS (ESI) m/z:
[M + H]+ calcd for C13H16N3O2, 246.1238; found, 246.1237.
Ethyl 1,5-Dimethyl-2-(pyridin-3-yl)-1H-imidazole-4-carboxylate
(3f). Orange oil, 198 mg, 81% yield. Silica gel TLC Rf = 0.52
(chloroform/MeOH = 19/1); 1H NMR (500 MHz, chloroform-d): δ
8.84 (s, 1H), 8.68 (d, J = 4.8 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.41
(dd, J = 7.8, 4.8 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.63 (s, 3H), 2.64
(s, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (126 MHz,
chloroform-d): δ 163.8, 150.1, 149.6, 144.4, 137.7, 136.9, 129.4,
126.5, 123.5, 60.5, 32.0, 14.6, 10.6. HRMS (ESI) m/z: [M + H]+
calcd for C13H16N3O2, 246.1238; found, 246.1235.
Ethyl 1,5-Dimethyl-2-(5-methylfuran-2-yl)-1H-imidazole-4-car-
boxylate (3g). Yellow solid, 102 mg, 41% yield, mp 68−69 °C.
1
Silica gel TLC Rf = 0.20 (hexane/EtOAc = 1/1); H NMR (500
MHz, chloroform-d): δ 6.79 (d, J = 3.2 Hz, 1H), 6.15−6.04 (m, 1H),
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4.38 (q, J = 7.1 Hz, 2H), 3.73 (s, 3H), 2.59 (s, 3H), 2.37 (s, 3H), 1.40
(t, J = 7.1 Hz, 3H). 13C{1H} NMR (126 MHz, chloroform-d): δ
164.0, 153.1, 143.1, 139.4, 136.9, 128.6, 111.7, 107.6, 60.3, 31.8, 14.5,
13.8, 10.2. HRMS (ESI) m/z: [M + H]+ calcd for C13H17N2O3,
249.1234; found, 249.1233.
Ethyl 1-Benzyl-2-isopropyl-5-methyl-1H-imidazole-4-carboxy-
late (3p). Light yellow oil, 202 mg, 71% yield. Silica gel TLC Rf =
1
0.39 (hexane/EtOAc = 1/1); H NMR (500 MHz, chloroform-d): δ
7.34−7.27 (m, 3H), 6.90 (d, J = 6.8 Hz, 2H), 5.10 (s, 2H), 4.38 (q, J
= 7.1 Hz, 2H), 2.92 (hept, J = 6.9 Hz, 1H), 2.42 (s, 3H), 1.40 (t, J =
7.1 Hz, 3H), 1.29 (d, J = 6.9 Hz, 6H). 13C{1H} NMR (126 MHz,
chloroform-d): δ 164.2, 153.3, 135.9, 135.7, 129.1, 127.9, 125.5, 60.3,
46.5, 26.6, 21.6, 14.6, 10.3. HRMS (ESI) m/z: [M + H]+ calcd for
C17H23N2O2, 287.1755; found, 287.1755.
Ethyl 1,2,5-Trimethyl-1H-imidazole-4-carboxylate (3h). Light
yellow oil, 127 mg, 70% yield. Silica gel TLC Rf = 0.41
1
(chloroform/MeOH = 19/1); H NMR (500 MHz, chloroform-d):
δ 4.35 (q, J = 7.2 Hz, 2H), 3.45 (s, 3H), 2.51 (s, 3H), 2.39 (s, 3H),
1.38 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (126 MHz, chloroform-d): δ
164.0, 144.4, 136.2, 127.1, 60.1, 30.3, 14.6, 13.5, 10.3. HRMS (ESI)
m/z: [M + H]+ calcd for C9H15N2O2, 183.1129; found, 183.1130.
Ethyl 2-Isopropyl-1,5-dimethyl-1H-imidazole-4-carboxylate (3i).
Light yellow solid, 111 mg, 53% yield, mp 73−74 °C. Silica gel TLC
Ethyl 1-Cyclohexyl-5-methyl-2-phenyl-1H-imidazole-4-carboxy-
late (3q). White solid, 116 mg, 37% yield, mp 103−105 °C. Silica gel
TLC Rf = 0.50 (hexane/EtOAc = 1/1); 1H NMR (500 MHz,
chloroform-d): δ 7.48−7.40 (m, 5H), 4.38 (q, J = 7.1 Hz, 2H), 4.08
(tt, J = 12.1, 4.0 Hz, 1H), 2.75 (s, 3H), 1.98−1.80 (m, 6H), 1.70−
1.63 (m, 1H), 1.39 (t, J = 7.1 Hz, 3H), 1.24−1.10 (m, 3H). 13C{1H}
NMR (126 MHz, chloroform-d): δ 164.3, 147.8, 136.3, 131.4, 129.9,
129.2, 128.3, 60.2, 57.8, 32.0, 26.1, 25.1, 14.6, 12.1. HRMS (ESI) m/
z: [M + H]+ calcd for C19H25N2O2, 313.1911; found, 313.1911.
Ethyl 1-(4-Fluorophenyl)-5-methyl-2-phenyl-1H-imidazole-4-
carboxylate (3r). Beige solid, 135 mg, 42% yield, mp 134−136 °C.
1
Rf = 0.07 (hexane/EtOAc = 1/1); H NMR (500 MHz, chloroform-
d): δ 4.36 (q, J = 7.1 Hz, 2H), 3.48 (s, 3H), 3.02 (hept, J = 6.9 Hz,
1H), 2.51 (s, 3H), 1.46−1.27 (m, 9H). 13C{1H} NMR (126 MHz,
chloroform-d): δ 164.2, 152.6, 136.1, 127.2, 60.2, 30.0, 26.6, 20.9,
14.6, 10.4. HRMS (ESI) m/z: [M + H]+ calcd for C11H19N2O2,
211.1442; found, 211.1438.
1
Silica gel TLC Rf = 0.87 (hexane/EtOAc = 1/1); H NMR (500
Ethyl 2-(tert-Butyl)-1,5-dimethyl-1H-imidazole-4-carboxylate
MHz, chloroform-d): δ 7.35 (d, J = 7.2 Hz, 2H), 7.27−7.18 (m, 3H),
7.17 (d, J = 6.4 Hz, 4H), 4.44 (q, J = 7.1 Hz, 2H), 2.41 (s, 3H), 1.43
(t, J = 7.1 Hz, 3H). 13C{1H} NMR (126 MHz, chloroform-d): δ
164.0, 162.6 (d, J = 250.8 Hz), 146.9, 138.1, 132.4, 129.8, 129.7,
129.5, 129.2, 128.8, 128.2, 116.96 (d, J = 23.0 Hz), 60.5, 14.6, 11.1.
19F NMR (471 MHz, chloroform-d): δ −113.9; HRMS (ESI) m/z:
(3j). Light yellow oil, 110 mg, 49% yield. Silica gel TLC Rf = 0.38
1
(hexane/EtOAc = 1/1); H NMR (500 MHz, chloroform-d): δ 4.34
(q, J = 7.1 Hz, 2H), 3.62 (s, 3H), 2.50 (s, 3H), 1.45 (s, 9H), 1.38 (t, J
= 7.1 Hz, 3H). 13C{1H} NMR (126 MHz, chloroform-d): δ 164.3,
154.0, 137.6, 126.3, 60.2, 33.3, 32.5, 29.1, 14.5, 10.5. HRMS (ESI) m/
z: [M + H]+ calcd for C12H21N2O2, 225.1598; found, 225.1594.
Ethyl 2-Heptyl-1,5-dimethyl-1H-imidazole-4-carboxylate (3k).
Light yellow oil, 144 mg, 54% yield. Silica gel TLC Rf = 0.21
[M + H]+ calcd for C19H18FN2O2, 325.1347; found, 325.1344.
tert-Butyl 1,5-Dimethyl-2-phenyl-1H-imidazole-4-carboxylate
(4a). White solid, 183 mg, 67% yield, mp 224−225 °C. Silica gel
TLC Rf = 0.25 (hexane/EtOAc = 1/1); 1H NMR (500 MHz,
chloroform-d): δ 7.62−7.52 (m, 2H), 7.47−7.38 (m, 3H), 3.57 (s,
3H), 2.58 (s, 3H), 1.60 (s, 9H). 13C{1H} NMR (126 MHz,
chloroform-d): δ 163.4, 147.3, 136.1, 130.3, 129.9, 129.2, 129.0,
128.5, 80.6, 32.0, 28.5, 10.7. HRMS (ESI) m/z: [M + H]+ calcd for
C16H21N2O2, 273.1598; found, 273.1599.
1
(hexane/EtOAc = 1/1); H NMR (500 MHz, chloroform-d): δ 4.36
(q, J = 7.1 Hz, 2H), 3.46 (s, 3H), 2.76−2.64 (m, 2H), 2.51 (s, 3H),
1.76−1.63 (m, 3H), 1.38 (t, J = 7.1 Hz, 3H), 1.36−1.23 (m, 7H),
0.88 (t, J = 6.7 Hz, 3H). 13C{1H} NMR (126 MHz, chloroform-d): δ
164.2, 148.4, 136.1, 127.3, 60.1, 31.7, 30.3, 29.5, 29.0, 28.1, 27.6, 22.6,
14.6, 14.1, 10.3. HRMS (ESI) m/z: [M + H]+ calcd for C15H27N2O2,
267.2068; found, 267.2069.
1-Methyl-2,4,5-triphenyl-1H-imidazole (4b). White solid, 222 mg,
Ethyl 2-Cyclopropyl-1,5-dimethyl-1H-imidazole-4-carboxylate
72% yield, mp 146−148 °C. Silica gel TLC Rf = 0.78 (hexane/EtOAc
(3l). Light yellow oil, 150 mg, 72% yield. Silica gel TLC Rf = 0.06
1
1
= 1/1); H NMR (500 MHz, chloroform-d): δ 7.75 (d, J = 7.5 Hz,
(hexane/EtOAc = 1/1); H NMR (500 MHz, chloroform-d): δ 4.34
2H), 7.55 (d, J = 7.7 Hz, 2H), 7.52−7.39 (m, 8H), 7.21 (t, J = 7.5 Hz,
2H), 7.14 (t, J = 7.3 Hz, 1H), 3.51 (s, 3H). 13C{1H} NMR (126
MHz, chloroform-d): δ 147.9, 137.7, 134.6, 131.2, 131.0, 130.9, 130.5,
129.1, 129.1, 128.8, 128.6, 128.1, 127.0, 126.3, 33.2. HRMS (ESI) m/
z: [M + H]+ calcd for C22H19N2, 311.1543; found, 311.1542.
5-(4-Methoxyphenyl)-1-methyl-2,4-diphenyl-1H-imidazole (4c).
White solid, 239 mg, 70% yield, mp 157−158 °C. Silica gel TLC Rf
(q, J = 7.1 Hz, 2H), 3.58 (s, 3H), 2.51 (s, 3H), 1.78−1.70 (m, 1H),
1.37 (t, J = 7.1 Hz, 3H), 1.08−1.00 (m, 2H), 0.98−0.90 (m, 2H).
13C{1H} NMR (126 MHz, chloroform-d): δ 164.1, 148.9, 136.3,
126.9, 60.1, 30.0, 14.5, 10.3, 7.5, 6.3. HRMS (ESI) m/z: [M + H]+
calcd for C11H17N2O2, 209.1285; found, 209.1281.
Ethyl 2-Cyclohexyl-1,5-dimethyl-1H-imidazole-4-carboxylate
(3m). Light yellow solid, 175 mg, 70% yield, mp 85−86 °C. Silica
1
1
= 0.69 (hexane/EtOAc = 1/1); H NMR (500 MHz, chloroform-d):
gel TLC Rf = 0.23 (hexane/EtOAc = 1/1); H NMR (500 MHz,
δ 7.74 (d, J = 7.5 Hz, 2H), 7.57 (d, J = 7.6 Hz, 2H), 7.49 (t, J = 7.5
Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H), 7.33 (d, J = 8.2 Hz, 2H), 7.22 (t, J =
7.6 Hz, 2H), 7.14 (t, J = 7.3 Hz, 1H), 7.01 (d, J = 8.2 Hz, 2H), 3.88
(s, 3H), 3.49 (s, 3H). 13C{1H} NMR (126 MHz, chloroform-d): δ
159.8, 147.6, 137.5, 134.8, 132.2, 131.1, 130.3, 129.1, 128.7, 128.6,
128.1, 126.8, 126.2, 123.3, 114.5, 55.3, 33.1. HRMS (ESI) m/z: [M +
H]+ calcd for C23H21N2O, 341.1649; found, 341.1648.
chloroform-d): δ 4.36 (q, J = 7.1 Hz, 2H), 3.47 (s, 3H), 2.63 (tt, J =
12.1, 3.4 Hz, 1H), 2.51 (s, 3H), 1.92−1.83 (m, 4H), 1.81−1.68 (m,
3H), 1.38 (t, J = 7.1 Hz, 3H), 1.34−1.29 (m, 3H). 13C{1H} NMR
(126 MHz, chloroform-d): δ 164.2, 151.9, 135.8, 127.4, 60.1, 36.4,
31.0, 30.0, 26.3, 25.6, 14.6, 10.3. HRMS (ESI) m/z: [M + H]+ calcd
for C14H23N2O2, 251.1755; found, 251.1756.
Ethyl 1,2-Diisopropyl-5-methyl-1H-imidazole-4-carboxylate
5-(4-Fluorophenyl)-1-methyl-2,4-diphenyl-1H-imidazole (4d).
White solid, 255 mg, 78% yield, mp 168−170 °C. Silica gel TLC Rf
(3n). Light yellow oil, 130 mg, 55% yield. Silica gel TLC Rf = 0.36
1
(hexane/EtOAc = 1/1); H NMR (500 MHz, chloroform-d): δ 4.53
1
= 0.77 (hexane/EtOAc = 1/1); H NMR (500 MHz, DMSO-d6): δ
(hept, J = 7.1 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.06 (hept, J = 6.9
Hz, 1H), 2.62 (s, 3H), 1.52 (d, J = 7.1 Hz, 6H), 1.38 (t, J = 7.1 Hz,
3H), 1.36 (d, J = 6.8 Hz, 6H). 13C{1H} NMR (126 MHz, chloroform-
d): δ 164.4, 60.1, 47.2, 27.2, 21.8, 14.6. HRMS (ESI) m/z: [M + H]+
calcd for C13H23N2O2, 239.1755; found, 239.1754.
7.79 (d, J = 7.5 Hz, 2H), 7.59−7.48 (m, 5H), 7.44 (d, J = 7.7 Hz,
2H), 7.39 (t, J = 8.6 Hz, 2H), 7.25 (t, J = 7.6 Hz, 2H), 7.16 (t, J = 7.4
Hz, 1H), 3.48 (s, 3H), 3.35 (s, 3H). 13C{1H} NMR (126 MHz,
DMSO-d6): δ 162.7 (d, J = 246.1 Hz), 147.4, 137.1, 135.1, 133.5 (d, J
= 8.3 Hz), 131.1, 129.9, 129.2, 129.0, 128.6, 127.6, 126.7, 116.6 (d, J
= 21.3 Hz), 33.5. 19F NMR (471 MHz, chloroform-d): δ −115.6;
HRMS (ESI) m/z: [M + H]+ calcd for C22H18FN2, 329.1449; found,
329.1447.
Ethyl 1-Benzyl-5-methyl-2-phenyl-1H-imidazole-4-carboxylate
(3o). Light yellow oil, 203 mg, 63% yield. Silica gel TLC Rf = 0.22
1
(hexane/EtOAc = 1/1); H NMR (500 MHz, chloroform-d): δ 7.51
(d, J = 6.7 Hz, 2H), 7.41−7.29 (m, 6H), 6.97 (d, J = 7.3 Hz, 2H),
5.19 (s, 2H), 4.42 (q, J = 7.1 Hz, 2H), 2.47 (s, 3H), 1.42 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (126 MHz, chloroform-d): δ 164.1, 148.1,
137.1, 136.0, 130.0, 129.4, 129.2, 128.5, 127.9, 125.6, 60.4, 48.1, 14.6,
10.5. HRMS (ESI) m/z: [M + H]+ calcd for C20H21N2O2, 321.1598;
found, 321.1596.
5-(4-Chlorophenyl)-1-methyl-2,4-diphenyl-1H-imidazole (4e).
White solid, 272 mg, 79% yield, mp 187−188 °C. Silica gel TLC Rf
1
= 0.81 (hexane/EtOAc = 2/1); H NMR (500 MHz, chloroform-d):
δ 7.73 (d, J = 7.4 Hz, 2H), 7.55−7.47 (m, 4H), 7.47−7.41 (m, 3H),
7.36 (d, J = 8.0 Hz, 2H), 7.24 (t, J = 7.5 Hz, 2H), 7.17 (t, J = 7.3 Hz,
3591
https://dx.doi.org/10.1021/acs.joc.9b03288
J. Org. Chem. 2020, 85, 3587−3595

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1H), 3.51 (s, 3H). 13C{1H} NMR (126 MHz, chloroform-d): δ 148.3,
138.2, 134.7, 134.4, 132.2, 130.8, 129.7, 129.4, 129.1, 128.9, 128.6,
128.2, 127.1, 126.6, 33.2. HRMS (ESI) m/z: [M + H]+ calcd for
C22H18ClN2, 345.1154 and 347.1124; found, 345.1155 and 347.1126.
5-Benzyl-1-methyl-2,4-diphenyl-1H-imidazole (4f). White solid,
146 mg, 45% yield, mp 160−161 °C. Silica gel TLC Rf = 0.69
(hexane/EtOAc = 1/1); 1H NMR (500 MHz, chloroform-d): δ 7.71−
7.64 (m, 4H), 7.46 (t, J = 7.3 Hz, 2H), 7.41 (t, J = 7.4 Hz, 1H), 7.35
(q, J = 7.8 Hz, 4H), 7.29−7.22 (m, 2H), 7.21 (d, J = 7.5 Hz, 2H),
4.28 (s, 2H), 3.46 (s, 3H). 13C{1H} NMR (126 MHz, chloroform-d):
δ 147.7, 139.4, 138.3, 135.0, 130.9, 129.1, 128.9, 128.7, 128.5, 128.5,
127.9, 127.3, 126.7, 126.7, 32.1, 30.5. HRMS (ESI) m/z: [M + H]+
calcd for C23H21N2, 325.1700; found, 325.1698.
2-(4-Methoxyphenyl)-1-methyl-4,5-diphenyl-1H-imidazole (6a).
White solid, 234 mg, 69% yield, mp 169−171 °C. Silica gel TLC Rf =
1
0.65 (hexane/EtOAc = 1/1); H NMR (500 MHz, chloroform-d): δ
7.67 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 7.6 Hz, 2H), 7.50−7.39 (m,
5H), 7.21 (t, J = 7.5 Hz, 2H), 7.14 (t, J = 7.3 Hz, 1H), 7.02 (d, J = 8.7
Hz, 2H), 3.87 (s, 3H), 3.48 (s, 3H). 13C{1H} NMR (126 MHz,
chloroform-d): δ 160.0, 147.9, 137.5, 134.7, 130.9, 130.5, 130.1,
129.0, 128.5, 128.1, 126.9, 126.3, 123.4, 114.0, 55.4, 33.1. HRMS
(ESI) m/z: [M + H]+ calcd for C23H21N2O, 341.1649; found,
341.1651.
1-Methyl-2-(5-methylfuran-2-yl)-4,5-diphenyl-1H-imidazole
(6b). White solid, 186 mg, 59% yield, mp 137−139 °C. Silica gel TLC
1
Rf = 0.44 (hexane/EtOAc = 4/1); H NMR (500 MHz, chloroform-
d): δ 7.52−7.48 (m, 2H), 7.47−7.43 (m, 3H), 7.37−7.34 (m, 2H),
7.21−7.16 (m, 2H), 7.15−7.10 (m, 1H), 6.77 (d, J = 3.3 Hz, 1H),
6.14−6.11 (m, 1H), 3.60 (s, 3H), 2.40 (s, 3H). 13C{1H} NMR (126
MHz, chloroform-d): δ 153.1, 143.7, 139.7, 137.9, 134.3, 131.0, 130.7,
130.0, 129.1, 128.7, 128.0, 127.1, 126.4, 111.1, 107.6, 32.7, 13.8.
HRMS (ESI) m/z: [M + H]+ calcd for C21H19N2O, 315.1492; found,
315.1493.
1,2-Dimethyl-4,5-diphenyl-1H-imidazole (6c). White solid, 172
mg, 69% yield, mp 109−110 °C. Silica gel TLC Rf = 0.17 (hexane/
EtOAc = 1/1); 1H NMR (500 MHz, chloroform-d): δ 7.47−7.40 (m,
5H), 7.32 (d, J = 7.6 Hz, 2H), 7.18 (t, J = 7.5 Hz, 2H), 7.11 (t, J = 7.3
Hz, 1H), 3.37 (s, 3H), 2.50 (s, 3H). 13C{1H} NMR (126 MHz,
chloroform-d): δ 144.7, 136.2, 134.7, 131.4, 130.9, 128.9, 128.9,
128.4, 128.1, 126.7, 126.1, 31.1, 13.6. HRMS (ESI) m/z: [M + H]+
calcd for C17H17N2, 249.1387; found, 249.1389.
tert-Butyl 2-Isopropyl-1,5-dimethyl-1H-imidazole-4-carboxylate
(5a). White solid, 116 mg, 49% yield, mp 99−101 °C. Silica gel TLC
1
Rf = 0.26 (hexane/EtOAc = 1/1); H NMR (500 MHz, chloroform-
d): δ 3.45 (s, 3H), 2.98 (hept, J = 6.9 Hz, 1H), 2.44 (s, 3H), 1.58 (s,
9H), 1.34 (d, J = 6.9 Hz, 6H). 13C{1H} NMR (126 MHz, chloroform-
d): δ 163.3, 152.4, 134.3, 128.6, 80.1, 30.0, 28.4, 26.6, 20.9, 10.5.
HRMS (ESI) m/z: [M + H]+ calcd for C13H23N2O2, 239.1755; found,
239.1753.
2-Isopropyl-1-methyl-4,5-diphenyl-1H-imidazole (5b). White
solid, 188 mg, 68% yield, mp 92−93 °C. Silica gel TLC Rf = 0.70
(hexane/EtOAc = 1/1); 1H NMR (500 MHz, chloroform-d): δ 7.48−
7.36 (m, 5H), 7.32 (d, J = 6.1 Hz, 2H), 7.17 (t, J = 7.6 Hz, 2H), 7.09
(t, J = 7.4 Hz, 1H), 3.39 (s, 3H), 3.09 (hept, J = 6.9 Hz, 1H), 1.44 (d,
J = 6.8 Hz, 6H). 13C{1H} NMR (126 MHz, chloroform-d): δ 152.8,
136.2, 135.1, 131.5, 130.9, 128.9, 128.6, 128.2, 128.0, 126.9, 125.9,
30.7, 26.7, 21.4. HRMS (ESI) m/z: [M + H]+ calcd for C19H21N2,
277.1700; found, 277.1701.
2-Isopropyl-5-(4-methoxyphenyl)-1-methyl-4-phenyl-1H-imida-
zole (5c). White solid, 204 mg, 67% yield, mp 156−158 °C. Silica gel
TLC Rf = 0.60 (hexane/EtOAc = 1/1); 1H NMR (500 MHz,
chloroform-d): δ 7.47 (d, J = 7.2 Hz, 2H), 7.24 (d, J = 8.7 Hz, 2H),
7.18 (t, J = 7.6 Hz, 2H), 7.09 (t, J = 7.3 Hz, 1H), 6.96 (d, J = 8.7 Hz,
2H), 3.86 (s, 3H), 3.37 (s, 3H), 3.08 (p, J = 6.9 Hz, 1H), 1.43 (d, J =
6.9 Hz, 6H). 13C{1H} NMR (126 MHz, chloroform-d): δ 159.6,
152.5, 136.0, 135.2, 132.2, 128.3, 128.0, 126.8, 125.8, 123.7, 114.4,
55.3, 30.6, 26.7, 21.4. HRMS (ESI) m/z: [M + H]+ calcd for
C20H23N2O, 307.1805; found, 307.1806.
2-(tert-Butyl)-1-methyl-4,5-diphenyl-1H-imidazole (6d). Light
beige solid, 146 mg, 50% yield, mp 123−124 °C. Silica gel TLC Rf
1
= 0.62 (hexane/EtOAc = 4/1); H NMR (500 MHz, chloroform-d):
δ 7.48−7.40 (m, 5H), 7.34−7.30 (m, 2H), 7.16 (t, J = 7.6 Hz, 2H),
7.08 (t, J = 7.3 Hz, 1H), 3.51 (s, 3H), 1.54 (s, 9H). 13C{1H} NMR
(126 MHz, chloroform-d): δ 153.9, 135.1, 135.0, 131.7, 131.2, 130.2,
128.9, 128.4, 128.0, 126.7, 125.8, 33.6, 33.2, 29.5. HRMS (ESI) m/z:
[M + H]+ calcd for C20H23N2, 291.1856; found, 291.1858.
2-Cyclopropyl-1-methyl-4,5-diphenyl-1H-imidazole (6e). White
solid, 160 mg, 58% yield, mp 110−111 °C. Silica gel TLC Rf = 0.24
(hexane/EtOAc = 4/1); 1H NMR (500 MHz, chloroform-d): δ 7.46−
7.38 (m, 5H), 7.34−7.30 (m, 2H), 7.16 (t, J = 7.8 Hz, 2H), 7.09 (t, J
= 7.3 Hz, 1H), 3.49 (s, 3H), 1.91−1.80 (m, 1H), 1.20−1.10 (m, 2H),
1.04−0.95 (m, 2H). 13C{1H} NMR (126 MHz, chloroform-d): δ
149.2, 135.9, 134.9, 131.4, 130.9, 128.9, 128.9, 128.3, 128.0, 126.8,
125.9, 30.8, 7.6, 6.6. HRMS (ESI) m/z: [M + H]+ calcd for C19H19N2,
275.1543; found, 275.1545.
5-(4-Fluorophenyl)-2-isopropyl-1-methyl-4-phenyl-1H-imidazole
(5d). White solid, 216 mg, 73% yield, mp 138−139 °C. Silica gel TLC
1
Rf = 0.29 (hexane/EtOAc = 4/1); H NMR (500 MHz, chloroform-
d): δ 7.43 (d, J = 7.0 Hz, 2H), 7.34−7.27 (m, 2H), 7.19 (t, J = 7.6 Hz,
3H), 7.16−7.09 (m, 2H), 3.38 (s, 3H), 3.09 (p, J = 6.9 Hz, 1H), 1.43
(d, J = 6.9 Hz, 6H). 13C{1H} NMR (126 MHz, chloroform-d): δ
162.70 (d, J = 248.1 Hz), 152.9, 136.5, 134.9, 132.8 (d, J = 8.2 Hz),
128.1, 127.5 (d, J = 3.1 Hz), 127.4, 126.9, 126.0, 116.1 (d, J = 21.8
Hz), 30.7, 26.7, 21.4. 19F NMR (471 MHz, chloroform-d): δ −116.3;
HRMS (ESI) m/z: [M + H]+ calcd for C19H20FN2, 295.1606; found,
295.1606.
5-(4-Chlorophenyl)-2-isopropyl-1-methyl-4-phenyl-1H-imida-
zole (5e). White solid, 224 mg, 72% yield, mp 132−133 °C. Silica gel
TLC Rf = 0.36 (hexane/EtOAc = 4/1); 1H NMR (500 MHz,
chloroform-d): δ 7.47−7.38 (m, 4H), 7.26 (d, J = 3.9 Hz, 2H), 7.20
(t, J = 7.5 Hz, 2H), 7.12 (t, J = 7.3 Hz, 1H), 3.39 (s, 3H), 3.08 (p, J =
6.9 Hz, 1H), 1.43 (d, J = 6.8 Hz, 6H). 13C{1H} NMR (126 MHz,
chloroform-d): δ 153.2, 136.8, 134.8, 134.3, 132.2, 129.9, 129.2,
128.2, 127.2, 127.0, 126.2, 30.8, 26.7, 21.4. HRMS (ESI) m/z: [M +
H]+ calcd for C19H20ClN2, 311.1310 and 313.1281; found, 311.1311
and 313.1283.
2-Cyclohexyl-1-methyl-4,5-diphenyl-1H-imidazole (6f). White
solid, 249 mg, 79% yield, mp 119−120 °C. Silica gel TLC Rf =
1
0.58 (hexane/EtOAc = 4/1); H NMR (500 MHz, chloroform-d): δ
7.48−7.36 (m, 5H), 7.35−7.29 (m, 2H), 7.17 (t, J = 7.6 Hz, 2H),
7.09 (t, J = 7.3 Hz, 1H), 3.39 (s, 3H), 2.71 (tt, J = 11.7, 3.5 Hz, 1H),
2.04−1.97 (m, 2H), 1.95−1.87 (m, 2H), 1.87−1.73 (m, 3H), 1.47−
1.33 (m, 3H). 13C{1H} NMR (126 MHz, chloroform-d): δ 152.2,
136.4, 135.2, 131.6, 130.9, 128.9, 128.4, 128.2, 128.0, 126.9, 125.9,
36.6, 31.6, 30.7, 26.5, 25.9. HRMS (ESI) m/z: [M + H]+ calcd for
C22H25N2, 317.2013; found, 317.2014.
1,2-Diisopropyl-4,5-diphenyl-1H-imidazole (6g). White solid, 72
mg, 24% yield, mp 171−172 °C. Silica gel TLC Rf = 0.51 (hexane/
EtOAc = 4/1); 1H NMR (500 MHz, chloroform-d): δ 7.44−7.41 (m,
3H), 7.37 (d, J = 7.3 Hz, 2H), 7.37−7.30 (m, 2H), 7.13 (t, J = 7.5 Hz,
2H), 7.05 (t, J = 7.3 Hz, 1H), 4.30 (p, J = 7.1 Hz, 1H), 3.18 (p, J = 6.8
Hz, 1H), 1.46 (d, J = 6.8 Hz, 6H), 1.39 (d, J = 7.1 Hz, 6H). 13C{1H}
NMR (126 MHz, chloroform-d): δ 152.6, 136.5, 135.2, 132.7, 131.8,
128.8, 128.4, 127.9, 127.4, 126.7, 125.7, 47.1, 27.8, 22.8, 22.6. HRMS
(ESI) m/z: [M + H]+ calcd for C21H25N2, 305.2013; found, 305.2014.
1-Cyclohexyl-2,4,5-triphenyl-1H-imidazole (6h). White solid, 121
mg, 32% yield, mp 165−166 °C. Silica gel TLC Rf = 0.81 (hexane/
EtOAc = 1/1); 1H NMR (500 MHz, chloroform-d): δ 7.66−7.60 (m,
2H), 7.51−7.39 (m, 10H), 7.14 (t, J = 7.5 Hz, 2H), 7.08 (t, J = 7.3
Hz, 1H), 3.97 (tt, J = 12.3, 3.5 Hz, 1H), 1.85 (d, J = 12.4 Hz, 2H),
1.68−1.49 (m, 4H), 1.45 (d, J = 13.5 Hz, 1H), 1.04 (qt, J = 13.0, 3.6
5-Benzyl-2-isopropyl-1-methyl-4-phenyl-1H-imidazole (5f).
White solid, 166 mg, 57% yield, mp 104−106 °C. Silica gel TLC Rf
1
= 0.58 (hexane/EtOAc = 1/1); H NMR (500 MHz, chloroform-d):
δ 7.60 (d, J = 7.3 Hz, 2H), 7.35−7.28 (m, 4H), 7.25−7.17 (m, 2H),
7.14 (d, J = 7.4 Hz, 2H), 4.16 (s, 2H), 3.32 (s, 3H), 3.03 (p, J = 6.9
Hz, 1H), 1.39 (d, J = 6.9 Hz, 6H). 13C{1H} NMR (126 MHz,
chloroform-d): δ 152.7, 138.7, 137.8, 135.5, 128.8, 128.4, 127.8,
127.2, 126.5, 126.3, 124.7, 30.2, 30.1, 26.5, 21.3. HRMS (ESI) m/z:
[M + H]+ calcd for C20H23N2, 291.1856; found, 291.1857.
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Hz, 2H), 0.73 (qt, J = 13.2, 3.7 Hz, 1H). 13C{1H} NMR (126 MHz,
chloroform-d): δ 147.7, 137.8, 134.7, 132.6, 132.5, 132.2, 130.1,
129.1, 128.9, 128.8, 128.7, 128.4, 127.9, 126.7, 126.0, 58.4, 33.6, 26.2,
25.1. HRMS (ESI) m/z: [M + H]+ calcd for C27H27N2, 379.2169;
found, 379.2168.
Organic Synthesis; Carreiras, M. C., Marco-Contelles, J., Eds.;
Research Signpost: Kerala, India, 2011; pp 145−172.
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H.; Xu, H.-D.; Zhou, H. Evolution of the Aza-Diels−Alder Reaction
1-Benzyl-2-isopropyl-4,5-diphenyl-1H-imidazole (6i). White
solid, 293 mg, 83% yield, mp 120−121 °C. Silica gel TLC Rf =
1
0.58 (hexane/EtOAc = 4/1); H NMR (500 MHz, chloroform-d): δ
of 2H-Azirines. Synlett 2016, 27, 2171−2177. (d) Alves, M. J.; Duraes,
̃
7.50 (d, J = 7.1 Hz, 2H), 7.35−7.24 (m, 5H), 7.24−7.16 (m, 5H),
7.11 (d, J = 7.3 Hz, 1H), 6.91 (d, J = 7.3 Hz, 2H), 4.99 (s, 2H), 2.90
(hept, J = 6.9 Hz, 1H), 1.34 (d, J = 6.8 Hz, 6H). 13C{1H} NMR (126
MHz, chloroform-d): δ 153.3, 137.6, 131.3, 131.1, 128.8, 128.8, 128.4,
128.3, 128.1, 127.4, 126.9, 126.0, 125.7, 46.7, 26.7, 22.0. HRMS (ESI)
m/z: [M + H]+ calcd for C25H25N2, 353.2013; found, 353.2016.
M. M.; Fortes, A. G. Diels−Alder Cycloaddition of 2-Azadienes to
Methyl 2-(2,6-Dichlorophenyl)-2H-azirine-3-carboxylate in the Syn-
thesis of Methyl 4-Oxo-1,3-diazabicyclo[4.1.0]heptane-6-carboxylates.
Tetrahedron 2004, 60, 6541−6553.
(4) (a) Khlebnikov, A. F.; Novikov, M. S. Recent advances in 2H-
̈
azirine chemistry. Tetrahedron 2013, 69, 3363−3401. (b) Muller, F.;
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of Photoinduced Electron Transfer: A New Method for the Synthesis
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50, 4809−4822. , and references cited therein
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.9b03288.
■
sı
Detailed optimization of the reaction conditions and
1
copies of H, 13C{1H}, and 2D NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
́
Ivan Kanizsai − AVIDIN Ltd., Szeged H-6726, Hungary;
orcid.org/0000-0003-0109-7097; Email: i.kanizsai@
avidinbiotech.com
Authors
́
Aniko Angyal − AVIDIN Ltd., Szeged H-6726, Hungary;
Department of Organic Chemistry, University of Szeged, H-
6720 Szeged, Hungary
́
́
Andras Demjen − AVIDIN Ltd., Szeged H-6726, Hungary
́
̈
Janos Wolfling − Department of Organic Chemistry, University
of Szeged, H-6720 Szeged, Hungary
́
́
́
Laszlo G. Puskas − AVIDIN Ltd., Szeged H-6726, Hungary
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.9b03288
Notes
(6) For selected examples, see: (a) Padwa, A.; Stengel, T. Grubbs
and Wilkinson catalyzed reactions of 2-phenyl-3-vinyl substituted 2H-
azirines. Arkivoc 2005, 2005, 21−32. (b) Hegedus, L. S.; Kramer, A.;
Yijun, C. Reactions of Chromium Carbene Complexes with 1-
Azirines. Synthesis of N-Vinylimidates. Organometallics 1985, 4,
1747−1750.
The authors declare no competing financial interest.
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