Synthesis of 1,2-diaryl- and 1-aryl-2-alkylimidazoles with sterically demanding substituents

Article abstract of DOI:10.1002/ejoc.201300688

1,2-Diarylimidazoles are an important class of compounds. They are frequently used as ligands for photophysically active metal complexes and also display physiological activity. We developed a new, high-yielding procedure for the synthesis of 1,2-diaryl-s

Full text of DOI:10.1002/ejoc.201300688

Job/Unit: O30688
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Date: 30-07-13 18:03:54
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FULL PAPER
DOI: 10.1002/ejoc.201300688
Synthesis of 1,2-Diaryl- and 1-Aryl-2-alkylimidazoles with Sterically
Demanding Substituents
Maik Micksch,[a] Mario Tenne,[a] and Thomas Strassner*[a]
Keywords: Nitrogen heterocycles / Synthetic methods / Steric hindrance / Substituent effects / Photophysics
1,2-Diarylimidazoles are an important class of compounds.
They are frequently used as ligands for photophysically
active metal complexes and also display physiological ac-
tivity. We developed a new, high-yielding procedure for the
synthesis of 1,2-diaryl-substituted imidazoles with sterically
demanding substituents at the respective ortho positions by
starting from commercially available anilines and benzoic
acids through the corresponding acid chlorides. The metal-
free method provides access to a variety of different substitu-
ents on the phenyl rings at N-1 and C-2 as well as at the 4,5-
positions of the imidazole backbone. Our new method is also
suitable for the preparation of 1-aryl-2-alkylimidazoles.
Introduction
of the cannabinoid CB1 receptor,[5] as serotonin antagonist
reuptake inhibitors,[6] and as COX-2 inhibitors.[7] Initially,
we set out to prepare 1-(2,6-diisopropylphenyl)-2-phenyl-
1H-imidazole (see Scheme 1) as a ligand for a new class of
platinum complexes. One approach to the desired product
appeared to be a copper-catalyzed C–N bond formation be-
tween 2-phenylimidazole and a 2,6-diisopropylphenyl hal-
ide. However, the low reactivity of the starting materials for
the coupling reaction (yields below 10%) and the expensive
aryl halides made this pathway inconvenient. Alternatively,
the product may be synthesized by a palladium-catalyzed
arylation of 2-bromo-1-(2,6-diisopropylphenyl)-1H-imid-
azole. The bromination of the 1-(2,6-diisopropylphenyl)-
1H-imidazole with N-bromosuccinimide to introduce a bro-
mine atom at the C-2 position of the imidazole ring led to
a complex reaction mixture, and we were unable to isolate
the corresponding 2-bromoimidazole. Rossi reported a
promising palladium-catalyzed and copper-mediated cou-
pling reaction between 1-arylimidazoles and aryl iodides,
1,2-Diarylimidazoles are a class of compounds that are
well known for their physiological effects, but they have re-
cently received much attention as ligands for photophysi-
cally active metal complexes for organic light-emitting di-
odes (OLED), dye-sensitized solar cells (DSSC), and light-
emitting electrochemical cells (LEC). Especially ligands
with sterically demanding ortho substituents at the N-1
phenyl ring of the imidazole are of current interest. A recent
Scifinder search of 1,2-diarylimidazoles with 2,6-disubsti-
tuted phenyl groups at N-1 led to 1184 hits. The majority of
the hits (Ͼ900) led to patents that describe cyclometalated
complexes of these imidazoles for applications as emitters
in OLEDs. Many cyclometalated iridium complexes with
1,2-diarylimidazoles[1] have been reported, but cyclomet-
alated complexes with 1-alkyl-2-arylimidazoles that contain
platinum,[2] ruthenium[3] and other metals[4] are also
known.
Imidazoles with aryl groups at the N-1 and C-2 positions
also exhibit biological activity, for example, as antagonists
Scheme 1. Synthetic pathways to 1-(2,6-diisopropylphenyl)-2-phenyl-1H-imidazole.
but in our hands, this method did not work for the prepara-
tion of 1-(2,6-diisopropylphenyl)-2-phenyl-1H-imidazole.[8]
Because we were unable to prepare the desired imidazole
through a transition-metal-catalyzed pathway, we looked
for a different synthetic strategy. In the literature, one can
find several one-pot procedures for the synthesis of imid-
[a] Physikalische Organische Chemie, Technische Universität
Dresden,
Bergstr. 66, 01069 Dresden, Germany
E-mail: thomas.strassner@chemie.tu-dresden.de
Homepage: http://www.chm.tu-dresden.de/oc3/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300688.
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FULL PAPER
Scheme 2. Retrosynthetic route to 1,2-diarylimidazoles.
azoles with a 1,2-diarylimidazole core, such as the iodine- Because of the large number of commercially available anil-
catalyzed[9] and MgSO4-[10] or FePO4-mediated[11] synthesis ines and carboxylic acids, this method allows for the prepa-
of 1,2,4,5-tetraarylimidazoles, the domino reaction of 2- ration of a wide range of possible products.
azido acrylates and nitrones to 1,2,4,5-tetrasubstituted
Anilines 1a–1e were treated with commercially available
imidazoles,[12] the zinc-catalyzed synthesis of di- and trisub- bromoacetaldehyde diethyl acetal to give the alkylated
stituted imidazoles,[13] the cyclization of benzaldehyde, anil- products 2a–2e in high yields (see Scheme 3). The α-amino-
ine, and a diketone,[1b] and the palladium-catalyzed synthe- ketones 3b and 3d were obtained from an acid-catalyzed
sis of 1,2-disubstituted benzimidazoles.[14] However, none of reaction between the corresponding aniline and commer-
these literature procedures were suitable for the preparation
of 1-(2,6-diisopropylphenyl)-2-phenyl-1H-imidazole, as
these methods were limited to the preparation of benzimid-
azoles or 4,5-disubstituted imidazoles.
We, therefore, looked for an alternative route to the syn-
thesis of 1,2-diarylimidazoles with sterically demanding
ortho substituents. On the basis of a previously reported
method for the synthesis of unsymmetrically substituted
imidazolium salts[15] we developed a new, flexible, and
metal-free procedure to synthesize 1,2-diarylimidazoles
with sterically demanding groups attached to the N-1
phenyl ring. Satisfactory yields resulted, even when the re-
action was carried out on a gram scale.
Results and Discussion
The retrosynthetic pathway is shown in Scheme 2. The
Scheme 3. Syntheses of alkylated anilines. Reagents and conditions:
1,2-diarylimidazole can be obtained from an oxazolium salt
(a) nBuLi, bromoacetaldehyde diethyl acetal, tetrahydrofuran
(THF), room temp., (b) 2-hydroxybutanone, cat. HCl, toluene, re-
by treatment with NH4Cl and HBF4, which in turn can be
prepared from an alkylated aniline and a carboxylic acid. flux.
Scheme 4. Preparation of 1,2-diarylimidazoles. Reagents and conditions: (a) 4a–4f, NEt3, dichloromethane (DCM), room temp., (b) para-
toluenesulfonic acid (p-TsOH), acetone/H2O (9:1), reflux, (c) HBF4 (aq.), acetic anhydride (Ac2O), room temp., (d) NH4OAc, HBF4 (aq.),
CH3CN, room temp. to reflux.
2
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Synthesis of 1,2-Diaryl- and 1-Aryl-2-alkylimidazoles
cially available 2-hydroxybutanone in toluene along with Table 1. 1,2-Diarylimidazoles prepared as described in Scheme 4.
the azeotropic removal of water.
Compounds 2a–2e, 3b, and 3d were treated with various
aroyl chlorides. We used either commercially available aroyl
chlorides or those prepared from their corresponding acids
and thionyl chloride without purification (4a–4f, see
Scheme 4). After removal of the solvent, the acetal group
of 2a–2e was cleaved by the addition of para-toluene-
sulfonic acid in acetone/water to obtain the corresponding
aldehyde A. After aqueous workup, the crude product was
dissolved in acetic anhydride. An aqueous solution of HBF4
was added to convert aldehyde A into oxazolium salt B (see
Scheme 4). Depending on the starting material, the back-
bone of the imidazole could be easily modified at the 4,5-
position (RЈЈ groups). The addition of diethyl ether led to
the precipitation of the oxazolium salt, which was removed
by filtration and then washed with diethyl ether. Without
further purification, oxazolium salt B was dissolved in ace-
tonitrile, and NH4OAc was added. To obtain a high conver-
sion, the reaction mixture was stirred for 1 d, and then an
aqueous solution of HBF4 was added. The procedure was
optimized to obtain high conversions at each step without
the need to isolate each intermediate. The only chromato-
graphic purification step that was required was at the end
of the procedure. For all other reactions, the crude products
were used. To validate the reaction pathway, we isolated and
characterized through NMR and GC–MS analysis all the
reported intermediates for the reaction of 2a with 4a.
We synthesized several 1,2-diarylimidazoles to prove the
versatility of the new procedure (see Table 1). All reactions
were carried out on a 10 mmol scale. The alkylated com-
pounds 2a–2e, 3b, and 3d underwent a reaction with acid
chlorides 4a–4f to give products in moderate to high yields
(39–84%). The identities of the products were determined
1
by H and 13C NMR spectroscopy and elemental analysis.
The solid-state structure of imidazoles 6 and 10 were ad-
ditionally confirmed by single-crystal X-ray structure analy-
sis (see Figures 1 and 2). In the case of 2e, we added a cata-
lytic amount of N,N-dimethylaminopyridine (DMAP) to
accelerate its reaction with 4a.
We were able to prepare imidazoles with different substit-
uents at the 4-position of the phenyl group at C-2 such as
the 4-methoxy and 4-fluoro groups (see Table 1, Entries 2
and 3, respectively) as well as imidazoles with substituted
phenyl groups at N-1 such as the 2,6-diisopropylphenyl and
4-bromo-2,6-dimethylphenyl groups (see Table 1, Entries 1
and 9). While electron-withdrawing substituents on the
phenyl group at C-2 decreased the yield only slightly, the
yields of the imidazoles with very bulky groups at N-1 (i.e.,
2,6-diphenylphenyl, see Table 1, Entry 10) or at C-2 (i.e.,
naphthyl, see Table 1, Entry 6) clearly decreased. With this
new synthetic route, 4,5-disubstituted imidazoles were ac-
cessible (see Table 1, Entries 11 and 12), which could be
synthesized in comparable yields to the corresponding un-
substituted imidazoles (see Table 1, Entries 7 and 9).
To demonstrate the high versatility of the procedure, we
additionally prepared several 1-aryl-2-alkylimidazoles from
[a] Isolated yield based on 2a–2e, 3b, and 3d, respectively.
2b. The reactions were carried out as described above with
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M. Micksch, M. Tenne, T. Strassner
FULL PAPER
Table 2. 1-Aryl-2-alkylimidazoles prepared as described in
Scheme 4.
Figure 1. Solid-state structure of 6. Thermal ellipsoids are drawn
at the 50% probability level.
[a] Isolated yield based on 2b.
transition-metal-free synthesis of a 1-aryl-2-trifluorome-
thyl-1H-imidazole. Previous syntheses required stoichio-
+
metric amounts of a copper salt and a CF3 precursor[16]
or used 2-trifluoromethyl-1H-imidazole as the starting ma-
terial of a copper-catalyzed coupling reaction.[17] Our pro-
cedure allows the synthesis of 1-aryl-2-trifluoromethyl-1H-
imidazoles from inexpensive trifluoroacetic anhydride.
Conclusions
We describe a new, metal-free access to 1,2-diaryl- and
1-aryl-2-alkyl-substituted imidazoles with sterically de-
manding groups at the phenyl ring attached at the N-1 atom
of the imidazole ring. All reactions were carried out on a
Figure 2. Solid-state structure of 10. Thermal ellipsoids are drawn
at the 50% probability level.
the activated alkyl carboxylic acid derivatives 17a–17d (see gram scale and occurred in high yields. This method allows
Table 2). To demonstrate the versatility of the reaction, in for the introduction of a wide range of substituents and
some cases, we also used the corresponding anhydrides 17a groups at N-1 and C-2 by starting from commercially avail-
and 17d instead of the acyl chlorides.
able and inexpensive anilines and carboxylic acids. We be-
We were able to synthesize imidazoles with primary, sec- lieve that this procedure will be very helpful for the prepara-
ondary, and tertiary alkyl groups at the C-2 position (see tion of new imidazoles. The synthetic pathway allows to
Table 2, Entries 1–3) in yields of 54–66%. The yields of the easily fine tune the electronic structure and charge density
1-aryl-2-alkylimidazoles are generally lower than the 1,2- of the C-2 phenyl group, which will be of interest for the
diarylimidazoles. We were also able to introduce a CF3 synthesis of cyclometalated complexes. In addition, the tol-
group at the C-2 position (see Table 2, Entry 4), but we erance of a halogen atom at the 4-position of the N-1
needed to modify the synthetic procedure. The correspond- phenyl group (as in 13 and 16) is of general interest, as it
ing oxazolium salt with the CF3 group was highly stable, allows for further functionalization by palladium-catalyzed
and, therefore, it was necessary to increase the temperature cross coupling reactions. We demonstrated the high versatil-
to 80 °C for the reaction of that oxazolium salt with ity of this procedure by preparing a 1-aryl-2-trifluorome-
NH4OAc. After this modification, we obtained imidazole thyl-1H-imidazole for the first time through a transition-
21 in 64% yield. To best of our knowledge, this is the first metal-free synthesis.
4
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Synthesis of 1,2-Diaryl- and 1-Aryl-2-alkylimidazoles
NMR (125 MHz, CDCl3): δ = 144.9, 131.2, 131.1, 113.8, 101.5,
62.3, 50.2, 18.3, 15.4 ppm. C14H22BrNO2 (315.08): calcd. C 53.17,
H 7.01, N 4.43; found C 53.39, H 7.23, N 4.64.
Experimental Section
General Methods: The NMR spectroscopic data were recorded with
300 (at 300.13, 75.45, and 282.40 MHz for 1H, 13C, and 19F NMR,
N-(2,2-Diethoxyethyl)-2,6-diphenylaniline (2e): nBuLi (1.6 m in hex-
ane, 11.1 mL, 17.8 mmol) was added to a solution of 1e (3.96 g,
16.2 mmol) in THF (80 mL) at 0 °C. Once the addition was com-
plete, the mixture was stirred for 30 min at room temperature fol-
lowed by addition of the bromoacetaldehyde diethyl acetal
(11.5 mL, 80.8 mmol). The reaction mixture was stirred overnight
at 60 °C. Subsequently, the solution was poured into a mixture of
saturated aqueous NaHCO3/H2O (1:1, 50 mL). The layers were
separated, and the aqueous phase was extracted with ethyl acetate
(2ϫ 80 mL). The combined organic layers were washed with brine
(30 mL), dried with MgSO4, and filtered. The solvent and the ex-
cess amount of bromoacetaldehyde diethyl acetal were removed in
vacuo. Purification by column chromatography on silica gel
(isohexane/ethyl acetate, 19:1) gave 2e (4.32 g, 74%) as a yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.54 (d, J = 7.2 Hz, 4 H), 7.44
(t, J = 7.7 Hz, 4 H), 7.35 (t, J = 7.4 Hz, 2 H), 7.19 (d, J = 7.6 Hz,
2 H), 7.02 (t, J = 7.6 Hz, 1 H), 4.10 (t, J = 5.7 Hz, 1 H), 3.14 (dq,
J = 7.1, 9.3 Hz, 2 H), 2.57 (d, J = 5.7 Hz, 2 H), 0.93 (t, J = 6.9 Hz,
6 H) ppm. The NH signal was not detected. 13C NMR (125 MHz,
CDCl3): δ = 140.5, 132.7, 130.5, 129.1, 128.6, 127.1, 101.3, 62.09,
50.0, 15.0 ppm. Two signals are missing, probably because of over-
lapping. C24H27NO2 (361.48): calcd. C 79.74, H 7.53, N 3.87; found
C 79.75, H 7.38, N 3.96.
1
respectively) and 500 MHz (at 500.13 and 125.48 MHz for H and
13C NMR, respectively) spectrometers. The chemical shifts (δ) were
measured in ppm with the solvent as the reference. The employed
abbreviations are s (singlet), d (doublet), t (triplet), m (multiplet),
dq (doublet of quintet), sept (septet), and br. s (broad singlet). Dry
DCM and THF were obtained from an auto-solvent purification
system. All other chemicals were used as received. Aniline 1e,[18]
N-alkylated anilines 2a,[15] 2b[15] and 3b,[15] and aroyl chlorides
4b[19] and 4d[20] were prepared according to literature procedures.
Acyl chlorides 4a, 4c, 4e, and 17a–17d were obtained from com-
mercial sources. Aroyl chloride 4f was prepared by treatment of 1-
naphthoic acid with thionyl chloride (5 equiv.) in toluene and heat-
ing the resulting mixture at reflux for 4 h followed by removing the
excess amount of thionyl chloride and toluene in vacuo.
4-Methoxy-2,6-dimethylaniline (1c): The synthesis was carried out
in a similar manner to the literature procedure.[21] 4-Amino-3,4-
dimethylphenol (3.11 g, 22 mmol) and potassium tert-butoxide
(3.74 g, 33 mmol) were dissolved in N,N-dimethylformamide
(DMF, 50 mL) under argon. At room temperature, a solution of
methyl iodide (1.3 mL, 20 mmol) in DMF (10 mL) was added over
a period of 6 h. After the addition was complete, the reaction mix-
ture was stirred overnight at room temperature. DCM (150 mL)
was added, and the combined organic layers were washed with
KOH (1 m solution, 3ϫ 50 mL) and brine (10 mL) and then dried
with MgSO4. After filtration, the solvent was removed in vacuo.
Purification by column chromatography on silica gel (isohexane/
ethyl acetate, 2:1) gave 1c (2.03 g, 67%) as a red solid; m.p. 29 °C.
1H NMR (500 MHz, CDCl3): δ = 6.57 (s, 2 H), 3.75 (s, 3 H), 3.33
(br. s, 2 H, NH2), 2.19 (s, 6 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 152.0, 136.4, 123.2, 113.9, 55.7, 18.0 ppm. C9H13NO (151.10):
calcd. C 71.49, H 8.67, N 9.26; found C 71.55, H 8.71, N 9.17.
3-[(4-Bromo-2,6-dimethylphenyl)amino]butan-2-one (3d): 4-Bromo-
2,6-dimethylaniline (1d, 4.00 g, 20 mmol), 3-hydroxybutan-2-one
(3.71 g, 40 mmol), toluene (70 mL), and concentrated HCl (two
drops) were combined, and the reaction mixture was stirred and
heated at reflux for 4 h along with the azeotropic removal of water
by using a Dean–Stark trap. Additional 3-hydroxybutan-2-one
(1.86 g, 20 mmol) was added, and the mixture was stirred and
heated at reflux for an additional 2 h. The mixture was cooled to
room temperature, and the solvent was removed in vacuo. Purifica-
tion by column chromatography on silica gel (isohexane/ethyl acet-
ate, 4:1) gave 3d (4.16 g, 77%) as a yellow oil. 1H NMR (500 MHz,
CDCl3): δ = 7.11 (s, 2 H), 4.07–4.09 (m, 2 H, NH, CH), 2.26 (s, 6
H), 2.21 (s, 3 H), 1.22 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 209.4, 143.3, 131.3, 131.0, 113.7, 60.8, 27.4,
18.8, 18.3 ppm. C12H16BrNO (269.04): calcd. C 53.35, H 5.97, N
5.18; found C 53.51, H 6.17, N 5.08.
N-(2,2-Diethoxyethyl)-4-methoxy-2,6-dimethylaniline (2c): nBuLi
(1.6 m in hexane, 10.4 mL, 17 mmol) was added to a solution of 1c
(2.39 g, 16 mmol) in THF (60 mL) at 0 °C. Once the addition was
complete, the mixture was stirred for 30 min at room temperature
followed by addition of the bromoacetaldehyde diethyl acetal
(2.8 mL, 17 mmol). The reaction mixture was stirred overnight at
room temperature. Subsequently, the solution was poured into a
mixture of saturated aqueous NaHCO3/H2O (1:1, 50 mL). The lay-
ers were separated, and the aqueous phase was extracted with ethyl
acetate (2ϫ 80 mL). The combined organic layers were washed
with brine (30 mL), dried with MgSO4, and filtered. The solvent
was removed in vacuo. Purification by column chromatography on
silica gel (isohexane/ethyl acetate, 3:1) gave 2c (3.70 g, 88%) as a
General Procedure for the Synthesis of the Imidazoles from 2a–2e,
3b, and 3d
Step I (2/3 Ǟ A): Under argon, triethylamine (2.8 mL, 20 mmol)
and acyl chloride 4a–4f (50 mmol) were added to a solution of
compound 2a–2e, 3b, or 3d (10 mmol) in DCM (20 mL) at 0 °C.
Then, the reaction was stirred overnight at room temperature, and
the solvent was removed in vacuo. The products of 2a–2e were
dissolved in acetone/water (9:1, 20 mL). para-Toluenesulfonic acid
(3.62 g, 21 mmol) was added, and the solution was stirred and
heated at reflux for 2 h. Subsequently, the solvent was removed in
vacuo. All residues were dissolved in EtOAc (80 mL), and the re-
sulting solution was washed with a saturated Na2CO3 solution
(80 mL). The aqueous phase was extracted with EtOAc (3ϫ
80 mL). The combined organic layers were washed with brine
(10 mL) and dried with MgSO4. After filtration, the solvent was
removed in vacuo.
1
yellow oil. H NMR (500 MHz, CDCl3): δ = 6.58 (s, 2 H), 4.60 (t,
J = 5.5 Hz, 1 H), 3.71–3.77 (m, 5 H), 3.56 (dq, J = 7.1, 9.3 Hz, 2
H), 3.16 (br. s, 1 H, NH), 3.01 (d, J = 5.7 Hz, 2 H), 2.29 (s, 6 H),
1.25 (t, J = 7.1 Hz, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
154.6, 138.9, 131.4, 113.8, 101.9, 62.3, 55.3, 51.0, 18.5, 15.4 ppm.
C15H25NO3 (267.18): calcd. C 67.38, H 9.42, N 5.24; found C
67.57, H 9.63, N 5.47.
N-(2,2-Diethoxyethyl)-4-bromo-2,6-dimethylaniline (2d): The syn-
thesis of 2d was carried out as described above for 2c starting from
4-bromo-2,6-dimethylaniline (1d). Purification by column
chromatography on silica gel (isohexane/ethyl acetate, 4:1) gave 2d
1
(3.76 g, 79%) as an orange oil. H NMR (500 MHz, CDCl3): δ =
Step II (A Ǟ B): The product of step I was dissolved in acetic anhy-
dride (15 mL), and the reaction mixture was cooled to 0 °C. An
aqueous solution of HBF4 (50%, 1.5 mL, 12 mmol) was added
slowly. Then, the reaction mixture was stirred overnight at room
7.11 (s, 2 H), 4.54 (t, J = 5.5 Hz, 1 H), 3.72 (dq, J = 7.1, 9.3 Hz, 2
H), 3.54 (dq, J = 7.1, 9.3 Hz, 2 H), 3.41 (br. s, 1 H, NH), 3.09 (d,
J = 5.4 Hz, 2 H), 2.26 (s, 6 H), 1.24 (t, J = 7.1 Hz, 6 H) ppm. 13C
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temperature. Diethyl ether (100 mL) was added to precipitate ox-
azolium salt B. The solid was filtered and washed with diethyl ether
(2ϫ 10 mL).
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.6, 145.8, 134.4,
134.0, 130.2, 129.5, 129.5, 129.3, 126.7, 124.5, 124.4, 52.1, 28.2,
25.1, 22.8 ppm. C23H26N2O2 (362.47): calcd. C 76.21, H 7.23, N
7.73; found C 76.47, H 7.35, N 7.81.
Step III (B Ǟ Imidazole): The product of step II was dissolved in
acetonitrile (30 mL). NH4OAc (1.32 g, 17 mmol) was added, and
the solution was stirred at room temperature for 1 d. Then, an
aqueous solution of HBF4 (50%, 2.1 mL, 17 mmol) was added.
The reaction mixture was stirred at 80 °C overnight. Subsequently,
the solvent was removed in vacuo, and the residue was dissolved in
EtOAc (80 mL). The resulting solution was washed with a satu-
rated Na2CO3 solution (80 mL). The aqueous phase was extracted
1-(2,6-Diisopropylphenyl)-2-thiophen-2-yl-1H-imidazole (9): Imid-
azole 9 was obtained from 2a and 4e by following the general pro-
cedure. Purification by column chromatography on silica gel
(DCM/ethyl acetate, 19:1) gave 9 (1.86 g, 60%) as a pale yellow
1
solid; m.p. 110 °C. H NMR (500 MHz, CDCl3): δ = 7.52 (t, J =
7.7 Hz, 1 H), 7.31 (d, J = 7.9 Hz, 2 H), 7.28 (d, J = 1.0 Hz, 1 H),
7.16 (d, J = 5.0 Hz, 1 H), 6.92 (d, J = 1.0 Hz, 1 H), 6.81 (t, J =
with EtOAc (3ϫ 80 mL). The combined organic layers were 5.0 Hz, 1 H), 6.59 (br. s, 1 H), 2.44 (sept, J = 6.9 Hz, 2 H), 1.12
washed with brine (10 mL) and dried with MgSO4. After filtration,
the solvent was removed, and the crude product was purified by
column chromatography on silica gel.
(d, J = 6.9 Hz, 6 H), 0.97 (d, J = 6.9 Hz, 6 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 146.6, 143.0, 133.3, 132.8, 130.3, 129.0,
127.2, 126.1, 125.1, 124.4, 122.6, 28.2, 25.0, 22.8 ppm. C19H22N2S
(310.15): calcd. C 73.51, H 7.14, N 9.02, S 10.33; found C 73.36,
H 7.28, N 9.00, S 10.37.
1-(2,6-Diisopropylphenyl)-2-phenyl-1H-imidazole (5): Imidazole 5
was obtained from 2a and 4a by following the general procedure.
Purification by column chromatography on silica gel (isohexane/
1-(2,6-Diisopropylphenyl)-2-(naphthalen-1-yl)-1H-imidazole
(10):
ethyl acetate, 2:1) gave 5 (2.37 g, 78%) as a pale yellow solid; m.p. Imidazole 10 was obtained from 2a and 4f by following the general
1
89 °C. H NMR (500 MHz, CDCl3): δ = 7.47 (t, J = 7.8 Hz, 1 H), procedure. Purification by column chromatography on silica gel
7.41–7.43 (m, 2 H), 7.32 (d, J = 1.3 Hz, 1 H), 7.26 (d, J = 7.9 Hz, (DCM/ethyl acetate, 19:1) gave 10 (1.67 g, 47%) as a pale yellow
2 H), 7.17–7.22 (m, 3 H), 6.94 (d, J = 1.3 Hz, 1 H), 2.47 (sept, J =
6.9 Hz, 2 H), 1.11 (d, J = 6.6 Hz, 6 H), 0.90 (d, J = 6.9 Hz, 6
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 147.0, 145.9, 134.2,
130.3, 129.8, 128.9, 128.13, 128.11, 127.1, 124.3, 123.5, 28.1, 25.1,
22.7 ppm. C21H24N2 (304.19): calcd. C 82.85, H 7.95, N 9.20; found
C 82.94, H 8.12, N 9.35.
solid; m.p. 97 °C. 1H NMR (500 MHz, CDCl3): δ = 8.52 (d, J =
8.2 Hz, 1 H), 7.80 (dd, J = 8.2, 1.3 Hz, 1 H), 7.74 (d, J = 8.2 Hz,
1 H), 7.55 (ddd, J = 8.4, 6.9, 1.4 Hz, 1 H), 7.49 (d, J = 1.3 Hz, 1
H), 7.48 (ddd, J = 8.1, 6.8, 1.3 Hz, 1 H), 7.31 (t, J = 8.2 Hz, 1 H),
7.17 (dd, J = 8.2, 7.3 Hz, 1 H), 7.11 (d, J = 7.9 Hz, 2 H), 7.09 (d,
J = 1.3 Hz, 1 H), 7.03 (d, J = 7.3 Hz, 1 H), 2.55 (sept, J = 6.7 Hz,
2 H), 1.11 (d, J = 6.9 Hz, 6 H), 0.70 (d, J = 6.9 Hz, 6 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 146.5, 146.1, 133.8, 133.3, 129.4,
132.4, 129.2, 128.5, 128.0, 127.6, 126.9, 126.9, 126.2, 125.9, 124.0,
123.8, 123.0, 28.1, 25.8, 22.3 ppm. C25H26N2 (345.21): calcd. C
84.71, H 7.39, N 7.90; found C 84.50, H 7.26, N 7.96. Single crys-
tals were obtained by slow evaporation of the ethyl acetate solution.
1-(2,6-Diisopropylphenyl)-2-(4-methoxyphenyl)-1H-imidazole
(6):
Imidazole 6 was obtained from 2a and 4b by following the general
procedure. Purification by column chromatography on silica gel
(isohexane/ethyl acetate, 2:1) followed by recrystallization from
ethyl acetate gave 6 (2.29 g, 69%) as a pale yellow solid; m.p. 92 °C.
1H NMR (500 MHz, CDCl3): δ = 7.46 (t, J = 7.7 Hz, 1 H), 7.34
(d, J = 9.1 Hz, 2 H), 7.27 (d, J = 0.6 Hz, 1 H), 7.26 (d, J = 7.9 Hz,
2 H), 6.90 (d, J = 1.3 Hz, 1 H), 6.72 (d, J = 8.8 Hz, 2 H), 3.75 (s,
3 H), 2.48 (sept, J = 6.8 Hz, 2 H), 1.11 (d, J = 6.9 Hz, 6 H), 0.91
(d, J = 6.9 Hz, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 159.4,
147.0, 146.0, 134.4, 129.8, 128.6, 128.4, 124.3, 123.2, 123.1, 113.5,
55.1, 28.1, 25.0, 22.8 ppm. C22H26N2O (334.20): calcd. C 79.00, H
7.84, N 8.38; found C 78.70, H 7.66, N 8.17. Single crystals were
obtained by slow evaporation of the ethyl acetate solution.
1-(2,4,6-Trimethylphenyl)-2-phenyl-1H-imidazole (11): Imidazole 11
was obtained from 2b and 4a by following the general procedure.
Purification by column chromatography on silica gel (isohexane/
ethyl acetate, 1:1) gave 11 (2.05 g, 78%) as a pale yellow solid; m.p.
1
85 °C. H NMR (500 MHz, CDCl3): δ = 7.41–7.43 (m, 2 H), 7.32
(d, J = 1.0 Hz, 1 H), 7.21–7.25 (m, 3 H), 6.96 (d, J = 0.6 Hz, 2 H),
6.89 (d, J = 1.3 Hz, 1 H), 2.36 (s, 3 H), 1.93 (s, 6 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 146.3, 138.8, 135.2, 134.6, 130.6,
129.32, 129.25, 128.3, 128.2, 126.7, 121.9, 21.1, 17.6 ppm.
C18H18N2 (262.15): calcd. C 82.41, H 6.92, N 10.68; found C 82.60,
H 6.63, N 10.59.
1-(2,6-Diisopropylphenyl)-2-(4-fluorophenyl)-1H-imidazole
(7):
Imidazole 7 was obtained from 2a and 4c by following the general
procedure. Purification by column chromatography on silica gel
(isohexane/ethyl acetate, 3:1) gave 7 (2.44 g, 76%) as a yellow oil.
1-(4-Methoxy-2,6-dimethylphenyl)-2-phenyl-1H-imidazole
(12):
1H NMR (500 MHz, CDCl3): δ = 7.48 (t, J = 7.7 Hz, 1 H), 7.38– Imidazole 12 was obtained from 2c and 4a by following the general
7.41 (m, 2 H), 7.31 (d, J = 0.6 Hz, 1 H), 7.27 (d, J = 7.9 Hz, 2 H),
6.94 (d, J = 0.6 Hz, 1 H), 6.87–6.91 (m, 2 H), 2.45 (sept, J = 6.8 Hz,
2 H), 1.11 (d, J = 6.9 Hz, 6 H), 0.91 (d, J = 6.9 Hz, 6 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 162.6 (d, J = 249.5 Hz), 146.1, 145.9,
134.0, 130.0, 129.0 (d, J = 8.5 Hz), 128.8, 126.51, 124.4, 123.6,
procedure. Purification by column chromatography on silica gel
(isohexane/ethyl acetate, 1:2) gave 12 (2.27 g, 82%) as a pale yellow
solid; m.p. 126 °C. 1H NMR (500 MHz, CDCl3): δ = 7.41–7.43 (m,
2 H), 7.31 (d, J = 1.3 Hz, 1 H), 7.21–7.25 (m, 3 H), 6.89 (d, J =
1.3 Hz, 1 H), 6.67 (s, 2 H), 3.83 (s, 3 H), 1.94 (s, 6 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 159.3, 146.5, 136.9, 130.7, 130.1,
129.3, 128.3, 128.1, 126.7, 122.2, 113.6, 55.3, 18.0 ppm. C18H18N2O
(278.14): calcd. C 77.67, H 6.52, N 10.06; found C 77.90, H 6.62,
N 10.12.
115.2 (d,
J =
22.0 Hz), 28.1, 25.1, 22.7 ppm. 19F NMR
(282.4 MHz, CDCl3): δ = –112.90 ppm. C21H23FN2 (322.18): calcd.
C 78.23, H 7.19, N 8.69; found C 78.32, H 7.31, N 8.84.
Methyl 4-[1-(2,6-Diisopropylphenyl)-1H-imidazol-2-yl]benzoate (8):
Imidazole 8 was obtained from 2a and 4d by following the general
procedure. Purification by column chromatography on silica gel
(DCM/ethyl acetate, 7:1) gave 8 (1.85 g, 51%) as a colorless solid;
1-(4-Bromo-2,6-dimethylphenyl)-2-phenyl-1H-imidazole (13): Imid-
azole 13 was obtained from 2d and 4a by following the general
procedure. Purification by column chromatography on silica gel
m.p. 135 °C. 1H NMR (500 MHz, CDCl3): δ = 7.87 (d, J = 8.8 Hz, (isohexane/ethyl acetate, 1:2) gave 13 (2.59 g, 79%) as a colorless
2 H), 7.47–7.51 (m, 3 H), 7.36 (d, J = 1.3 Hz, 1 H), 7.28 (d, J = solid; m.p. 119 °C. 1H NMR (500 MHz, CDCl3): δ = 7.38–7.40 (m,
7.5 Hz, 2 H), 6.99 (d, J = 1.0 Hz, 1 H), 3.87 (s, 3 H), 2.43 (sept, J
2 H), 7.33 (d, J = 1.3 Hz, 1 H), 7.32 (s, 2 H), 7.25–7.28 (m, 3 H),
= 6.9 Hz, 2 H), 1.11 (d, J = 6.9 Hz, 6 H), 0.90 (d, J = 6.9 Hz, 6 6.88 (d, J = 1.3 Hz, 1 H), 1.95 (s, 6 H) ppm. 13C NMR (125 MHz,
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

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Date: 30-07-13 18:03:54
Pages: 10
Synthesis of 1,2-Diaryl- and 1-Aryl-2-alkylimidazoles
CDCl3): δ = 146.3, 137.7, 136.3, 131.5, 130.2, 129.8, 128.51, 128.47,
126.7, 122.6, 121.5, 17.6 ppm. C17H15BrN2 (326.04): calcd. C 62.40,
H 4.62, N 8.56; found C 62.47, H 4.61, N 8.56.
80 mL). The combined organic layers were washed with brine
(10 mL) and dried with MgSO4. After filtration, the solvent was
removed in vacuo. The residue was dissolved in acetic anhydride
(15 mL), and the solution was cooled to 0 °C. An aqueous solution
of HBF4 (50%, 1.5 mL, 12 mmol) was slowly added. Afterwards,
the reaction was stirred overnight at room temperature. Diethyl
ether (100 mL) was added, which resulted in the separation of an
oil. The supernatant organic phase was removed by decantation,
and the residue was dried in vacuo. Subsequently, step III was car-
ried out without further modifications. Purification by column
chromatography on silica gel (isohexane/ethyl acetate, 1:2) gave 16
(2.97 g, 84%) as a colorless solid; m.p. 122 °C. 1H NMR (500 MHz,
CDCl3): δ = 7.34–7.36 (m, 2 H), 7.33 (s, 2 H), 7.19–7.21 (m, 3 H),
2.31 (s, 3 H), 1.92 (s, 6 H), 1.86 (s, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 143.8, 138.4, 135.5, 134.5, 131.5, 130.8, 128.3, 127.8,
126.3, 123.7, 122.5, 17.6, 12.9, 8.7 ppm. C19H19BrN2 (354.07):
calcd. C 64.23, H 5.39, N 7.89; found C 64.17, H 5.34, N 7.77.
1-(2,6-Diphenylphenyl)-2-phenyl-1H-imidazole (14): Imidazole 14
was obtained from 2e and 4a by following a modified procedure:
Under argon, triethylamine (2.8 mL, 20 mmol) and benzoyl chlor-
ide 4a (5.8 mL, 50 mmol) were added to a solution of 2e (10 mmol)
and DMAP (122 mg, 1 mmol) in DCM (20 mL) at 0 °C. The reac-
tion was stirred overnight at room temperature. The solvent was
removed in vacuo and the residue dissolved in acetone/water (9:1,
20 mL). para-Toluenesulfonic acid (3.62 g, 21 mmol) was added,
and the solution was stirred and heated at reflux for 2 h. Sub-
sequently, the solvent was removed in vacuo. The residue was dis-
solved in EtOAc (80 mL), and the solution was washed with a satu-
rated Na2CO3 solution (80 mL). The aqueous phase was extracted
with DCM (3ϫ 80 mL). The combined organic layers were washed
with brine (10 mL) and dried with MgSO4. After filtration, the
solvent was removed in vacuo. Subsequently, steps II and III were
carried out without further modifications. Purification by column
chromatography on silica gel (DCM/ethyl acetate, 6:1) gave 14
(1.46 g, 39%) as a pale brown solid; m.p. 179 °C. 1H NMR
(500 MHz, CDCl3): δ = 7.59 (t, J = 7.3 Hz, 1 H), 7.47 (d, J =
7.6 Hz, 2 H), 7.18–7.23 (m, 3 H), 7.13–7.18 (m, 4 H), 7.09 (t, J =
7.7 Hz, 2 H), 7.03–7.05 (m, 2 H), 6.98 (d, J = 1.3 Hz, 1 H), 6.87–
6.92 (m, 4 H), 6.69 (d, J = 1.3 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 147.0, 139.6, 138.0, 133.6, 130.6, 130.4, 129.2, 128.8,
128.2, 128.1, 127.8, 127.8, 127.3, 127.0, 123.4 ppm. C27H20N2
(372.16): calcd. C 87.07, H 5.41, N 7.52; found C 86.93, H 5.52, N
7.56.
2-Methyl-1-(2,4,6-trimethylphenyl)-1H-imidazole (18): Imidazole 18
was obtained from 2b and 17a by following the general procedure.
Purification by column chromatography on silica gel (ethyl acetate)
1
gave 18 (1.32 g, 66%) as a pale brown solid; m.p. 57 °C. H NMR
(500 MHz, CDCl3): δ = 7.08 (s, 1 H), 6.96 (s, 2 H), 6.75 (s, 1 H),
2.33 (s, 3 H), 2.10 (s, 3 H), 1.92 (s, 6 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 144.8, 138.7, 135.5, 133.4, 129.0, 128.0, 119.5, 21.0,
17.3, 12.7 ppm. C13H16N2 (200.13): calcd. C 77.96, H 8.05, N
13.99; found C 78.29, H 7.96, N 13.76.
2-Cyclohexyl-1-(2,4,6-trimethylphenyl)-1H-imidazole (19): Imid-
azole 19 was obtained from 2b and 17b by following the general
procedure. Purification by column chromatography on silica gel
(isohexane/ethyl acetate, 1:9) gave 19 (1.45 g, 54%) as a pale brown
solid; m.p. 62 °C. 1H NMR (500 MHz, CDCl3): δ = 7.14 (d, J =
1.3 Hz, 1 H), 6.98 (s, 2 H), 6.69 (d, J = 1.3 Hz, 1 H), 2.36 (s, 3 H),
2.13–2.19 (m, 1 H), 1.95 (s, 6 H), 1.67–1.76 (m, 6 H), 1.60–1.65
(m, 1 H), 1.21–1.29 (m, 1 H), 1.08–1.17 (m, 2 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 152.7, 138.5, 135.5, 133.3, 129.1, 128.1,
118.9, 35.8, 32.0, 26.2, 25.7, 21.1, 17.4 ppm. C18H24N2 (268.19):
calcd. C 80.55, H 9.01, N 10.44; found C 80.20, H 9.25, N 10.25.
4,5-Dimethyl-2-phenyl-1-(2,4,6-trimethylphenyl)-1H-imidazole (15):
Imidazole 15 was obtained from 3b and 4a by following a modified
procedure. Under argon, triethylamine (2.8 mL, 20 mmol) and ben-
zoyl chloride 4a (5.8 mL, 50 mmol) were added to a solution of 3b
(2.05 g, 10 mmol) in DCM (20 mL) at 0 °C. The reaction was
stirred overnight at room temperature. The reaction mixture was
washed with a saturated Na2CO3 solution (80 mL). The aqueous
phase was extracted with DCM (3ϫ 80 mL). The combined or-
ganic layers were washed with brine (10 mL) and dried with
MgSO4. After filtration, the solvent was removed in vacuo. The
residue was dissolved in acetic anhydride (15 mL), and the solution
was cooled to 0 °C. An aqueous solution of HBF4 (50%, 1.5 mL,
12 mmol) was slowly added. Afterwards, the reaction was stirred
overnight at room temperature. Diethyl ether (100 mL) was added,
which resulted in the separation of an oil. The supernatant organic
phase was removed by decantation, and the residue was dried in
vacuo. Subsequently, step III was carried out without further modi-
fications. Purification by column chromatography on silica gel
(isohexane/ethyl acetate, 1:2) gave 15 (2.21 g, 76%) as a pale yellow
2-(1,1-Dimethylethyl)-1-(2,4,6-trimethylphenyl)-1H-imidazole (20):
Imidazole 20 was obtained from 2b and 17c by following the gene-
ral procedure. Purification by column chromatography on silica gel
(DCM/ethyl acetate, 1:1) gave 20 (1.32 g, 55%) as a pale brown
solid; m.p. 66 °C. 1H NMR (500 MHz, CDCl3): δ = 7.09 (d, J =
1.3 Hz, 1 H), 6.94 (s, 2 H), 6.61 (d, J = 1.3 Hz, 1 H), 2.34 (s, 3 H),
1.99 (s, 6 H), 1.21 (s, 9 H) ppm. 13C NMR (125 MHz, CDCl3): δ
= 154.1, 138.5, 135.9, 135.8, 128.9, 127.1, 121.4, 34.3, 29.7, 21.0,
17.8 ppm. C16H22N2 (242.18): calcd. C 79.29, H 9.15, N 11.56;
found C 79.12, H 9.46, N 11.51.
2-(Trifluoromethyl)-1-(2,4,6-trimethylphenyl)-1H-imidazole
(21):
1
solid; m.p. 63 °C. H NMR (500 MHz, CDCl3): δ = 7.37–7.39 (m,
Imidazole 21 was obtained from 2b and 17d. Under argon, triethyl-
amine (2.8 mL, 20 mmol) and 17d (7.0 mL, 50 mmol) were added
to a solution of 2b (2.51 g, 10 mmol) in DCM (20 mL) at 0 °C.
Then, the reaction was stirred overnight at room temperature. The
solvent was removed in vacuo, and the residue dissolved in acetone/
water (9:1, 20 mL). para-Toluenesulfonic acid (3.62 g, 21 mmol)
2 H), 7.16–7.17 (m, 3 H), 6.97 (s, 2 H), 2.35 (s, 3 H), 2.31 (s, 3 H),
1.90 (s, 6 H), 1.86 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ
= 143.7, 138.6, 135.8, 134.0, 133.7, 131.1, 129.3, 128.1, 127.5, 126.3,
124.1, 21.1, 17.6, 13.0, 8.7 ppm. C20H22N2 (290.18): calcd. C 82.72,
H 7.64, N 9.65; found C 82.56, H 7.66, N 9.44.
1-(4-Bromo-2,6-dimethylphenyl)-4,5-dimethyl-2-phenyl-1H-imid- was added, and the solution was stirred and heated at reflux for
azole (16): Imidazole 16 was obtained from 3d and 4a by following
modified procedure. Under argon, triethylamine (2.8 mL,
2 h. Subsequently, the solvent was removed in vacuo. The residue
was dissolved in EtOAc (80 mL), and the solution was washed with
a saturated Na2CO3 solution (80 mL). The aqueous phase was ex-
tracted with EtOAc (3ϫ 80 mL). The combined organic layers were
washed with brine (10 mL), dried with MgSO4, and filtered. The
solvent was removed in vacuo. The residue was dissolved in acetic
anhydride (15 mL), and the reaction mixture was cooled to 0 °C.
a
20 mmol) and benzoyl chloride 4a (5.8 mL, 50 mmol) were added
to a solution of 3d (2.70 g, 10 mmol) in DCM (20 mL) at 0 °C.
Afterwards, the reaction was stirred overnight at room temperature.
The reaction mixture was washed with a saturated Na2CO3 solu-
tion (80 mL), and the aqueous phase was extracted with DCM (3ϫ
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7

Job/Unit: O30688
/KAP1
Date: 30-07-13 18:03:54
Pages: 10
M. Micksch, M. Tenne, T. Strassner
FULL PAPER
An aqueous solution of HBF4 (50%, 1.5 mL, 12 mmol) was added
slowly. Then, the reaction was stirred overnight at room tempera-
ture. Subsequently, the solvent was removed in vacuo. Crystalli-
zation was initiated by cooling the flask with liquid nitrogen. The
solid was washed with cool (0 °C) diethyl ether (3ϫ 10 mL) and
then dried in vacuo. The filtrate was stored at –8 °C overnight,
which resulted in the precipitation of additional oxazolium salt.
The precipitate was filtered and washed with cool diethyl ether (2ϫ
5 mL). The combined solids were dissolved in acetonitrile (30 mL).
NH4OAc (1.32 g, 17 mmol) was added, and the mixture was stirred
overnight at room temperature. Diethyl ether (5 mL) was added to
precipitate the oxazolium salt. The solid was separated by filtration
and washed with diethyl ether (2ϫ 3 mL) to give intermediate B
1
(186 mg, 87%) as a colorless solid. H NMR (300 MHz, CDCl3):
δ = 7.87–7.92 (m, 1 H), 7.57–7.71 (m, 6 H), 7.42–7.50 (m, 2 H),
5.02 (dd, J = 7.0, 14.2 Hz, 1 H), 4.60 (dd, J = 2.7, 14.1 Hz, 1 H),
3.26 (quin, J = 6.6 Hz, 1 H), 2.70 (quin, J = 6.7 Hz, 1 H), 1.26 (dd,
J = 3.0, 6.6 Hz, 6 H), 1.09 (d, J = 6.6 Hz, 3 H), 0.73 (d, J = 6.8 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 197.2, 172.0, 170.0,
169.8, 168.2, 145.4, 145.0, 143.8, 138.3, 137.9, 133.7, 132.5, 131.0,
at 80 °C for 1 d. Then, an aqueous solution of HBF4 (50%, 2.1 mL, 130.5, 123.0, 129.3, 128.9, 128.3, 127.6, 126.3, 124.6, 119.0, 96.5,
17 mmol) was added. The reaction was stirred at 80 °C overnight.
Subsequently, the solvent was removed in vacuo, and the residue
was dissolved in EtOAc (80 mL). The solution was washed with a
saturated Na2CO3 solution (80 mL). The aqueous phase was ex-
tracted with EtOAc (3ϫ 80 mL). The combined organic layers were
washed with brine (10 mL), dried with MgSO4, and filtered, and
the solvent was removed in vacuo. Purification by column
chromatography on silica gel (isohexane/ethyl acetate, 4:1) gave 21
(1.62 g, 64%) as a pale yellow solid; m.p. 80 °C. 1H NMR
(500 MHz, CDCl3): δ = 7.31 (d, J = 1.3 Hz, 1 H), 6.98 (s, 2 H),
6.96 (d, J = 1.0 Hz, 1 H), 2.35 (s, 3 H), 1.96 (s, 6 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 139.7, 136.0 (d, J = 38.7 Hz), 135.5,
131.9, 129.4, 129.0, 124.0, 118.6 (d, J = 270.1 Hz), 21.1, 17.0 ppm.
19F NMR (282.4 MHz, CDCl3): δ = –62.74 ppm. C13H13F3N2
(254.10): calcd. C 61.41, H 5.15, N 11.02; found C 61.07, H 5.39,
N 10.85.
61.2, 40.4, 40.1, 39.8, 39.5, 39.2, 39.0, 38.7, 28.1, 27.7, 27.6, 25.1,
24.9, 24.2, 23.0, 22.7, 22.5, 21.0, 20.5 ppm. 19F NMR (282.4 MHz,
CDCl3): δ = –148.3 ppm.
CCDC-943755 (for 6) and -943756 (for 10) contain the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra of all new compounds
and detailed crystallographic information.
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Intermediates A and B: In general, we did not isolate intermedi-
ates A and B. The crude products were used directly in the next
reaction steps, but to confirm their identity, we isolated and charac-
terized them from the reaction of N-(2,2-diethoxyethyl)-2,6-diiso-
propylaniline (2a) with benzoyl chloride 4a. The synthesis and ex-
perimental data of the corresponding intermediates are described
below.
N-(2,6-Diisopropylphenyl)-N-(2-oxoethyl)benzamide (Example for
Intermediate A): Under argon, triethylamine (0.2 mL, 1.4 mmol)
and 4a (0.2 mL, 1.4 mmol) were added to a solution of 2a (200 mg,
0.7 mmol) in DCM (5 mL) at 0 °C. Afterwards, the reaction was
stirred overnight at room temperature. The solvent was removed in
vacuo, and the residue was dissolved in acetone/water (9:1, 5 mL).
p-Toluenesulfonic acid (246 mg, 1.4 mmol) was added, and the
solution was stirred and heated at reflux for 2 h. Subsequently, the
solvent was removed in vacuo. The residue was dissolved in DCM
(10 mL), and the solution was washed with a saturated Na2CO3
solution (10 mL). The aqueous phase was extracted with DCM
(3ϫ 10 mL). The combined organic layers were washed with brine
(5 mL), dried with MgSO4, and filtered, and the solvent was re-
moved in vacuo. Purification by column chromatography on silica
gel (petroleum ether/ethyl acetate, 3:1) gave intermediate A
(186 mg, 84%) as a pale yellow solid. 1H NMR (300 MHz, CDCl3):
δ = 9.87 (t, J = 1.4 Hz, 1 H), 7.20–7.30 (m, 4 H), 7.06–7.13 (m, 4
H), 4.18 (d, J = 1.3 Hz, 2 H), 3.16 (quin, J = 6.8 Hz, 2 H), 1.14
(d, J = 6.8 Hz), 0.94 (d, J = 6.8 Hz, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 196.6, 170.9, 145.7, 138.5, 133.4, 130.7, 129.4, 129.0,
127.6, 124.9, 61.7, 28.3, 25.4, 22.8 ppm. GC–MS: m/z (%) = 323
(1) [M]+, 295 (15), 280 (9), 146 (8), 105 (100), 77 (37).
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5-Acetoxy-3-(2,6-diisopropylphenyl)-2-phenyl-4,5-dihydrooxazol-3-
ium Tetrafluoroborate (Example for Intermediate B): N-(2,6-Diiso-
propylphenyl)-N-(2-oxoethyl)benzamide (152 mg, 0.5 mmol) was
dissolved in acetic anhydride (3 mL), and the solution was cooled
to 0 °C. An aqueous solution of HBF4 (50% aq. 0.07 mL,
0.5 mmol) was slowly added. Afterwards, the reaction was stirred
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8
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30688
/KAP1
Date: 30-07-13 18:03:54
Pages: 10
Synthesis of 1,2-Diaryl- and 1-Aryl-2-alkylimidazoles
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Received: May 10, 2013
Published Online: ᭿
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9

Job/Unit: O30688
/KAP1
Date: 30-07-13 18:03:54
Pages: 10
M. Micksch, M. Tenne, T. Strassner
FULL PAPER
Synthetic Methods
A high-yielding, metal-free procedure is de-
scribed for the synthesis of 1,2-diarylimid-
azoles with sterically demanding substitu-
ents. This procedure allows for the vari-
ation of groups at the N-1 and C-2 pos-
itions of the imidazole ring and starts from
inexpensive anilines and carboxylic acids.
Because the method is highly versatile, 1-
aryl-2-alkylimidazoles could also be pre-
pared.
M. Micksch, M. Tenne,
T. Strassner* ................................... 1–10
Synthesis of 1,2-Diaryl- and 1-Aryl-2-
alkylimidazoles with Sterically Demanding
Substituents
Keywords: Nitrogen heterocycles / Synthetic
methods / Steric hindrance / Substituent ef-
fects / Photophysics
10
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Eur. J. Org. Chem. 0000, 0–0