Modular Synthesis of Di- A nd Trisubstituted Imidazoles from Ketones and Aldehydes: A Route to Kinase Inhibitors

Article abstract of DOI:10.1021/acs.joc.9b01844

A one-pot and modular approach to the synthesis of 2,4(5)-disubstituted imidazoles was developed based on ketone oxidation, employing catalytic HBr and DMSO, followed by imidazole condensation with aldehydes. This methodology afforded twenty-nine disubstituted NH-imidazoles (23%-85% yield). A three-step synthesis of 20 kinase inhibitors was achieved by employing this oxidation-condensation protocol, followed by bromination and Suzuki coupling in the imidazole ring to yield trisubstituted NH-imidazoles (23%-69%, three steps). This approach was also employed in the synthesis of known inhibitor GSK3037619A.

Full text of DOI:10.1021/acs.joc.9b01844

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Note
Modular Synthesis of Di- and Tri-substituted Imidazoles
from Ketones and Aldehydes: A Route to Kinase Inhibitors
Ian de Toledo, Thiago Augusto Grigolo, James M. Bennett, Jonathan M Elkins, and Ronaldo A. Pilli
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01844 • Publication Date (Web): 28 Aug 2019
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Modular Synthesis of Di- and Tri-substituted Imidazoles from Ketones and
Aldehydes: A Route to Kinase Inhibitors
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Ian de Toledo1, Thiago A. Grigolo1 James M. Bennett2, Jonathan M. Elkins2,3, Ronaldo A. Pilli1*.
,
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1 Department of Organic Chemistry, Institute of Chemistry, University of Campinas, UNICAMP, Campinas,
CEP 13083-970 (Brazil)
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Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Old Road
Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK
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Structural Genomics Consortium, Departamento de Genética e Evolução, Instituto de Biologia,
UNICAMP, Campinas, SP, 13083-886, Brazil
*e-mail: pilli@iqm.unicamp.br
Table of Contents Graphic
Abstract
An one-pot and modular approach to the synthesis of 2,4(5)-disubstituted imidazoles was
developed based on ketone oxidation, employing catalytic HBr and DMSO, followed by
imidazole condensation with aldehydes. This methodology afforded twenty-nine
disubstituted NH-imidazoles (23%-85% yield). A three step synthesis of twenty kinase
inhibitors was achieved by employing this oxidation-condensation protocol, followed by
bromination and Suzuki coupling in the imidazole ring to yield trisubstituted NH-
imidazoles (23%-69%, three steps). This approach was also employed in the synthesis of
known inhibitor GSK3037619A.
Accessibility and availability of small organic molecules remains one of the major
challenges in the drug discovery process1. Efficient and rapid approaches to access these
molecules are highly desirable in order to provide medicinal chemists and chemical
biologists the right tools in their scientific endeavors2. In this context, synthetic organic
chemistry plays a pivotal role in creating pathways to access these molecules in a short,
economic and efficient way from commercially and widely available building blocks.
Moreover, the synthetic approach must offer versatility by allowing modular changes in
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a divergent fashion in order to generate several different molecules from a single
precursor.
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Substituted imidazoles are one class of such small organic molecules with broad
interest, ranging from applications in materials and polymer science3,4 to their use as ionic
liquids5, and as therapeutic agents6 and bioactive molecules such as the marine alkaloids
Nortopsentins A-C7 (Figure 1). Methods to access these scaffolds have been intensely
explored and can be roughly divided into two approaches. The first approach involves the
formation of the imidazole ring from suitable precursors8 while the second involves the
functionalization of a preformed imidazole ring9. Combinations of both approaches can
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also be employed to efficiently assemble substituted imidazoles10–14
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In our search for selective and potent inhibitors of the kinase STK1015, which is a
serine-threonine kinase important due to its role in lymphocyte migration16–19, we were
challenged with the task of providing an efficient, modular and divergent synthetic route
for rapid evaluation of the structure-activity relationship (SAR) of trisubstituted pyridyl-
imidazole 1 (Figure 1), focusing on changes in the naphthyl moiety since previous
synthetic approach introduced the naphthalene in the first step of a six-step route20.
Figure 1. Bioactive Nortopsentins A-C and pyridyl-imidazole kinase inhibitor SB-633825 (1)
Previous work from Laufer12 and Springer21 already provided access to
trisubstituted pyridyl imidazoles in a divergent and modular fashion, although with the
use of protecting groups thus increasing the step count by two (Figure 2). The use of
oxalyl boronates by Yudin offers a regioselective, protecting group-free and modular
approach to imidazoles. However, the key intermediate is accessed in five steps and the
cross-coupled product is obtained in moderate yields11 (Figure 2).
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Figure 2. Modular Access to 2,4,5-trisubstituted imidazoles
We sought to address both challenges by implementing an efficient step- and
redox-economical approach to disubstituted 2,4(5)-NH imidazoles, followed by Suzuki
reaction to introduce the aromatic substituent in a protecting group-free fashion. Herein,
we report an improved one-pot approach to disubstituted 2,4(5)-NH imidazoles consisting
of a sequential Kornblum oxidation22, followed by Radziszewski23 imidazole
condensation which allowed the synthesis of twenty-nine 2,4(5)-disubstituted imidazoles
in yields ranging from 23% to 85%. Moreover, representative imidazoles 32 and 36 were
further functionalized to rapidly access a small kinase inhibitor library of twenty
trisubstituted 2,4,5-NH imidazoles in yields ranging from 23% to 69% for three steps.
Initially, we investigated the possibility of obtaining the 2,4(5)-NH imidazole 5
employing the sequential oxidation-condensation protocol with acetophenone 2 and p-
tolualdehyde 4 as representative carbonyl substrates. After extensive optimization, it was
found that formation of glyoxal (3) from acetophenone (2) could be achieved employing
a catalytic amount (10 mol%) of aqueous HBr in DMSO at 85 ºC and after addition of the
glyoxal 3 in a MeOH:DMSO (6:4) solution to a mixture of p-tolualdehyde 4 and NH4OAc
in MeOH, the desired imidazole was isolated in 69% yield (Table 1, Entry 1).
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Table 1. Optimization of the reaction conditions for the synthesis of the disubstituted imidazole 5
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Decreasing HBr loading (entries 2-3 and 4-5) resulted in longer reaction times
(oxidation step) with a some improvement in the yield. Importantly, increasing reaction
temperature did not have an impact on the yield (entries 4-5) but the oxidation reaction
proceeded faster. When the reaction was carried out in the absence of HBr (entry 6),
neither glyoxal 3 nor imidazole 5 were observed. When the amount of acetophenone was
increased (entry 1), a better yield was observed and 1.25 equiv. was selected as the
optimum amount. Changing from MeOH to EtOH (oxidation step, entry 8) or adding
polar aprotic solvents (DMF and DMSO, entries 7 and 9) and apolar solvents (PhMe,
entry 10) in the condensation step did not provide better yields. (See Supp. Info. Table S1
for all conditions employed).
The substrate scope (Scheme 1) was then explored using different methyl ketones
and aldehydes. The transformation proved to tolerate well the electronic properties of the
substituted acetophenones employed. Notably, substituted acetophenones bearing
electron-donating (6, 14), electron-withdrawing (10, 11, 12, 15), electron-neutral (13) and
pyridine (8) were good substrates for this transformation and products were isolated in
yields ranging from 56-72% (Scheme 1a). However, the 3-indole and 2-furyl derivatives
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7 and 9, respectively, performed poorly under standard conditions while 2-
hydroxyacetophenone (37) did not show reactivity even when higher amounts of HBr
(300 mol%) were employed. For 3-acetylindole (38), it was necessary to increase the HBr
loading to 300 mol% at 85 ºC to accomplish consumption of the starting material but the
imidazole product was not obtained under these conditions. Saturated ketones (40 and 41)
were consumed under standard oxidation conditions without formation of the imidazole
product (Scheme 1d). Interestingly, when 4-aminoacetophenone (42) was reacted with
110 mol% of HBr, the brominated side product 43 was obtained (Scheme 1e).
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Considering the aldehyde scope, benzaldehydes bearing electron-withdrawing
groups (17, 18, 20, 21, 23, 24, 27), such as halides and nitro groups, performed better than
those bearing electron donating groups (19, 22) with the exception of the phenolic
derivative 16 which was isolated in 85% yield. This behavior might be due to the electron
distribution in the aromatic ring of the substituted benzaldehyde which is more reactive
when electron withdrawing groups are present. Interestingly, saturated cyclic aldehydes
such as cyclopropyl (31) and cyclohexyl (28) carboxyaldehydes were good substrates for
this transformation (70% and 83% yield, respectively), although n-butyraldehyde
derivative 30 was isolated in only 36%. Overall, the imidazoles 16-31 from the aldehyde
scope were isolated in yields ranging from 23-85% from the corresponding aldehydes
(Scheme 1b). The disubstituted imidazole 32 was obtained in 67% yield after
optimization of the reaction conditions for this specific substrate (See Supp. Info. Table
S2). It was also possible to employ the commercially available Boc-protected aldehyde
35 under a slightly modified conditions using NH4OH as a basic ammonia source to
neutralize the HBr in order to avoid unwanted deprotection. The disubstituted imidazole
36 was isolated in 85% yield in 0.3 mmol scale and the reaction proved to be scalable in
a 3.0 mmol scale, affording 36 in 82% yield. (Scheme 1c). This one-pot approach for di-
substituted imidazoles has the following advantages when compared to stepwise
procedure: 1) avoids glyoxal isolation which can be troublesome23; 2) starts from
ubiquitous and/or easily accessible starting materials; 3) employs aqueous HBr as the
catalyst and DMSO as oxidant, and 4) is amenable to scale-up. On the other hand, the
4(5)-position of the imidazole ring is restricted to aryl substitutents and is not compatible
with acid sensitive substrates, such as indoles. (Scheme 1d).
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Scheme 1. Scope of the oxidation-condensation approach to 2,4(5)-disubstituted imidazoles
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To show further applicability of the method, disubstituted imidazole 32 was
functionalized at C-5 position of the imidazole ring to afford a small library of pyridyl-
imidazoles inhibitors for testing against STK10 and SLK kinases15. This was
accomplished by bromination of the 2,4-disubstituted imidazole24 32, followed by
Suzuki-Miyaura cross coupling25 with boronic acids or esters (Scheme 2a). In this case,
nineteen 2,4,5-trisubstituted imidazoles 46-64 were obtained in yields ranging from 37-
97% from the common intermediate 44 (Scheme 2b). Interestingly, it was possible to
perform a one-pot Miyaura borylation and Suzuki cross-coupling starting from bromide
65 to access trisubstituted imidazole 67 in 52% yield (Scheme 2c). Moreover, the
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trisubstituted imidazole 71, which was synthetized by Yudin in six steps (12% overall
yield)11, could be accessed in three steps (69% overall yield) from 4-acetylpyridine (68)
employing the same strategy as for imidazoles 46-64 (Scheme 2d). From this advanced
intermediate 71, the known inhibitor GSK3037619A (72) could be synthesized in a one-
pot procedure in 70% yield (Scheme 2d).
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Compounds 57 (R = OMe) and 59 (R = Oc-Pr) were subjected to binding
displacement assays11 against STK10 and SLK kinases and displayed Ki values of 146
nM and 700 nM, respectively, against STK10, and 180 nM and 230 nM, respectively, for
SLK. The weaker binding of the cyclopropyl derivative to STK10 might be explained by
a more significant space restriction in the hydrophobic pocket of STK10 to bulkier
substituents at the 6-position compared to SLK.
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Scheme 2. Synthesis of 2,4,5-trisubstituted imidazole STK10 kinase inhibitors
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In conclusion, we developed an improved one-pot procedure for the synthesis of
2,4(5)-disubstituted NH-imidazoles employing widely available starting materials such
as methyl ketones and aldehydes and demonstrated the utility of the methodology by
using it as a key step in a short, modular and divergent synthetic route to 2,4,5-
trisubstituted pyridyl-imidazole inhibitors of the STK10 kinase and for the synthesis of
the GSK3037619A in 4 steps (48% overall yield). This approach enabled rapid
exploration of the SAR at the C-5 position of the imidazole ring and permits
regioselective variation at the C-2 and C-4 positions for future exploration.
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1. Experimental Section
General Information
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Unless stated otherwise, synthesis of 2,4-disubstituted imidazoles was performed
using undistilled solvent, without any precaution to exclude air and moisture, in 5 mL
vials and was stirred with Teflon-coated magnetic bars (1 cm x 0.5 cm). Suzuki couplings
for preparation of 2,4,5-trisubstituted imidazoles were performed under nitrogen
atmosphere in 100 mm x 13 mm (9 mL) culture tubes and were stirred with Teflon-coated
magnetic bars (1 cm x 0.5 cm). Dry dimethoxyethane (DME, 99.5%) and dry
dimethylformamide (DMF, 99.5%) were purchased from Sigma-Aldrich and stored under
3Å molecular sieves and nitrogen-purged before use. Dichloromethane (DCM) and
triethylamine (Et3N) were pretreated with calcium hydride and distilled before use.
Pyridine was distilled from calcium hydride and stored over 4Å molecular sieves.
Tetrahydrofuran was dried over 4Å molecular sieves and distilled from sodium metal and
benzophenone before use. All other solvents and commercial reagents were used as
supplied without further purification unless stated otherwise. All reactions involving
heating were carried out using aluminum blocks and a contact thermometer. Reactions
were monitored by thin layer chromatography (silica gel 60 F254 in aluminum foil,
Merck) and visualization was achieved under UV light (254 nm) followed by staining in
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potassium
permanganate
(KMnO4),
Dragendorff
stain
(Dragendorff),
dinitrophenylhydrazine stain (DNFH), p-Anisaldehyde stain (p-ASD) or Curcumin stain
and heating. Silica gel 60 F254 (200-400 Mesh, Merck) was used for purifications by
standard flash column chromatography. NMR spectra were recorded on a Bruker Avance
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DPX 250MHz (250 MHz H, 63 MHz C), Bruker Avance III 400 (400 MHz H, 101
MHz 13C), Bruker Avance III 500 (500 MHz 1H, 126 MHz 13C) or Bruker Avance III 600
(600 MHz 1H, 151 MHz 13C). The chemical shifts are expressed in parts per million (ppm)
relative to the residual solvent signal as an internal reference ([1] CDCl3: 1H RMN = 7.26,
13C RMN = 77.16; [2] DMSO-d6: 1H RMN = 2.50, 13C RMN = 39.52; [3] Acetone-d6: 1H
RMN = 2.05, 13C RMN = 206.26; [4] Methanol-d4: 1H RMN = 3.31, 13C RMN = 49.00.).
Multiplicities are reported with the following symbols: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet and multiples thereof. High resolution mass spectra (ESI) were
acquired on a Xevo Q-Tof Mass Spectrometer (Waters, Manchester, UK) equipped with
a nanoESI type ionization source. IR spectra were recorded using a Thermo Scientific
Nicolet IS5 spectrometer, using Thermo Scientific ID3 ATR. Melting points were
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recorded on a MP50 Metler-Toledo melting point apparatus and are uncorrected. STK10
and SLK binding displacement assays were performed as previously described11.
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Optimization of the reaction conditions. 5-phenyl-2-(p-tolyl)-1H-imidazole (5).
A 6 mL vial was charged with acetophenone 2 (46.0 mg, 0.375 mmol, 1.25 equiv.),
DMSO (0.75 mL, 0.5 M), concentrated aqueous HBr (48% w/w, 8.9 M) (4.24 ꢀL, 0.03
mmol, 10 mol%), deionized water (71 ꢀL) and a magnetic stirrer bar under air. The
reaction mixture was stirred in a pre-heated aluminum block at 85 ºC and was followed
by TLC analysis (30% EtOAc/Hex, p-ASD). After consumption of starting material, the
reaction mixture was cooled to room temperature and diluted with MeOH (1.25 mL, 0.19
M, final concentration relative to acetophenone 2, 2:8 mixture of DMSO:MeOH). This
stock DMSO:MeOH solution was added dropwise over 30 minutes via syringe to a 6 mL
vial containing p-tolualdehyde 4 (37.0 mg, 0.30 mmol, 1.00 equiv.), NH4OAc (116 mg,
1.50 mmol, 5.00 equiv.) and MeOH (1.5 mL, 0.2 M in relation to 4). The reaction mixture
was stirred at room temperature for 18h and then poured directly into a separatory funnel
containing a mixture of satd. NaHCO3 and satd. Na2S2O3 (1:1, 1x 20 mL) and EtOAc (10
mL). The phases were separated and the aqueous phase was extracted with EtOAc (5x 5
mL). The organic phases were combined, washed with satd. NaCl solution (1x 5 mL),
dried over Na2SO4, filtered and concentrated in the rotaevaporator. The residue was
diluted with EtOAc (5 mL) and a 1 mL aliquot was taken and concentrated in vacuo. To
this, 1,3,5-trimethoxybenzene (10.2 mg, 0.06 mmol) and acetone-d6 (0.6 mL) was added
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and the sample was analyzed by H NMR. The crude mixtures were combined and
purification of the residue by silica gel chromatography, eluting with EtOAc in hexanes
(19 cm x 20 mm, gradient elution, 0% → 30%, 5% increases, 50 mL runs, 5-10 mL
fractions) yielded 5 as a white solid (69% yield, 48.0 mg, 0.21 mmol). Rf = 0.30 (30%
EtOAc/Hex, UV, Dragendorff stain); 1H NMR (500 MHz, DMSO-d6) δ 12.55 (s, 1H),
7.89 (d, J = 7.9 Hz, 2H), 7.86 (d, J = 7.6 Hz, 2H), 7.72 (s, 1H), 7.36 (t, J = 7.5 Hz, 2H),
7.28 (d, J = 7.9 Hz, 2H), 7.20 (t, J = 7.2 Hz, 1H), 2.34 (s, 3H).;13C{1H} NMR (126 MHz,
DMSO-d6) δ 146.0, 140.9, 137.5, 134.8, 129.3, 128.4, 126.1, 125.2, 124.9, 124.4, 114.0,
20.9. Spectroscopic data are in accordance with the literature26
Ketone Scope: General Procedure A. A 6 mL vial was charged with the
corresponding acetophenone (0.375 mmol, 1.25 equiv.), DMSO (0.75 mL, 0.5 M),
concentrated aqueous HBr (48% w/w, 8.9 M) (4.24 ꢀL, 0.03 mmol, 10 mol%), deionized
water (71 ꢀL) and a magnetic stirrer bar under air. The reaction mixture was stirred in a
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pre-heated aluminum block at 85 ºC and was followed by TLC analysis (EtOAc/Hex, p-
ASD). After consumption of starting material, the reaction mixture was cooled to room
temperature and diluted with MeOH (1.25 mL, 0.19 M, final concentration relative to the
corresponding acetophenone, 4:6 mixture of DMSO:MeOH). This stock DMSO:MeOH
solution was added dropwise over 30 minutes via syringe to a 6 mL vial containing
benzaldehyde (32.0 mg, 0.30 mmol, 1.00 equiv.), NH4OAc (116 mg, 1.50 mmol, 5.00
equiv.) and MeOH (1.5 mL, 0.2 M in relation to benzaldehyde). The reaction mixture was
stirred at room temperature for 18h and then poured directly into a separatory funnel
containing a mixture of satd. NaHCO3 and satd. Na2S2O3 (1:1, 1x 20 mL) and EtOAc (10
mL). The phases were separated, and the aqueous phase was extracted with EtOAc (5x 5
mL). The organic phases were combined, washed with satd. NaCl solution (1x 5 mL),
dried over Na2SO4, filtered and concentrated in the rotaevaporator. The residue was
purified by silica gel column chromatography.
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Aldehyde Scope: General Procedure B. A 6 mL vial was charged with
acetophenone (46.0 mg, 0.375 mmol, 1.25 equiv.), DMSO (0.75 mL, 0.5 M),
concentrated aqueous HBr (48% w/w, 8.9 M) (4.24 ꢀL, 0.0375 mmol, 10 mol%),
deionized water (71 ꢀL) and a magnetic stirrer bar under air. The reaction mixture was
stirred in a pre-heated aluminum block at 85 ºC and was followed by TLC analysis
(EtOAc/Hex, p-ASD). After consumption of starting material, the reaction mixture was
cooled to room temperature and diluted with MeOH (1.25 mL, 0.19 M, final concentration
relative to the corresponding acetophenone, 4:6 mixture of DMSO:MeOH). This stock
DMSO:MeOH solution was added dropwise over 30 minutes via syringe to a 6 mL vial
containing the corresponding aldehyde (0.30 mmol, 1.00 equiv.), NH4OAc (116 mg, 1.50
mmol, 5.00 equiv.) and MeOH (1.5 mL, 0.2 M in relation to the aldehyde). The reaction
mixture was stirred at room temperature for 18h and then poured directly into a separatory
funnel containing a mixture of satd. NaHCO3 and satd. Na2S2O3 (1:1, 1x 20 mL) and
EtOAc (10 mL). The phases were separated, and the aqueous phase was extracted with
EtOAc (5x 5 mL). The organic phases were combined, washed with satd. NaCl solution
(1x 5 mL), dried over Na2SO4, filtered and concentrated in the rotaevaporator. The residue
was purified by silica gel column chromatography.
4-(4-Methoxyphenyl)-2-phenyl-1H-imidazole (6). The title compound was
prepared according to general procedure A, using 4’-methoxyacetophenone (58.0 mg,
0.375 mmol, 1.25 equiv.), benzaldehyde (32.0 mg, 0.30 mmol, 1.00 equiv.). Purification
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by silica gel chromatography, eluting with EtOAc in hexanes (19 cm x 20 mm, gradient
elution, 0% → 30%, 5% increases, 50 mL runs, 5-10 mL fractions) yielded 6 as a pale
yellow solid (59% yield, 44.0 mg, 0.18 mmol). Rf = 0.12 (30% EtOAc/Hex, Dragendorff
stain); 1H NMR (500 MHz, DMSO-d6) δ 12.55 (br. s, 1H), 7.99 (d, J = 7.4 Hz, 2H), 7.78
(d, J = 8.7 Hz, 2H), 7.63, (d, J = 1.4 Hz, 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.35 (t, J = 7.3 Hz,
1H), 6.95 (d, J = 8.7 Hz, 2H), 3.77 (s, 3H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 158.3,
157.9, 146.3, 145.5, 141.0, 130.7, 128.7, 128.6, 128.0, 127.5, 125.9, 125.6, 125.5, 125.0,
124.8, 114.3, 113.9, 113.0, 55.2, 55.0; vmax (cm-1, thin film, ATR): 2925 (br), 1602 (s),
1517 (w), 1480 (w), 1443 (w), 1312 (s), 1213 (w), 1147 (s), 1109 (m), 1075 (w), 1075
(w), 999 (w), 958 (m), 877 (w), 768 (s), 762 (s), 744 (s), 733 (s), 700 (m); HRMS
(ESI+/TOF) m/z: [M+H]+ Calcd for C16H15N2O 251.1184; Found 251.1173; mp: 175.0
– 177.8 °C (EtOAc) (lit. 170 – 174 °C). Spectroscopic data are in accordance with the
literature27.
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3-(2-Phenyl-1H-imidazol-5-yl)-1-tosyl-1H-indole (7). The title compound was
prepared according to general procedure A, using 1-(1-tosyl-1H-indol-3-yl)ethanone (S2)
(58.0 mg, 0.375 mmol, 1.25 equiv.), benzaldehyde (32.0 mg, 0.30 mmol, 1.00 equiv.).
Purification by silica gel chromatography, eluting with EtOAc in hexanes (17 cm x 20
mm, gradient elution, 0% → 60%, 5% increases, 45 mL runs, 15 mL fractions) yielded 7
as a white solid (35% yield, 44.0 mg, 0.11 mmol). Rf = 0.17 (30% EtOAc/Hex, UV,
Dragendorff stain). 1H NMR (600 MHz, DMSO-d6/D2O/TFA) δ 8.54 (s, 1H), 8.30 (s,
1H), 8.10 – 8.07 (m, 2H), 8.01 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.91 (d, J =
8.5 Hz, 2H), 7.71 – 7.68 (m, 3H), 7.49 (t, J = 7.8 Hz, 1H), 7.44 – 7.39 (m, 3H), 2.30 (s,
3H). 13C{1H} NMR (151 MHz, DMSO-d6/D2O/TFA) δ 146.6, 144.5, 134.5, 133.8,
132.8, 130.8, 129.9, 127.5, 127.2, 127.0, 126.4, 126.3, 125.6, 124.8, 123.1, 121.0, 117.3,
113.8, 109.8, 21.3. vmax (cm-1, thin film, ATR): 2847 (br), 1594 (w), 1460 (w), 1445 (m),
1396 (w), 1376 (m), 1304 (w), 1279 (w), 1176 (s), 1133 (m), 1113 (m), 1092 (m), 1050
(w), 1024 (w), 985 (m), 966 (w), 903 (w), 817 (w), 746 (s), 709 (s), 688 (s), 660 (s).
HRMS (ESI+/TOF) m/z: [M+H]+ Calcd for C24H20N3O2S 414.1276; Found 414.1264.
mp: 249.0 °C (dec.).
4-(2-Phenyl-1H-imidazol-5-yl)pyridine (8). The title compound was prepared
according to general procedure A, using 4-acetylpyridine (68) (47.0 mg, 0.375 mmol,
1.25 equiv.), benzaldehyde (32.0 mg, 0.30 mmol, 1.00 equiv.). Purification by silica gel
chromatography, eluting with MeOH in DCM (19 cm x 20 mm, gradient elution, 0% →
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6%, 0.5% increases, 30 mL runs, 7 mL fractions) yielded 8 as a yellow solid (56% yield,
1
37.0 mg, 0.17 mmol). Rf = 0.18 (EtOAc, Dragendorff stain); H NMR (500 MHz,
DMSO-d6) δ 12.90 (br s, 1H), 8.53 (d, J = 5.0 Hz, 2H), 8.10 – 7.98 (m, 3H), 7.80 (d, J =
6.0 Hz, 2H), 7.49 (t, J = 7.4 Hz, 2H), 7.39 (t, J = 7.4 Hz, 2H); 13C{1H} NMR (125 MHz,
DMSO-d6) δ 150.3, 147.2, 142.1, 139.1, 130.7, 129.3, 129.0, 125.6, 119.3, 117.9; νmax
(cm-1, thin film, ATR): 2923, 1601, 1571, 1493, 1458, 1424, 1159, 1093, 999, 950, 821,
838, 780, 774, 712, 705, 694, 685, 677; HRMS (ESI+/TOF) m/z: [M+H]+ Calcd for
C14H12N3 222.1031; Found 222.1037; mp: 209.5 – 210.6 °C (lit. 212 – 214 °C).
Spectroscopic data are in accordance with the literature10.
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4-(Furan-2-yl)-2-phenyl-1H-imidazole (9). The title compound was prepared
according to general procedure A, using 4-acetylfuran (41.0 mg, 0.375 mmol, 1.25
equiv.), benzaldehyde (32.0 mg, 0.30 mmol, 1.00 equiv.). Purification by silica gel
chromatography, eluting with EtOAc in hexanes (18 cm x 15 mm, gradient elution, 0%
→ 35%, 5% increases, 30 mL runs, 7 mL fractions) yielded a yellow oil which was
triturated with 5% DCM/hexanes to yield 9 as a white solid (30% yield, 19.0 mg, 0.09
mmol). Rf = 0.33 (30% EtOAc/Hex, Dragendorff stain); 1H NMR (500 MHz, DMSO-
d6) δ 12.71 (br s, 1H), 7.97 (d, J = 7.3, 2H), 7.62 (s, 1H), 7.52 (s, 1H), 7.46 (t, J = 7.6
13
Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H) 6.59 (s, 1H), 6.53 (s, 1H); C{1H} NMR (126 MHz,
DMSO-d6) δ 150.3, 146.0, 141.1, 133.9, 130.3, 128.7, 128.3, 125.0, 113.9, 111.4, 103.7;
vmax (cm-1, thin film, ATR): 3130 (w), 2739 (w, br), 1560 (w), 1494 (w), 1460 (w), 1407
(w), 1297 (w), 1212 (w), 1160 (m), 1143 (m), 1092 (w), 1068 (w), 1011 (m), 969 (m),
889 (m), 786 (s), 741 (s), 719 (s), 695 (s), 681 (s); HRMS (ESI+/TOF) m/z: [M+H]+
Calcd for C13H11N2O 211.0871; Found 211.0878.; mp: 145.4 – 148.7 °C (EtOAc) (lit.
154 – 156 °C (EtOH)).
5-(3-Nitrophenyl)-2-phenyl-1H-imidazole (10). The title compound was prepared
according to general procedure A, using 3’-nitroacetophenone (63.0 mg, 0.375 mmol,
1.25 equiv.), benzaldehyde (32.0 mg, 0.30 mmol, 1.00 equiv.). Purification by silica gel
chromatography, eluting with EtOAc in hexanes (18 cm x 15 mm, gradient elution, 0%
→ 35%, 5% increases, 30 mL runs, 7 mL fractions) yielded 10 as a bright yellow solid
1
(69% yield, 55.0 mg, 0.21 mmol). Rf = 0.17 (30% EtOAc/Hex, Dragendorff stain); H
NMR (500 MHz, DMSO-d6) δ 12.87 (br s, 1H), 8.68 (s, 1H), 8.30 (d, J = 7.7 Hz, 1H),
8.10 – 8.00 (m, 4H) 7.67 (t, J = 8.0 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H) 7.40 (t, J = 7.2 Hz,
13
1H); C{1H} NMR (126 MHz, DMSO-d6) δ 148.4, 146.5, 138.9, 136.5, 130.5, 130.2,
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130.0, 128.8, 128.4, 125.1, 120.7, 118.4, 116.3; vmax (cm-1, thin film, ATR): 3383 (m),
1561 (w), 1541 (w), 1516 (s), 1290 (w), 1118 (m), 1103 (w), 893 (m), 872 (w), 821 (m),
782 (s), 745 (s), 737 (s), 718 (s), 695 (s), 687 (s); HRMS (ESI+/TOF) m/z: [M+H]+
Calcd for C15H12N3O2 266.0930 ; Found 266.0933. mp: 183.7 – 185.3 °C (EtOAc) (lit.
181.1 – 183.9 °C). Spectroscopic data are in accordance with the literature28
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5-(4-Nitrophenyl)-2-phenyl-1H-imidazole (11). The title compound was prepared
according to general procedure A, using 4’-nitroacetophenone (63.0 mg, 0.375 mmol,
1.25 equiv.), benzaldehyde (32.0 mg, 0.30 mmol, 1.00 equiv.). Purification by silica gel
chromatography, eluting with EtOAc in hexanes (18 cm x 15 mm, gradient elution, 0%
→ 35%, 5% increases, 30 mL runs, 7 mL fractions) yielded 11 as a bright yellow solid
1
(64% yield, 51.0 mg, 0.19 mmol). Rf = 0.20 (30% EtOAc/Hex, Dragendorff stain); H
NMR (500 MHz, DMSO-d6) δ 12.97 (br s, 1H), 8.25 (d, J = 8.8 Hz, 2H), 8.14 – 8.10 (m,
3H), 8.30 (d, J = 7.8 Hz, 2H), 7.49 (t, J = 7.6 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H); 13C{1H}
NMR (125 MHz, DMSO-d6) δ 147.0, 145.3, 141.4, 139.1, 130.1, 128.8, 125.1, 124.8,
124.1, 118.0; νmax (cm-1, ATR): 3352, 2359, 2344, 1598, 1506, 1489, 1458, 1333, 1178,
1131, 1109, 945, 858, 791, 780, 753, 717, 696; HRMS (ESI+/TOF) m/z: [M+H]+ Calcd
for C15H12N3O2 266.0930; Found 266.0929; mp: 187.2 – 188.7 °C (EtOAc) (lit. 190 –
191 °C)– turned brown upon heating. Spectroscopic data are in accordance with the
literature29.
4-(2-Phenyl-1H-imidazol-5-yl)benzonitrile (12). The title compound was prepared
according to general procedure A, using 4-acetylbenzonitrile (55.0 mg, 0.375 mmol, 1.25
equiv.), benzaldehyde (32.0 mg, 0.30 mmol, 1.00 equiv.). Purification by silica gel
chromatography, eluting with EtOAc in hexanes (18 cm x 15 mm, gradient elution, 0%
→ 60%, 5% increases, 12x 30 mL runs, then 10% increases, 2x 30 mL runs, 10 mL
fractions) yielded 12 as a yellow solid (68% yield, 50.0 mg, 0.20 mmol). Rf = 0.18 (30%
1
EtOAc/Hex, Dragendorff stain); H NMR (500 MHz, DMSO-d6) δ 12.88 (br. s, 1H),
8.10 – 7.97 (m, 5H), 7.82 (d, J = 8.2 Hz, 2H), 7.49 (t, J = 7.7 Hz, 2H), 7.39 (t, J = 7.5 Hz,
13
1H); C{1H} NMR (126 MHz, DMSO-d6) δ 146.6, 139.4, 139.2, 132.5, 130.2, 128.8,
125.0, 124.8, 119.3, 117.1, 108.0; νmax (cm-1, thin film, ATR): 3294 (m) , 2923 (w) ,
2851 (w), 2539 (w), 2226 (m), 1604 (m), 1539 (w), 1491 (w), 1458 (w), 1416 (w), 1133
(m), 945 (w), 849 (m), 728 (s), 699 (s); HRMS (ESI+/TOF) m/z: [M+H]+ Calcd for
C16H12N3 246.1031; Found 246.1032. mp 209.0 – 211.8 °C (EtOAc)
5-(Naphthalen-2-yl)-2-phenyl-1H-imidazole (13). The title compound was
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prepared according to general procedure A, using 2’-acetonaphtone (64.0 mg, 0.375
mmol, 1.25 equiv.), benzaldehyde (32.0 mg, 0.30 mmol, 1.00 equiv.). Purification by
silica gel chromatography, eluting with MeOH in DCM (18 cm x 15 mm, gradient elution,
0% → 5%, 0.5% increases, 30 mL runs, 7 mL fractions) yielded 13 as a pale yellow solid
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(67% yield, 54.0 mg, 0.20 mmol). Rf = 0.33 (30% EtOAc/Hex, Dragendorff stain); H
NMR (500 MHz, DMSO-d6) δ 12.73 (br. s, 1H), 8.38 (s, 1H), 8.10 – 8.00 (m, 3H), 7.97
– 7.85 (m, 4H), 7.54 – 7.48 (m, 3H), 7.45 (t, J = 7.5 Hz, 1H), 7.38 (t, J = 7.4 Hz, 1H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 146.1, 141.0, 133.4, 132.2, 131.9, 130.5, 128.7,
128.2, 127.9, 129.7, 127.6, 126.3, 125.2, 125.0, 123.7, 121.8, 115.0; νmax (cm-1, thin film,
ATR): 2850, 1630, 1602, 1572, 1500, 1484, 1464, 1454, 1401, 1263, 1138, 1126, 1070,
891, 859, 820, 792, 784, 748, 693; HRMS (ESI+/TOF) m/z: [M+H]+ Calcd for C19H15N2
271.1235; Found 271.1231. mp 223.9 – 225.0 °C (MeOH/DCM).
5-(4-Methylphenyl)-2-phenyl-1H-imidazole (14). The title compound was
prepared according to general procedure A, using 4’-methylacetophenone (53.0 mg,
0.375 mmol, 1.25 equiv.), benzaldehyde (32.0 mg, 0.30 mmol, 1.00 equiv.). Purification
by silica gel chromatography, eluting with EtOAc in hexanes (18 cm x 15 mm, gradient
elution, 0% → 25%, 5% increases, 30 mL runs, 7 mL fractions) yielded 14 as a pale
yellow solid (65% yield, 46.0 mg, 0.20 mmol). Rf = 0.37 (30% EtOAc/Hex, Dragendorff
stain); 1H NMR (500 MHz, DMSO-d6) δ 12.60 (br s, 1H), 8.00 (d, J = 7.1 Hz, 2H), 7.80
– 7.64 (m, 3H), 7.46 (t, J = 7.8 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 7.18 (d, J = 7.0 Hz, 2H),
2.31 (s, 3H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 145.6, 141.2, 135.2, 131.9, 130.7,
129.4, 129.0, 128.7, 128.0, 124.9, 124.4, 113.7, 20.8; νmax (cm-1, thin film, ATR): 2985,
1606, 1576, 1498, 1458, 1399, 1137, 1084, 962, 823, 803, 786, 721, 710, 695; HRMS
(ESI+/TOF) m/z: [M+H]+ Calcd for C16H15N2 235.1235; Found 235.1222; mp: 172.8 –
174.0 °C (EtOAc) (lit 179 °C [benzene]) – turned violet upon heating. Spectroscopic data
are in accordance with the literature30,31
5-(4-Bromophenyl)-2-phenyl-1H-imidazole (15). The title compound was prepared
according to general procedure A, using 4’-bromoacetophenone (75.0 mg, 0.375 mmol,
1.25 equiv.), benzaldehyde (32.0 mg, 0.30 mmol, 1.00 equiv.). Purification by silica gel
chromatography, eluting with EtOAc in hexanes (18 cm x 15 mm, gradient elution, 0%
→ 25%, 5% increases, 30 mL runs, 7 mL fractions) yielded 15 as a pale yellow solid
1
(72% yield, 65.0 mg, 0.22 mmol). Rf = 0.21 (30% EtOAc/Hex, Dragendorff stain); H
NMR (500 MHz, DMSO-d6) δ 12.72 (br s, 1H), 7.99 (d, J = 7.5 Hz, 2H), 7.86 – 7.80 (m,
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3H), 7.55 (d, J = 8.3 Hz, 2 H), 7.47 (t, J = 7.6 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H); 13C{1H}
NMR (125 MHz, DMSO-d6) δ 146.1, 139.9, 134.0, 131.4, 130.4, 128.8, 128.3, 126.4,
125.0, 118.9, 115.0; vmax (cm-1, thin film, ATR): 2925 (br), 2360 (w), 1602 (s), 1517
(w), 1480 (w), 1443 (w), 1312 (s), 1213 (w), 1147 (s), 1109 (m), 1075 (w), 1075 (w), 999
(w), 958 (m), 877 (w), 768 (s), 762 (s), 744 (s), 733 (s), 700 (m); HRMS (ESI+/TOF)
m/z: [M+H]+ Calcd for C15H12N2Br 299.0184, 301.0164; Found 299.0180, 301.0167;
mp: 169.2 – 172.5 (EtOAc) (lit. 169 - 171 °C) – turned brown upon heating.
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Spectroscopic data are in accordance with the literature28,30
.
3-(5-Phenyl-1H-imidazol-2-yl)phenol (16). The title compound was prepared
according to general procedure B, using acetophenone (46.0 mg, 0.375 mmol, 1.25
equiv.), 3-hydroxybenzaldehyde (37.0 mg, 0.30 mmol, 1.00 equiv.). Purification by silica
gel chromatography, eluting with EtOAc in hexanes (19 cm x 20 mm, gradient elution,
0% → 30%, 5% increases, 50 mL runs, 5-10 mL fractions) yielded 16 as a white yellow
solid (85% yield, 60.0 mg, 0.25 mmol). Rf = 0.30 (30% EtOAc/Hex, UV, Dragendorff
1
stain); H NMR (400 MHz, MeOD-d4) δ 7.76 (dd, J = 1.1, 8.3 Hz, 2H), 7.44 (s, 1H),
13
7,41 – 7.36 (m, 4H), 7.30 – 7.23 (m, 2H), 6.83 (ddd, J = 1.1, 2.4, 8.0 Hz, 1H); C{1H}
NMR (126 MHz, MeOD-d4) δ 159.1, 149.0, 132.7, 131.0, 129.7, 128.0, 126.1, 117.9,
116.9, 113.7 (Note: Due to slow relaxation, some 13C{1H} NMR signals were difficult to
identify28. Concerning this compound, three signals are missing); HRMS (ESI+/TOF)
m/z: [M+H]+ Calcd for C15H13N2O 237.1028; Found 237.1011.
2-(3-Chlorophenyl)-5-phenyl-1H-imidazole (17). The title compound was
prepared according to general procedure B, using acetophenone (46.0 mg, 0.375 mmol,
1.25 equiv.) and 3-chlorobenzaldehyde (42.0 mg, 0.30 mmol, 1.00 equiv.). Purification
by silica gel chromatography, eluting with EtOAc in hexanes (19 cm x 20 mm, gradient
elution, 0% → 30%, 5% increases, 50 mL runs, 5-10 mL fractions) yielded 17 as a pale
yellow solid (69% yield, 53.0 mg, 0.21 mmol). Rf = 0.40 (30% EtOAc/Hex, UV,
Dragendorff stain); 1H NMR (500 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.06 (s, 1H), 7.97
(d, J = 7.5 Hz, 1H), 7. 91 – 7.76 (m, 3H), 7.50 (t, J = 7.9 Hz, 1H), 7.42 (ddd, J = 8.0, 2.1,
0.9 Hz, 1H), 7.38 (t, J = 7.3 Hz, 2H), 7.22 (t, J = 6.9 Hz, 1H); 13C{1H} NMR (126 MHz,
DMSO-d6) δ 144.4, 141.4, 133.6, 132.5, 130.7, 128.9, 128.5, 127.8, 127.0, 126.4, 124.4,
123.4, 114.9; HRMS (ESI+/TOF) m/z: [M+H]+ Calcd for C15H12ClN2 255.0689,
257.0663; Found 255.0693, 257.0670. Spectroscopic data are in accordance with the
literature23.
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2-(4-Nitrophenyl)-5-phenyl-1H-imidazole (18). The title compound was prepared
according to general procedure B, using acetophenone (46.0 mg, 0.375 mmol, 1.25
equiv.) and 4-nitrobenzaldehyde (46.0 mg, 0.30 mmol, 1.00 equiv.). Purification by silica
gel chromatography, eluting with EtOAc in hexanes (19 cm x 20 mm, gradient elution,
0% → 30%, 5% increases, 50 mL runs, 5-10 mL fractions) yielded 18 as an orange solid
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(67% yield, 53.0 mg, 0.21 mmol). Rf = 0.20 (30% EtOAc/Hex, Dragendorff stain); H
NMR (500 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.34 (d, J = 8.9 Hz, 2H), 8.23 (d, J = 8.8
Hz, 2H), 7.93 (s, 1H), 7.89 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.24 (t, J = 7.3
Hz, 1H); 13C{1H} NMR (63 MHz, DMSO-d6) δ 146.5, 143.8, 142.4, 136.3, 134.1, 128.5,
126.7, 125.5, 124.5, 124.3, 116.3; HRMS (ESI+/TOF) m/z: [M+H]+ Calcd for
C15H12N3O2 266.0930; Found 266.0933. Spectroscopic data are in accordance with the
literature32.
4-(4-Phenyl-1H-imidazol-2-yl)phenol (19). The title compound was prepared
according to general procedure B, using acetophenone (46.0 mg, 0.375 mmol, 1.25
equiv.) and 4-hydroxybenzaldehyde (37.0 mg, 0.30 mmol, 1.00 equiv.). Purification by
silica gel chromatography, eluting with EtOAc in hexanes (19 cm x 20 mm, gradient
elution, 0% → 30%, 5% increases, 50 mL runs, 5-10 mL fractions) yielded 19 as a yellow
solid (51% yield, 36.0 mg, 0.15 mmol). Rf = 0.30 (30% EtOAc/Hex, Dragendorff stain);
1H NMR (250 MHz, DMSO-d6) δ 12.34 (s, 1H), 9.68 (s, 1H), 7.90 – 7.71 (m, 4H), 7.65
(s, 1H), 7.35 (t, J = 7.6 Hz, 2H), 7.18 (t, J = 7.2 Hz, 1H), 6.84 (d, J = 8.5 Hz, 2H). 13C{1H}
NMR (63 MHz, DMSO-d6) δ 157.6, 146.4, 140.5, 134.9, 128.4, 126.5, 126.0, 124.3,
122.0, 115.4, 113.3 vmax (cm-1, thin film, ATR): 3221, 2926, 1773,1701, 1609, 1541,
1496, 1460, 1367, 1275, 1175, 1099, 1029, 948, 908, 837, 761, 738, 694, 661, 635.
HRMS (ESI+/TOF) m/z: [M+H]+ Calcd for C15H13N2O 237,1028; Found 237,1013. mp:
227 ºC (dec.).
2-(3-Chlorophenyl)-5-phenyl-1H-imidazole (20). The title compound was
prepared according to general procedure B, using acetophenone (46.0 mg, 0.375 mmol,
1.25 equiv.) and 4-chlorobenzaldehyde (42.0 mg, 0.30 mmol, 1.00 equiv.). Purification
by silica gel chromatography, eluting with EtOAc in hexanes (19 cm x 20 mm, gradient
elution, 0% → 30%, 5% increases, 50 mL runs, 5-10 mL fractions) yielded 20 as a pale
yellow solid (72% yield, 55.0 mg, 0.22 mmol). Rf = 0.40 (30% EtOAc/Hex, UV,
Dragendorff stain); 1H NMR (500 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.01 (d, J = 8.5 Hz,
2H), 7.86 (d, J = 7.4 Hz, 2H), 7.79 (d, J = 1.8 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.37 (t, J
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= 7.7 Hz, 2H), 7.21 (t, J = 7.3 Hz, 1H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 144.8,
141.3, 134.5, 132.6, 129.4, 128.8, 128.4, 126.5, 126.3, 124.4, 114.7; HRMS (ESI+/TOF)
m/z: [M+H]+ Calcd for C15H12ClN2 255.0689, 257.0663; Found 255.0694, 257.0677.
Spectroscopic data are in accordance with the literature32.
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2-(3-Nitrophenyl)-5-phenyl-1H-imidazole (21). The title compound was prepared
according to general procedure B, using acetophenone (46.0 mg, 0.375 mmol, 1.25
equiv.) and 3-nitrobenzaldehyde (46.0 mg, 0.30 mmol, 1.00 equiv.). Purification by silica
gel chromatography, eluting with EtOAc in hexanes (19 cm x 20 mm, gradient elution,
0% → 30%, 5% increases, 50 mL runs, 5-10 mL fractions) yielded 21 as a yellow solid
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(67% yield, 53.0 mg, 0.21 mmol). Rf = 0.20 (30% EtOAc/Hex, Dragendorff stain); H
NMR (250 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.84 (s, 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.20
(dd, J = 8.1, 2.1 Hz, 1H), 7.93 – 7.91 (m, 4H), 7.39 (t, J = 7.5 Hz, 2H), 7.24 (t, J = 7.0
Hz, 1H); 13C{1H} NMR (63 MHz, DMSO-d6) δ 148.4, 143.8, 141.7, 134.2, 132.1, 130.9,
130.5, 128.5, 126.5, 124.5, 122.5, 119.2, 115.4; HRMS (ESI+/TOF) m/z: [M+H]+ Calcd
for C15H12N3O2 266.0930; Found 266.0950.
2-(4-Methoxyphenyl)-5-phenyl-1H-imidazole (22). The title compound was
prepared according to general procedure B, using acetophenone (46.0 mg, 0.375 mmol,
1.25 equiv.) and p-anisaldehyde (41.0 mg, 0.30 mmol, 1.00 equiv.). Purification by silica
gel chromatography, eluting with EtOAc in hexanes (19 cm x 20 mm, gradient elution,
0% → 40%, 5% increases, 50 mL runs, 5-10 mL fractions) yielded 22 as a white solid
(50% yield, 38.0 mg, 0.15 mmol); Rf = 0.30 (30% EtOAc/Hex, UV, Dragendorff stain);
1H NMR (400 MHz, DMSO-d6/D2O/TFA) δ 7.99 (s, 1H), 7.95 (d, J = 8.8 Hz, 2H), 7.80
(d, J = 7.6 Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.43 (t, J = 7.2 Hz, 1H), 7.16 (d, J = 8.8 Hz,
2H), 3.82 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6/D2O/TFA) δ 163.0, 145.3,
133.9, 130.1, 130.0, 129.8, 127.2, 126.4, 116.3, 115.7, 115.6, 56.3; HRMS (ESI+/TOF)
m/z: [M+H]+ Calcd for C16H15N2O 251.1184; Found 251.1186.
2-(2-Chlorophenyl)-5-phenyl-1H-imidazole (23). The title compound was
prepared according to general procedure B, using acetophenone (46.0 mg, 0.375 mmol,
1.25 equiv.) and 2-chlorobenzaldehyde (42.0 mg, 0.30 mmol, 1.00 equiv.). Purification
by silica gel chromatography, eluting with EtOAc in hexanes (19 cm x 20 mm, gradient
elution, 0% → 30%, 5% increases, 50 mL runs, 5-10 mL fractions) yielded 23 as a white
solid (63% yield, 48.0 mg, 0.19 mmol). Rf = 0.50 (30% EtOAc/Hex, UV, Dragendorff
stain); 1H NMR (500 MHz, DMSO-d6) δ 12.43 (s, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.88 –
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7.84 (m, 3H), 7.58 (dd, J = 1.9, 7.2 Hz, 1H), 7.48 – 7.43 (m, 2H), 7.37 (t, J = 7.6 Hz, 2H),
7.21 (t, J = 7.3 Hz, 1H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 143.3, 140.8, 134.5,
131.2, 130.8, 130.2, 130.0, 129.9, 128.4, 127.3, 126.3, 124.4, 114.5; vmax (cm-1, thin film,
ATR): 3059, 1708, 1607, 1567, 1482, 1453, 1111, 1086, 1049, 946, 694. HRMS
(ESI+/TOF) m/z: [M+H]+ Calcd for C15H12ClN2 255.0689, 257.0663; Found 255.0690,
257.0670; mp: 161.0 – 162.0 °C (EtOAc).
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2-(4-Fluorophenyl)-5-phenyl-1H-imidazole (24). The title compound was
prepared according to general procedure B, using acetophenone (46.0 mg, 0.375 mmol,
1.25 equiv.) and 4-fluorobenzaldehyde (38.0 mg, 0.30 mmol, 1.00 equiv.). Purification
by silica gel chromatography, eluting with EtOAc in hexanes (19 cm x 20 mm, gradient
elution, 0% → 30%, 5% increases, 50 mL runs, 5-10 mL fractions) yielded 24 as a pale
yellow solid (57% yield, 41.0 mg, 0.17 mmol). Rf = 0.30 (30% EtOAc/Hex, UV,
Dragendorff stain); 1H NMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.04 (dd, J = 8.6,
5.5 Hz, 2H), 7.86 (d, J = 7.4 Hz, 2H), 7.76 (s, 1H), 7.37 (t, J = 7.6 Hz, 2H), 7.32 (t, J =
8.8 Hz, 2H), 7.21 (t, J = 7.3 Hz, 1H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 162.0
(d, 1JCF = 245.1 Hz), 145.1, 141.1, 134.6, 128.5, 127.30 (d, 4JCF = 2.5 Hz, 1C), 127.04
(d, 3JCF = 8.4 Hz), 126.2, 124.4, 115.74 (d, 2JCF = 22.1 Hz), 114.3; HRMS (ESI+/TOF)
m/z: [M+H]+ Calcd for C15H12FN2 239.0984; Found 239.0985. Spectroscopic data are in
accordance with the literature33.
N,N-Dimethyl-4-(5-phenyl-1H-imidazol-2-yl)aniline (25). The title compound was
prepared according to general procedure B, using acetophenone (46.0 mg, 0.375 mmol,
1.25 equiv.) and 4-(dimethylamino)benzaldehyde (46.0 mg, 0.30 mmol, 1.00 equiv.).
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Purification by silica gel chromatography, eluting with EtOAc in hexanes (19 cm x 20
mm, gradient elution, 30% → 50%, 5% increases, 50 mL runs, 5-10 mL fractions) yielded
25 as a yellow solid (23% yield, 18.0 mg, 0.07 mmol). Rf = 0.40 (30% EtOAc/Hex, UV,
Dragendorff stain); 1H NMR (400 MHz, DMSO-d6/D2O/TFA) δ 7.88 (s, 1H), 7.83 (d, J
= 9.1 Hz, 2H), 7.77 (d, J = 7.1 Hz, 1H), 7.49 (t, J = 7.5 Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H),
6.85 (d, J = 9.2 Hz, 2H), 2.98 (s, 6H); 13C{1H} NMR (101 MHz, DMSO-d6/D2O/TFA)
δ 153.1, 146.4, 133.3, 130.0, 129.0, 127.5, 126.3, 115.7, 112.7, 109.5, 40.4; vmax (cm-1,
thin film, ATR): 2919, 2850, 1615, 1545, 1500, 1443, 1396, 1363, 1227, 1202, 1170,
945, 820, 760, 738, 695; HRMS (ESI+/TOF) m/z: [M+H]+ Calcd for C17H18N3
264,1501; Found 264,1502; mp: 142.0 – 145.0 °C (EtOAc).
2-(Furan-2-yl)-5-phenyl-1H-imidazole (26). The title compound was prepared
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according to general procedure B, using acetophenone (46.0 mg, 0.375 mmol, 1.25
equiv.) and furfural (29.0 mg, 0.30 mmol, 1.00 equiv.). Purification by silica gel
chromatography, eluting with EtOAc in hexanes (19 cm x 20 mm, gradient elution, 0%
→ 20%, 5% increases, 50 mL runs, 5-10 mL fractions) yielded 26 as a white solid (34%
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yield, 22.0 mg, 0.11 mmol). Rf = 0.10 (30% EtOAc/Hex, UV, Dragendorff stain); H
NMR (400 MHz, DMSO-d6/D2O/TFA) δ 8.00 (s, 1H), 7.99 (s, 1H), 7.78 (d, J = 7.5 Hz,
2H), 7.50 (t, J = 7.5 Hz, 2H), 7.46 – 7.41 (m, 2H), 6.80 (dd, J = 3.3, 1.5 Hz, 1H); 13C{1H}
NMR (101 MHz, DMSO-d6/D2O/TFA) δ 147.8, 138.8, 136.7, 134.0, 130.3, 130.1,
127.1, 126.3, 116.4, 115.5, 113.9; HRMS (ESI+/TOF) m/z: [M+H]+ Calcd for
C13H11N2O 211.0871; Found 211.0871. Spectroscopic data are in accordance with the
literature34
2-(4-Bromophenyl)-5-phenyl-1H-imidazole (27). The title compound was prepared
according to general procedure B, using acetophenone (46.0 mg, 0.375 mmol, 1.25
equiv.) and 4-bromobenzaldehyde (56.0 mg, 0.30 mmol, 1.00 equiv.). Purification by
silica gel chromatography, eluting with EtOAc in hexanes (19 cm x 20 mm, gradient
elution, 0% → 30%, 5% increases, 50 mL runs, 5-10 mL fractions) yielded 27 as a white
solid (61% yield, 55.0 mg, 0.18 mmol). Rf = 0.20 (30% EtOAc/Hex, UV, Dragendorff
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stain); H NMR (500 MHz, DMSO-d6) δ 12.75 (s, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.86
(d, J = 7.2 Hz, 2H), 7.79 (s, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.37 (t, J = 7.7 Hz, 2H), 7.21
(t, J = 7.3 Hz, 1H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 144.8, 141.3, 134.5, 131.7,
129.8, 128.5, 126.9, 126.3, 124.4, 121.2, 114.7; vmax (cm-1, thin film, ATR): 3069, 1703,
1603, 1486, 1466, 1452, 1431, 1364, 1298, 1269, 1228, 1143, 1085, 1971, 1010, 949,
911, 830, 729, 694; HRMS (ESI+/TOF) m/z: [M+H]+ Calcd for C15H12BrN2 299.0184,
301.0164; Found 299.0186, 301.0171; mp: 196.0 – 198.0 °C (EtOAc).
2-Cyclohexyl-5-phenyl-1H-imidazole (28). The title compound was prepared
according to general procedure B, using acetophenone (46.0 mg, 0.375 mmol, 1.25
equiv.) and cyclohexanecarboxaldehyde (34.0 mg, 0.30 mmol, 1.00 equiv.). Purification
by silica gel chromatography, eluting with EtOAc in hexanes (19 cm x 20 mm, gradient
elution, 0% → 40%, 5% increases, 50 mL runs, 5-10 mL fractions) yielded 28 as a white
solid (83% yield, 56.0 mg, 0.25 mmol). Rf = 0.20 (30% EtOAc/Hex, UV, Dragendorff
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stain); H NMR (500 MHz, CDCl3) δ 8.35 (br s, 1H), 7.66 (d, J = 7.3 Hz, 2H), 7.32 (t, J
= 7.7 Hz, 2H), 7.22 – 7.17 (m, 2H), 2.74 (tt, J = 12.0, 3.5 Hz, 1H), 1.98 (d, J = 11.7 Hz,
2H), 1.75 (d, J = 13.2 Hz, 2H), 1.66 (d, J = 12.6 Hz, 1H), 1.50 (dq, J = 12.4, 3.1 Hz, 2H),
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1.32 – 1.12 (m, 3H); C{1H} NMR (126 MHz, CDCl3) δ 153.9, 137.1, 133.1, 128.7,
126.7, 124.9, 115.7, 38.1, 32.2, 26.2, 25.9; HRMS (ESI+/TOF) m/z: [M+H]+ Calcd for
C15H19N2 227.1548; Found 227.1558. Spectroscopic data are in accordance with the
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4-(5-Phenyl-1H-imidazol-2-yl)pyridine (29). The title compound was prepared
according to general procedure B, using acetophenone (46.0 mg, 0.375 mmol, 1.25
equiv.) and 4-pyridinecarboxaldehyde (33.0 mg, 0.30 mmol, 1.00 equiv.). Purification by
silica gel chromatography, eluting with EtOAc in hexanes (19 cm x 20 mm, gradient
elution, 50% → 100%, 5% increases, 50 mL runs, 5-10 mL fractions) yielded 29 as a pale
yellow solid (83% yield, 56.0 mg, 0.25 mmol). Rf = 0.01 (30% EtOAc/Hex, UV,
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Dragendorff stain); H NMR (400 MHz, DMSO-d6/D2O/TFA) δ 8.81 (d, J = 6.6 Hz,
2H), 8.40 (d, J = 6.6 Hz, 2H), 8.04 (s, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.45 (t, J = 7.6 Hz,
2H), 7.34 (t, J = 7.3 Hz, 1H); 13C{1H} NMR (101 MHz, DMSO-d6/D2O/TFA) δ 143.5,
143.2, 142.0, 141.6, 131.4, 129.8, 129.1, 125.9, 122.2, 122.0; HRMS (ESI+/TOF) m/z:
[M+H]+ Calcd for C14H12N3 222.1031; Found 222.1030. Spectroscopic data are in
accordance with the literature23.
5-Phenyl-2-propyl-1H-imidazole (30). The title compound was prepared according
to general procedure B, using acetophenone (46.0 mg, 0.375 mmol, 1.25 equiv.) and
butyraldehyde (23.0 mg, 0.30 mmol, 1.00 equiv.). Purification by silica gel
chromatography, eluting with EtOAc in hexanes (19 cm x 20 mm, gradient elution, 30%
→ 70%, 5% increases, 50 mL runs, 5-10 mL fractions) yielded 30 as a white solid (36%
1
yield, 20.0 mg, 0.11 mmol). Rf = 0.10 (30% EtOAc/Hex, UV, Dragendorff stain); H
NMR (500 MHz, CDCl3) δ 7.84 (s, 1H), 7.67 (d, J = 7.4 Hz, 2,H), 7.33 (t, J = 7.7 Hz,
2H), 7.23 – 7.17 (m, 2H), 2.68 (t, J = 7.6 Hz, 2H), 1.70 (sx, J = 7.5 Hz, 2H), 0.89 (t, J =
7.4 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 149.7, 137.6, 133.1, 128.8, 126.8,
124.8, 115.5, 30.6, 22.2, 13.9; HRMS (ESI+/TOF) m/z: [M+H]+ Calcd for C12H15N2
187.1235; Found 187.1243. Spectroscopic data are in accordance with the literature36,37
.
2-Cyclopropyl-5-phenyl-1H-imidazole (31). The title compound was prepared
according to general procedure B, using acetophenone (46.0 mg, 0.375 mmol, 1.25
equiv.) and cyclopropanecarboxaldehyde (23.0 mg, 0.30 mmol, 1.00 equiv.). Purification
by silica gel chromatography, eluting with EtOAc in hexanes (19 cm x 20 mm, gradient
elution, 0% → 40%, 5% increases, 50 mL runs, 5-10 mL fractions) yielded 31 as a white
solid (70% yield, 39.0 mg, 0.21 mmol). Rf = 0.10 (30% EtOAc/Hex, UV, Dragendorff
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stain); H NMR (400 MHz, DMSO-d6/D2O/TFA) δ 7.76 (s, 1H), 7.67 (d, J = 7.4 Hz,
2H), 7.46 (t, J = 7.5 Hz, 2H), 7.39 (t, J = 7.3 Hz, 1H), 2.30 – 2.20 (m, 1H), 1.28 – 1.20
(m, 2H), 1.18 – 1.11 (m, 2H); 13C{1H} NMR (101 MHz, DMSO-d6/D2O/TFA) δ 150.9,
132.5, 130.0, 129.9, 127.3, 125.9, 114.7, 9.7, 7.5; vmax (cm-1, thin film, ATR): 3034,
2910, 1606, 1566, 1545, 1524, 1483, 1451, 1425, 1313, 1166, 1135, 1090, 1027, 1005,
881, 756, 727, 693; HRMS (ESI+/TOF) m/z: [M+H]+ Calcd for C12H13N2 185.1079;
Found 185.1080; mp: 160.0 – 162.0 °C (EtOAc).
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4-(2-(2-Methyl-4-(methylsulfonyl)phenyl)-1H-imidazol-5-yl)pyridine (32). A 10
mL round-bottom flask was charged with 4-acetylpyridine (68) (219 mg, 1.70 mmol, 1.70
equiv.), magnetic stirrer bar and DMSO (3.5 mL, 0.5 M) under air and concentrated HBr
aqueous (48% w/w, 8.9 M) (595 mL, 5.25 mmol, 3.0 equiv.) was added dropwise. The
reaction mixture was stirred in pre-heated oil bath at 60 ºC for 8h. After consumption of
the starting material, indicated by TLC analysis (EtOAc, p-ASD), the reaction mixture
was left to reach room temperature and MeOH (5.7 mL, 0.19 M) was added. This reaction
mixture was added dropwise over 30 minutes via syringe to a solution of 2-methyl-4-
(methylsulfonyl)benzaldehyde (S5) (198 mg, 1.00 mmol, 1.00 equiv.) and NH4OAc (771
mg, 10.0 mmol, 10.0 equiv.) in MeOH (5 mL, 0.2 M in relation to S5) at room
temperature. The reaction mixture was stirred at room temperature for 18h and the solvent
was removed in the rotaevaporator, the residue was diluted with 10% MeOH/DCM (10
mL) and poured into separatory funnel containing satd. NaHCO3 (1x 40 mL) and 10%
MeOH/DCM (1x 15 mL). The phases were separated, and the aqueous phase was
extracted with 10% MeOH/DCM (7x 10 mL). The organic phases were combined, dried
over MgSO4, filtered and concentrated in the rotaevaporator. Purification by silica gel
chromatography, eluting with MeOH in DCM (gradient elution 5% → 9%) yielded 31 as
a pale yellow solid (67% yield, 210 mg, 0.67 mmol). Rf = 0.17 (EtOAc, Dragendorff
stain); 1H NMR (500 MHz, DMSO-d6) δ 12.92 (br. s, 1H), 8.54 (d, J = 5.9 Hz, 2H), 8.14
(s, 1H), 7.94 – 7.90 (m, 2H), 7.85 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 5.9 Hz, 2H), 3.26 (s,
3H), 2.75 (s, 3H); C{1H} NMR (126 MHz, DMSO-d6) δ 149.9, 145.4, 141.5, 140.0,
13
138.8, 137.6, 134.1, 129.6, 128.9, 124.4, 118.8, 117.7, 43.5, 21.4; νmax (cm-1, ATR):
2673, 1607, 1302, 1150, 1106, 1077, 1004, 965, 950, 828, 763, 739, 709, 690; HRMS
(ESI+/TOF) m/z: [M+H]+ Calcd for C16H16N3O2S 314.0963; Found 314.0938.; mp
225.4 – 227.3 °C (MeOH/DCM).
tert-Butyl 4-(5-(pyridin-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate (36). A
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50 mL round-bottom flask was charged with 4-acetylpyridine (68) (645 mg, 5.16 mmol,
1.75 equiv.), magnetic stirrer bar and DMSO (10.8 mL, 0.5 M) under air and concentrated
HBr aqueous (48% w/w, 8.9 M) (1.75 mL, 15.5 mmol, 3.0 equiv.) was added dropwise.
The reaction mixture was stirred in pre-heated oil bath at 60 ºC for 4h. After consumption
of the starting material, indicated by TLC analysis (EtOAc, p-ASD), the reaction mixture
was left to reach room temperature and MeOH (18.3 mL, 0.18 M relative to 4-
acetylpyridine) was added. This reaction mixture was added dropwise over 30 minutes
via syringe to a solution of 1-(tert-Butoxycarbonyl)-4-piperidinecarboxaldehyde (35)
(629 mg, 2.95 mmol, 1.00 equiv.) and NH4OH (6.4 mL, 44.3 mmol, 15.0 equiv.) in MeOH
(14.8 mL, 0.2 M in relation to 35) at room temperature. The reaction mixture was stirred
at room temperature for 4h and poured into separatory funnel containing satd. NaHCO3
(1x 40 mL) and EtOAc (1x 40 mL). The phases were separated, and the aqueous phase
was extracted with EtOAc (3x 40 mL), dried over Na2SO4, filtered and concentrated in
the rotaevaporator. Purification by silica gel chromatography, eluting with
EtOH:EtOAc:NH4OH:Hexane (11:34:5:50) (18 cm x 40 mm, isocratic elution,
(11:34:5:50) EtOH:EtOAc:NH4OH:Hex, 1 L run, 20 mL fractions) yielded 36 as a white
solid (82% yield, 793 mg, 2.40 mmol). Rf = 0.40 (EtOH:EtOAc:NH4OH:Hexane
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(11:34:5:50), UV, Dragendorff stain). H NMR (500 MHz, DMSO-d6) δ 12.10 (br. s,
1H), 8.46 (d, J = 6.0 Hz, 2H), 7.77 (br. s, 1H), 7.66 (d, J = 6.0 Hz, 2H), 3.99 (d, J = 12.4
Hz, 2H), 2.96 – 2.78 (m, 3H), 1.90 (dd, J = 13.0, 2.3 Hz, 2H), 1.59 (dq, J = 12.3, 3.9 Hz,
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2H), 1.41 (s, 9H). C{1H} NMR (126 MHz, DMSO-d6) δ 153.9, 152.1, 149.7, 118.5,
13
78.6, 43.2, 35.2, 30.4, 28.1. Note: Due to slow relaxation, some C{1H} NMR signals
13
were not identified in the spectra28. Specifically, the C{1H} NMR data for compound
36 lacks three of the twelve expected signals. vmax (cm-1, thin film, ATR): 2867 (br),
1690 (s), 1603 (s), 1553 (w), 1429 (m), 1363 (w), 1285 (w), 1248 (w), 1230 (w), 1212
(w), 1173 (s), 1151 (m), 1126 (m), 1038 (w), 1004 (m), 942 (w), 876 (w), 766 (s), 720
(w), 686 (m). HRMS (ESI+/TOF) m/z: [M+H]+ Calcd for C18H25N4O2 329.1978; Found
329.1964 . mp: 215.0 °C (dec.)
1-(4-Amino-3-bromophenyl)ethenone (43). A 6 mL vial was charged with the 4’-
aminoacetophenone (51.0 mg, 0.375 mmol, 1.00 equiv.), DMSO (0.75 mL, 0.5 M),
concentrated aqueous HBr (48% w/w, 8.9 M) (47 ꢀL, 0.41 mmol, 110 mol%), deionized
water (47 ꢀL) and a magnetic stirrer bar under air. The reaction mixture was stirred in a
pre-heated aluminum block at 85 ºC and was followed by TLC analysis (30% EtOAc/Hex,
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p-ASD). The reaction mixture was poured directly into a separatory funnel containing a
mixture of satd. NaHCO3 and satd. Na2S2O3 (1:1, 1x 20 mL) and EtOAc (10 mL). The
phases were separated, and the aqueous phase was extracted with EtOAc (5x 5 mL). The
organic phases were combined, washed with satd. NaCl solution (1x 5 mL), dried over
Na2SO4, filtered and concentrated in the rotaevaporator. Purification by silica gel
chromatography, eluting with EtOAc in hexanes (18 cm x 15 mm, gradient elution, 0%
→ 35%, 5% increases, 30 mL runs, 10 mL fractions) yielded 33 as a pale yellow solid
(99% yield, 64.0 mg, 0.30 mmol). Rf = 0.53 (30% EtOAc/Hex, p-ASD); 1H NMR (500
MHz, CDCl3) δ 8.05 (d, J = 1.8 Hz, 1H), 7.73 (dd, J = 8.4, 1.8 Hz, 1H), 6.74 (d, J = 8.4
Hz, 1H), 4.60 (br s, 2H), 2.49 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 195.5, 148.5,
133.9, 129.5, 128.9, 114.3, 108.3, 26.2. Spectroscopic data are in accordance with the
literature38.
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4-(4-Bromo-2-(2-methyl-4-(methylsulfonyl)phenyl)-1H-imidazol-5-yl)pyridine
(44). Following a modified literature procedure24, a 25 mL round-bottom flask was
charged with 32 (595 mg, 1.90 mmol, 1.00 equiv.), dry DCM (8.4 mL), dry pyridine (2.1
mL) and a magnetic stirrer bar under inert atmosphere. The RBF was covered with
aluminum foil and the reaction mixture was cooled to 0 ºC in an ice/water bath and stirred
for 15 minutes. Solid Py•HBr•Br2 (pyridinium hydrobromide perbromide, 743 mg, 2.09
mmol, 1.10 equiv.) was added in portions, by briefly removing the Suba seal, and the
reaction mixture was stirred at 0 ºC for 1 hour. After consumption of the starting material,
indicated by TLC analysis (100% EtOAc, Dragendorff), the solvent was removed in the
rotaevaporator. The residue was partitioned between 1M aq. NaHSO3 (1x 75 mL) and
10% MeOH/DCM (1x 60 mL). The phases were separated and the aqueous layer was
extracted with 10% MeOH/DCM (3x 60 mL). The organic phases were combined, dried
over MgSO4, filtered and concentrated in the rotaevaporator. The residue was triturated
with hexanes, filtered and washed with hexanes until all pyridine was removed, indicated
by TLC analysis, and dried in vacuo to afford 44 as a yellow solid (96% yield, 716 mg,
1.83 mmol). Rf = 0.47 (EtOAc, UV, Dragendorff stain); 1H NMR (500 MHz, DMSO-
d6) δ 13.32 (s, 1H), 8.70 (s, 2H), 8.00 – 7.79 (m, 5H), 3.28 (s, 3H), 2.65 (s, 3H); 13C{1H}
NMR (126 MHz, DMSO-d6) δ 150.5, 146.7, 141.3, 138.6, 136.1, 133.7, 130.4, 129.9,
126.6, 124.8, 120.8, 116.0, 43.9, 21.3; vmax (cm-1, thin film, ATR): 2765 (br), 1606 (s),
1573 (w), 1533 (w), 1491 (w), 1448 (w), 1422 (w), 1301 (s), 1222 (w), 1205 (w), 1150
(s), 1105 (m), 1077 (m), 1004 (m), 986 (w), 964 (m), 950 (m), 892 (w), 875 (w), 828 (s),
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762 (s), 739 (m), 708 (w), 699 (w); HRMS (ESI+/TOF) m/z: [M+H]+ Calcd for
C16H15BrN3O2S 392.0068, 394.0049; Found 392.0053, 394.0034; mp: 225.0 °C (dec.) –
turned brown at 210.0 °C.
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Suzuki-Miyaura Cross-Coupling: General Procedure C. A culture tube (13 mm
x 100 mm, 9 mL) was charged with the corresponding bromo-imidazol (0.10 mmol, 1.00
equiv.), corresponding boronic ester or boronic acid (0.125 mmol, 1.25 equiv.) and a
magnetic stirrer bar under inert atmosphere. Then, degassed DME (0.5 mL) was added
followed by addition of a premixed solution of Pd(OAc)2 (10 mol%) and Aphos (24
mol%) in degassed DME (0.25 mL). The reaction mixture was stirred for 5 minutes at
room temperature and then 1.2 M aqueous K2CO3 (0.25 mL, 3.00 equiv.) degassed
solution was added and the mixture was stirred for additional 5 minutes. After this time,
the reaction mixture was stirred in a pre-heated aluminum block at 80 ºC for 18h. After
consumption of the starting material, indicated by TLC analysis (7% EtOH/CHCl3,
Dragendorff), the reaction mixture was allowed to reach room temperature and it was
diluted with 10% MeOH/DCM (~7 mL), filtered through a pad (20 mm diameter)
composed of Celite (top, 1 cm) and silica gel (bottom, 3 cm). The pad was washed with
10% MeOH/DCM (25-50 mL) and the filtrate was concentrated under in the reduced
pressure. The crude product was adsorbed over basic alumina and purification was
performed by silica gel column chromatography.
4-(2-(2-Methyl-4-(methylsulfonyl)phenyl)-4-phenyl-1H-imidazol-5-yl)pyridine
(46). The title compound was prepared according to general procedure C, using 44 (39.0
mg, 0.10 mmol, 1.00 equiv.), phenylboronic acid (15.0 mg, 0.125 mmol, 1.25 equiv.),
Pd(OAc)2 (2.3 mg, 10 mol%) and Aphos (6.7 mg, 24 mol%). Purification by silica gel
chromatography, eluting with EtOH in CHCl3 (21 cm x 10 mm, gradient elution, 0% →
4%, 0.5% increases, 20 mL runs, 3-4 mL fractions) followed by repurification in silica
gel using EtOAc (4 cm x 30 mm, isocratic elution, 100% EtOAc, 150 mL run, 10 mL
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fractions) yielded 46 as a white solid (71% yield, 28.0 mg, 0.07 mmol). H NMR (500
MHz, DMSO-d6/D2O/TFA) δ 8.66 (d, J = 7.0 Hz, 2H), 8.05 (d, J = 7.0 Hz, 2H), 7.99 (d,
J = 8.2 Hz 1H), 7.93 (d, J = 1.1 Hz, 2H), 7.87 (dd, J = 8.2, 1.5 Hz, 1H) 7.66 – 7.61 (m,
2H), 7.60 – 7.55 (m, 2H), 3.24 (s, 3H), 2.75 (s, 3H); 13C{1H} NMR (126 MHz, DMSO-
d6/D2O/TFA) δ 150.9, 146.8, 141.5, 141.1, 138.9, 137.3, 133.5, 131.5, 130.3, 130.2,
129.9, 129.8, 129.5, 129.5, 124.8, 122.4, 43.8, 21.5; vmax (cm-1, thin film, ATR): 3084
(br), 2928 (w), 1601 (s), 1501 (w), 1486 (w), 1444 (w), 1327 (m), 1303 (s), 1214 (w),
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1147 (s), 1108 (m), 1074 (m), 999 (w), 962 (m), 951 (m), 879 (w), 832 (s), 777 (m), 762
(s), 742 (s), 702 (s); HRMS (ESI+/TOF) m/z: [M+H]+ Calcd for C22H20N3O2S 390.1276;
Found 390.1273. mp: 265.0 °C (dec.).
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4-(4-(4-(Benzyloxy)phenyl)-2-(2-methyl-4-(methylsulfonyl)phenyl)-1H-imidazol-
5-yl)pyridine (47). The title compound was prepared according to general procedure C,
using 44 (39.0 mg, 0.10 mmol, 1.00 equiv.), 4-benzyloxyphenylboronic acid (29.0 mg,
0.125 mmol, 1.25 equiv.), Pd(OAc)2 (2.3 mg, 10 mol%) and Aphos (6.7 mg, 24 mol%).
Purification by silica gel chromatography, eluting with EtOH in CHCl3 (21 cm x 10 mm,
gradient elution, 0% → 6%, 0.5% increases, 20 mL runs, 3-4 mL fractions) followed by
repurification in silica gel using MeOH in DCM eluent (21 cm x 10 mm, gradient elution,
0% → 6%, 0.5% increases, 20 mL runs, 7 mL fractions) yielded 47 as a pale yellow solid
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(69% yield, 34.0 mg, 0.07 mmol). H NMR (500 MHz, DMSO-d6/D2O/TFA) δ 8.57
(d, J = 7.0 Hz, 2H), 8.04 (d, J = 7.0 Hz, 1H), 7.93 – 7.88 (m, 2H), 7.84 (dd, J = 8.1, 1.6
Hz, 1H), 7.52 (d, J = 8.7 Hz, 2H), 7.44 (d, J = 7.5 Hz, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.32
(t, J = 7.2 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H), 5.14 (s, 2H), 3.20 (s, 3H), 2.67 (s, 3H);
13C{1H} NMR (126 MHz, DMSO-d6/D2O/TFA) δ 160.3, 151.0, 146.9, 141.7, 141.5,
139.5, 137.6, 137.3, 133.6, 131.4, 131.0, 130.8, 130.2, 129.4, 129.0, 128.6, 125.3, 122.9,
121.6, 116.5, 70.3, 44.1, 21.5; vmax (cm-1, thin film, ATR): 3041 (w), 2921 (w), 1732
(w), 1605 (s), 1513 (m), 1488 (w), 1469 (w), 1445 (w), 1303 (m), 1289 (m), 1243 (m),
1151 (s), 1143 (s), 1072 (w), 974 (m), 831 (s), 808 (w), 767 (s), 742 (m); HRMS
(ESI+/TOF) m/z: [M+H]+ Calcd for C29H26N3O3S 496.1695 466.1589; Found 496.1688;
mp: 245.0 – 248.5 °C (MeOH/DCM) – turned brown upon heating
4-(4-(4-(Methoxymethoxy)phenyl)-2-(2-methyl-4-(methylsulfonyl)phenyl)-1H-
imidazol-5-yl)pyridine (48). The title compound was prepared according to general
procedure C, using 44 (39.0 mg, 0.10 mmol, 1.00 equiv..), 4-(methoxymethoxy)phenyl
boronic acid (23.0 mg, 0.125 mmol, 1.25 equiv.), Pd(OAc)2 (2.3 mg, 10 mol%) and Aphos
(6.7 mg, 24 mol%). Purification by silica gel chromatography, eluting with EtOH in
CHCl3 (21 cm x 10 mm, gradient elution, 0% → 6%, 0.5% increases, 20.0 mL runs, 3-4
mL fractions) followed by repurification in silica gel using MeOH in DCM eluent (21 cm
x 10 mm, gradient elution, 0% → 6%, 0.5% increases, 20 mL runs, 7 mL fractions)
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yielded 48 as a white solid (73% yield, 33.0 mg, 0.07 mmol). H NMR (500 MHz,
DMSO-d6/D2O) δ 8.38 (d, J = 4.7 Hz, 2H), 7.89 – 7.83 (m, 2H), 7.80 (d, J = 8.53, 1H),
7.50 (d, J =4.7 Hz, 2H), 7.42 (d, J = 8.53, 2H) 7.10 (d, J = 8.15 Hz, 2H), 5.20 (s, 2H),
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3.37 (s, 3H), 3.19 (s, 3H), 2.66 (s, 3H); 13C{1H} NMR (126 MHz, DMSO-d6/D2O) δ
157.8, 150.0, 145.7, 143.2, 140.6, 139.0, 134.9, 134.4, 131.9, 130.9, 130.5, 130.1, 125.1,
123.8, 121.8, 117.4, 94.5, 56.6, 44.2, 21.6 (Note: extra signals in the 13C{1H} NMR
spectra are due to the presence of tautomers); vmax (cm-1, thin film, ATR): 2925 (w),
1600 (s), 1513 (m), 1491 (w), 1444 (w), 1309 (m), 1238 (m), 1214 (w), 1200 (w), 1143
(s), 1108 (m), 1000 (m), 970 (s), 955 (m), 918 (w), 834 (s), 761 (s), 741 (s); HRMS
(ESI+/TOF) m/z: [M+H]+ Calcd for C24H24N3O4S 450.1487; Found 450.1467; mp:
225.0 – 226.4 °C (MeOH/DCM).
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3-(2-(2-Methyl-4-(methylsulfonyl)phenyl)-5-(pyridin-4-yl)-1H-imidazol-4-
yl)benzenesulfonamide (49). The title compound was prepared according to general
procedure C, using 44 (39.0 mg, 0.10 mmol, 1.00 equiv..), (3-
aminosulfonylphenyl)boronic acid (26.0 mg, 0.125 mmol, 1.25 equiv.), Pd(OAc)2 (2.3
mg, 10 mol%) and Aphos (6.7 mg, 24 mol%). Purification by preparative TLC, eluting
with EtOH in CHCl3 (20 cm x 20 cm plate, 10% EtOH/CHCl3, two runs) yielded 49 as a
white solid (62% yield, 29.0 mg, 0.06 mmol). 1H NMR (500 MHz, DMSO-d6/D2O/TFA)
δ 8.66 (d, J = 6.2 Hz, 2H), 8.06 – 8.01 (m, 3H), 7.99 - 7.90 (m, 3H), 7.89 – 7.84 (m, 2H),
7.75 (t, J = 7.7, 1H) 3.23 (s, 3H), 2.73 (s, 3H); 13C{1H} NMR (126 MHz, DMSO-
d6/D2O/TFA) δ 150.5, 147.5, 145.2, 141.8, 141.3, 139.1, 136.0, 133.6, 133.0, 131.8,
130.8, 130.6, 130.4, 130.0, 127.1, 126.5, 125.0, 123.0, 43.9, 21.5; vmax (cm-1, thin film,
ATR): 3296 (br), 2931 (w), 1606 (m), 1479 (w), 1410 (w), 1342 (m), 1303 (m), 1205
(w), 1161 (s), 1156 (s), 1118 (w), 1079 (w), 1108 (w), 976 (w), 859 (w), 833 (m), 806
(w), 764 (m), 746 (m), 690 (s); HRMS (ESI+/TOF) m/z: [M+H]+ Calcd for
C22H21N4O4S2 469.1004; Found 469.0997; mp: 234.0 – 236.2 °C (EtOH/CHCl3).
N-Cyclopropyl-3-(2-(2-methyl-4-(methylsulfonyl)phenyl)-5-(pyridin-4-yl)-1H-
imidazol-4-yl)benzenesulfonamide (50). The title compound was prepared according to
general procedure C, using 44 (39.0 mg, 0.10 mmol, 1.00 equiv..), 3-
(cyclopropylsulfamoyl)phenylboronic acid (31.0 mg, 0.125 mmol, 1.25 equiv.),
Pd(OAc)2 (2.3 mg, 10 mol%) and Aphos (6.7 mg, 24 mol%). Purification by silica gel
chromatography, eluting with EtOH in CHCl3 (21 cm x 10 mm, gradient elution, 3% →
8%, 0.5% increases, 20 mL runs, 3-4 mL fractions) yielded 50 as a white solid (57% yield,
29.0 mg, 0.06 mmol). 1H NMR (500 MHz, DMSO-d6/D2O/TFA) δ 8.63 (d, J = 6.8 Hz,
2H), 8.02 (d, J = 6.8 Hz, 2H), 7.97-7.84 (m, 6H), 7.79 (t, J = 7.7 1H), 3.21 (s, 3H), 2.70
(s, 3H). 2.15 - 2.09 (m, 1H), 0.51 - 0.45 (m, 2H), 0.41 - 0.36 (m, 2H); 13C{1H} NMR (126
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MHz, DMSO-d6/D2O/TFA) δ 150.6, 147.7, 141.9, 141.7, 141.5, 139.4, 136.1, 133.8,
133.7, 131.9, 131.3, 130.9, 130.8, 130.1, 128.6, 127.7, 125.2, 123.4, 44.1, 24.7, 21.5, 5.9;
vmax (cm-1, thin film, ATR): 3077 (br), 2925 (w), 2835 (w), 1608 (m), 1539 (w), 1475
(w), 1413 (w), 1334 (m), 1318 (m), 1222 (w), 1161 (s), 1119 (w), 1103 (w), 1030 (w),
1008 (w), 961 (m), 890 (w), 836 (m), 765 (w), 695 (m); HRMS (ESI+/TOF) m/z:
[M+H]+ Calcd for C25H25N4O4S2 509.1317; Found 509.1317; mp: 212.7 – 215.7 °C
(EtOH/CHCl3).
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1-Methyl-5-(2-(2-methyl-4-(methylsulfonyl)phenyl)-5-(pyridin-4-yl)-1H-imidazol-
4-yl)-1H-indole (51). The title compound was prepared according to general procedure
C, using 44 (39.0 mg, 0.10 mmol, 1.00 equiv..), N-methylindole-5-boronic acid (22.0 mg,
0.125 mmol, 1.25 equiv.), Pd(OAc)2 (2.3 mg, 10 mol%) and Aphos (6.7 mg, 24 mol%).
Purification by silica gel chromatography, eluting with EtOH in CHCl3 (21 cm x 10 mm,
gradient elution, 0% → 6%, 0.5% increases, 20 mL runs, 3-4 mL fractions) followed by
repurification in silica gel using MeOH in DCM eluent (21 cm x 10 mm, gradient elution,
0% → 6%, 0.5% increases, 20 mL runs, 7 mL fractions) yielded 41 as a white solid (56%
yield, 25.0 mg, 0.06 mmol). Rf = 0.45 (7% EtOH/CHCl3, Dragendorff stain); 1H NMR
(400 MHz, DMSO-d6/D2O/TFA) δ 8.56 (d, J = 7.0 Hz, 2H), 8.04 (d, J = 7.0 Hz, 2H),
7.97 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 1.4 Hz, 1H), 7.86 (dd, J = 1.6, 8.2 Hz, 1H), 7.83
(d, J = 1.2 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 3.0 Hz, 1H), 7.34 (dd, J = 8.5,
1.5 Hz, 1H), 6.54 (d, J = 3.0 Hz, 1H), 3.82 (s, 3H), 3.22 (s, 1H), 2.73 (s, 3H). (Note:
signal at δ 8.09 ppm corresponds to residual CHCl3 in the sample). 13C{1H} NMR (126
MHz, DMSO-d6/D2O/TFA) δ 151.1, 146.5, 141.5, 141.3, 139.5, 139.2, 137.5, 133.5,
131.8, 130.8, 130.6, 130.1, 129.0, 125.1, 122.5, 122.4, 122.0, 119.6, 111.4, 44.0, 33.2,
21.5 (Note: signal at δ 79.5 ppm corresponds to residual CHCl3 in the sample and one
carbon signal missing in the spectra); vmax (cm-1, thin film, ATR): 2914 (w), 2683 (br),
1603 (s), 1507 (w), 1485 (w), 1441 (w), 1430 (w), 1378 (w), 1309 (s), 1286 (w), 1243
(w), 1210 (w), 1154 (s), 1112 (m), 1090 (m), 1071 (w), 1003 (w), 964 (m), 951 (m), 893
(w), 832 (s), 815 (w), 763 (m), 741 (m), 730 (m), 701 (w); HRMS (ESI+/TOF) m/z:
[M+H]+ Calcd for C25H23N4O2S 443.1542; Found 443.1529; mp: 294.0 °C (dec.).
4-(4-(Benzofuran-5-yl)-2-(2-methyl-4-(methylsulfonyl)phenyl)-1H-imidazol-5-
yl)pyridine (52). The title compound was prepared according to general procedure C,
using 44 (39.0 mg, 0.10 mmol, 1.00 equiv.), benzofuran-5-boronic acid (21.0 mg, 0.125
mmol, 1.25 equiv.), Pd(OAc)2 (2.3 mg, 10 mol%) and Aphos (6.7 mg, 24 mol%).
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Purification by silica gel chromatography, eluting with EtOH in CHCl3 (21 cm x 10 mm,
gradient elution, 0% → 6%, 0.5% increases, 20 mL runs, 3-4 mL fractions) followed by
repurification in silica gel using MeOH in DCM eluent (21 cm x 10 mm, gradient elution,
0% → 6%, 0.5% increases, 20 mL runs, 7 mL fractions) yielded 52 as a white solid (59%
yield, 26.0 mg, 0.06 mmol). Rf = 0.45 (7% EtOH/CHCl3, Dragendorff stain); 1H NMR
(500 MHz, DMSO-d6/D2O/TFA) δ 8.57 (d, J = 6.9 Hz, 1H), ), 8.04 – 8.00 (m, 3H), 7.95
(d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.86 (dd, J = 8.5, 1.4 Hz, 1H), 7.76 (d, J =
8.5 Hz, 1H), 7.52 (dd, J = 8.4, 1.8 Hz, 1H), 7.03 (d, J = 1.4 Hz, 1H), 3.21 (s, 3H), 2.72 (s,
3H) (Note: signal at δ 8.09 ppm corresponds to residual CHCl3 in the sample); 13C{1H}
NMR (126 MHz, DMSO-d6/D2O/TFA) δ 155.6, 151.0, 147.9, 146.9, 141.6, 141.4,
139.4, 138.0, 133.7, 131.4, 130.7, 130.1, 128.9, 126.2, 125.2, 124.3, 123.1, 122.8, 113.1,
107.8, 44.1, 21.6 (Note: signal at δ 79.5 ppm corresponds to residual CHCl3 in the
sample); vmax (cm-1, thin film, ATR): 2925 (w), 1601 (s), 1457 (w), 1444 (w), 1307 (m),
1210 (w), 1196 (w), 1150 (s), 1107 (m), 1086 (w), 1070 (w), 956 (m), 869 (w), 833 (m),
763 (s), 743 (s); HRMS (ESI+/TOF) m/z: [M+H]+ Calcd for C24H20N3O3S 430.1225;
Found 430.1207; mp: 232.0 – 233.4 °C (MeOH/DCM).
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4-(4-(Benzo[b]thiophen-5-yl)-2-(2-methyl-4-(methylsulfonyl)phenyl)-1H-
imidazol-5-yl)pyridine (53). The title compound was prepared according to general
procedure C, using 44 (39.0 mg, 0.10 mmol, 1.00 equiv.), 2-(benzo[b]thiophen-5-yl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane39 (S6) (33.0 mg, 0.125 mmol, 1.25 equiv.),
Pd(OAc)2 (2.3 mg, 10 mol%) and Aphos (6.7 mg, 24 mol%). Purification by silica gel
chromatography, eluting with EtOH in CHCl3 (21 cm x 10 mm, gradient elution, 0% →
6%, 0.5% increases, 20 mL runs, 3-4 mL fractions) followed by repurification in silica
gel using MeOH in DCM eluent (21 cm x 10 mm, gradient elution, 0% → 6%, 0.5%
increases, 20 mL runs, 7 mL fractions) yielded 53 as a yellow solid (34% yield, 15.0 mg,
1
0.03 mmol). Rf = 0.45 (7% EtOH/CHCl3, Dragendorff stain); H NMR (500 MHz,
DMSO-d6/D2O/TFA) δ 8.56 (d, J = 6.9 Hz, 2H), 8.16 – 8.12 (m, 2H), 8.04 (d, J = 6.9
Hz, 2H), 7.95 (d, J = 8.2 Hz, 1H), 7.85 (dd, J =8.1, 1.6 Hz, 1H) 7.81 (d, J = 5.4 Hz, 1H),
7.54 (dd, J = 8.5, 1.6 Hz, 1H), 7.52 (d, J = 5.4 Hz, 1H), 3.21 (s, 3H), 2.71 (s, 3H); 13C{1H}
NMR (126 MHz, DMSO-d6/D2O/TFA) δ 151.1, 147.2, 141.7, 141.4, 141.3, 140.8,
139.5, 137.9, 133.8, 131.5, 130.8, 130.2, 129.9, 125.6, 125.5, 125.3, 125.1, 125.0, 124.5,
123.0, 44.1, 21.6; vmax (cm-1, thin film, ATR): 2919 (w), 2853 (w), 1602 (s), 1488 (w),
1434 (m), 1427 (w), 1304 (s), 1213 (w), 1201 (w), 1142 (s), 1103 (m), 1072 (w), 1049
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