Synthesis of Polysubstituted 2-Aminoimidazoles via Alkene-Diamination of Guanidine with Conjugated α-Bromoalkenones

Article abstract of DOI:10.1021/acs.joc.6b03021

A step-economical access to polysubstituted aminoimidazoles has been accomplished via alkene vicinal C-N bonds formation of 2-bromo-2-alkenones with guanidine avoiding its NH-protection/derivatization prerequisite for electronic modulation. The approach has excellent substrate scope, is amenable to diverse guanidine-containing substrates, and introduces distinctive substitutions/functionalities into aminoimidazole core. It is also applicable to preparation of fused-imidazoles. The reaction involves a tandem pathway of aza-Michael addition, S_N2, and a unique redox-neutral process, as evident by spectroscopic study and control experiments.

Full text of DOI:10.1021/acs.joc.6b03021

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Note
Synthesis of polysubstituted 2-aminoimidazoles via alkene-
diamination of guanidine with conjugated #-bromoalkenones
Sankar K. Guchhait, Neha Hura, and Archana P. Shah
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b03021 • Publication Date (Web): 14 Feb 2017
Downloaded from http://pubs.acs.org on February 17, 2017
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Synthesis of polysubstituted 2ꢀaminoimidazoles via alkeneꢀdiamination of guanidine
with conjugated αꢀbromoalkenones
7
8
Sankar K. Guchhait,* Neha Hura and Archana P. Shah
9
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and
Research (NIPER), Sector 67, SAS Nagar (Mohali), Punjab 160062, India, Fax: +91 172
2214692; Tel: +91 172 2214683
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Eꢀmail: skguchhait@niper.ac.in.
ABSTRACT: A stepꢀeconomical access to polysubstituted aminoimidazoles has been
accomplished via alkene vicinal CꢀN bonds formation of 2ꢀbromoꢀ2ꢀalkenones with
guanidine avoiding its NHꢀprotection/derivatization prerequisite for electronic modulation.
The approach has excellent substrate scope, is amenable to diverse guanidineꢀcontaining
substrates, and introduces distinctive substitutions/functionalities into aminoimidazole core. It
is also applicable to preparation of fusedꢀimidazoles. The reaction involves a tandem pathway
of azaꢀMichael addition, SN2, and a unique redoxꢀneutral process, as evident by spectroscopic
study and control experiments.
2ꢀAminoimidazoles are omnipresent in the marineꢀsponge alkaloids1 and
therapeutic/bioactive agents.2 2ꢀAminoimidazole core has an interesting hydrogenꢀbondꢀ
donor/acceptor patterns, and with varied polyꢀsubstitutions/functionalities exhibit diverse
bioactivities, selectivity in enzymeꢀinhibition, and important physicochemical properties.3 In
addition, 2ꢀaminoimidazoles are employed as synthones,4 organocatalysts,5 metalꢀligands,6
and anionꢀrecognizing agents.7 Therefore, the synthesis of highly functionalized 2ꢀ
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aminoimidazole core is of increasing demand. There are two major approaches for
preparation of multiꢀsubstituted 2ꢀaminoimidazoles,8,9 1) the condensation of αꢀhaloketone
with an acetylated guanidine or condensation of an αꢀaminoketone with cyanamide,9,10 and 2)
functionalization of imidazole scaffold via protection, C2ꢀamination, introducing substituents
and deprotection.11 While the first approach is incompetent in introducing important
functionalꢀdiversity and uses unstable precursors, the latter method requires multiꢀstep
reactions. Moreover, the assembly of particular substituents/functionalities into 2ꢀ
aminoimidazoles requires postꢀmodification or use of starting substrates which are not readily
available. 5ꢀAroyl substituted 2ꢀaminoimidazole has been prepared by an olefinicꢀamination
of cyanamide with αꢀazido functionalized chalcone.12 Recently reported methods to access
substituted 2ꢀaminoimidazoles from propargyl guanidine represent a remarkable route
(Scheme 1ꢀA1). They include lanthanideꢀmediated intramolecular hydroamination–
isomerization of propargyl guanidine prepared in situ by amineꢀaddition to propargyl
cyanamide,13 a sequence of guanylation of propargylamines with N,N´ꢀbisꢀBocꢀprotected
thiourea, Ag(I)ꢀmediated 5ꢀexoꢀdig heterocyclization, deprotection and isomerization,14 and a
method of Pdꢀcatalyzed carboamination with aryl triflates.15 Here, we report an approach of
direct assembly of guanidine into a conjugated αꢀbromoketone via alkene vicinal CꢀN bonds
formation, which provides 4ꢀaryl/alkyl and 5ꢀacyl substituted and Nꢀfunctionalized 2ꢀ
aminoimidazoles (Scheme 1ꢀB).
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Scheme 1: Previous and present work
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Intramolecular transfer of various nitrogen sources such as guanidine,16 urea,17 sulfamide,18
oxalimide,17 to alkene via oxidative vicinal diamination with transitionꢀmetal (mostly Pd) or
halogenꢀcatalysis is an active area of research (Scheme 1ꢀA2).19,20,21 The electronic property
of the involved nitrogen atoms as sufficiently nucleophilic in suitable NHꢀprotected forms
(e.g., Tos, Boc, Cbz ) has been found to be crucial.22 In addition, the process is dependent on
nature of alkene, majorly preferred for terminal alkene.23 The use of free guanidine in alkeneꢀ
diamination has never been known, which would produce the 2ꢀaminoimidazole core.24 In
contrast, the reaction of guanidine with α,βꢀunsaturated carbonyls produces 2ꢀ
aminopyrimidines and is considered as a useful method.25 Recently, Hajra et al reported an
alkeneꢀdiamination of conjugated enone with 2ꢀaminobenzthiazole.26 Notably, guanidine in
reaction with 1,3ꢀdiꢀyne undergoes 1,3ꢀdiamination.27 In present work, free guanidine has
been rendered as effective substrate for alkene vicinal CꢀN bonds formation with conjugated
αꢀbromoketone.
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The mechanism of alkeneꢀdiamination by metal or bromide catalysis19,21 involves a related
pathway. The reaction undergoes via vicinal aminoꢀmetalation/bromination, and subsequent
alkyl CꢀN bond formation through SN2 (a concomitant transient metalꢀoxidation taking place
in metalꢀcatalysis). The mechanistic path incited us to identify a substrate suitable for
diamination of free guanidine in a transitionꢀmetalꢀfree process. We considered that α,βꢀ
unsaturated ketone bearing αꢀbromo functionality could be an effective substrate. Vicinal
diamination of guanidine can be obtained by azaꢀMichael addition and subsequently SN2. It is
worth to mention that there is no report of azaꢀMichael addition28 of guanidine to α,βꢀ
unsaturated ketone and, in fact, Nꢀacetylguanidine in a reaction with 2,3ꢀalkenone undergoes
exclusively 1,2ꢀaddition for imine formation.9 Therefore, in the reaction of guanidine with 2ꢀ
bromoꢀ2,3ꢀalkenone, a crucial task is to accomplish switching from imineꢀforming route to a
pathway of azaꢀMichael addition–SN2–oxidation that can produce 2ꢀaminoimidazole.
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We initiated the study for the reaction of αꢀbromochalcone (Eꢀisomer) with guanidine
hydrochloride preꢀtreated with NaH base. Desired 4ꢀarylꢀ5ꢀbenzoylꢀ2ꢀaminoimidazole was
obtained in 40% yield and, however, the side product 2ꢀaminopyrimidine was also produced
in 30% yield. The reaction was found to be nonꢀinfluenced by stereoisomeric (E/Z) aspect of
αꢀbromochalcone, Therefore, E/Zꢀisomer as obtained in preparation following a reported
method29 was utilized as substrate in next experiments. We investigated various bases (table
1, entry 1ꢀ9). K2CO3 was found to be best. On the other hand, addition of a Lewis acid, e.g.,
FeCl3, ZrCl4, or In(OTf)3 resulted in enhanced formation of 2ꢀaminopyrimidine (40ꢀ45%
yields, data not shown) and decreased production of 2ꢀaminoimidazole (25ꢀ33% yields),
evidently indicating a preference for imineꢀforming route. Increased yield of the substituted
2ꢀaminoimidazole as well as diminished formation of side products including 2ꢀ
aminopyrimidine was observed with an optimum enhanced dilution of the reaction mixture
along with elevated temperature. Preꢀtreatment of guanidine·HCl with base was found
unnecessary. Optimal quantity of guanidine and potassium carbonate (3.0 and 3.5 equiv.,
respectively) improved slightly the yield (entries 5, 10, and 11). Interestingly, use of an
oxidizing agent MnO2 boosted the formation of the desired 2ꢀaminoimidazole in significantly
higher yield (entry 10 vs 12). However, other tested oxidizing agents were found to be nonꢀ
efficient for the reaction. Screening of solvents indicated superior efficiency of 1,4ꢀdioxane.
Importantly, 2ꢀaminopyrimidine side product was obtained in trace quantity (3% yield) under
optimized conditions. During these investigations, Li et al reported a reaction of diarylꢀ
amidine and chalcone with FeCl3/I2ꢀcatalysis producing imidazoles, which involved a related
pathway.30 The transformation is limited to NHꢀarylated arylamidine and lowꢀyielding for
alkylamidine, clearly indicating the necessity of sufficient nucleophilicity of nitrogen for CꢀN
bond formations. We evaluated the feasibility of such FeCl3/I2ꢀcatalysis for the present
reaction, however, the substrates remained nearly intact and the desired product did not form.
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This implies that the exceptional behavior of free guanidine as poorly nucleophilic is
responsible for guiding the reactions away from alkeneꢀdiamination pathway. A reaction of
guanidine with chalcone replacing αꢀbromochalcone under optimized conditions was
performed. Desired 2ꢀaminoimidazole did not form and, conversely, 2ꢀaminopyrimidine was
obtained in considerable quantity (40% yield). These indicate that αꢀbromoalkenone as an
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effective substrate as well as optimized conditions enabled the chemoselective vicinal CꢀN
bond formation with free guanidine.
Table 1. Evaluation of reagents and conditionsa
Entry
Guanidine
(equiv)c
Base
Solvent
Oxidant
Yield
( % )b
(equiv)
(anhyd, 5 mL)
1,4ꢀDioxane
1,4ꢀDioxane
(1.5 equiv)
1
2
2
2
2
2
2
2
2
2
3
NaH (2.2)
ꢀ
ꢀ
40
NR
30
25
45
35
40
20
5
2
No base
1,4ꢀDioxane
1,4ꢀDioxane
1,4ꢀDioxane
1,4ꢀDioxane
1,4ꢀDioxane
1,4ꢀDioxane
1,4ꢀDioxane
1,4ꢀDioxane
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
3
KOtBu (2.2)
LiOH (2.2)
K2CO3 (2.2)
Na2CO3 (2.2)
Cs2CO3 (2.2)
DBU (2.2)
4
5
6
7
8
9
DIPEA (2.2)
K2CO3 (3.5)
K2CO3 (4)
10
11
12
13
14
15
16e
17
18
19e
20f
21
22
51
51
70
5
3.5
3
1,4ꢀDioxane
1,4ꢀDioxane
ꢀ
K2CO3 (3.5)
K2CO3 (3.5)
K2CO3 (3.5)
K2CO3 (3.5)
K2CO3 (3.5)
K2CO3 (3.5)
K2CO3 (3.5)
K2CO3 (3.5)
K2CO3 (3.5)
K2CO3 (3.5)
K2CO3 (3.5)
MnO2
DDQ
K2S2O8
TBHPd
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
1,4ꢀDioxane
1,4ꢀDioxane
1,4ꢀDioxane
3
3
20
33
40
35
30
50
20
NR
30
3
3
MeCN
3
DMF
3
DMSO
EtOH
3
3
PEG 400
toluene
DioxaneꢀH2O
(5:1)
3
3
aSubstrates, reagents and conditions: αꢀBromochalcone (0.25 mmol) and
others as mentioned in the table, 100 °C; bYield for maximum conversion
in optimum time; cGuanidine·HCl received commercially was used without
preꢀneutralisation; dTBHP (in decane); eReaction temperature is 80 °C;
f2 mL solvent.
Structure of the product was confirmed by spectroscopies and Xꢀray crystallographic analysis
(Figure 1).
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Figure 1 ORTEP diagram of 4ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀ(3,4,5ꢀtrimethoxybenzoyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine (1a)
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With optimized conditions, we next investigated the generality of the protocol and
preparation of varied 2ꢀaminoimidazole derivatives. We were pleased to find that the method
was found to be flexible in accommodating a variety of substrates (Table 2).
Table 2. Substrate scopea,b
R2
O
NH.HCl
N NH2
K2CO3, MnO2
N
NH2
R2
1,4- dioxane (anhyd. ), 100 °C,
under N2
H2
Br
N
H
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R1
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O
1a-x
MeO
MeO
MeO
N
N
N
N
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NH2
NH2
NH2
NH2
N
N
N
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N
H
H
O
H
MeO
O
O
O
1b, 60%
1c, 65%
1d, 58%
1a,70%
NC
H3
C
N
N
N
H3
C
N
Cl
Br
NH2
NH2
NH2
NH2
N
N
N
H
N
H
H
O
H
O
O
O
1e, 55%
1f, 58%
1g, 61%
1h, 60%
Cl
MeO
MeO
N
N
N
N
MeO
MeO
O2
N
NH2
NH2
NH2
NH2
NH
N
H
N
H
N
MeO
MeO
H
O
O
O
O
1i, 55%
1j, 68%
1k, 65%
1l, 60%
OMe
H3
C
BnO
MeO
F
MeO
MeO
MeO
N
N
N
N
MeO
NH2
MeO
MeO
MeO
NH2
NH2
NH2
N
H
N
H
N
H
N
H
MeO
MeO
MeO
MeO
O
O
O
O
1n, 65%
1o, 60%
1p, 70%
1m, 58%
OMe
OMe
OMe
OBn
OMe
MeO
MeO
MeO
MeO
MeO
MeO
MeO
N
N
N
N
MeO
MeO
MeO
NH2
NH2
NH2
NH2
N
N
H
N
N
H
H
H
MeO
MeO
MeO
O
O
O
O
1r, 55%
1s, 65%
1t, 60%
1q, 75%
OMe
MeO
MeO
MeO
MeO
MeO
MeO
N
N
S
N
N
N
N
MeO
MeO
MeO
NH2
NH2
NH2
NH2
MeO
N
N
H
N
H
N
H
MeO
MeO
MeO
H
O
O
O
MeO
O
1v, 58%
1w, 56%
1x,60%
1u, 65%
aSubstrates, reagents and conditions: αꢀbromochalcone (0.5 mmol), guanidine
HCl (3 equiv), K2CO3 (3.5 equiv), MnO2 (1.5 equiv), 1,4ꢀDioxane (anhyd.,8 mL),
100 °C; bYield for maximum conversion in optimum time.
2ꢀBromoalkenones containing electronꢀdonating or withdrawing functionalities were
compatible. In general, electron donating functionalities provided relatively higher yields
compared to the electron withdrawing groups. Heterocyclic αꢀbromochalcones were
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congruent to this protocol. Aliphatic ketone substrate underwent diamination smoothly. The
presence of biologically relevant (hetero)aryl motifs in the substrates were also compatible in
the reaction.
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Table 3. Substrate scopea,b
aSubstrates, reagents and conditions: αꢀbromochalcone (0.5 mmol), guanidine
containing motifs (3 equiv), K2CO3 (3.5 equiv), MnO2 (1.5 equiv), 1,4ꢀDioxane
(anhyd., 8 mL), 100 °C; bYield for maximum conversion in optimum time.
We were then interested to investigate the method’s applicability to versatile guanidineꢀ
containing motifs (Table 3). Delightfully, the reaction underwent smoothly with
Nꢀ
amino/cyano/arylꢀsubstituted guanidines. Interestingly, the reaction for these nonꢀ
symmetrical guanidines was found to be chemoselective and only one product was obtained.
The structure of these regioisomeric products were unambiguously confirmed by their
spectroscopic data. The products indicated that functionalized amineꢀnitrogen site underwent
Michael addition with chalcones. The products obtained using these guanidineꢀcontaining
motifs are biologically important. In case of 2ꢀaminobenzimidazole also, desired imidazoleꢀ
fused scaffold was obtained, albeit the formation of fused pyrimidine via imineꢀforming route
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in significant quantity was observed. Such ringꢀannulation of alkene is attractive and has
potential application, since 2ꢀaminoimidazole motif is omnipresent in marineꢀbased NPs,
drugs and bioactive agents, and the fused heterocyclic products are biologically important.31
The protocol proved also to be amenable to a scaleꢀup synthesis (investigated up to 5 mmol)
without significant decrease in yield. In contrast to the conventional/classical methods known
for synthesis of the title compounds, the present approach is stepꢀeconomical and convenient,
uses easily accessible and economical starting substrates, and has an excellent substrate
scope. More importantly, substitutions/functionalities distinctive from literature have been
introduced easily into the 2ꢀaminoimidazole ring.
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Scheme 2: Plausible mechanism
We were then interested in gaining insight to the possible mechanism. Under optimized
conditions or lowering the temperature, none of the intermediate formed in isolable quantity.
In correlation with literature, it is expected that vicinal CꢀN bonds formation occurred
possibly via Michael addition–SN2 process.30,32 A control reaction without MnO2 under
otherwise identical conditions (entry 10 vs 12, Table 1) produced desired product, 4ꢀ(4ꢀ
methoxyphenyl)ꢀ5ꢀ(3,4,5ꢀtrimethoxybenzoyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine (1a) in significant yield
(51%). Another control reaction without MnO2 in the second most effective solvent EtOH
produced also the desired product (1a) in 30% yield. These clearly suggest that the
conversion of imidazoline to imidazole, subsequent to vicinal CꢀN bonds formation, did not
involve direct dehydrogenative oxidation by MnO2. In the reaction, chalcones were obtained
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in trace quantity, ruling out the possibility of intermolecular hydrogen transfer from
imidazoline to bromochalcones. On the other hand, interestingly, use of MnO2 significantly
enhanced the yield of 2ꢀaminoimidazole (51% to 70% yield, entry 10 vs 12). Mass
spectrometry of crude mixture obtained at interval time for multiple experiments was studied
(see SI). The characteristic peaks agreeably indicated the formation of pertinent intermediates
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(A
,
B,
C
; Scheme 2) and an unprecedented internal redoxꢀneutral process involved in the
generation of 4ꢀarylꢀ5ꢀaroylꢀ1 ꢀimidazoleꢀ2ꢀamine. MnO2 oxidizes methanetriamine to
H
generate back guanidine. For conversion of imidazoline to imidazole, this redoxꢀneutral
process is distinctive, while the dehydrogenative oxidation29 is usual method.
In conclusion, we have developed an unprecedented alkeneꢀvicinal CꢀN bonds formation of
conjugated αꢀbromoketone with guanidine avoiding its electronicꢀmodulation, which affords
an efficient route to polyꢀsubstituted/functionalized 2ꢀaminoimidazoles. The reaction
proceeds via a tandem pathway of azaꢀMichael addition, SN2, and a unique redoxꢀneutral
process, a new pathway switched from literatureꢀknown route of producing 2ꢀ
aminopyrimidines. For synthesis of the title compounds, the present approach has several
attributes, stepꢀeconomy, convenient procedure, excellent substrate scope, introduction of
distinctive substitutions/functionalities into 2ꢀaminoimidazole core, and use of
economical/easilyꢀaccessible starting substrates and reagents. Moreover, the present strategy
can provide impetus of investigating alkeneꢀdiamination of other frequently used nitrogen
sources without their electronic modulation.
Experimental
General Information: ATR & IR (KBr) Microscope spectrometer was used to record
1
Infrared (IR) spectra. H NMR spectra were measured on a 400 MHz spectrometer. Data
were reported as follows: chemical shifts in ppm from tetramethylsilane as an internal
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standard in CDCl3/DMSOꢀ
d
6 integration, multiplicity (s = singlet, d = doublet, t = triplet, q =
5
6
quartet, m = multiplet, dt = doublet of triplet, dd = doublet of doublet, br = broad), and
7
8
13
coupling constants (Hz). C NMR spectra were measured on a 100 MHz spectrometer with
9
complete proton decoupling. Chemical shifts were reported in ppm. Highꢀresolution mass
spectra (HRMS) were performed on a highꢀresolution LCMS/MS instrument with “QTOF”
mass analyzer. For thinꢀlayer chromatography (TLC) analysis throughout this work,
commerically supplied precoated TLC plates (silica gel 60 GF434, 0.43 mm) were used. The
products were purified by column chromatography silica gel 100−200 (silica gel 100−200
mesh, neutral, spherical).The starting materials and solvents were used as received from
commercially without further purification.
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Representative experimental procedure for synthesis of 4ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀ(3,4,5ꢀ
trimethoxybenzoyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine (1a): αꢀBromochalcone (E/Zꢀmixture, 0.5
mmol), guanidine·HCl (1.5 mmol, 143 mg, 3 equiv), K2CO3 (1.75 mmol, 242 mg, 3.5 equiv),
and manganese dioxide (0.75 mmol, 65 mg, 1.5 equiv) were taken under nitrogen in an ovenꢀ
dried sealed tube equipped with a rubber septum and magnetic bar. Dioxane (anhyd., 8 mL)
was added under nitrogen. The tube was then sealed. The mixture was stirred at 100 °C and
the reaction was monitored by TLC. The reaction after 16 h was allowed to cool to room
temperature and diluted with EtOAcꢀMeOH (1:1, 60 mL). The resultant mixture was filtered
through celite and concentrated under reduced pressure. The column chromatographic
purification of crude mass was performed on silica gel (100ꢀ200 mesh) partiallyꢀdeacidified
by passing triethylamine (1−4 mL) using MeOHꢀEtOAc (5:95) as eluting solvent. It provided
4ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀ(3,4,5ꢀtrimethoxybenzoyl)ꢀ1
70%).
Hꢀimidazoleꢀ2ꢀamine (1a) (134 mg,
Products (1bꢀx, Table 2) were prepared following this representative procedure.
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Products (2aꢀf, Table 3) were also prepared following this representative procedure. In the
method, guanidineꢀcontaining motifs were used in place of guanidine·HCl.
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Characterization data of the synthesized compounds (1aꢀx, 2aꢀf)
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4ꢀ(4ꢀMethoxyphenyl)ꢀ5ꢀ(3,4,5ꢀtrimethoxybenzoyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine (1a): Yellow
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solid; 134 mg, 70%, mp >200 °C; 1H NMR (400 MHz, DMSOꢀ
d6): δ 10.91 ( s, NH), 7.16 (d,
J
= 8.1 Hz, 2H), 6.7 ( s, 2H), 6.67 (d,
J = 8.3 Hz, 2H), 5.98 (s, 2H ), 3.68 (s, 3H), 3.62 (s,
3H), 3.54 (s, 6H) ppm; 13C{1H} NMR (100 MHz, CDCl3)):
δ
181.8, 158.6, 152.8, 152.1,
148.5, 139.6, 133.8, 130.4, 127.4, 121.3, 112.6, 106.2, 59.9, 55.4, 55.0 ppm; IR (KBr): νmax
3422, 2922, 1654, 1561, 1514, 1387, 1250, 1123 cmꢀ1; HRMS (ESI) m/z : calcd for
C20H22N3O5 [M + H]+ 384.1559, found: 384.1550.
5ꢀBenzoylꢀ4ꢀphenylꢀ1Hꢀimidazoleꢀ2ꢀamine (1b): Yellow solid; 79 mg, 60%; mp >200 °C;
1H NMR (400 MHz, DMSOꢀ
d
6):
δ
11.01 ( s,
N
H), 7.39ꢀ7.34 (m, 3H), 7.24ꢀ7.07 ( m, 7H),
6): 183.6, 153.4, 149.4, 139.5, 135.1,
13
6.02 (s,2H) ppm; C{1H} NMR (100 MHz, DMSOꢀ
d
δ
131.3, 129.6, 129.1, 128.2, 127.9, 127.8, 122.4 ppm; IR(KBr): νmax 3425, 3061, 1650, 1551,
1528, 1381, 1299, 1171 cmꢀ1; HRMS (ESI) m/z : calcd for C16H14N3O [M + H]+ 264.1137,
found: 264.1138.
5ꢀBenzoylꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine (1c): Yellow solid; 95 mg, 65%;
1
mp >200 °C; H NMR (400 MHz, DMSOꢀ
d
6):
δ
10.83 ( s,
N
H), 7.40 (d,
J
= 7.08 Hz, 2H),
= 7.6 Hz, = 7.6
7.35 ( dd,
Hz, 2H), 6.63 (d,
DMSOꢀ 6):
J
= 7.4 Hz,
J
= 7.4 Hz, 1H), 7.25 (d,
J
= 8.8 Hz, 2H), 7.21(dd,
J
J
13
J
= 8.8 Hz, 2H), 5.98 (s,2H), 3.68 (s, 3H) ppm; C{1H} NMR (100 MHz,
d
δ
183.3, 159.2, 153.3, 149.4, 139.7, 131.1, 130.9, 128.9, 128.3, 127.4, 121.9,
113.3, 55.5 ppm; IR (KBr): νmax 3409, 2997, 1648, 1543, 1508, 1383, 1247, 1170 cmꢀ1;
HRMS (ESI) m/z : calcd for C17H16N3O2 [M + H]+ 294.1242, found: 294.1245
5ꢀBenzoylꢀ4ꢀ(4ꢀchlorophenyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine (1d): Yellow solid; 86 mg, 58%; mp
>200 °C; 1H NMR (400 MHz, DMSOꢀ
d6): δ 11.05 ( s, NH), 7.43ꢀ 7.38 (m, 3H), 7.32 ( d, J =
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8.0 Hz, 2H), 7.23 (dd,
J
= 7.2 Hz,
J
= 7.1 Hz, 2H), 7.13(d,
J = 8.0 Hz, 2H), 6.05 (s,2H) ppm;
13C{1H} NMR (100 MHz, DMSOꢀ
d
6): 183.5, 153.4, 147.9, 139.5, 133.9, 132.5,131.4,
δ
7
8
9
131.2, 129.1, 128.3, 127.8, 122.5 ppm; IR (KBr): νmax 3442, 2923, 1662, 1546, 1527, 1379,
1264, 1180, 738 cmꢀ1; HRMS (ESI) m/z : calcd for C16H1335ClN3O [M + H]+ 298.0747,
found: 298.0741.
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5ꢀBenzoylꢀ4ꢀ(4ꢀcyanophenyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine (1e): Yellow solid; 79 mg, 55%; mp
>200 °C; 1H NMR (400 MHz, DMSOꢀ
d
6):
δ
11.19 ( s,
= 7.9 Hz,
183.7, 153.5, 146.8, 139.7, 139.3, 131.7, 130.2,
N
H), 7.54 (d,
J = 8.5 Hz, 2H), 7.49 ( d,
J
= 8.4 Hz, 2H), 7.44 – 7.39 (m, 3H), 7.24 (dd,
J
J
= 7.4 Hz, 2H), 6.09 (s,2H) ppm;
13C{1H} NMR (100 MHz, DMSOꢀ
d
6):
δ
129.1, 128.4, 123.2, 119.3, 110.0 ppm; IR (KBr): νmax 3423, 3074, 2225, 1654, 1552, 1510,
1373, 1268, 1172 cmꢀ1; HRMS (ESI) m/z : calcd for C17H13N4O [M + H]+ 289.1089, found:
289.1082.
5ꢀ(4ꢀMethylbenzoyl)ꢀ4ꢀphenylꢀ1Hꢀimidazoleꢀ2ꢀamine (1f): Yellow solid; 80 mg, 58%; mp
>200 °C; 1H NMR (400 MHz, DMSOꢀ
d
6):
δ
10.96 ( s,
= 7.7 Hz, 2H), 6.00 (s, 2H), 2.24 (s, 3H) ppm;
183.4, 153.2, 148.7, 141.3, 136.8, 135.2, 129.6,
NH), 7.32 (d, J = 8.1 Hz, 2H), 7.30 (d,
J
= 8.0 Hz, 2H), 7.14 – 7.07 (m, 3H), 6.99 (d, J
13C{1H} NMR (100 MHz, DMSOꢀ
d
6):
δ
129.3, 128.8, 127.8, 122.3, 21.4 ppm; IR (KBr): νmax 3432, 3296, 3060, 1654, 1579 cmꢀ1;
HRMS (ESI) m/z : calcd for C17H16N3O [M + H]+ 278.1293, found: 278.1201.
5ꢀ(4ꢀChlorobenzoyl)ꢀ4ꢀ(pꢀtolyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine (1g): Yellow solid; 95 mg, 61%;
mp >200 °C; 1H NMR (400 MHz, DMSOꢀ
d
6):
= 7.7 Hz, 2H), 6.91 (d,
6): 181.9, 153.6, 150.1, 138.4, 137.3, 135.8,
δ
11.01 ( s,
NH), 7.38 (d, J = 8.2 Hz, 2H), 7.22
(d,
J
= 8.2 Hz, 2H), 7.15 (d,
J
J
= 7.7 Hz, 2H), 6.08 (s, 2H), 2.22 (s,
13
3H) ppm; C{1H} NMR (100 MHz, DMSOꢀ
d
δ
132.1, 130.9, 129.6, 128.4, 128.2, 122.1, 21.2 ppm; IR (KBr): νmax 3441, 3246, 3094, 1654,
1576, 753 cmꢀ1; HRMS (ESI) m/z : calcd for C17H15ClN3O [M + H]+ 312.0903,
found:312.0749.
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5ꢀ(4ꢀBromobenzoyl)ꢀ4ꢀphenylꢀ1Hꢀimidazoleꢀ2ꢀamine (1h): Yellow solid; 103 mg, 60%;
mp >200 °C; 1H NMR (400 MHz, DMSOꢀ
d
6):
δ 11.09 ( s, NH), 7.34 (d, J = 7.9 Hz, 2H), 7.30
7
8
(d,
J
= 8.0 Hz, 2H), 7.23 (d,
J
= 7.2 Hz, 2H), 7.19 – 7.08 (m, 3H), 6.12 (s, 2H) ppm; 13C{1H}
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NMR (100 MHz, DMSOꢀ
d
6):
δ 181.5, 153.1, 149.5, 138.1, 134.4, 130.5, 129.2, 127.4, 127.2,
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124.1,121.7 ppm; IR (KBr): νmax 3433, 3412, 3261, 3059, 2924, 1651, 1576 cmꢀ1; HRMS
(ESI) m/z : calcd for C16H13BrN3O [M + H]+ 342.0242, found: 342.0028.
5ꢀ(4ꢀNitrobenzoyl)ꢀ4ꢀphenylꢀ1Hꢀimidazoleꢀ2ꢀamine (1i): Yellow solid; 85mg, 55%; mp
>200 °C; 1H NMR (400 MHz, DMSOꢀ
d
6):
δ
11.24 ( s,
= 7.2 Hz,
6): δ 180.9, 154.3, 151.7, 148.4, 145.6, 134.7,
N
H), 7.94 (d,
J = 8.2 Hz, 2H), 7.55 (d,
J
= 8.2 Hz, 2H), 7.19 – 7.11 (m, 3H), 7.04 (dd,
J
J
= 7.1 Hz, 2H), 6.256 (s, 2H)
ppm; 13C{1H} NMR (100 MHz, DMSOꢀ
d
130.3, 129.8, 128.2, 127.8, 123.2, 122.6 ppm; IR (KBr): νmax 3416, 3250, 3059, 1653, 1552,
1533 cmꢀ1; HRMS (ESI) m/z : calcd for C16H13N4O3 [M + H]+ 309.0987, found: 309.0978.
5ꢀAcetylꢀ4ꢀphenylꢀ1Hꢀimidazoleꢀ2ꢀamine (1j): Yellow solid; 68 mg, 68%; mp: charred at
138–140 °C; 1H NMR (400 MHz, DMSOꢀ
7.33 (m, 3H), 5.88 (s,2H), 2.08 (s, 3H) ppm; C{1H} NMR (100 MHz, DMSOꢀ
d6): δ 10.89 (s, NH), 7.65 (d, J = 6.8 Hz, 2H), 7.41ꢀ
13
d
6): δ 157.1,
134.4, 133.2, 133.0, 32.6 ppm; IR (KBr): νmax 3440, 3224, 3063, 1646, 1574, 1538, 1385,
1323 cmꢀ1; HRMS (ESI) m/z : calcd for C11H12N3O [M + H]+ 202.0980, found: 202.0981.
4ꢀPhenylꢀ5ꢀ(3,4,5ꢀtrimethoxybenzoyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine (1k): Yellow solid; 115 mg,
65%; mp >200 °C; 1H NMR (400 MHz, DMSOꢀ
(m, 3H), 6.74 (s, 2H), 6.02 (s,2H), 3.61 (s, 3H), 3.52 (s, 6H ) ppm; 13C{1H} NMR (100 MHz,
d6): δ 7.23 (d, J = 7.0 Hz, 2H), 7.16 – 7.09
DMSOꢀd6): δ 182.9, 153.2, 152.6, 140.5, 135.2, 134.2, 129.7, 127.8, 127.7, 107.0, 60.4, 55.9
ppm; IR (KBr): νmax 3433, 3278, 2937, 1660, 1584, 1549, 1531, 1375, 1234, 1126 cmꢀ1;
HRMS (ESI) m/z : calcd for C19H20N3O4 [M + H]+ 354.1454, found: 354.1458.
4ꢀ(4ꢀChlorophenyl)ꢀ5ꢀ(3,4,5ꢀtrimethoxybenzoyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine (1l): Yellow
1
solid; 116 mg, 60%; mp >200 °C; H NMR (400 MHz, DMSOꢀ
d
6):
δ
11.13 (s,
N
H), 7.21 (d,
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= 7.0 Hz, 2H), 7.15 (d,
J
= 7.6 Hz, 2H), 6.68 (s, 2H), 6.04 (s,2H), 3.62 (s, 3H), 3.56 (s, 6H )
ppm; 13C{1H} NMR (100 MHz, DMSOꢀ
d6): δ 182.7, 153.4, 152.7, 147.8, 140.5, 134.3,
7
8
9
132.5, 131.2, 127.7, 122.5, 106.9, 60.6, 56.1 ppm; IR (KBr): νmax 3437, 3301, 3235, 2936,
1646, 1583, 1561, 1533, 1382, 1236, 1125, 732 cmꢀ1; HRMS (ESI) m/z : calcd for
C19H1935ClN3O4 [M + H]+ 388.1064, found: 388.1056.
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4ꢀ(4ꢀFluorophenyl)ꢀ5ꢀ(3,4,5ꢀtrimethoxybenzoyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine (1m): Yellow
solid; 108 mg, 58%; mp >200 °C; 1H NMR (400 MHz, DMSOꢀ
d6): δ 11.11 (s, NH), 7.20 (s,
2H), 6.91 (dd,
J = 8.2 Hz, J = 8.1 Hz, 2H), 6.66 (s, 2H), 6.03 (s,2H), 3.59 (s, 3H), 3.54 (s, 6H
) ppm; 13C{1H} NMR (100 MHz, DMSOꢀ
d
6):
δ
187.7, 166.7 (d,
J
CꢀF = 244 Hz), 158.1, 157.4,
152.9, 145.1, 138.9, 136.3 (d, JCꢀCꢀCꢀF = 8 Hz), 127.1, 119.4 (d, JCꢀCꢀF = 21 Hz ), 111.6, 65.2,
60.8 ppm; IR (KBr): νmax 3449, 3318, 2924, 1634, 1581, 1558, 1507, 1144, 1222, 1124 cmꢀ1;
HRMS (ESI) m/z : calcd for C19H19FN3O4 [M + H]+ 372.1359, found: 372.1356.
4ꢀ(pꢀTolyl)ꢀ5ꢀ(3,4,5ꢀtrimethoxybenzoyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine (1n): Yellow solid; 120
1
mg, 65%; mp >200 °C; H NMR (400 MHz, DMSOꢀ
d
6):
δ
10.97 (s,
NH), 7.09 (d,
J
= 7.6
Hz, 2H), 6.90 (d,
J = 7.6 Hz, 2H), 6.68 (s, 2H), 5.98 (s,2H), 3.60 (s, 3H), 3.51 (s, 6H ), 2.19
(s, 3H) ppm; 13C{1H} NMR (100 MHz, DMSOꢀ
d
6): δ 187.3, 158.1, 157.4, 153.9, 145.2,
141.8, 139.1, 137.4, 134.3, 133.0, 126.9, 111.7, 65.2, 60.7, 25.9 ppm; IR (KBr): νmax 3437,
3316, 2938, 1643, 1580, 1538, 1383, 1235, 1125 cmꢀ1; HRMS (ESI) m/z : calcd for
C20H22N3O4 [M + H]+ 368.1610, found: 368.1601.
4ꢀ(3ꢀMethoxyphenyl)ꢀ5ꢀ(3,4,5ꢀtrimethoxybenzoyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine (1o): Yellow
1
solid; 115 mg, 60%; mp >200 °C; H NMR (400 MHz, DMSOꢀ
d
6):
δ
11.06 (s,
N
H), 7.06
(dd,
J = 7.8 Hz, J = 7.7 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H), 6.71ꢀ 6.64 (m, 4H), 6.03 (s,2H),
3.60 (s, 3H), 3.52 (s, 6H ), 3.49 (s, 3H ) ppm; 13C{1H} NMR (100 MHz, DMSOꢀ
d
6): δ 182.6,
158.8, 153.4, 152.6, 148.9, 140.4, 136.8, 134.4, 128.8, 122.4, 121.9, 114.6, 114.5, 106.9,
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60.3, 55.9, 55.1 ppm; IR (KBr): νmax 3427, 3225, 2923, 1644, 1553, 1499, 1376, 1233, 1124
cmꢀ1; HRMS (ESI) m/z : calcd for C20H22N3O5 [M + H]+ 384.1559, found: 384.1555.
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8
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4ꢀ(4ꢀ(Benzyloxy)phenyl)ꢀ5ꢀ(3,4,5ꢀtrimethoxybenzoyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine
(1p):
H),
1
Yellow solid; 161 mg, 70%; mp >200 °C; H NMR (400 MHz, DMSOꢀ
d
6):
δ
10.93 (s,
N
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11
12
13
14
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7.39–7.30 (m, 5H), 7.15 (d,
J = 8.1 Hz, 2H), 6.75 (d, J = 8.2 Hz, 2H), 6.69 (s, 2H), 5.98
(s,2H), 5.03 (s, 2H), 3.61 (s, 3H), 3.51 (s, 6H) ppm; 13C{1H} NMR (100 MHz, DMSOꢀ
d
6): δ
181.8, 157.7, 152.8, 152.0, 148.3, 139.7, 136.9, 133.8, 130.4, 128.3, 127.7, 127.3, 121.2,
113.5, 106.3, 69.0, 59.9, 55.4 ppm; IR (KBr): νmax 3422, 3230, 2923, 1656, 1552, 1514,
1386, 1232, 1129 cmꢀ1; HRMS (ESI) m/z : calcd for C26H26N3O5 [M + H]+ 460.1872, found:
460.1865.
4ꢀ(3,4ꢀDimethoxyphenyl)ꢀ5ꢀ(3,4,5ꢀtrimethoxybenzoyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine
(1q):
H),
1
Yellow solid; 155 mg, 75%, mp >200 °C; H NMR (400 MHz, DMSOꢀ
d
6):
δ
10.95 (s,
N
6.94 (d,
J = 8.0 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 6.72 (s, 2H), 6.61 (s, 1H), 6.00 (s,2H),
3.69 (s, 3H), 3.60 (s, 3H ), 3.53 (s, 6H ), 3.42 (s, 3H) ppm; 13C{1H} NMR (100 MHz,
DMSOꢀd6): δ 182.5, 153.3, 152.6, 149.2, 148.8, 148.0, 140.3, 134.5, 128.1, 121.9, 113.8,
111.5, 106.9, 60.4, 56.0, 55.9, 55.3 ppm; IR (KBr): νmax 3432, 3245, 2939, 1640, 1540,
1514, 1253, 1231, 1126 cmꢀ1; HRMS (ESI) m/z : calcd for C21H24N3O6 [M + H]+ 414.1665,
found: 414.1665.
4ꢀ(2,5ꢀDimethoxyphenyl)ꢀ5ꢀ(3,4,5ꢀtrimethoxybenzoyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine
(1r):
H),
= 8.9
1
Yellow solid; 114 mg, 55%; mp >200 °C; H NMR (400 MHz, DMSOꢀ
d
6):
δ
11.03 (s,
N
6.89 (d,
J = 2.9 Hz, 1H), 6.69 (dd, J = 8.9 Hz, J = 2.9 Hz, 1H), 6.64 (s, 2H), 6.48 (d, J
Hz, 1H), 5.95 (s, 2H), 3.64 (s, 3H), 3.56 (s, 3H ), 3.52 (s, 6H ), 3.16 (s, 3H) ppm; C{1H}
13
NMR (100 MHz, DMSOꢀd6): δ 182.5, 152.8, 152.4, 151.5, 149.9, 143.3, 139.3, 134.1, 125.3,
122.7, 115.7, 114.1, 110.8, 105.2, 59.7, 55.2, 54.6 ppm; IR (KBr): νmax 3432, 3245, 2922,
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1639, 1580, 1503, 1252, 1230, 1124 cmꢀ1; HRMS (ESI) m/z : calcd for C21H24N3O6 [M + H]+
414.1665, found: 414.1657.
6
7
8
4ꢀ(3ꢀ(Benzyloxy)ꢀ4ꢀmethoxyphenyl)ꢀ5ꢀ(3,4,5ꢀtrimethoxybenzoyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine
9
(1s) : Yellow solid; 159 mg, 65%; mp >200 °C; 1H NMR (400 MHz, DMSOꢀ
d6): δ 11.04 (s,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
H), 7.39 – 7.29 (m, 5H), 6.98 (dd, = 8.4 Hz, = 1.6 Hz, 1H), 6.83 ( d, = 8.4 Hz, 1H ),
J
J
J
6.70 (s, 2H), 6.55 (s, 1H), 6.01 (s,2H), 4.51 (s, 2H ), 3.68 (s, 3H), 3.55 (s, 3H), 3.49 (s, 6H)
ppm; 13C{1H} NMR (100 MHz, DMSOꢀ
d
6): δ 182.9, 153.1, 152.6, 149.1, 147.1, 140.3,
137.1, 134.3, 128.9, 128.4, 127.9, 122.2, 115.3, 111.8, 106.8, 69.9, 60.5, 56.1, 55.9 ppm; IR
(KBr): νmax 3432, 3322, 2936, 1639, 1583, 1508, 1384, 1253, 1134 cmꢀ1; HRMS (ESI) m/z :
calcd for C27H28N3O6 [M + H]+ 490.1978, found: 490.1970.
5ꢀBenzoylꢀ4ꢀ(3,4,5ꢀtrimethoxyphenyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine (1t): Yellow solid; 106 mg,
1
60%; mp >200 °C; H NMR (400 MHz, DMSOꢀ
d
6):
δ
10.98 ( s,
NH), 7.41 (d, J = 7.2 Hz,
2H), 7.35 ( dd,
J
= 7.4 Hz,
J
= 7.4 Hz, 1H), 7.20 (dd,
J
= 7.6 Hz, J = 7.6 Hz, 2H), 6.56 (s,
2H), 6.06 (s,2H), 3.58 (s, 3H ), 3.50 (s, 6H ) ppm; C{1H} NMR (100 MHz, DMSOꢀ
d
6): δ
13
183.3, 153.3, 152.3, 149.1, 139.7, 137.5, 131.3, 130.3, 129.2, 128.1, 122.3, 107.2, 60.4, 55.8
ppm; IR (KBr): νmax 3397, 3316, 2923, 1654, 1587, 1500, 1377, 1229, 1125 cmꢀ1; HRMS
(ESI) m/z : calcd for C19H20N3O4 [M + H]+ 354.1454, found: 354.1447.
4ꢀ(3,4,5ꢀTrimethoxyphenyl)ꢀ5ꢀ(3,4,5ꢀtrimethoxybenzoyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine
(1u):
H),
1
Yellow solid; 144 mg, 65%; mp >200 °C; H NMR (400 MHz, DMSOꢀ
d
6):
δ
11.05 (s,
N
6.70 (s, 2H), 6.47 (s, 2H), 6.05 (s,2H), 3.60 (s, 3H), 3.58 (s, 3H), 3.55 (s, 6H), 3.52 (s, 6H)
ppm; 13C{1H} NMR (100 MHz, DMSOꢀ
d
6): δ 182.6, 153.4, 152.6, 152.4, 140.3, 137.5,
134.6, 130.8,122.3, 107.2, 106.8, 60.3, 60.2, 55.9, 55.8 ppm; IR (KBr): νmax 3422, 3175,
2928, 1638, 1582, 1505, 1381, 1232, 1123 cmꢀ1; HRMS (ESI) m/z : calcd for C22H26N3O7 [M
+ H]+ 444.1771, found: 444.1764.
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4ꢀ(Pyridinꢀ3ꢀyl)ꢀ5ꢀ(3,4,5ꢀtrimethoxybenzoyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine (1v): Yellow solid;
1
103 mg, 58%; mp >200 °C; H NMR (400 MHz, DMSOꢀ
d
6):
δ
11.24 (s,
N
H), 8.39 (s, 1H),
7
8
8.33 (dd,
J = 4.8 Hz, J = 1.5 Hz, 1H), 7.59 (d, J = 7.3 Hz, 1H), 7.17 (dd, J = 7.7 Hz, J = 4.8
9
Hz, 1H), 6.75 (s, 2H), 6.10 (s,2H), 3.62 (s, 3H), 3.56 (s, 6H) ppm; 13C{1H} NMR (100 MHz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
DMSOꢀ
d
6):
δ
182.7, 153.6, 152.7, 149.9, 148.5, 140.5, 136.5, 134.0, 131.2, 122.9, 106.9,
max 3329, 3178, 2926, 1650, 1609, 1568, 1412, 1339,1301,1230,
60.4, 56.1 ppm; IR (KBr):
ν
1124 cmꢀ1; HRMS (ESI) m/z : calcd for C18H19N4O4 [M + H]+ 355.1406, found: 355.1396.
4ꢀ(Thiophenꢀ2ꢀyl)ꢀ5ꢀ(3,4,5ꢀtrimethoxybenzoyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine (1w): Yellow
solid; 101 mg, 56%; mp >200 °C; 1H NMR (400 MHz, DMSOꢀ
d6): δ 10.84 (s, NH), 7.46 (d,
J
= 4.8 Hz, 1H), 7.42 (d,
J = 2.7 Hz, 1H), 6.93ꢀ6.89 (m, 3H), 6.05 (s,2H), 3.72 (s, 6H), 3.71
(s, 3H) ppm; 13C{1H} NMR (100 MHz, DMSOꢀ
d
6): δ 181.2, 152.5, 142.1, 140.0,
137.6,134.4, 127.4, 127.1, 126.8, 120.5, 105.9, 60.1, 55.7 ppm; IR (KBr): νmax 3245, 2959,
1637, 1500, 1380, 1263, 1124 cmꢀ1; HRMS (ESI) m/z : calcd for C17H18N3O4S [M + H]+
360.1018, found: 360.1014.
4ꢀ(Quinolinꢀ3ꢀyl)ꢀ5ꢀ(3,4,5ꢀtrimethoxybenzoyl)ꢀ1Hꢀimidazoleꢀ2ꢀamine (1x): Yellow solid;
121 mg, 60%; mp >200 °C; 1H NMR (400 MHz, DMSOꢀ
Hz, 1H), 8.13 (s, 1H), 7.90 (d, = 8.4 Hz, 1H), 7.74 (d,
d
6):
δ
11.32 (s,
NH), 8.74 (d,
J = 1.4
J
J
= 8.0 Hz, 1H), 7.68 (dt, J
= 6.9 Hz,
J
= 1.2 Hz, 1H), 7.52 (dd,
J = 7.2 Hz, J = 7.2 Hz, 1H), 6.78 (s, 2H), 6.15 (s,2H), 3.48 (s, 6H),
3.33 (s, 3H) ppm; 13C{1H} NMR (100 MHz, DMSOꢀ
d
6): δ 182.4, 153.2, 152.1, 150.5, 146.2,
139.7, 135.2, 133.7, 129.4, 128.3, 128.0, 127.9, 126.7, 126.6, 106.4, 59.5, 55.4 ppm; IR
(KBr): νmax 3432, 3260, 2938, 1639, 1580, 1540, 1503, 1414, 1252, 1231, 1125 cmꢀ1; HRMS
(ESI) m/z : calcd for C22H21N4O4 [M + H]+ 405.1563, found: 405.1555.
4ꢀ(4ꢀMethoxyphenyl)ꢀ5ꢀ(3,4,5ꢀtrimethoxybenzoyl)ꢀNꢀaminoꢀimidazoleꢀ2ꢀamine
(2a):
1
Yellow amorphous solid; 129 mg, 65%; mp: 92–94 °C; H NMR (400 MHz, DMSOꢀ
d
6):
δ
7.40 (d, J = 8.7 Hz, 2H), 7.33 (s, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.72 (s,2H), 5.43 (s,2H), 3.77
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(s, 3H), 3.75 (s, 6H), 3.68 (s, 3H) ppm; 13C{1H} NMR (100 MHz, DMSOꢀ
d6): δ 186.6, 159.3,
5
6
7
8
152.3, 149.6, 140.7, 135.9, 134.8, 132.5, 129.8, 122.2, 113.4, 108.2, 60.5, 56.3, 55.6 ppm; IR
(KBr): νmax 3473, 3327, 2929, 1692, 1582, 1503, 1249, 1125 cmꢀ1; HRMS (ESI) m/z : calcd
for C20H23N4O5 [M + H]+ 399.1668, found: 399.1663.
9
10
11
12
13
14
15
16
17
18
19
20
21
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24
25
26
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45
46
47
48
49
50
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52
53
54
55
56
57
58
59
60
5ꢀBenzoylꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀNꢀaminoꢀimidazoleꢀ2ꢀamine
(2b): Yellow amorphous
1
solid; 92 mg, 60%; mp: 153–155 °C; H NMR (400 MHz, DMSOꢀ
d
6):
δ
J
7.95 (d,
= 8.8 Hz, 2H), 5.74
6): 187.9, 159.4,
J = 8.3 Hz,
2H), 7.49ꢀ7.45 (m, 3H), 7.39 (dd,
J
= 7.6 Hz,
J
= 7.2 Hz, 2H), 6.93 (d,
13
(s,2H), 5.45 (s,2H), 3.79 (s, 3H) ppm; C{1H} NMR (100 MHz, DMSOꢀ
d
δ
149.5, 139.9, 135.9, 132.5, 131.5, 130.3, 129.7, 127.9, 122.0, 113.4, 55.6 ppm; IR (KBr): νmax
3332, 3203, 2925, 1610, 1553, 1362, 1275, 1259, 1177 cmꢀ1; HRMS (ESI) m/z : calcd for
C17H17N4O2 [M + H]+ 309.1351, found:309.1346.
4ꢀ(4ꢀMethoxyphenyl)ꢀ5ꢀ(3,4,5ꢀtrimethoxybenzoyl)ꢀNꢀcyanoꢀimidazoleꢀ2ꢀamine
(2c):
Yellow amorphous solid; 129 mg, 60%; mp:147ꢀ149 °C; 1H NMR (400 MHz, DMSOꢀ
d
6):
δ
7.14 (d,
J
= 8.7 Hz, 2H), 6.81 (s, 2H), 6.75 (d,
J
= 8.7 Hz, 2H), 3.69 (s, 3H), 3.59 (s, 3H),
6): 183.8, 163.2, 160.3, 152.7, 141.3,
3.58 (s, 6H) ppm; 13C{1H} NMR (100 MHz, DMSOꢀ
d
δ
132.4, 131.6, 120.9, 118.9, 113.7, 107.2, 60.5, 56.2, 55.8 ppm; IR (KBr): νmax 3427, 3330,
3147, 2203, 2158, 1626, 1566, 1504, 1098, 1252 cmꢀ1; HRMS (ESI) m/z : calcd for
C21H20N4O5 [M + Na]+ 431.1332, found: 431.1326.
5ꢀBenzoylꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀNꢀ(4ꢀmethoxyphenyl)ꢀimidazoleꢀ2ꢀamine
(2d): Yellow
amorphous solid; 63 mg, 25%; mp: charred at 168 – 170 °C; 1H NMR (400 MHz, DMSOꢀ
d
6):
δ
8.03 (dd, J = 8.5 Hz, J = 1.4 Hz, 2H), 7.52 – 7.48 (m, 1H), 7.41 (dd, J = 7.7 Hz, J = 7.2 Hz,
2H), 7.16 (d,
J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.74 (d, J =
8.8 Hz, 2H), 5.53 (s,2H), 3.75 (s, 3H), 3.69 (s, 3H) ppm; 13C{1H} NMR (100 MHz, DMSOꢀ
d
6): δ 188.2, 159.4, 159.0, 149.5, 139.6, 135.7, 133.2, 132.4, 131.7, 130.3, 129.9, 128.1,
127.8, 122.5, 115.0, 113.4, 55.8, 55.4 ppm; IR (KBr): νmax 3454, 3295, 2958, 1639, 1566,
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1512, 1498, 1248 cmꢀ1; HRMS (ESI) m/z : calcd for C24H21N3O3 [M + Na]+ 422.1481,
found: 422.1468.
6
7
8
4ꢀ(4ꢀMethoxyphenyl)ꢀ5ꢀ(3,4,5ꢀtrimethoxybenzoyl)ꢀ1Hꢀbenzo[d]imidazo[1,2ꢀa]imidazole
9
(
2e): Yellow amorphous solid; 57 mg, 25%; mp >200 °C; 1H NMR (400 MHz, DMSOꢀ
d6): δ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12.00 (s, H), 7.58 (d, = 8.6 Hz, 2H), 7.46–7.44 (m, 3H), 7.32 (dd, = 7.8 Hz, J = 7.6 Hz,
N
J
J
1H), 7.22 (d,
J = 8.0 Hz, 1H), 7.09–7.04 (m, 3H), 3.84 (s, 3H), 3.78 (s, 6H), 3.72 (s, 3H)
ppm; 13C{1H} NMR (100 MHz, DMSOꢀ
d
6): δ 187.4, 159.9, 152.5, 148.1, 141.3, 134.0,
132.0, 127.9, 125.1, 124.6, 121.7, 120.2, 114.1, 112.2, 108.4, 60.6, 56.4, 55.7 ppm; IR
(KBR): νmax 3063, 2939, 1634, 1611, 1579, 1469, 1251, 1234, 1124 cmꢀ1; HRMS (ESI) m/z :
calcd for C26H24N3O5 [M + H]+ 458.1716, found: 458.1716.
4ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀ(3,4,5ꢀtrimethoxyphenyl)benzo[4,5]imidazo[1,2ꢀa]pyrimidine
1
(2f): Yellow amorphous solid; 33 mg, 30%; mp >200 °C; H NMR (400 MHz, DMSOꢀ
d
6):
δ
7.82 (d,
7.8 Hz,
J
= 8.12 Hz, 1H), 7.79 (s, 1H), 7.75 (d,
J
= 8.6 Hz, 2H), 7.69 (s, 2H), 7.45 (dd,
J
=
J
= 7.4 Hz, 1H), 7.28 (d, = 8.6 Hz, 2H), 7.09 (dd,
J
J
= 8.2 Hz, J = 7.4 Hz, 1H), 6.69
13
(d,
DMSOꢀ
J
= 8.4 Hz, 1H), 3.94 (s, 6H), 3.93 (s, 3H), 3.77 (s, 3H) ppm; C{1H} NMR (100 MHz,
d
6): δ 161.1, 160.0, 153.2, 151.5, 149.5, 144.9, 140.3, 131.7, 130.3, 127.2, 125.5,
124.5, 120.7,119.2, 114.5, 114.4, 105.4, 105.0, 60.2, 56.1, 55.5 ppm; IR (KBr): νmax 2937,
1596, 1496, 1251, 1125 cmꢀ1; HRMS (ESI) m/z : calcd for C26H24N3O4 [M + H]+ 442.1767,
found:442.1759.
Acknowledgment: We gratefully acknowledge financial support from CSIR, New Delhi, for
this investigation. NH is thankful to DST, New Delhi, for her DSTꢀINSPIRE fellowship.
Supporting Information: The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Mass spectra for mechanistic investigation, NMR spectra (PDF) and Xꢀray crystallographic
data for product 1a (CCDC 1509458)32
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