Transition-metal-catalyzed arylation of nitroimidazoles and further transformations of manipulable nitro group

Article abstract of DOI:10.1021/jo5025927

Pd- or Ni-catalyzed C-H arylation of 4-nitroimidazole derivatives directed by a manipulable nitro group was developed. The reaction tolerates a wide range of substituted aryl halides and 4-nitroimidazoles. The experiments indicated that the nitro group has influence on regioselectivity of the reaction. In addition, we have shown that the efficiency of the Suzuki-Miyaura cross-coupling reaction of nitroimidazoles is slightly lower in comparison to the direct C-H arylation. The exploration of the chemical potential of the nitro group and a putative reaction mechanism are discussed.

Full text of DOI:10.1021/jo5025927

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Article
Transition Metal-Catalysed Arylation of Nitroimidazoles
and Further Transformations of Manipulable Nitro Group
Viktor O. Iaroshenko, Ashot Gevorgyan, Satenik Mkrtchyan, Knar Arakelyan,
Tatevik Grigoryan, Julietta Yedoyan, Alexander Villinger, and Peter Langer
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 23 Jan 2015
Downloaded from http://pubs.acs.org on January 27, 2015
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Transition Metal-Catalyzed Arylation of Nitroimidazoles and
Further Transformations of Manipulable Nitro Group
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Viktor O. Iaroshenko,*a,b, Ashot Gevorgyan,a Satenik Mkrtchyan,a Knar Arakelyan,a Tatevik
Grigoryan,a Julietta Yedoyan,a Alexander Villingera and Peter Langer.*a,c
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a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b National Taras Shevchenko University, 62 Volodymyrska st., Kyiv-33, 01033, Ukraine. E-mail: iva108@gmail.com
c Leibniz-Institut für Katalyse e. V. Universität Rostock Albert-Einstein-Str. 29a, 18059 Rostock, Germany. E-mail: peter.langer@uni-
rostock.de
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Abstract: Pdꢀ or Niꢀcatalyzed CꢀH arylation of 4ꢀnitroimidazole derivatives directed by a manipulable nitro group was
developed. The reaction tolerates a wide range of substituted aryl halides and 4ꢀnitroimidazoles. The experiments indicated
that the nitro group has influence on regioselectivity of the reaction. In addition we could show that the efficiency of Suzukiꢀ
Miyaura crossꢀcoupling reaction of nitroimidazoles is slightly lower in comparison to the direct CꢀH arylation. The
exploration of chemical potential of nitro group and a putative reaction mechanism are discussed.
Introduction
Substituted imidazoles are important heteroaromatic compounds which are known to exhibit a broad range of biological
activities.1 They are also important building blocks found in naturally occurring compounds,2 besides imidazoles are
versatile precursors to Nꢀheterocyclic carbenes useful as ligands in various catalytically active transition metal complexes3
and in organocatalysis.4 Moreover, imidazolium salts can be used as environmentally friendly ionic solvents.5 Accordingly, a
number of methodologies for construction and/or substitution of various imidazoles have been intensively developed during
the last few decades.6 In this context there are a number of established de novo methods for construction of imidazole ring
with appropriate substituents via cyclocondensation reactions (for an example see Figure 1 A).6 Although these traditional
approaches have been greatly improved, in most cases, the synthesis of each analogue of the library will require the entire de
novo synthetic sequence, which usually results in complications in terms of formation of regioisomers etc.6c On the other
hand, the formation of a single CꢀC or CꢀX bounds by catalytic crossꢀcoupling reactions of imidazole derivatives eliminates
most of the problems typical for de novo synthesis of imidazole derivatives (Figure 1 B).6a,7 Though this approach has been
greatly improved over the past decades,7 the need for preparation of preꢀfunctionalized starting materials along with needs of
''Green Chemistry'' indicated its scope and efficiency limitations. However, during the last few years direct transition metal
catalyzed CꢀH activation reactions of privileged (hetero)arenes provides highly efficient means to synthesize functionalized
(hetero)arenes8 utilized extensively throughout the pharmaceutical and materials industries (Figure 1 C).9,6
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Figure 1. Common approaches for synthesis of functionalized imidazoles.
This approach eliminates the need for the organometallic starting materials required in traditional crossꢀcoupling methods,7
in addition, commonly these methods reduce reaction byꢀproducts, increase the number of available substrates and decrease
the synthetic effort required for formation of the desired CꢀC and/or CꢀX bonds. Nevertheless, despite the cutting edge
innovations achieved in this field, a selective functionalization of a particular CꢀH bond of interest still remains a complex
task. One of the possible solutions involves the employment of directing groups (DG).10 However, in most of the cases these
efficient moieties cannot be removed easily, or they are not apt to undergo further functionalizations. Due to this fact,
substantial effort has been directed toward the discovery of multiꢀfunctional directing groups for direct CꢀH activation of
(hetero)arenes.11 A clear example is the use of oxidizing directing groups that contains a covalent bond which is responsible
for oxidation of the metal, eliminating the need of external oxidants which usually generates waste subproducts.12 Another
way to plan the multiꢀtask character of the directing groups is the use of ''removable'' functional groups.11,13
In this context the nitro group is almost the paradigm of what a manipulable directing group could be. It can behave as a
classical directing group,14 selecting the positions where the metal has to be incorporated and, typically, forming part of the
target molecule via additional functionalizations after the CꢀH activation step. This twoꢀstep approach undoubtedly has a
huge synthetic capacity.15
Scheme 1. The synthetic potential of TMꢀcatalyzed nitro group directed CꢀH arylation of heteroarenes.
The use of the nitro group as a regiodirecting substituent in CꢀH activations has scarcely been reported to date.16 Examples
include the Pdꢀcatalyzed ortho CꢀH arylation of nitrobenzene derivatives16a as well as the CꢀH arylation of positions 4 and 5
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of 3ꢀnitropyridine.16b In spite of this, the authors did not demonstrate the vast chemical potential of nitro group. In contrast to
this, recently we communicated the selective and guided functionalization of 4ꢀnitropyrazoles, fused 3ꢀnitropyridines, 2ꢀ
nitrothiophene and 4ꢀnitroꢀ1Hꢀpyrroles by Pdꢀ and Niꢀcatalyzed CꢀH arylation, that was followed by demonstration of multiꢀ
purpose character of nitro group as directing group (Scheme 1).17 In our present study we would like to continue the
amplification of this chemistry on the example of several Nꢀsubstituted 4ꢀnitroimidazoles (Scheme 1).
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Results and discussion
Inspired by the tremendous chemical potential of nitro group15 and our recent successful results on CꢀH arylation of different
nitroꢀsubstituted heteroarenes,17 we started the present study on CꢀH arylation of nitroimidazoles. Accordingly, the starting
Nꢀsubstituted 4ꢀnitroimidazoles 3a-h were prepared using simple alkylation of commercially available 4(5)ꢀnitroimidazole 1
with appropriate alkyl bromides as depicted in Table 1.
Based on our experience and following the general movements in the field, in order to achieve the desired highly efficient Cꢀ
H arylation, a number of decisive challenges had to be overcome: 1) the first challenge is the optimizing reaction conditions,
so that only the stoichiometric amounts of coupling partners can be used; 2) the second challenge is the investigation of
regioselectivity in three potential active positions in the imidazole ring (positions 2, 4 and 5); 3) in this context interrelation
between ''guided'' and ''innate'' CꢀH arylation reactions should be investigated (Figure 1). Subsequently the following
criterias for design of an ideal directing group for CꢀH transformations should be fulfilled: 1) corresponding directing group
should be capable of coordinating the catalyst; 2) the directing group should be sufficiently stable under typical transition
metalꢀcatalyzed CꢀH activation reaction conditions; 3) and finally the directing group should be prone to undergo some
further transformations, thereby allowing the synthesis of multiꢀfunctionalized target compounds.
Table 1. Synthesis of starting Nꢀsubstituted 4ꢀnitroimidazoles 3a-h.
3
a
b
c
d
e
f
g
h
R1
Me
Me
Me
H
Me
Me
Me
Me
R2
yield (%)
Ethyl
nꢀButyl
82
88
93
80
78
89
83
83
(CH2)2Ph
(CH2)2Ph
(CH2)3Ph
(CH2)2OPh
CH2ꢀ4ꢀTol
2ꢀBrC6H4
With the set of Nꢀsubstituted 4ꢀnitroimidazoles 3a-h in hand we have focused as next on setting up optimal reaction
conditions. For this end, in order to avoid further complications, we decided to use as a model compound 2ꢀmethylꢀ4ꢀnitroꢀ1ꢀ
(3ꢀphenylpropyl)ꢀ1Hꢀimidazole 3e. Basing on our previous results we considered the Pd catalysts with CuI as additive to be
the starting point in this study.17,18 To our delight, pilot experiments have indicated that indeed Pd/CuI system is rather
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efficient in order to activate C(5)ꢀH bond of 4ꢀnitroimidazole 3e (Table 2, entry 1ꢀ5), namely the best catalyst for the model
compound 3e turn up PdCl2(PPh3)2, we obtained the desired product with 96 % yield (entry 4). We found that addition of
phosphine ligands has no real impact on overall yields of the reaction (entry 1, 2, 4). Notably the copper salt such as CuI in
stoichiometric amounts provides desired product in almost quantitative yield (entry 4). Though, absence or subꢀ
stoichiometric amounts of CuI does not stop the reaction, namely we could isolate the product with reduced yield (entry 5).
Table 2. Optimization of reaction conditions for the synthesis of compound 4a.
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a
entry
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2
3
4
5
6
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8
catalyst
ligand
additive 1
CuI
CuI
CuI
CuI
ꢀ
CuCl
Ag2CO3
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
additive 2
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
ꢀ
Ph3CCO2H
PivOH
ꢀ
PivOH
PivOH
PivOH
PivOH
PivOH
base
solvent
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMF
NMP
1,4ꢀdioxane
toluene
DMA
oC
%
Pd(OAc)2
Pd(OAc)2
Cy3PxHBF4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
KOAc
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
130
130
130
130
130
130
130
130
130
130
130
130
130
100
100
130
78
76
ꢀ
ꢀ
ꢀ
-
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
-
ꢀ
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
NiCl2(PPh3)2
96
71
83
63
25
22
46
80
94
90
ꢀ
9
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16
15
64
a Isolated yields.
Interestingly the use of Lewis acids like CuCl or Ag2CO3 still provides the formation of desired product, however with
reduced yields (entry 6, 7). The best base for the reaction was found to be K2CO3/PivOH system; any change in the system
decreased the yields (entry 8ꢀ11). Employment of different solvents and temperatures has shown that the reaction runs
effectively in DMF, DMA and NMP without any notable differences in yields (entry 4, 12ꢀ15). Finally, the usage of the
other catalysts turned to be ineffective. Among these, perhaps, unsurprisingly the reaction catalyzed by NiCl2(PPh3)2
occurred uneventfully and furnished the desired product, although the conversion of reactants was not that high (entry 16).
Next, the generality of this protocol toward coupling partners was examined (Scheme 2). To our delight, it was found that
this transformation worked well for both electronꢀrich and electronꢀdeficient arenes. Notably, a broad number of
functionalities, such as F (4p), Cl (4h), CF3 (4a,e,h,m), OMe (4d,i,o,r,t), and variety of other functional groups, such as
ketone (4s), NO2 (4b), and even aldehyde (4c,d,g,i,j,l,t) as well as heterocycles (4f,n,q) were perfectly tolerated under these
reaction conditions, providing target arylated nitroimidazoles in high to quantitative yields. Expectedly, the functional group
tolerance was equally actual in a wide range of substituted 4ꢀnitroimidazoles with no changes in the reaction conditions. The
usage of aryl iodides resulted in formation of a great amount of bipheniles via homocoupling induced by CuI: this demanded
the large excess of the aryl halide, and the overall yields were visibly lower than with aryl bromides (4a,b,e,o). Together
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with this, aryl chlorides, in general, were not active enough in these reaction conditions (4h). Subsequently, the scope of the
Niꢀcatalyzed CꢀH arylation reaction of corresponding 4ꢀnitroimidazoles was examined. We have found that the reaction has
general character allowing an efficient introduction of an aryl group into the imidazole ring in moderate yields
(4b,e,f,g,k,m,n,r).
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Scheme 2. Scope of the reaction with respect to aryl bromides and Nꢀsubstituted 4ꢀnitroimidazoles.* In the brackets on red are mentioned the
yields of CꢀH arylation catalyzed by Ni.** In the brackets on blue are mentioned the yields of CꢀH arylation with appropriate aryl iodides.
Surprisingly, during the course of reaction conditions optimisation we observed another interesting process. Namely when
CuI was replaced by Ag2CO3 along with CꢀH arylation by aryl bromide (63 %), a Pdꢀcatalyzed intramolecular
dehydrogenative twofold CꢀH crossꢀcoupling occurred (Table 2, entry 7, Scheme 3).18a,19 Initially we observed traces of
cyclisation product 5a (8 %) together with CꢀH arylation product 4a (63 %), nevertheless reducing amount of aryl bromide
dramatically increased the yield of intramolecular dehydrogenative twofold CꢀH crossꢀcoupling reaction. In this context, this
search found that in the absence of aryl halide presence of an oxidant (in this case Ag2CO3) can initiate an intramolecular
dehydrogenative twofold CꢀH crossꢀcoupling of 4ꢀnitroimidazoles leading to different fused systems 5a-c from good to
excellent yields (Scheme 3).
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Naturally, after the development of an efficient Pdꢀ and Niꢀcatalyzed arylation of simple 4ꢀnitroimidazoles, next we were
interested in exploration of this reaction procedure also for 2,5ꢀunsubstituted 4ꢀnitroimidazole 3d. It is known from the
literature that the regioselectivity of Pdꢀcatalyzed CꢀH activation of imidazoles depends on the used catalytic system.6a
Empirical studies indicated that the Cꢀ5 position of imidazoles exhibits higher reactivity, than that at the Cꢀ2 position,
towards the Pdꢀcatalyzed arylation in the presence of weak bases and phosphine ligands. The Cꢀ4 position is relatively less
reactive in this respect. It was also demonstrated that the addition of Cu(I) salts alters the bias toward the Cꢀ2 position.6a This
reactivity pattern is consistent also with theoretically calculated CMD barriers for Nꢀmethylimidazole.20
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Scheme 3. Synthesis of fused systems 5a-c.
However, in our case the situation is different due to the nitro group that can direct the reaction. Thus, when we performed
the reaction of 4ꢀnitroimidazole 3d with 2.5 equivalents of aryl bromide in standard reaction conditions, corresponding 2,5ꢀ
disubstituted products 6 were observed (Scheme 4). Nevertheless, when the amount of aryl bromide was decreased to 1.1
equivalents, remarkably Cꢀ5 substituted 4ꢀnitroimidazoles 7 were the only observed regioisomer (Scheme 4). When we
performed the reaction in the absence of CuI the yield of reaction decreased without any changes in regioselectivity (see also
Table 2, entry 4, 5). This means that in 4ꢀnitroimidazole 3d the ''guiding'' effect of nitro group dramatically changes the
regioselectivity of the reaction, even though in the reaction medium stoichiometric amount of CuI was presented.6a,20 Having
these results in hand, further a stepwise synthesis of 2,5ꢀdiarylꢀ4ꢀnitroimidazole with two different aryl groups was
performed. Starting from compound 7c using standard reaction conditions corresponding 2,5ꢀdisubstituted imidazole 8a was
successfully isolated in 78 % yield (Scheme 4).
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Scheme 4. The regioselective CꢀH arylation of 4ꢀnitroimidazoles; i: PdCl2(PPh3)2 (5 mol%), CuI (1.2 equiv.), PivOH (0.3 equiv.), K2CO3
o
(2.3 equiv.), DMA, under Ar, 130 C, 14 h; ii: PdCl2(PPh3)2 (5 mol%), CuI (1.2 equiv.), PivOH (0.3 equiv.), K2CO3 (1.3 equiv.), DMA,
under Ar, 130 oC, 14 h.
6
7
8
9
Inspired by the successful results on regioselective CꢀH arylation of positions 2 and 5 of 4ꢀnitroimidazoles, next we
envisioned that the CꢀH arylation of position 4 in 5ꢀnitroimidazole can be an excellent extension of scope of the reaction. For
this end, we designed and tested a number of reaction conditions, nevertheless the reactions failed, in spite of partial
conversion of reactants only an inseparable mixture of compounds was observed. Further we tried to overcome this problem
by finding another suitable procedure towards 4ꢀarylaed 5ꢀnitroimidazoles. For this purpose the SuzukiꢀMiyaura crossꢀ
coupling reaction of 5(4)ꢀbromoꢀ4(5)ꢀnitroimidazoles 10, 11 was tested (Table 3). To this end 5(4)ꢀbromoꢀ4(5)ꢀnitroꢀ1Hꢀ
imidazole 9 was alkylated in order to prepare desired starting Nꢀsubstituted imidazoles 10, 11. It should be mentioned that
unlike alkylation of simple 4ꢀnitroimidazoles (Table 1), the alkylation reaction of 5(4)ꢀbromoꢀ4(5)ꢀnitroimidazoles leaded to
a mixture of 5ꢀbromoꢀ4ꢀnitroimidazole 10 and 4ꢀbromoꢀ5ꢀnitroimidazole 11, approximately in 2:1 ratio. Tree pairs of Nꢀ
substituted nitroimidazoles were synthesised applying this procedure (Table 3).
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Table 3. Synthesis of Nꢀsubstituted 5(4)ꢀbromoꢀ4(5)ꢀnitroimidazoles 10, 11.
10, 11
R2
10 (%)
57
58
11 (%)
31
38
a
b
c
(CH2)2Ph
(CH2)2OPh
(CH2)3Ph
55
40
In the hope of identifying a practical and versatile catalytic procedure, we thoroughly examined the reaction parameters
including metal catalyst, base, and loading of reactants, solvent and temperature, the selected results are listed in Table 4.
According to the new pathway for the test reaction we used imidazole 10a and 2ꢀformylphenylboronic acid as an aryl source
(Table 4). As a catalyst for this transformation Pd(PPh3)4 was chosen, since the literature data shows that it is the most
successful Pd source for SuzukiꢀMiyaura crossꢀcoupling reaction.7 During optimization of the reaction conditions a number
of solvents were tested such as dioxane, toluene etc. Unfortunately all our initial attempts to perform the desired coupling
appeared unsuccessful (Table 4, entry 1, 2). Hence, we tried to use different combination of solvents. Gratifyingly, we found
that when the reaction was performed in standard solvents (mentioned above) using a drop of water the desired product
forms in 20 % and 27 % yields in dioxane/H2O and toluene/H2O systems respectively (Table 4, entry 3, 4).
Table 4. Optimization of reaction conditions for the synthesis of compound 12a.
a
entry
1
catalyst
ArB(OH)2
1.3 equiv.
base
solvent
%
Pd(PPh3)4 10 mol%
K2CO3 (2 equiv.)
Dioxane
trace
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10
Pd(PPh3)4 10 mol%
Pd(PPh3)4 10 mol%
Pd(PPh3)4 10 mol%
Pd(PPh3)4 10 mol%
Pd(PPh3)4 10 mol%
Pd(PPh3)4 10 mol%
Pd(PPh3)4 10 mol%
Pd(PPh3)4 10 mol%
Pd(PPh3)4 5 mol%
1.3 equiv.
1.3 equiv.
1.3 equiv.
1.3 equiv.
1.3 equiv.
1.3 equiv.
1.0 equiv.
2.0 equiv.
1.3 equiv.
K2CO3 (2 equiv.)
K2CO3 (2 equiv.)
K2CO3 (2 equiv.)
K3PO4 (2 equiv.)
K2CO3 (2 equiv.)
2M aq. K2CO3 (1 ml)b
2M aq. K2CO3 (1 ml)b
2M aq. K2CO3 (1 ml)b
2M aq. K2CO3 (1 ml)b
Toluene
trace
20
27
15
36
62
50
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Dioxane/H2O (4:1)
Toluene/H2O (4:1)
Toluene/H2O (4:1)
Toluene/MeOH (5:1)
Toluene/MeOH (5:1)
Toluene/MeOH (5:1)
Toluene/MeOH (5:1)
Toluene/MeOH (5:1)
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a Isolated yields. b For 1 mmol of starting imidazole.
Meanwhile, the change of K2CO3 to K3PO4 decreased the yield of product (Table 4, entry 5), therefore during further
optimisation only K2CO3 was used as a base. In addition, once MeOH was used instead of water, curiously the yield of the
reaction increased up to 36 % (Table 4, entry 6). Furthermore, via using an aqueous solution of K2CO3 as a base we could
obtain the desired product in 62 % yield (Table 4, entry 7). During the next steps of optimisation we tried to increase the
yields by changing quantities of boronic acid. Nevertheless we could not get any positive result, 1.3 equivalent of boronic
acid showed the best efficiency (Table 4, entry 8, 9). Finally, it should be mentioned that performing the reaction at slightly
higher temperature (under reflux) in inert atmosphere provided better yields of arylation products.
Naturally, after development of an efficient Pdꢀcatalyzed SuzukiꢀMiyaura crossꢀcoupling reaction of 5ꢀbromoꢀ4ꢀ
nitroimidazoles 10, further under the newly developed conditions we tried to prepare similar arylation products to those that
were prepared by CꢀH arylation (Scheme 5). The comparison of these two procedures seems to be an actual task since
SuzukiꢀMiyaura crossꢀcoupling reaction requires more synthetic effort and expensive starting materials. In this context, we
could demonstrate that the yields of SuzukiꢀMiyaura crossꢀcoupling reaction of 5ꢀbromoꢀ4ꢀnitroimidazoles 10 were slightly
lower in comparison to the yields obtained for similar compounds in direct CꢀH activation reaction (Scheme 2). This may be
the result of steric factors and/or poor solubility of the reaction components.
Scheme 5. Scope of the SuzukiꢀMiyaura crossꢀcoupling reaction. *In the brackets on red are mentioned the yields of CꢀH arylation (Scheme
2).
Although the C(4)ꢀH bond of nitroimidazoles exhibits very low reactivity in the Pdꢀ and Niꢀcatalyzed CꢀH arylation
described above, precluding direct arylation of this position, nevertheless we could overcome this problem applying the
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SuzukiꢀMiyaura crossꢀcoupling reaction of 4ꢀbromoꢀ5ꢀnitroimidazoles 11. Using this procedure we successfully prepared a
number of 4ꢀarylatedꢀ5ꢀnitroimidazoles 13 with good yields (Scheme 6).
6
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9
Eventually, to fully demonstrate the synthetic potential of this methodology, we briefly explored the chemical versatility of
directing group. The simple reduction of nitro group was tested first (Scheme 7). Not surprisingly, we got an inseparable
mixture of products, along with this intensive polymerization was observed, most probably because of instability of formed
aminoimidazoles 14.21 Moreover, we got similar results when the reduction was performed in the presence of an excess of
formalin, that is instead of N,Nꢀdimethylamines 15 we obtained a mixture of products. Fortunately, we could demonstrate
that the reduction of arylated nitroimidazoles containing an ortho carbonyl group 4t 12a,b 13a,e leads to the formation of
1Hꢀimidazo[4,5ꢀc]isoquinoline system 16 as a single product with good yields (Scheme 7). In this case probably the
reduction product amine undergoes a subsequent interaction with carbonyl group leading to the aromatic isoquinoline
system.
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Scheme 6. Scope of the SuzukiꢀMiyaura crossꢀcoupling reaction.
Scheme 7. Reduction of the nitro group; i: MeOH, H2, Pd/C (10 mol%), 20 °C, 5 h. ii: MeOH, H2, Pd/C (10 mol%), CH2O in H2O (37 %, 6
equiv.), 20 °C, 5 h.
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The structure of the synthesized arylated nitroimidazoles was mainly established by 1D and 2D NMR methods. The
structures of compounds 3g, 4d,t, 5b, 7a,c, 10a and 12a (4g) were independently confirmed by Xꢀray single crystal analyses
(Figures 1ꢀ8, supplementary information).22
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To gain more insight into the reaction pattern, a competitive experiment was conducted between imidazole 3c and
electronically different aryl bromides, namely with 1ꢀbromoꢀ3ꢀmethoxybenzene and 1ꢀbromoꢀ3ꢀnitrobenzene (Scheme 8).
The goal was to identify the comparable reactivity of different aryl bromides bearing either an electron donating or an
electron withdrawing group. The results revealed that the reaction favoured by electronꢀdeficient aryl bromides. Setting up
the competitive arylation with two different aryl bromides (Scheme 8, A), we could isolate only one product 4u in 82 %
yield corresponding to CꢀH arylation with 1ꢀbromoꢀ3ꢀnitrobenzene (Scheme 8). This experiment clearly shows that aryl
bromides with electron withdrawing groups are much more reactive in CꢀH arylation reactions than the respective aryl
bromides with an electron donating group. The competitive experiment between two various imidazoles 3c and 3g along
with 1ꢀbromoꢀ3ꢀnitrobenzene was also performed (Scheme 8, B). In this case the goal was to identify the comparable
reactivity between two different Nꢀsubstituted imidazoles, in order to understand the impact of the steric influences of the
substituent in the position 1 of the imidazole ring. During the course of study we found that there was almost no distinction
between two imidazoles. In this case a mixture of two products with almost similar quantities was observed (Scheme 8, see
also supplementary information).
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Scheme 8. The competitive experiments between imidazoles and aryl bromides; i: PdCl2(PPh3)2 (5 mol%), CuI (1.2 equiv.), PivOH (0.3
equiv.), K2CO3 (1.3 equiv.), DMA, under Ar, 130 oC, 14 h.
In order to obtain more insights into reaction mechanism and the directing ability of the nitro group, we designed the
imidazole 3i which then was subjected to our standard Pdꢀcatalyzed reaction conditions (Scheme 9). Nevertheless, all
attempts to perform the CꢀH arylation in standard conditions, developed for nitroimidazoles, were unsuccessful; we got an
inseparable mixture of products along with starting imidazole 3i. These findings clearly show the crucial effect of nitro
group on the outcome of the reaction.
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N
i or ii
Me
Mixture of indefinite
products and starting imidazole
+
Br
N
H
CF3
5
6
Ph
3i 1 equiv.
2 equiv
7
8
9
Scheme 9. Exploration of directing ability of nitro group; i: PdCl2(PPh3)2 (5 mol%), CuI (1.2 equiv.), PivOH (0.3 equiv.), K2CO3 (1.3
equiv.), DMA, under Ar, 130 oC, 14 h; ii: PdCl2(PPh3)2 (5 mol%), PivOH (0.3 equiv.), K2CO3 (1.3 equiv.), DMA, under Ar, 130 oC, 14 h.
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Finally, the regioselectivity might be explained, by an assumption that the catalyst (Pd or Ni) coordinated by the nitro group
initiates C(5)ꢀarylation of imidazole ring via concerted metalationꢀdeprotonation (CMD), as illustrated in Scheme 10 (B).20
In this context it should be mentioned that the salt of copper via double chelation by nitro group and nitrogen of imidazole
ring can immobilize the nitro group in the plane of imidazole ring, thus supporting the CꢀH bond cleavage by Pd or Ni
(Scheme 10, A, B). In this connection recently Huang et al. showed that the lone pair on the nitrogen atom in benzothiazole,
Nꢀmethylbenzoimidazole and related systems can bind to the copper centre thereby initiating Pdꢀcatalyzed CꢀH bond
cleavage.23 For C(2)ꢀarylation of imidazole ring we assume that a cooperative action of Pd and Cu catalysts chelated by a
bidentate ligand (solvent) may enable the direct CꢀH activation (Scheme 10, C).24 Concerning the low reactivity of C(4)ꢀH
bond of imidazoles, several authors following the analogy with unreactive αꢀposition of pyridines described this
phenomenon by the electronic repulsion between the electron lone pair on the Nꢀ3 and the CꢀPd bond (Scheme 10,
D).25,16b,17a Eventually, we do not exclude the formation of appropriate cuprates of imidazole that is followed by
transmetallation to Pd or Ni (Scheme 10, E and F), since recently DFT calculations made by Fu et al. indicate that the CꢀH
activity of different ArꢀH species, and both the dissociation of the ArꢀH bond and the formation of the ArꢀCu bond make
important contributions to the concerted CꢀH activation.26
Scheme 10. Proposed mechanistic explanation of the regioselectivity.
Conclusions
In conclusion, we have studied in detail the transition metalꢀcatalyzed CꢀH arylation of nitroimidazoles by two different dꢀ
metals, namely Pd and Ni, using CuI as additive. The use of Pd proved to give better yields than Ni. Furthermore, we
succeeded to activate the CꢀH bond using stoichiometric amounts of coupling partners. The scope of the reaction with
respect to the aryl halogenide coupling partner as well as for nitroimidazoles was examined. The competitive experiments
showed that aryl bromides with an electron withdrawing group are much more reactive than the respective aryl bromides
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with an electron donating group. In addition we observed no differences in reactivity of different nitroimidazoles.
Interestingly, during the course of optimisation of the reaction conditions we observed a Pdꢀcatalyzed intramolecular
dehydrogenative twofold CꢀH crossꢀcoupling reaction initiated by oxidant (Ag2CO3). Next, we performed a regioselective Cꢀ
H arylation of 2,5ꢀunsubstituted 4ꢀnitroimidazole ''guided'' by the nitro group. Furthermore, a stepwise synthesis of 2,5ꢀ
diarylꢀ4ꢀnitroimidazole with two different aryl groups was accomplished. For arylation of position 4 of imidazole ring an
efficient Pdꢀcatalyzed SuzukiꢀMiyaura crossꢀcoupling reaction of 5(4)ꢀbromoꢀ4(5)ꢀnitroimidazoles was developed.
Interestingly we could demonstrate that the yields of SuzukiꢀMiyaura crossꢀcoupling reaction of 5ꢀbromoꢀ4ꢀnitroimidazoles
were slightly lower in comparison to the yields obtained for similar compounds in direct CꢀH activation reaction. Within the
course of study the multiꢀpurpose character of nitro group was demonstrated. A mechanistic explanation of results was
proposed. The developed method shows a number of advantages, including high experimental simplicity, catalyst efficiency,
functional group compatibility, low cost of the catalytic system and reactants. Further exploration of this chemistry is in
progress in our laboratory.
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Experimental Section
General Information
The dry solvents were purchased. Other solvents were purified by distillation. For 1H, 19F and 13C NMR spectra, the
deuterated solvents indicated were used. NMR peaks were assigned by standard means of 2D NMR methods, such as HꢀH
COSY, HMBC and HMQC; selected spectra are enclosed in SI. Mass spectrometric data (MS) were obtained by electron
ionization (EI, 70 eV), chemical ionization (CI, isobutane), or electrospray ionization (ESI, mass analyzer type was ESIꢀ
TOF/MS). For preparative scale chromatography, silica gel 60 (0.063ꢀ0.200 mm, 70ꢀ230 mesh) was used. The solvents for
column chromatography were distilled before use.
General procedure for the synthesis of N-substituted imidazoles by alkylation. Synthesis of compounds 3a-i, 10a-c
and 11a-c: Corresponding imidazole (1 equiv.) and K2CO3 (3 equiv.) successively were weighed to air and placed in a
Schlenk flask, equipped with a magnetic stir bar, which then was capped with a rubber septum. The reaction vessel was
evacuated and back filled with argon. The dry DMF (8 ml for 1 g of imidazole) and corresponding alkyl bromide (1.3 equiv.)
were added via a syringe, and the reaction was heated to 90 °C for 8 h. Upon completion, the reaction was cooled to room
temperature and concentrated under vacuum. The crude mass was washed with water, which was extracted with chloroform.
Finally, the organic phase was dried (Na2SO4), filtered, and evaporated to dryness, or (if necessary) the residue was purified
by column chromatography typically using heptane/ethyl acetate mixtures to provide the desired alkylated product.
General procedure for direct C-H arylation of N-substituted 4-nitroimidazoles. Synthesis of compounds 4a-t, 8a:
Corresponding Nꢀsubstituted 4ꢀnitroimidazole 3b,c,e-g 7c (1 equiv.), CuI (1.2 equiv.), K2CO3 (1.3 equiv.), (CH3)3CCO2H
(0.3 equiv.), and PdCl2(PPh3)2 (or NiCl2(PPh3)2) (0.05 equiv.) successively were weighed to air and placed in a Schlenk
flask, equipped with a magnetic stir bar, which then was capped with a rubber septum. The reaction vessel was evacuated
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and back filled with argon (three times). The dry DMA (8 ml for 0.3 g of Nꢀsubstituted 4ꢀnitroimidazole) and aryl bromide
(2 equiv.) were added via a syringe (in case of solid aryl bromide, first it was dissolved in dry DMA under inert atmosphere),
and the reaction was heated to 130 °C for 14 h. Upon completion, the reaction was cooled to room temperature and
concentrated under vacuum. The residue was purified by column chromatography typically using heptane/ethyl acetate
mixtures to provide the desired arylated product.
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The competitive experiment between imidazole 3c and electronically different aryl bromides. Synthesis of compound
4u: Corresponding Nꢀsubstituted 4ꢀnitroimidazole 3c (1 equiv.), CuI (1.2 equiv.), K2CO3 (1.3 equiv.), (CH3)3CCO2H (0.3
equiv.), and PdCl2(PPh3)2 (0.05 equiv.) successively were weighed to air and placed in a Schlenk flask, equipped with a
magnetic stir bar, which then was capped with a rubber septum. The reaction vessel was evacuated and back filled with
argon (three times). The dry DMA (8 ml for 0.3 g of Nꢀsubstituted 4ꢀnitroimidazole) and aryl bromides (from each 1 equiv.)
were added via a syringe (in case of solid aryl bromide, first it was dissolved in dry DMA under inert atmosphere), and the
reaction was heated to 130 °C for 14 h. Upon completion, the reaction was cooled to room temperature and concentrated
under vacuum. The residue was purified by column chromatography typically using heptane/ethyl acetate mixtures.
The competitive experiment between two various imidazoles. Synthesis of compounds 4u, 4w: Corresponding Nꢀ
substituted 4ꢀnitroimidazoles 3c 3g (from each 1 equiv.), CuI (1.2 equiv.), K2CO3 (1.3 equiv.), (CH3)3CCO2H (0.3 equiv.),
and PdCl2(PPh3)2 (0.05 equiv.) successively were weighed to air and placed in a Schlenk flask, equipped with a magnetic stir
bar, which then was capped with a rubber septum. The reaction vessel was evacuated and back filled with argon (three
times). The dry DMA (8 ml for 0.6 g of Nꢀsubstituted 4ꢀnitroimidazoles) and aryl bromide (1.1 equiv.) were added via a
syringe (in case of solid aryl bromide, first it was dissolved in dry DMA under inert atmosphere), and the reaction was
heated to 130 °C for 14 h. Upon completion, the reaction was cooled to room temperature and concentrated under vacuum.
The mixture of compounds 4u and 4w was purified by column chromatography typically using heptane/ethyl acetate
mixtures.
General procedure for Pd-catalyzed intramolecular dehydrogenative twofold C-H cross-coupling reaction. Synthesis
of compounds 5a-c: Corresponding Nꢀsubstituted 4ꢀnitroimidazole 3c,e,f (1 equiv.), Ag2CO3 (1.2 equiv.), K2CO3 (1.3
equiv.), (CH3)3CCO2H (0.3 equiv.), and PdCl2(PPh3)2 (0.05 equiv.) successively were weighed to air and placed in a Schlenk
flask, equipped with a magnetic stir bar, which then was capped with a rubber septum. The reaction vessel was evacuated
and back filled with argon (three times). The dry DMA (8 ml for 0.3 g of Nꢀsubstituted 4ꢀnitroimidazole) was added via a
syringe, and the reaction was heated to 130 °C for 14 h. Upon completion, the reaction was cooled to room temperature and
concentrated under vacuum. The residue was purified by column chromatography typically using heptane/ethyl acetate
mixtures to provide the desired product.
General procedure for direct C-H arylation of 2,5-unsubstituted 4-nitroimidazole. Synthesis of compounds 6a-c:
Corresponding Nꢀsubstituted 4ꢀnitroimidazole 3d (1 equiv.), CuI (1.2 equiv.), K2CO3 (2.3 equiv.), (CH3)3CCO2H (0.3
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equiv.), and PdCl2(PPh3)2 (0.05 equiv.) successively were weighed to air and placed in a Schlenk flask, equipped with a
magnetic stir bar, which then was capped with a rubber septum. The reaction vessel was evacuated and back filled with
argon (three times). The dry DMA (8 ml for 0.3 g of Nꢀsubstituted 4ꢀnitroimidazole) and aryl bromide (2.5 equiv.) were
added via a syringe (in case of solid aryl bromide, first it was dissolved in dry DMA under inert atmosphere), and the
reaction was heated to 130 °C for 14 h. Upon completion, the reaction was cooled to room temperature and concentrated
under vacuum. The residue was purified by column chromatography typically using heptane/ethyl acetate mixtures to
provide the desired arylated product.
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General procedure for regioselective C(5)-H arylation of 2,5-unsubstituted 4-nitroimidazole. Synthesis of compounds
7a-c: Corresponding Nꢀsubstituted 4ꢀnitroimidazole 3d (1 equiv.), CuI (1.2 equiv.), K2CO3 (1.3 equiv.), (CH3)3CCO2H (0.3
equiv.), and PdCl2(PPh3)2 (0.05 equiv.) successively were weighed to air and placed in a Schlenk flask, equipped with a
magnetic stir bar, which then was capped with a rubber septum. The reaction vessel was evacuated and back filled with
argon (three times). The dry DMA (8 ml for 0.3 g of Nꢀsubstituted 4ꢀnitroimidazole) and aryl bromide (1.1 equiv.) were
added via a syringe (in case of solid aryl bromide, first it was dissolved in dry DMA under inert atmosphere), and the
reaction was heated to 130 °C for 14 h. Upon completion, the reaction was cooled to room temperature and concentrated
under vacuum. The residue was purified by column chromatography typically using heptane/ethyl acetate mixtures to
provide the desired arylated product.
General procedure for Pd-catalyzed Suzuki-Miyaura cross-coupling reaction of 5(4)-bromo-4(5)-nitroimidazoles.
Synthesis of compounds 12a-f and 13a-e: Corresponding 5(4)ꢀbromoꢀ4(5)ꢀnitroimidazole 10, 11 (1 equiv.), arylboronic
acid (1.3 equiv.), and Pd(PPh3)4 (0.10 equiv.) successively were weighed to air and placed in a Schlenk flask (under the flow
of Ar), equipped with a magnetic stir bar, which then was set with reflux and capped with a rubber septum. The
Toluene/MeOH (5:1) system (8 ml for 0.3 g of 5(4)ꢀbromoꢀ4(5)ꢀnitroimidazole) and 2M aqueous K2CO3 (1 ml for 1 mmol
of starting nitroimidazole) were added via a syringe (under the flow of Ar), and the reaction mixture was refluxed for 5 h in
inert atmosphere (Ar balloon). Upon completion, the reaction was cooled to room temperature and concentrated under
vacuum. The residue was purified by column chromatography typically using heptane/ethyl acetate mixtures to provide the
desired arylated product.
General procedure for reduction of arylated nitroimidazoles containing a carbonyl group. Synthesis of compounds
16a-e: To a Schlenk flask equipped with a magnetic stir bar and filled with corresponding arylated nitroimidazole 4t 12a,b,
13a,e (1 equiv.) was added 10% Pd/C (0.1 equiv.). The flask was fitted with a rubber septum and then held under vacuum for
3 min, after that it was filled with MeOH (25 ml for 0.3 g of arylated nitroimidazole) and hydrogen. Holding under vacuum
was repeated one more time, and after sequential filling with hydrogen, the reaction mixture was stirred for 5 h under H2
atmosphere. After the reaction was stopped, the mixture was filtered through a Celite pad. The filtrate was evaporated to
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dryness and purified by column chromatography typically using heptane/ethyl acetate mixtures to provide the desired
product.
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o
1
1-ethyl-2-methyl-4-nitro-1H-imidazole (3a). White solid (1.271 g, 82%), mp 64ꢀ65 C. H NMR (300 MHz, CDCl3): δ =
1.46 (t, 3H, 3J = 7.0 Hz, CH2CH3), 2.42 (s, 3H, Me), 3.96 (t, 2H, 3J = 7.0 Hz, CH2CH3), 7.69 (s, 1H, CH).
13C NMR (62.9 MHz, CDCl3): δ = 13.0, 15.5 (Me), 42.0 (CH2), 118.9 (CH), 144.4 (C).
MS (GC, 70eV): m/z (%) = 155 (M+, 61), 83 (20), 56 (41), 43 (100).
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HRMS (EI): Calcd for C6H9N3O2 (M+) 155.06893. Found 155.06894.
~
IR (ATR, cmꢀ1):
= 3108 (w), 1532 (s), 1495 (m), 1453 (w), 1423 (m), 1399 (s), 1332 (s), 1292 (s), 1259 (s), 1190 (w),
ν
1149 (m), 1082 (m), 1034 (w), 991 (m), 964 (m), 835 (s), 803 (m), 757 (s), 681 (s), 639 (w).
o
1
1-butyl-2-methyl-4-nitro-1H-imidazole (3b). White solid (1.610 g, 88%), mp 55ꢀ57 C. H NMR (300 MHz, CDCl3): δ =
0.83 (t, 3H, 3J = 6.7 Hz, CH2CH2CH2CH3), 1.18ꢀ1.31 (m, 2H, CH2CH2CH2CH3), 1.56ꢀ1.70 (m, 2H, CH2CH2CH2CH3), 2.29
(s, 3H, Me), 3.81 (t, 2H, 3J = 7.3 Hz, CH2CH2CH2CH3), 7.59 (s, 1H, CH).
13C NMR (62.9 MHz, CDCl3): δ = 12.7, 13.1 (Me), 19.3, 31.9, 46.6 (CH2), 119.5 (CH), 144.4, 145.9 (C).
MS (GC, 70eV): m/z (%) = 183 (M+, 58), 168 (21), 141 (64), 43 (100).
HRMS (EI): Calcd for C8H13N3O2 (M+) 183.10023. Found 183.100133.
~
IR (ATR, cmꢀ1):
= 3119 (w), 2960 (m), 2874 (w), 1531 (s), 1496 (m), 1466 (s), 1379 (m), 1330 (s), 1290 (s), 1261 (s),
ν
1186 (m), 1135 (m), 1095 (m), 994 (m), 827 (s), 757 (s), 682 (m), 663 (m).
2-methyl-4-nitro-1-phenethyl-1H-imidazole (3c). White solid (2.150 g, 93%), mp 111ꢀ113 oC. 1H NMR (300 MHz, CDCl3):
δ = 2.08 (s, 3H, Me), 3.07 (t, 2H, 3J = 6.8 Hz, CH2), 4.24 (t, 2H, 3J = 6.8 Hz, CH2), 7.00ꢀ7.03 (m, 2H, CHAr), 7.16ꢀ7.17 (m,
1H, CHAr), 7.23ꢀ7.30 (m, 3H, CHAr), 7.48 (s, 1H, Imidazole).
13C NMR (62.9 MHz, CDCl3): δ = 11.8 (Me), 37.2, 49.8 (CH2), 119.1, 127.5, 128.4 (CHAr), 128.6, 128.9 (C), 129.0, 135.9,
136.0 (CHAr), 147.9 (C).
MS (GC, 70eV): m/z (%) = 231 (M+, 40), 105 (25), 91 (100).
HRMS (EI): Calcd for C12H13N3O2 (M+) 231.10023. Found 231.100263.
~
ꢀ1
ν
IR (ATR, cm ):
= 3115 (w), 1516 (m), 1481 (s), 1438 (m), 1404 (m), 1377 (s), 1333 (s), 1286 (s), 1159 (w), 1124 (m),
1048 (w), 1015 (w), 982 (m), 863 (m), 822 (s), 751 (s), 698 (s), 654 (s), 621 (w), 564 (m).
4-nitro-1-phenethyl-1H-imidazole (3d). White solid (1.736 g, 80%), mp 81ꢀ83 oC. 1H NMR (300 MHz, CDCl3): δ = 3.07 (t,
3
2H, 3J = 6.9 Hz, CH2), 4.24 (t, 2H, J = 6.9 Hz, CH2), 7.00ꢀ7.03 (m, 2H, CHAr), 7.17 (d, 1H, 4J = 1.4 Hz, imidazole), 7.21ꢀ
7.27 (m, 3H, CHAr), 7.58 (d, 1H, 4J = 1.4 Hz, imidazole).
13C NMR (62.9 MHz, CDCl3): δ = 37.2, 49.8 (CH2), 119.1, 127.5, 128.4 (CH), 128.6, 128.9 (C), 129.1, 135.9 (CH), 136.0,
147.9 (C).
MS (GC, 70eV): m/z (%) = 217 (M+, 40), 105 (25), 91 (100).
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HRMS (EI): Calcd for C11H11N3O2 (M+) 217.22394. Found 217.22396.
4
5
~
ꢀ1
ν
IR (ATR, cm ):
= 3115 (w), 1516 (m), 1481 (s), 1438 (m), 1404 (m), 1377 (m), 1333 (s), 1286 (s), 1159 (w), 1124 (m),
6
7
1079 (w), 1048 (w), 982 (m), 932 (w), 863 (m), 822 (s), 751 (s), 698 (s), 672 (m), 654 (s), 564 (m).
8
9
o
1
2-methyl-4-nitro-1-(3-phenylpropyl)-1H-imidazole (3e). White solid (1.911 g, 78%), mp 82ꢀ84 C. H NMR (300 MHz,
CDCl3): δ = 2.17ꢀ2.29 (m, 2H, CH2), 2.42 (s, 3H, Me), 2.77 (t, 2H, J = 7.4 Hz, CH2), 3.97 (t, 2H, 3J = 7.4 Hz, CH2), 7.22ꢀ
3
10
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51
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55
56
57
58
59
60
7.24 (m, 2H, CHAr), 7.31ꢀ7.43 (m, 3H, CHAr), 7.74 (s, 1H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 13.0 (Me), 31.3, 32.3, 46.3 (CH2), 119.4, 126.7, 128.2, 128.8 (CHAr), 139.4, 144.7, 146.5
(C).
MS (GC, 70eV): m/z (%) = 245 (M+, 34), 141 (100), 117 (25), 91 (76), 43 (68).
HRMS (EI): Calcd for C13H15N3O2 (M+) 245.11588. Found 245.11586.
~
ꢀ1
ν
IR (ATR, cm ):
= 3104 (w), 3023 (w), 1531 (s), 1494 (s), 1464 (m), 1454 (m), 1419 (m), 1401 (m), 1358 (s), 1326 (s),
1289 (s), 1233 (w), 4498 (w), 1143 (m), 1039 (w), 991 (m), 910 (w), 833 (s), 747 (s), 698 (s), 681 (m), 641 (w), 618 (w), 591
(w), 572 (m).
o
1
2-methyl-4-nitro-1-(2-phenoxyethyl)-1H-imidazole (3f). White solid (2.198g, 89%), mp 100ꢀ101 C. H NMR (300 MHz,
CDCl3): δ = 2.48 (s, 3H, Me), 4.24ꢀ4.30 (m, 4H, 2xCH2), 6.80ꢀ6.83 (m, 2H, CHAr), 6.93ꢀ6.98 (m, 1H, CHAr), 7.22ꢀ7.27 (m,
2H, CHAr), 7.81 (s, 1H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 13.1 (Me), 46.5, 66.1 (CH2), 114.3, 120.2, 121.8, 129.6 (CH), 145.2, 146.4, 157.4 (C).
MS (GC, 70eV): m/z (%) = 247 (M+, 100), 120 (60), 107 (72), 77 (73).
HRMS (EI): Calcd for C12H13N3O3 (M+) 247.09514. Found 247.09556.
~
ꢀ1
ν
IR (ATR, cm ):
= 3118 (w), 1588 (w), 1531 (m), 1495 (m), 1469 (m), 1385 (m), 1329 (s), 1290 (s), 1237 (s), 1161 (m),
1079 (m), 1050 (m), 993 (m), 907 (m), 827 (m), 787 (m), 753 (s), 690 (s), 678 (m), 617 (w), 599 (m), 568 (w).
o
1
1-(4-methylbenzyl)-2-methyl-4-nitro-1H-imidazole (3g). White solid (1.917 g, 83%), mp 104ꢀ105 C. H NMR (300 MHz,
CDCl3): δ = 2.33 (s, 3H, Me), 2.38 (s, 3H, Me), 5.03 (s, 2H, CH2), 7.02 (d, 2H, 3J = 8.1 Hz, CHAr), 7.18 (d, 2H, 3J = 8.1 Hz,
CHAr), 7.60 (s, 1H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 13.3, 21.1 (Me), 50.8 (CH2), 120.0, 127.3, 130.1 (CH), 130.7, 139.0, 145.0, 146.4 (C).
MS (GC, 70eV): m/z (%) = 231 (M+, 11), 105 (100).
HRMS (EI): Calcd for C12H13N3O2 (M+) 231.10023.Found 231.10038.
~
IR (ATR, cmꢀ1):
= 3099 (w), 1533 (s), 1493 (m), 1462 (m), 145 (w), 1396 (s), 1350 (m), 1329 (s), 1314 (m), 1286 (s),
ν
1226 (m), 1141 (m), 1036n (w), 993 (m), 833 (m), 756 (s), 681 (s), 662 (m), 616 (w), 574 (m).
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1-(2-brombenzyl)-2-methyl-4-nitro-1H-imidazole (3h). Brown solid (2.449 g, 83%), mp 91ꢀ92 C. H NMR (300 MHz,
4
5
6
3
4
CDCl3): δ = 2.43 (s, 3H, Me), 5.15 (s, 2H, CH2), 6.95 (dd, 1H, J = 7.6 Hz, J = 1.7 Hz, CHAr), 7.24ꢀ7.34 (m, 2H, CHAr),
7.56 (s, 1H, CHAr), 7.64 (dd, 1H, 3J = 7.8 Hz, 4J = 1.3 Hz, CHAr).
7
8
9
13C NMR (62.9 MHz, CDCl3): δ = 13.3 (Me), 51.0 (CH2), 119.8 (CH), 123.3 (C), 128.5, 129.2, 130.8 (CH), 133.1 (C), 133.7
(CH), 145.2, 146.5 (C).
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MS (GC, 70eV): m/z (%) = 296 (M+, 9), 296 (1), 295 (10), 171 (100), 169 (97), 90 (34), 89 (32).
HRMS (EI): Calcd for C11H10N3O2Br (M+) 296.12000. Found 296.12012.
~
ꢀ1
ν
IR (ATR, cm ):
= 3127 (w), 1588 (w), 1532 (s), 1493 (s), 1438 (m), 1413 (m), 1380 (m), 1358 (m), 1324 (m), 1291 (s),
1268 (s), 1142 (m), 1127 (m), 1030 (m), 992 (m), 943 (w), 829 (m), 783 (m), 752 (s), 659 (m).
1
2-methyl-1-(3-phenylpropyl)-1H-imidazole (3i). White viscous oil (1.345 g, 41%). H NMR (300 MHz, CDCl3): δ = 2.02ꢀ
3
3
2.12 (m, 2H, CH2), 2.32 (s, 3H, Me), 2.64 (t, 2H, J = 7.4 Hz, CH2), 3.82 (t, 2H, J = 7.2 Hz, CH2), 6.81ꢀ6.82 (m, 1H,
imidazole), 6.91ꢀ6.92 (m, 1H, imidazole), 7.13ꢀ7.32 (m, 5H, CHAr).
13C NMR (75.4 MHz, CDCl3): δ = 13.0 (Me), 32.0, 32.6, 45.3 (CH2), 119.0, 126.4, 127.0, 128.3, 128.6 (CHAr), 140.4, 144.4,
(C).
MS (GC, 70eV): m/z (%) = 200 (M+, 50), 117 (17), 117 (25), 96 (76), 91 (45).
HRMS (ESI): Calcd for C13H16N2 (M+H) 201.13862. Found 201.13866.
~
IR (ATR, cmꢀ1):
= 3034 (w), 2928 (w), 1589 (w), 1531 (m), 1492 (m), 1423 (m), 1349 (w), 1277 (w), 1232 (w), 1153
ν
(w), 1095 (w), 1045 (w), 926 (w), 857 (w), 768 (s), 738 (s), 704 (s), 669 (s), 619 (w), 577 (m).
5-(4-(trifluoromethyl)phenyl)-2-methyl-4-nitro-1-(3-phenylpropyl)-1H-imidazole (4a). Green solid (0.373 g, 96%Pd),
(0.276 g, 71%ArꢀI), mp 118ꢀ120 oC. 1H NMR (300 MHz, DMSOꢀd6): δ = 1.77ꢀ1.87 (m, 2H, CH2), 2.31 (s, 3H, Me), 2.71ꢀ2.77
(m, 2H, CH2), 3.99ꢀ4.05 (m, 2H, CH2), 65.8ꢀ6.88 (m, 2H, CHAr), 7.19ꢀ7.22 (m, 3H, CHAr), 7.62ꢀ7.77 (m, 3H, CHAr), 7.88ꢀ
7.91 (m, 1H, CHAr).
19F NMR (235 MHz, DMSOꢀd6): δ = ꢀ62.7 (CF3).
1
13C NMR (62.9 MHz, DMSOꢀd6): δ = 13.4 (Me), 31.3, 32.4, 44.2 (CH2), 123.5 (q, J = 274.3 Hz, CF3), 126.7 (CH), 126.8
3
2
(q, J = 8 Hz, C), 127.9 (CH), 128.4 (C), 128.7, 129.5 (CH), 130.2 (C), 131.3 (q, J = 32.8 Hz, CCF3), 133.5 (CH), 139.1,
143.5, 143.9 (C).
MS (GC, 70eV): m/z (%) = 389 (M+, 100), 285 (12), 211 (20), 198 (39), 178 (11), 117 (11), 91 (55).
HRMS (EI): Calcd for C20H18N3O2F3 (M+) 389.13456. Found 389.13444.
~
IR (ATR, cmꢀ1):
= 2956 (w), 1602 (w), 1573 (w), 1533 (w), 1504 (s), 1437 (m), 1402 (m), 1331 (s), 1291 (s), 1245 (m),
ν
1222 (w), 1190 (m), 1163 (m), 1120 (s), 1081 (s), 1020 (w), 930 (w), 872 (m), 804 (m), 778 (w), 750 (m), 732 (m), 698 (s),
674 (m), 565 (m).
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2-methyl-4-nitro-5-(3-nitrophenyl)-1-(3-phenylpropyl)-1H-imidazole (4b). Green solid (0.296 g, 81%Pd), (0.157 g, 48%Ni),
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5
6
7
o
1
(0.216 g, 59%ArꢀI), mp 164ꢀ166 C. H NMR (300 MHz, DMSOꢀd6): δ = 1.69ꢀ1.79 (m, 2H, CH2), 2.41ꢀ2.46 (m, 5H, Me,
CH2), 3.72ꢀ3.78 (m, 2H, CH2), 6.94ꢀ6.97 (m, 2H, CHAr), 7.06ꢀ7.17 (m, 3H, CHAr), 7.74ꢀ7.80 (m, 1H, CHAr), 7.92ꢀ7.95 (m,
1H, CHAr), 8.33ꢀ8.37 (m, 2H, CHAr).
8
9
13C NMR (62.9 MHz, DMSOꢀd6): δ = 13.0 (Me), 30.3, 31.5, 43.7 (CH2), 124.5, 124.9, 125.8, 127.9, 128.1 (CH), 129.4,
130.1 (C), 130.2, 137.0 (CH), 140.1, 142.7, 144.3, 147.6 (C).
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MS (GC, 70eV): m/z (%) = 366 (M+, 47), 175 (25), 117 (18), 91 (100).
HRMS (EI): Calcd for C19H18N4O4 (M+) 366.37062. Found 366.37064.
~
IR (ATR, cmꢀ1):
= 3060 (w), 1526 (s), 1504 (m), 1441 (w), 1402 (w), 1349 (s), 1290 (s), 1242 (m), 1099 (m), 1018 (w),
ν
932 (w), 890 (w), 861 (w), 814 (m), 755 (s), 733 (m), 694 (s), 668 (m), 578 (w).
2-(2-methyl-4-nitro-1-(3-phenylpropyl)-1H-imidazol-5-yl)benzaldehyde (4c). Yellow solid (0.314 g, 90%Pd), mp 126ꢀ128
oC. 1H NMR (300 MHz, CDCl3): δ = 1.71ꢀ1.82 (m, 2H, CH2), 2.40 (s, 3H, Me), 2.44 (t, 2H, 3J = 7.3 Hz, CH2), 3.47ꢀ3.71 (m,
2H, CH2), 6.88ꢀ6.92 (m, 2H, CHAr), 7.11ꢀ7.18 (m, 2H, CHAr), 7.27ꢀ7.31 (m, 1H, CHAr), 7.37ꢀ7.55 (m, 1H, CHAr), 7.66ꢀ7.74
(m, 2H, CHAr), 7.94ꢀ8.00 (m, 1H, CHAr), 9.85 (s, 1H, CHO).
13C NMR (62.9 MHz, CDCl3): δ = 13.4 (Me), 30.9, 32.3, 44.2 (CH2), 126.4, 127.9 (CH), 128.3 (C), 128.6, 130.7 (CH), 131.7
(C), 131.9, 132.1, 134.0, 135.1 (CH), 139.2, 143.6 (C), 190.4 (CH).
MS (GC, 70eV): m/z (%) = 349 (M+, 1), 303 (100), 91 (44).
HRMS (ESI): Calcd for C20H20N3O3 (M+H) 350.14992. Found 350.15086.
~
ꢀ1
ν
IR (ATR, cm ):
= 1683 (s), 1599 (w), 1564 (w), 1542 (m), 1490 (s), 1453 (m), 1398 (m), 1353 (m), 1337 (s), 1294 (s),
1269 (m), 1254 (m), 1225 (m), 1197 (m), 1120 (w), 1032 (w), 1005 (w), 978 (w), 850 (m), 823 (m), 764 (m), 738 (s), 698
(s), 671 (s), 614 (m), 540 (m).
4,5-dimethoxy-2-(2-methyl-4-nitro-1-(3-phenylpropyl)-1H-imidazol-5-yl)benzaldehyde (4d). Yellow solid (0.360 g,
o
1
88%Pd), mp 165ꢀ167 C. H NMR (300 MHz, DMSOꢀd6): δ = 1.77ꢀ1.82 (m, 2H, CH2), 2.41ꢀ2.51 (m, 5H, Me, CH2), 3.56ꢀ
3.72 (m, 2H, CH2), 3.87 (s, 3H, OMe), 4.02 (s, 3H, OMe), 6.67 (s, 1H, CHAr), 6.89ꢀ6.92 (m, 3H, CHAr), 7.17ꢀ7.19 (m, 2H,
CHAr), 7.46 (br. s, 1H, CHAr), 9.63 (s, 1H, CHO).
13C NMR (62.9 MHz, DMSOꢀd6): δ = 13.6 (Me), 30.3, 31.5, 43.8 (CH2), 55.7, 56.2 (OMe), 111.5, 113.8 (CH), 123.3, 125.8
(C), 127.9, 128.1, 128.8 (CH), 129.6 (C), 131.4, 131.5 (CH), 132.0, 140.2, 143.4, 144.3, 149.7, 153.2 (C), 190.0 (CHO).
MS (GC, 70eV): m/z (%) = 409 (M+, 1), 363 (100), 91 (25).
HRMS (ESI): Calcd for C22H24N3O5 (M+H) 410.17105. Found 410.17082.
~
ꢀ1
ν
IR (ATR, cm ):
= 2938 (w), 1681 (m), 1591 (m), 1514 (s), 1494 (m), 1441 (m), 1397 (m), 1352 (m), 1329 (m), 1268 (s),
1227 (m), 1145 (s), 1100 (m), 1021 (m), 866 (w), 824 (w), 749 (m), 699 (s), 641 (w), 586 (m), 540 (w).
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5-(3-(trifluoromethyl)phenyl)-2-methyl-4-nitro-1-phenethyl-1H-imidazole (4e). Green solid (0.368 g, 98%Pd), (0.274 g,
4
5
o
1
73%Ni), (0.281 g, 75%ArꢀI), mp 164ꢀ166 C. H NMR (300 MHz, DMSO): δ = 2.31 (s, 3H, Me), 2.71ꢀ2.77 (m, 2H, CH2),
6
3.99ꢀ4.05 (m, 2H, CH2), 6.58ꢀ6.88 (m, 2H, CHAr), 7.19ꢀ7.22 (m, 3H, CHAr), 7.62ꢀ7.77 (m, 3H, CHAr), 7.88ꢀ7.91 (m, 1H,
7
8
CHAr).
9
19F NMR (235 MHz, DMSO): δ = ꢀ61.03.
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1
13C NMR (62.9 MHz, DMSO): δ = 12.9 (Me), 34.8, 46.0 (CH2), 123.8 (q, J = 271 Hz, CF3), 126.3, 126.8, 127.0, 128.5,
128.5 (CH), 129.3 (q, 2J = 31 Hz, CCF3), 129.7 (CH), 131.0 (C), 134.0 (CH), 137.0, 142.6, 144.4 (C).
MS (GC, 70eV): m/z (%) = 375 (M+, 94), 105 (100), 91 (80).
HRMS (EI): Calcd for C19H16N3O2F3 (M+) 375.11891. Found 375.11871.
~
IR (ATR, cmꢀ1):
= 1565 (w), 1533 (w), 1498 (m), 1440 (w), 1388 (w), 1354 (m), 1329 (s), 1308 (s), 1288 (s), 1254 (m),
ν
1224 (w), 1201 (w), 1167 (m), 1117 (s), 1073 (s), 1020 (w), 935 (m), 900 (w), 856 (m), 806 (s), 755 (m), 698 (s), 672 (m),
649 (w).
5-(2-methyl-4-nitro-1-phenethyl-1H-imidazol-5-yl)pyrimidine (4f). Yellow solid (0.247 g, 80%Pd), (0.163 g, 53%Ni), mp
o
1
3
3
183ꢀ185 C. H NMR (300 MHz, CDCl3): δ = 2.45 (s, 3H, Me), 2.86 (t, 2H, J = 6.4 Hz, CH2), 4.10 (t, 2H, J = 6.4 Hz,
CH2), 6.76ꢀ6.78 (m, 2H, CHAr), 7.22ꢀ7.32 (m, 3H, CHAr), 8.37 (s, 2H, CHAr), 9.29 (s, 1H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 13.5 (Me), 35.9, 46.3 (CH2), 122.7, 125.5 (C), 127.8, 128.5, 129.2 (CH), 131.9, 135.3,
144.2, 145.2 (C), 157.4, 158.9 (CH).
MS (GC, 70eV): m/z (%) = 309 (M+, 98), 105 (90), 91 (100), 77 (33).
HRMS (EI): Calcd for C16H15N5O2 (M+) 309.12203. Found 309.12208.
~
IR (ATR, cmꢀ1):
= 2920 (w), 1609 (w), 1549 (w), 1505 (s), 1453 (w), 1408 (s), 1342 (s), 1298 (m), 1253 (m), 1187 (m),
ν
1119 (w), 997 (m), 919 (m), 865 (m), 754 (m), 724 (s), 705 (s), 665 (m), 625 (s), 564 (m).
2-(2-methyl-4-nitro-1-phenethyl-1H-imidazol-5-yl)benzaldehyde (4g). Yellow solid (0.322 g, 96%Pd), (0.218 g, 65%Ni), mp
o
1
3
162ꢀ164 C. H NMR (300 MHz, CDCl3): δ = 2.26 (s, 3H, Me), 2.70 (t, 2H, J = 7.1 Hz, CH2), 3.72ꢀ3.81 (m, 1H, CH2),
3.96ꢀ4.06 (m, 2H, CH2), 6.78ꢀ6.81 (m, 2H, CHAr), 7.11ꢀ7.13 (m, 1H, CHAr), 7.17ꢀ7.22 (m, 2H, CHAr), 7.42ꢀ7.53 (m, 2H,
CHAr), 7.62ꢀ7.73 (m, 1H, CHAr), 8.00ꢀ8.03 (m, 1H, CHAr), 9.81 (s, 1H, CHO).
13C NMR (62.9 MHz, CDCl3): δ = 13.4 (Me), 36.0, 46.5 (CH2), 127.4 (CH), 128.4 (C), 128.6, 129.0, 130.6, 131.7, 132.1
(CH), 133.9, 135.1, 136.1 (C), 190.4 (CH).
MS (GC, 70eV): m/z (%) = 335 (M+, 1), 289 (100), 105 (39), 91 (15), 77 (14).
HRMS (ESI): Calcd for C19H18N3O3 (M+H) 336.13427. Found 336.1346.
~
ꢀ1
ν
IR (ATR, cm ):
= 1695 (m), 1599 (w), 1531 (m), 1496 (s), 1437 (m), 1384 (m), 1319 (s), 1293 (s), 1270 (m), 1236 (s),
1201 (m), 1120 (w), 1092 (w), 1003 (w), 931 (w), 850 (m), 824 (m), 757 (s), 702 (s), 673 (m), 569 (m).
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5-(2-chloro-5-(trifluoromethyl)phenyl)-2-methyl-4-nitro-1-(2-phenoxyethyl)-1H-imidazole (4h). Green solid (0.318 g,
30%Pd), mp 180ꢀ181 oC. 1H NMR (300 MHz, DMSOꢀd6): δ = 2.63 (s, 3H, Me), 3.93ꢀ4.19 (m, 4H, CH2), 6.69ꢀ6.72 (m, 2H,
CHAr), 6.94ꢀ6.98 (m, 1H, CHAr), 7.21ꢀ7.26 (m, 2H, CHAr), 7.67ꢀ7.76 (m, 3H, CHAr).
19F NMR (235 MHz, DMSOꢀd6): δ = ꢀ62.5 (CF3).
9
13C NMR (62.9 MHz, DMSOꢀd6): δ = 13.9 (Me), 44.7, 65.6 (CH2), 114.1, 121.9 (CH), 123.4 (q, 1J = 273 Hz, CF3), 127.5,
128.1 (C), 128.5 (q, 3J = 4 Hz, CH), 129.3 (q, 3J = 4 Hz, CH), 129.7 (CH), 130.2 (C), 130.8 (CH), 138.9, 144.1, 145.5, 157.4
(C).
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MS (GC, 70eV): m/z (%) = 425 (M+, 16), 390 (59), 360 (100), 77 (39).
HRMS (ESI): Calcd for C19H16N3O3F3Cl (M+H) 426.08249.Found 426.08249.
~
ꢀ1
ν
IR (ATR, cm ):
= 1738 (w), 1673 (w), 1588 (w), 1532 (w), 1504 (s), 1406 (m), 1329 (s), 1285 (m), 1239 (s)(, 1168 (s),
1121 (s), 1078 (s), 1017 (m), 918 (m), 859 (m), 814 (m), 791 (m), 753 (s), 689 (m), 605 (w), 535 (m).
4,5-dimethoxy-2-(2-methyl-4-nitro-1-(2-phenoxyethyl)-1H-imidazol-5-yl)benzaldehyde (4i). Yellow solid (0.333 g, 81%Pd),
mp 141ꢀ143 oC. 1H NMR (300 MHz, DMSOꢀd6): δ = 2.56 (s, 3H, Me), 3.85 (s, 3H, OMe), 3.93 (s, 3H, OMe), 3.96ꢀ4.26 (m,
4H, 2xCH2), 6.73 (d, 2H, 3J = 8.0 Hz, CHAr), 6.91 (t, 1H, 3J = 7.1 Hz, CHAr), 7.19ꢀ7.25 (m, 3H, CHAr), 7.56 (s, 1H, CHAr),
9.67 (s, 1H, CHO).
13C NMR (62.9 MHz, DMSOꢀd6): δ = 13.0 (Me), 43.6 (CH2), 55.2, 55.8 (OMe), 65.2 (CH2), 110.7, 113.7, 120.5 (CH),
123.0, 127.9, 128.1, 128.3, 128.9 (C), 129.4 (CH), 143.2, 144.6, 149.3, 152.7, 157.1 (C), 189.4 (CHO).
MS (GC, 70eV): m/z (%) = 411 (M+, 1), 365 (100), 77 (18).
HRMS (ESI): Calcd for C21H22N3O6 (M+H) 412.15031. Found 412.15044.
~
IR (ATR, cmꢀ1):
= 2933 (w), 1737 (w), 1678 (m), 1586 (m), 1537 (m), 1495 (s), 1445 (m), 1398 (m), 1353 (m), 1329
ν
(m), 1283 (s), 1222 (s), 1155 (s), 1119 (m), 1036 (m), 1016 (m), 882 (s), 856 (m), 815 (m), 743 (s), 691 (m), 585 (m).
2-(2-methyl-4-nitro-1-(2-phenoxyethyl)-1H-imidazol-5-yl)benzaldehyde (4j). Yellow solid (0.263 g, 75%Pd), mp 148ꢀ150
1
oC. H NMR (300 MHz, CDCl3): δ = 2.57 (s, 3H, Me), 3.96ꢀ4.24 (m, 4H, 2xCH2), 6.70ꢀ6.74 (m, 2H, CHAr), 6.88ꢀ6.93 (m,
1H, CHAr), 7.19ꢀ7.25 (m, 2H, CHAr), 7.59ꢀ7.64 (m, 1H, CHAr), 7.77ꢀ7.89 (m, 2H, CHAr), 8.10 (dd, 1H, 3J = 7.3 Hz, 4J = 1.2
Hz, CHAr), 9.86 (s, 1H, CHO).
13C NMR (62.9 MHz, CDCl3): δ = 13.4 (Me), 44.1, 65.6 (CH2), 114.2, 121.0, 128.7, 129.4 (CH), 130.6 (C), 130.7, 131.4,
131.5, 132.0, 134.2 (CH), 135.0, 143.3, 145.2, 157.5 (C), 194.8 (CHO).
MS (GC, 70eV): m/z (%) = 351 (M+, 1), 305 (21), 44 (100).
HRMS (EI): Calcd for C19H17N3O4 (M+) 351.35598.Found 351.35599.
~
IR (ATR, cmꢀ1):
= 2927 (w), 1690 (m), 1600 (m), 1565 (w), 1538 (w), 1496 (s), 1396 (m), 1353 (m), 1330 (s), 1293 (m),
ν
1269 (m), 1230 (s), 1179 (m), 1119 (w), 1085 (m), 1051 (m), 962 (w), 908 (w), 886 (w), 849 (m), 828 (m), 757 (s), 721 (m),
692 (s), 670 (m), 631 (w), 592 (w), 539 (m).
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1-(4-methylbenzyl)-2-methyl-4-nitro-5-(phenanthren-10-yl)-1H-imidazole (4k). Dark brown viscous oil (0.258 g, 80%Pd),
(0.162 g, 40%Ni). 1H NMR (300 MHz, CDCl3): δ = 2.15 (s, 3H, Me), 2.39 (s, 3H, Me), 4.62 (d, 1H, 3J = 15.0 Hz, CH2), 4.84
(d, 1H, 3J = 15.0 Hz, CH2), 6.55 (d, 2H, 3J = 7.9 Hz, CHAr), 6.86 (d, 2H, 3J = 7.9 Hz, CHAr), 7.36ꢀ7.67 (m, 7H, CHAr), 8.60
(t, 2H, 3J = 9.8 Hz, CHAr).
9
13C NMR (62.9 MHz, CDCl3): δ = 13.7, 18.4, 20.9 (Me), 48.1 (CH2), 126.3, 127.0, 129.5 (CH), 130.7, 131.7 (C), 134.2
(CH), 137.1, 137.9, 143.4, 144.1, 144.7 (C) 149.9 (CH).
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MS (GC, 70eV): m/z (%) = 407 (M+, 53), 105 (100).
HRMS (EI): Calcd for C26H21N3O2 (M+) 407.16283. Found 407.16301.
~
IR (ATR, cmꢀ1):
= 1537 (m), 1504 (s), 1446 (m), 1385 (m), 1336(s), 1293 (s), 1222 (m), 1124 (w), 1018 (m), 933 (w),
ν
859 (s), 796 (s), 766 (m), 756 (m), 719 (m), 665 (m), 624 (m), 594 (w).
3-(1-(4-methylbenzyl)-2-methyl-4-nitro-1H-imidazol-5-yl)benzaldehyde (4l). Yellow solid (0.285 g, 85%Pd), mp 139ꢀ141
oC. 1H NMR (300 MHz, DMSOꢀd6): δ = 2.21 (s, 3H, Me), 2.39 (s, 3H, Me), 4ꢀ88ꢀ5.03 (m, 2H, CH2), 6.74 (d, 2H, 3J = 8.0
3
Hz, CHAr), 7.03 (d, 2H, J = 8.0 Hz, CHAr), 7.48ꢀ7.51 (m, 1H, CHAr), 7.72ꢀ7.77 (m, 2H, CHAr), 7.95ꢀ7.99 (m, 1H, CHAr),
9.73 (s, 1H, CHO).
13C NMR (62.9 MHz, DMSOꢀd6): δ = 13.4, 20.5 (Me), 47.6 (CH2), 126.4, 127.5 (CH), 128.4 (C), 129.1, 129.5, 130.5 (CH),
130.6 (C), 130.9, 131.5 (CH), 132.0 (C), 134.0, 134.7 (CH), 137.0, 143.4, 144.8 (C), 191.4 (CHO).
MS (GC, 70eV): m/z (%) = 335 (M+, 1), 105 (100).
HRMS (ESI): Calcd for C19H18N3O3 (M+H) 336.13427. Found 336.1342.
~
IR (ATR, cmꢀ1):
= 2841 (w), 2751 (w), 1699 (m), 1601 (w), 1568 (w) 1533 (m), 1494 (s), 1435 (m), 1397 (m), 1377 (s),
ν
1328 (s), 1288 (s), 1249 (s), 1199 (m), 1121 (m), 1036 (w), 1003 (w), 859 (m), 813 (s), 785 (s), 765 (s), 723 (m), 670 (m),
610 (m), 541 (s).
1-(4-methylbenzyl)-5-(3-(trifluoromethyl)phenyl)-2-methyl-4-nitro-1H-imidazole (4m). Green solid (0.368 g, 92%Pd),
o
1
(0.191 g, 62%Ni), mp 152ꢀ154 C. H NMR (300 MHz, DMSOꢀd6): δ = 2.31 (s, 3H, Me), 2.43 (s, 3H, Me), 4.90 (s, 2H,
CH2), 6.71 (d, 2H, 3J = 6.0 Hz, CHAr), 7.45 (d, 2H, 3J = 6.0 Hz, CHAr), 7.45ꢀ7.56 (m, 3H, CHAr), 7.68ꢀ7.71 (m, 1H, CHAr).
19F NMR (235 MHz, DMSOꢀd6): δ = ꢀ62.9 (CF3).
13C NMR (62.9 MHz, DMSOꢀd6): δ = 13.7, 21.0 (Me), 48.2 (CH2), 123.4 (q, 1J = 273.2 Hz, CF3), 125.7 (CH), 126.7 (q, 3J =
4.1 Hz, CH), 127.1 (q, 3J = 4.1 Hz, CH), 128.2 (C), 129.3 (CH), 129.9 (C), 130.7 (CH), 131.1 (q, 2J = 32.6 Hz, CCF3), 131.3
(C), 133.5 (CH), 138.4, 143.5, 144.7 (C).
MS (GC, 70eV): m/z (%) = 375 (M+, 10), 105 (100).
HRMS (EI): Calcd for C19H16N3O2F3 (M+) 375.11891. Found 375.11887.
~
ꢀ1
ν
IR (ATR, cm ):
= 1538 (m), 1499 (m), 1429 (w), 1399 (m), 1328 (s), 1288 (s), 1252 (m), 1184 (m), 1164 (s), 1111 (s),
1076 (s), 1024 (m), 926 (m), 857 (m), 812 (m), 796 (s), 766 (m), 726 (m), 700 (m), 663 (m), 644 (w), 599 (w).
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5-(1-(4-methylbenzyl)-2-methyl-4-nitro-1H-imidazol-5-yl)pyrimidine (4n). Yellow solid (0.253 g, 82%Pd), (0.157 g, 51%Ni),
mp 183ꢀ185 oC. 1H NMR (300 MHz, DMSOꢀd6): δ = 2.25 (s, 3H, Me), 2.39 (s, 3H, Me), 5.14 (s, 2H, CH2), 6.82 (d, 2H, 3J =
8.1 Hz, CHAr), 7.10 (d, 2H, 3J = 8.1 Hz, CHAr), 8.84 (s, 2H, CHAr), 9.25 (s, 1H, CHAr).
13C NMR (62.9 MHz, DMSOꢀd6): δ = 13.2, 20.6 (Me), 47.5 (CH2), 123.0 (C), 126.1 (CH), 126.8 (C), 128.6, 129.4, 131.4,
131.5 (CH), 132.0, 137.1, 143.8, 145.5 (C), 157.7, 158.7 (CH).
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MS (GC, 70eV): m/z (%) = 309 (M+, 10), 105 (100).
HRMS (EI): Calcd for C16H15N5O2 (M+) 309.12203. Found 309.12176.
~
ꢀ1
ν
IR (ATR, cm ):
= 2965 (w), 1551 (w), 1529 (w), 1501 (s), 1432 (m), 1401 (m), 1339 (s), 1299 (m), 1271 (m), 1189 (m),
1120 (m), 1002 (m), 917 (w), 858 (m), 789 (m), 756 (w), 723 (s), 694 (m), 665 (m), 628 (m), 537 (m).
1-(4-methylbenzyl)-5-(4-methoxyphenyl)-2-methyl-4-nitro-1H-imidazole (4o). Yellow viscous oil (0.226 g, 67%Pd), (0.155
g, 46%ArꢀI). 1H NMR (300 MHz, CDCl3): δ = 2.29 (s, 3H, Me), 2.33 (s, 3H, Me), 3.79 (s, 3H, OMe), 4.91 (s, 2H, CH2), 6.75
(d, 2H, 3J = 7.6 Hz, CHAr), 6.90 (d, 2H, 3J = 8.5 Hz, CHAr), 7.09 (d, 2H, 3J = 7.6 Hz, CHAr), 7.19 (d, 2H, 3J = 8.5 Hz, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 13.8, 21.0 (Me), 47.8 (CH2), 55.3 (OMe), 114.2 (CH), 115.4, 119.0 (C), 125.8, 128.7,
129.8, 130.1, 131.6 (CH), 133.1, 138.1, 143.2, 144.1, 160.8 (C).
MS (GC, 70eV): m/z (%) = 337 (M+, 32), 105 (100).
HRMS (EI): Calcd for C19H19N3O3 (M+) 337.14209. Found 337.14203.
~
IR (ATR, cmꢀ1):
= 2926 (w), 1666 (w), 1613 (w), 1506 (s), 1441 (w), 1335 (s), 1288 (s), 1247 (s), 1176 (s), 1110 (w),
ν
1032 (m), 856 (s), 797 (m), 717 (m), 669 (w), 620 (w), 596 (m), 529 (m).
1-(4-methylbenzyl)-5-(2-fluorophenyl)-2-methyl-4-nitro-1H-imidazole (4p). Green solid (0.166 g, 51%Pd), mp 115ꢀ117 C.
1H NMR (300 MHz, DMSOꢀd6): δ = 2.26 (s, 3H, Me), 2.34 (s, 3H, Me), 4.82ꢀ4.99 (m, 2H, CH2), 6.72 (d, 2H, 3J = 8.0 Hz,
CHAr), 7.05 (d, 2H, 3J = 8.0 Hz, CHAr), 7.09ꢀ7.22 (m, 3H, CHAr), 7.39ꢀ7.46 (m, 1H, CHAr).
19F NMR (235 MHz, DMSOꢀd6): δ = ꢀ111.23 (CF).
o
13C NMR (62.9 MHz, DMSOꢀd6): δ = 13.4, 20.8 (Me), 48.0 (CH2), 115.2 (d, 3J = 15.4 Hz, C), 115.9 (d, 2J = 22.2 Hz, CH),
124.3 (d, J = 4.1 Hz, C), 125.8 (CH), 126.5 (C), 129.5, 131.1, 131.5, 132.1, 132.3 (CH), 137.9, 143.9, 144.9 (C), 159.3 (d, 1J
= 249.7 Hz, CF).
MS (GC, 70eV): m/z (%) = 325 (M+, 21), 105 (100).
HRMS (ESI): Calcd for C18H17N3O2F (M+H) 326.12993. Found 326.13006.
~
IR (ATR, cmꢀ1):
= 1532 (m), 1495 (s), 1444 (m), 1397 (m), 1378 (m), 1328 (s), 1288 (m), 1269 (m), 1251 (m), 1221 (m),
ν
1116 (w), 1095 (w), 1007 (w), 863 (w), 840 (m), 808 (s), 765 (s), 716 (m), 665 (m), 607 (m).
2-methyl-5-(2-methyl-1-(4-methylbenzyl)-4-nitro-1H-imidazol-5-yl)pyridine (4q). Yellow viscous oil (0.220 g, 54%Pd). H
NMR (300 MHz, CDCl3): δ = 2.25 (s, 3H, Me), 2.36 (s, 6H, Me), 5.16 (s, 2H, CH2), 6.76 (d, 2H, 3J = 8.0 Hz, CHAr), 7.02 (d,
2H, 3J = 8.0 Hz, CHAr), 7.45 (d, 1H, 3J = 8.0 Hz, CHAr), 7.53ꢀ7.56 (m, 1H, CHAr), 8.51 (s, 1H, CHAr).
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13C NMR (62.9 MHz, CDCl3): δ = 13.7, 18.4, 20.6 (Me), 48.0 (CH2), 126.3, 127.1, 129.5 (CH), 130.8, 131.8, 134.2 (C),
137.1 (CH), 137.9, 143.5, 144.1, 144.8 (C), 150.0 (CH).
MS (GC, 70eV): m/z (%) = 322 (M+, 10), 305 (100), 263 (34), 146 (26), 119 (23), 105 (52).
HRMS (EI): Calcd for C18H18N4O2 (M+) 322.14243. Found 322.14228.
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ꢀ1
ν
IR (ATR, cm ):
= 1733 (w), 1668 (w), 1564 (w), 1497 (s), 1441 (m), 1384 (m), 1336 (s), 1282 (m), 1226 (w), 1136 (m),
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1039 (w), 901 (m), 864 (w), 839 (w), 810 (w), 749 (s), 725 (s), 616 (m).
1-(4-methylbenzyl)-5-(3-methoxyphenyl)-2-methyl-4-nitro-1H-imidazole (4r). Yellow solid (0.263 g, 78%Pd), (0.145 g,
o
1
43%Ni), mp 146ꢀ148 C. H NMR (300 MHz, CDCl3): δ = 2.31 (s, 3H, Me), 2.35 (s, 3H, Me), 3.67 (s, 3H, OMe), 4.91 (s,
2H, CH2), 6.75ꢀ6.77 (m, 3H, CHAr), 6.84ꢀ6.87 (m, 1H, CHAr), 6.95ꢀ6.99 (m, 1H, CHAr), 7.09ꢀ7.12 (m, 2H, CHAr), 7.29ꢀ7.34
(m, 1H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 13.8, 21.0 (Me), 47.9 (CH2), 55.2 (OMe), 115.4, 115.9, 122.2, 125.8 (CH), 128.3 (C),
129.7, 129.8 (CH), 131.8, 132.8, 138.1, 144.2, 159.5 (C).
MS (GC, 70eV): m/z (%) = 337 (M+, 24), 105 (100).
HRMS (EI): Calcd for C19H19N3O3 (M+) 337.14209. Found 337.14198.
~
ꢀ1
ν
IR (ATR, cm ):
= 2919 (w), 1589 (m), 1568 (m), 1536 (m), 1503 (s), 1451 (m), 1398 (s), 1344 (s), 1292 (s), 1223 (s),
1180 (m), 1125 (m), 1039 (m), 1016 (m), 897 (m), 873 (m), 829 (m), 786 (s), 765 (m), 706 (m), 689 (m), 665 (m), 555 (w).
1-(3-(2-methyl-1-(4-methylbenzyl)-4-nitro-1H-imidazol-5-yl)phenyl)ethanone (4s). Yellow solid (0.251 g, 72%Pd), mp 173ꢀ
174 oC. 1H NMR (300 MHz, DMSOꢀd6): δ = 2.23 (s, 3H, Me), 2.34 (s, 3H, Me), 2.49 (s, 3H, Me), 5.03 (s, 2H, CH2), 6.80 (d,
2H, 3J = 7.5 Hz, CHAr), 7.09 (d, 2H, 3J = 7.5 Hz, CHAr), 7.58ꢀ7.70 (m, 2H, CHAr), 7.91 (br. s, 1H, CHAr), 8.01ꢀ8.05 (m, 1H,
CHAr).
13C NMR (62.9 MHz, DMSOꢀd6): δ = 13.2, 20.5, 26.6 (Me), 47.3 (CH2), 126.0 (CH), 128.0 (C), 129.0, 129.1, 129.3, 130.0
(CH), 132.2, 132.4 (C), 134.8 (CH), 136.8, 136.9, 142.7, 144.4 (C), 197.2 (COMe).
MS (GC, 70eV): m/z (%) = 349 (M+, 8), 105 (100).
HRMS (EI): Calcd for C20H19N3O3 (M+) 349.14209. Found 349.14266.
~
IR (ATR, cmꢀ1):
= 2921 (w), 1683 (s), 1564 (w), 1535 (w), 1501 (s), 1424 (w), 1396 (m), 1335 (s), 1274 (s), 1231 (s),
ν
1122 (w), 1020 (w), 958 (w), 904 (w), 796 (m), 766 (m), 693 (m), 588 (m).
2-(1-butyl-2-methyl-4-nitro-1H-imidazol-5-yl)-4,5-dimethoxybenzaldehyde (4t). Brown solid (0.295 g, 85%Pd), mp 212ꢀ214
oC. 1H NMR (300 MHz, DMSO): δ = 0.67 (t, 3H, 3J = 7.3 Hz, CH2CH2CH2CH3), 1.04ꢀ1.17 (m, 2H, CH2CH2CH2CH3), 1.33ꢀ
1.42 (m, 2H, CH2CH2CH2CH3), 2.46 (s, 3H, Me), 3.61 ꢀ3.82 (m, 2H, CH2CH2CH2CH3), 3.85 (s, 3H, OMe), 3.92 (s, 3H,
OMe), 7.19 (m, 1H, CHAr), 7.58 (s, 1H, CHAr), 9.70 (s, 1H, CHO).
13C NMR (62.9 MHz, DMSOꢀd6): δ = 13.1, 13.2 (Me), 18.9, 31.1, 44.2 (CH2), 55.7, 56.3 (OMe), 111.6, 114.5 (CH), 123.5,
128.2, 129.6, 132.0, 143.4, 149.8, 153.2 (C), 189.9 (CHO).
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MS (GC, 70eV): m/z (%) = 347 (M+, 1), 303 (100), 91 (44).
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HRMS (ESI): Calcd for C17H21N3O5 (M+H) 348.1554. Found 348.1560.
~
6
7
IR (ATR, cmꢀ1):
= 2957 (w), 1666 (m), 1582 (m), 1498 (s), 1447 (w), 14023 (m), 1351 (m), 1291 (m), 1276 (s), 1222 (s),
ν
8
1132 (s), 1132 (s), 1077 (m), 1019 (m), 978 (w), 889 (m), 859 (w), 814 (m), 749 (m), 720 (m), 698 (m), 585 (m), 539 (m).
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5-(3-(nitrophenyl)-2-methyl-4-nitro-1-phenethyl-1H-imidazole (4u). Green solid (0.290 g, 82%Pd), mp 132ꢀ133 oC. 1H
NMR (300 MHz, DMSOꢀd6): δ = 2.31 (s, 3H, Me), 2.74 (d, 2H, 3J = 7.0 Hz, CH2), 4.07 (d, 2H, 3J = 7.0 Hz, CH2), 6.84ꢀ6.88
(m, 2H, CHAr), 7.15ꢀ7.17 (m, 3H, CHAr), 7.75ꢀ7.77 (m, 2H, CHAr), 8.04ꢀ8.05 (m, 1H, CHAr), 8.33ꢀ8.36 (m, 1H, CHAr).
13C NMR (62.9 MHz, DMSOꢀd6): δ = 12.9 (Me), 34.9, 46.0 (CH2), 124.3, 125.3, 126.7, 128.4, 128.6, 128.8 (CH), 129.1
(C), 130.1, 131.5 (CH), 132.0 (C), 136.7 (CH), 137.0, 142.6, 144.6, 147.7 (C).
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MS (GC, 70eV): m/z (%) = 352 (M+, 100), 105 (85), 91 (80).
HRMS (EI): Calcd for C18H16N4O4 (M+) 352.34404. Found 352.34406.
~
ꢀ1
ν
IR (ATR, cm ):
= 3056 (w), 1520 (s), 1494 (m), 1402 (w), 1342 (s), 1291 (s), 1247 (m), 1162 (w), 1120 (w), 1086 (w),
1019 (w), 929 (w), 884 (w), 856 (s), 837 (w), 810 (w), 767 (w), 745 (s), 735 (s), 693 (s), 667 (m), 566 (w), 540 (m).
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3-methyl-1-nitro-6,7-dihydro-5H-benzo[c]imidazo[1,5-a]azepine (5a). Yellow viscous oil (0.199 g, 82%Pd). H NMR (300
3
3
MHz, CDCl3): δ = 2.23 (t, 2H, J = 6.8 Hz, CH2), 2.48 (s, 3H, Me), 2.64 (t, 2H, J = 6.6 Hz, CH2), 3.76 (br. s, 2H, CH2),
7.27ꢀ7.31 (m, 1H, CHAr), 7.38ꢀ7.42 (m, 2H, CHAr), 7.74ꢀ7.78 (m, 1H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 13.1 (Me), 29.9, 30.8, 42.5 (CH2), 126.9 (CH), 127.3 (C), 129.0, 130.5, 131.5 (CH),
132.2, 138.3, 142.3 (C).
MS (GC, 70eV): m/z (%) = 243 (M+, 100), 212 (11), 156 (22), 144 (45), 128 (31), 116 (66).
HRMS (EI): Calcd for C13H13N3O2 (M+) 243.10023. Found 243.10027.
~
ꢀ1
ν
IR (ATR, cm ):
= 2922 (w), 2854 (w), 1577 (w), 1562 (w), 1529 (m), 1494 (s), 1454 (m), 1399 (m), 1380 (m), 1329 (s),
1316 (s), 1279 (s), 1238 (m), 1120 (w), 1025 (w), 1004 (m), 956 (w), 855 (s), 822 (m), 772 (m), 757 (s), 722 (m), 690 (m),
665 (m).
3-methyl-1-nitro-5,6-dihydroimidazo[5,1-a]isoquinoline (5b). Yellow solid (0.222 g, 97%Pd), mp 151ꢀ152oC. 1H NMR (300
3
3
MHz, DMSOꢀd6): δ = 2.40 (s, 3H, Me), 3.09 (t, 2H, J = 6.6 Hz, CH2), 4.08 (t, 2H, J = 6.8 Hz, CH2), 7.36ꢀ7.44 (m, 2H,
CHAr), 8.25ꢀ8.29 (m, 2H, CHAr).
13C NMR (62.9 MHz, DMSOꢀd6): δ = 12.6 (Me), 28.4, 40.8 (CH2), 124.2 (C), 127.0, 127.4, 128.2, 129.9 (CH), 134.8, 142.9
(C).
MS (GC, 70eV): m/z (%) = 229 (M+, 85), 159 (15), 140 (34), 130 (100), 115 (41), 103 (29).
HRMS (EI): Calcd for C12H11N3O2 (M+) 229.08458. Found 229.08425.
~
IR (ATR, cmꢀ1):
= 2957 (w), 1741 (w), 1610 (w), 1531 (m), 1480 (m), 1403 (m), 1375 (m), 1344 (m), 1309 (w), 1269 (s),
ν
1066 (m), 1131 (m), 1043 (m), 1002 (m), 937 (m), 845 (s), 780 (s), 761 (s), 700 (m), 683 (m), 650 (m).
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3-methyl-1-nitro-5,6-dihydrobenzo[f]imidazo[1,5-d][1,4]oxazepine (5c). Yellow viscous oil (0.186 g, 76%Pd). 1H NMR
4
5
3
(300 MHz, CDCl3): δ = 2.51 (s, 3H, Me), 4.01 (t, 2H, 3J = 5.9 Hz, CH2), 4.49 (t, 2H, 3J = 5.9 Hz, CH2), 7.20 (dd, 1H, J =
8.0 Hz, 4J = 1.1 Hz, CHAr), 7.31 (dt, 1H, 3J = 7.6 Hz, 4J = 1.3 Hz, CHAr), 7.47 (dt, 1H, 3J = 7.6 Hz, 4J = 1.9 Hz, CHAr), 7.84
(dd, 1H, 3J = 7.8 Hz, 4J = 1.7 Hz, CHAr).
6
7
8
9
13C NMR (62.9 MHz, CDCl3): δ = 13.0 (Me), 42.7, 73.8 (CH2), 121.8 (CH), 122.6 (C), 125.0 (CH), 130.1 (C), 132.1, 132.2
(CH), 142.0, 153.3 (C).
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18
19
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22
23
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27
28
29
30
31
32
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35
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37
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40
41
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44
45
46
47
48
49
50
51
52
53
54
55
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58
59
60
MS (GC, 70eV): m/z (%) = 245 (M+, 100).
HRMS (EI): Calcd for C12H11N3O3 (M+) 245.08004. Found 245.08010.
~
ꢀ1
ν
IR (ATR, cm ):
= 2881 (w), 1743 (w), 1531 (m), 1504 (m), 1450 (m), 1402 (m), 1380 (m), 1329 (s), 1275 (s), 1231 (m),
1145 (w), 1109 (w), 1043 (m), 884 (w), 837 (m), 799 (m), 753 (m), 663 (w).
2,5-bis(4-methoxyphenyl)-4-nitro-1-phenethyl-1H-imidazole (6a). Yellow solid (0.249 g, 58%Pd), mp 153ꢀ155 oC. 1H NMR
(300 MHz, CDCl3): δ = 2.47ꢀ2.51 (m, 2H, CH2), 3.04 (s, 3H, OMe), 3.85 (s, 3H, OMe), 4.16 (t, 2H, 3J = 7.2 Hz, CH2), 6.64ꢀ
6.67 (m, 2H, CHAr), 7.07ꢀ7.17 (m, 7H, CHAr), 7.32ꢀ7.34 (m, 2H, CHAr), 7.55 (d, 2H, 3J = 9.0 Hz, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 34.5, 46.7 (CH2), 55.2, 55.3 (OMe), 114.0, 114.2 (CH), 119.3, 121.4 (C), 126.7, 128.3,
128.5, 130.4, 131.7 (CH), 133.6, 136.7, 143.2, 145.4, 160.2, 160.3 (C).
MS (GC, 70eV): m/z (%) = 429 (M+, 100), 135 (27), 105 (60).
HRMS (EI): Calcd for C25H23N3O4 (M+) 429.46782. Found 429.46784.
~
ꢀ1
ν
IR (ATR, cm ):
= 1613 (m), 1575 (w), 1505 (m), 1489 (m), 1454 (m), 1379 (m), 1341 (m), 1289 (m), 1245 (s), 1171 (s),
1110 (m), 1020 (m), 861 (m), 833 (s), 797 (m), 739 (s), 697 (s), 645 (m), 535 (m).
4,4'-(4-nitro-1-phenethyl-1H-imidazole-2,5-diyl)dibenzonitrile (6b). Brown solid (0.264 g, 63%Pd), mp 224ꢀ226 oC. 1H
NMR (300 MHz, CDCl3): δ = 2.46 (t, 2H, 3J = 6.8 Hz, CH2), 4.15 (t, 2H, 3J = 6.8 Hz, CH2), 6.47ꢀ6.50 (m, 2H, CHAr), 7.05ꢀ
7.19 (m, 3H, CHAr), 7.25ꢀ7.29 (m, 2H, CHAr), 7.55ꢀ7.58 (m, 2H, CHAr), 7.69ꢀ7.74 (m, 4H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 35.9, 47.5 (CH2), 114.1, 114.3, 117.8 (C), 127.7, 128.3, 129.1, 129.6, 131.1 (CH), 131.4
(C), 131.6 (CH), 132.6 (C), 132.6 (CH), 132.9, 135.1, 144.5, 144.9 (C).
MS (GC, 70eV): m/z (%) = 419 (M+, 86), 389 (22), 128 (22), 105 (100), 91 (62).
HRMS (ESI): Calcd for C25H18N5O2 (M+H) 420.1455. Found 420.14487.
~
IR (ATR, cmꢀ1):
= 2233 (m), 1514 (s), 1480 (m), 1453 (w), 1393 (m), 1346 (s), 1308 (m), 1260 (m), 1181 (w), 1078 (w),
ν
1007 (w), 918 (w), 858 (m), 845 (s), 754 (m), 746 (m), 699 (s), 659 (m), 557 (s), 549 (s).
2,5-bis(3-(trifluoromethyl)phenyl)-4-nitro-1-phenethyl-1H-imidazole (6c). Yellow solid (0.308 g, 61%Pd), mp 184ꢀ185 oC.
1H NMR (300 MHz, CDCl3): δ = 2.53 (t, 2H, 3J = 6.7 Hz, CH2), 4.20 (t, 2H, J = 6.7 Hz, CH2), 6.54ꢀ6.57 (m, 2H, CHAr),
3
7.10ꢀ7.20 (m, 3H, CHAr), 7.46ꢀ7.53 (m, 2H, CHAr), 7.62ꢀ7.82 (m, 6H, CHAr).
19F NMR (235 MHz, DMSO): δ = ꢀ62.7 (CF3).
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13C NMR Due to bed solubility it was not possible to measure.
4
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MS (GC, 70eV): m/z (%) = 505 (M+, 51), 173 (14), 145 (13), 105 (100), 91 (24).
HRMS (EI): Calcd for C25H17N3O2F6 (M+) 505.12195. Found 505.12226.
7
8
9
~
ꢀ1
ν
IR (ATR, cm ):
= 1568 (w), 1505 (s), 1456 (w), 1381 (w), 1325 (s), 1311 (s), 1240 (m), 1167 (s), 1120 (s), 1072 (s), 923
(m), 900 (m), 851 (m), 811 (m), 795 (s), 751 (m), 728 (w), 715 (m), 695 (s), 671 (m), 648 (m).
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11
12
13
14
15
16
17
18
19
20
21
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29
30
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46
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48
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52
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55
56
57
58
59
60
o
1
4-(4-nitro-1-phenethyl-1H-imidazol-5-yl)benzonitrile (7a). Yellow solid (0.267 g, 84%Pd), mp 131ꢀ133 C. H NMR (300
MHz, CDCl3): δ = 2.90 (t, 2H, 3J = 6.8 Hz, CH2), 4.07 (t, 2H, 3J = 6.8 Hz, CH2), 6.82ꢀ6.85 (m, 2H, CHAr), 7.18ꢀ7.29 (m, 3H,
CHAr), 7.43ꢀ7.67 (m, 3H, CHAr), 7.72ꢀ7.74 (m, 2H, CHAr).
13C NMR (125.7 MHz, CDCl3): δ = 37.0, 47.6 (CH2), 113.8 (CH), 118.0 (C), 127.5 (CH), 128.2 (C), 128.4, 128.5 (CH),
128.7 (C), 128.8, 129.1, 129.7 (CH), 130.3, 130.7 (C), 131.0, 132.4, 132.6 (CH), 133.0 (C).
MS (GC, 70eV): m/z (%) = 318 (M+, 83), 105 (56), 91 (100).
HRMS (EI): Calcd for C18H14N4O2 (M+) 318.11113. Found 318.111300.
~
ꢀ1
ν
IR (ATR, cm ):
= 2233 (m), 1574 (w), 1514 (s), 1496 (s), 1437 (m), 1405 (w), 1337 (s), 1275 (m), 1226 (m), 1190 (m),
1112 (m), 1028 (w), 1000 (m), 933 (w), 845 (s), 748 (s), 720 (m), 697 (s), 655 (s), 566 (m), 541 (s).
o
1
5-(4-nitro-1-phenethyl-1H-imidazol-5-yl)pyrimidine (7b). Yellow solid (0.242 g, 82%Pd), mp 137ꢀ139 C. H NMR (300
MHz, CDCl3): δ = 2.90 (t, 2H, 3J = 6.6 Hz, CH2), 4.20 (t, 2H, 3J = 6.6 Hz, CH2), 6.94ꢀ6.97 (m, 2H, CHAr), 7.21ꢀ7.23 (m, 2H,
CHAr), 7.57ꢀ7.63 (m, 1H, CHAr), 8.07 (s, 1H, CHAr), 8.74 (s, 2H, CHAr), 9.31 (s, 1H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 35.8, 47.0 (CH2), 122.3, 126.2 (C), 126.8, 128.6, 128.8, 131.4, 131.5 (CH), 136.9 (C),
137.5 (CH), 144.5 (C) 157.7, 158.8 (CH).
MS (GC, 70eV): m/z (%) = 295 (M+, 38), 278 (12), 105 (40), 91 (100), 77 (27).
HRMS (EI): Calcd for C15H13N5O2 (M+) 295.10638. Found 295.10607.
~
ꢀ1
ν
IR (ATR, cm ):
= 3127 (w), 1714 (w), 1599 (w), 1552 (m), 1495 (s), 1454 (m), 1408 (m), 1371 (s), 1333 (s), 1266 (s),
1223 (m), 1189 (m), 1156 (m), 1119 (m), 1080 (w), 996 (m), 913 (w), 864 (w), 831 (s), 760 (s), 725 (s), 702 (s), 652 (m),
628 (s), 588 (w), 566 (m), 539 (s).
o
1
4-nitro-5-(3-nitrophenyl)-1-phenethyl-1H-imidazole (7c). Yellow solid (0.220 g, 65%Pd), mp 128ꢀ130 C. H NMR (300
MHz, DMSOꢀd6): δ = 2.85 (t, 2H, 3J = 6.7 Hz, CH2), 4.13 (t, 2H, 3J = 6.7 Hz, CH2), 6.89ꢀ6.92 (m, 2H, CHAr), 7.17ꢀ7.19 (m,
3H, CHAr), 7.74ꢀ7.81 (m, 2H, CHAr), 8.03 (br. s, 1H, CHAr), 8.09 (br. s, 1H, CHAr), 8.35ꢀ8.37 (m, 1H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 35.7, 46.9 (CH2), 124.5, 125.2, 126.7, 128.4 (CH), 128.4 (C), 128.5, 128.8 (CH), 130.0
(C), 130.1, 131.5 (CH), 132.0 (C), 136.7, 136.8 (CH), 137.0, 147.7 (C).
MS (GC, 70eV): m/z (%) = 338 (M+, 70), 105 (46), 91 (100).
HRMS (EI): Calcd for C17H14N4O4 (M+) 338.10096. Found 338.10087.
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~
ꢀ1
IR (ATR, cm ): ν
= 3126 (w), 1526 (s), 1496 (s), 1436 (m), 1383 (w), 1345 (s), 1296 (s), 1249 (w), 1212 (m), 1158 (m),
1103 (m), 1028 (w), 1004 (m), 902 (m), 829 (s), 763 (m), 731 (s), 692 (s), 647 (s), 538 (s).
6
7
8
9
2-(4-nitro-5-(3-nitrophenyl)-1-phenethyl-1H-imidazol-2-yl)benzaldehyde (8a). Yellow solid (0.345 g, 78%Pd), mp 152ꢀ154
oC. 1H NMR (300 MHz, DMSO): δ = 2.84 (t, 2H, 3J = 6.6 Hz, CH2), 3.98 (t, 2H, 3J = 6.6 Hz, CH2), 6.52ꢀ6.55 (m, 2H, CHAr),
7.04ꢀ7.15 (m, 3H, CHAr), 7.33ꢀ7.36 (m, 1H, CHAr), 7.61ꢀ7.74 (m, 4H, CHAr), 7.96ꢀ7.99 (m, 1H, CHAr), 8.12ꢀ8.13 (m, 1H,
CHAr), 8.30ꢀ8.34 (m, 1H, CHAr), 9.90 (s, 1H, CHO).
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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
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
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58
59
60
13C NMR (62.9 MHz, CDCl3): δ = 35.8, 47.1 (CH2), 123.9, 124.8, 125.4, 127.5, 127.6, 138.4 (CH), 128.7 (C), 129.0, 130.0
(CH), 130.2 (C) 131.2 (CH), 132.0 (C), 134.0, 134.9, 135.1 (CH), 135.6 (C), 136.4 (CH), 144.2, 144.6, 148.2 (C), 190.9
(CHO).
MS (GC, 70eV): m/z (%) = 442 (M+, 70), 310 (77), 264 (22), 105 (100).
HRMS (ESI): Calcd for C24H18N4O5 (M+H) 443.1350. Found 443.13495.
~
ꢀ1
IR (ATR, cm ): ν
= 3084 (w), 2858 (w), 1693 (m), 1600 (w), 1525 (s), 1470 (m), 1453 (m), 1389 (m), 1346 (s), 1246 (m),
1196 (m), 1137 (w), 1078 (w), 906 (w), 876 (w), 829 (m), 776 (m), 739 (s), 698 (s), 573 (w).
o
1
5-bromo-2-methyl-4-nitro-1-phenethyl-1H-imidazole (10a). Brown solid (1.767 g, 57%), mp 127ꢀ129 C. H NMR (300
MHz, CDCl3): δ = 2.01 (s, 3H, Me), 3.02 (t, 2H, 3J = 7.0 Hz, CH2), 4.18 (t, 2H, 3J = 7.0 Hz, CH2), 6.98ꢀ7.01 (m, 2H, CHAr),
7.25ꢀ7.27 (m, 3H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 13.5 (Me), 35.6, 48.0 (CH2), 104.2 (C), 127.5, 128.7, 129.1 (CHAr), 136.0, 145.3 (C).
MS (GC, 70eV): m/z (%) = 309 (M+, 4), 230 (100), 213 (50), 105 (70), 91 (99), 77 (35).
HRMS (EI): Calcd for C12H12N3BrO2 (M+) 309.01074. Found 309.010864.
~
ꢀ1
ν
IR (ATR, cm ):
= 2927 (w), 1724 (w), 1632 (w), 1599 (w), 1537 (w), 1515 (s), 1476 (m), 1453 (m), 1381 (s), 1281 (s),
1239 (m), 1181 (w), 1153 (m), 1082 (w), 1040 (m), 1013 (m), 930 (w), 899 (w), 842 (m), 759 (m), 750 (s), 673 (m), 634
(m), 570 (m).
o
1
5-bromo-2-methyl-4-nitro-1-(2-phenoxyethyl)-1H-imidazole (10b). Brown solid (1.891 g, 58%), mp 93ꢀ95 C. H NMR
(300 MHz, CDCl3): δ = 2.63 (s, 3H, Me), 4.28 (t, 2H, 3J = 5.0 Hz, CH2), 4.44 (t, 2H, 3J = 5.0 Hz, CH2), 6.81ꢀ6.85 (m, 2H,
CHAr), 6.95ꢀ7.02 (m, 1H, CHAr), 7.25ꢀ7.31 (m, 2H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 14.3 (Me), 45.8, 65.3 (CH2), 104.4 (C), 114.0, 121.6, 129.5 (CHAr), 146.2, 157.3 (C).
MS (GC, 70eV): m/z (%) = 325 (M+, 1), 246 (100), 107 (15), 77 (31).
HRMS (ESI): Calcd for C12H12N3BrO3 (M+H) 326.01348. Found 326.0141.
~
ꢀ1
ν
IR (ATR, cm ):
= 2931 (w), 1587 (w), 1526 (s), 1494 (s), 1466 (m), 1376 (m), 1336 (s), 1279 (m), 1244 (s), 1157 (w),
1080 (m), 1057 (m), 1038 (m), 916 (m), 882 (w), 842 (m), 788 (m), 753 (s), 687 (s), 603 (m).
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5-bromo-2-methyl-4-nitro-1-(3-phenylpropyl)-1H-imidazole (10c). Brown solid (1.782 g, 55%), mp 62ꢀ64 C. H NMR
4
5
3
(300 MHz, CDCl3): δ = 2.01ꢀ2.12 (m, 2H, CH2), 2.37 (s, 3H, Me), 2.72 (t, 2H, J = 7.5 Hz, CH2), 3.93ꢀ3.98 (m, 2H, CH2),
6
7.16ꢀ7.34 (m, 5H, CHAr).
7
8
9
13C NMR (62.9 MHz, CDCl3): δ = 13.9 (Me), 30.7, 32.5, 45.7 (CH2), 104.5 (C), 126.6, 128.1, 128.7 (CHAr), 139.4, 144.6
(C).
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11
12
13
14
15
16
17
18
19
20
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22
23
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25
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28
29
30
31
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41
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47
48
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56
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60
MS (GC, 70eV): m/z (%) = 323 (M+, 1), 244 (24), 198 (100), 117 (18), 91 (64).
HRMS (EI): Calcd for C13H14N3BrO2 (M+) 323.02639. Found 323.02638.
~
IR (ATR, cmꢀ1):
= 1519 (s), 1479 (m), 1384 (s), 1334 (s), 1285 (s), 1254 (s), 1173 (w), 1148 (m), 1084 (w), 1028 (m),
ν
907 (w), 867 (m), 834 (m), 752 (m), 718 (s), 693 (s), 670 (m), 631 (w).
o
1
4-bromo-2-methyl-5-nitro-1-phenethyl-1H-imidazole (11a). Brown solid (0.960 g, 31%), mp 125ꢀ127 C. H NMR (300
MHz, CDCl3): δ = 2.01 (s, 3H, Me), 3.03 (t, 2H, 3J = 7.0 Hz, CH2), 4.49 (t, 2H, 3J = 7.0 Hz, CH2), 7.02ꢀ7.05 (m, 2H, CHAr),
7.27ꢀ7.29 (m, 3H, CHAr).
13C NMR (62.96 MHz, CDCl3): δ = 13.6 (Me), 36.4, 49.2 (CH2), 120.8 (C), 127.4, 128.7, 129.0 (CH), 136.4, 149.1 (C).
MS (GC, 70eV): m/z (%) = 309 (M+, 1), 263 (44), 184 (100), 104 (72), 91 (76), 77 (41).
HRMS (EI): Calcd for C12H12N3BrO2 (M+) 309.01074. Found 309.011022.
~
IR (ATR, cmꢀ1):
= 2931 (w), 1526 (s), 1497 (w), 1462 (m), 1415 (m), 1384 (m), 1357 (s), 1332 (s), 1275 (w), 1249(s),
ν
1192 (m), 1175 (s), 1085 (w), 1032 (w), 1002 (m), 852 (w), 830 (s), 802 (w), 755 (s), 741 (m), 704 (s), 686 (m), 671 (m),
630 (w), 610 (w), 563 (m).
o
1
4-bromo-2-methyl-5-nitro-1-(2-phenoxyethyl)-1H-imidazole (11b). Brown solid (1.239 g, 38%), mp 100ꢀ102 C. H NMR
(300 MHz, CDCl3): δ = 2.60 (s, 3H, Me), 4.29 (t, 2H, 3J = 5.0 Hz, CH2), 4.70 (t, 2H, 3J = 5.0 Hz, CH2), 6.76ꢀ6.80 (m, 2H,
CHAr), 6.92ꢀ6.98 (m, 1H, CHAr), 7.22ꢀ7.28 (m, 2H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 14.6 (Me), 47.2, 66.3 (CH2), 114.1 (CH), 121.2 (C), 121.7, 129.6 (CH), 150.4, 157.5 (C).
MS (GC, 70eV): m/z (%) = 325 (M+, 5), 263 (44), 281 (85), 232 (71), 200 (56), 107 (26), 77 (100).
HRMS (EI): Calcd for C12H12N3BrO3 (M+H) 326.01348. Found 326.0141.
~
ꢀ1
ν
IR (ATR, cm ):
= 2930 (w), 1586 (w), 1516 (s), 1488 (m), 1454 (s), 1413 (s), 1355 (s), 1329 (s), 1235 (s), 1172 (s), 1083
(m), 1063 (m), 1022 (m), 912 (m), 890 (w), 829 (m), 758 (s), 693 (s), 632 (w), 591 (m).
o
1
4-bromo-2-methyl-5-nitro-1-(3-phenylpropyl)-1H-imidazole (11c). Brown solid (1.296 g, 40%), mp 50ꢀ52 C. H NMR
(300 MHz, CDCl3): δ = 1.94ꢀ2.06 (m, 2H, CH2), 2.24 (s, 3H, Me), 2.64 (t, 2H, 3J = 7.5 Hz, CH2), 4.18 (t, 2H, 3J = 7.5 Hz,
CH2), 7.09ꢀ7.25 (m, 5H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 13.7 (Me), 31.0, 32.4, 46.8 (CH2), 120.3 (C), 126.3, 128.0, 128.5 (CH), 139.5, 148.4 (C).
MS (GC, 70eV): m/z (%) = 323 (M+, 1), 277 (52), 198 (50), 175 (32), 117 (51), 91 (100).
HRMS (ESI): Calcd for C13H15N3BrO2 (M+H) 324.03422. Found 324.03456.
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~
IR (ATR, cmꢀ1):
= 1514 (s), 1495 (m), 1452 (s), 1409 (s), 1378 (m), 1343 (s), 1250 (s), 1230 (s), 1170 (s), 1032 (m), 910
ν
(w), 885 (w), 830 (s), 765 (s), 745 (s), 721 (s), 695 (s), 643 (w), 585 (w).
6
7
8
9
1-(2-(2-methyl-4-nitro-1-(2-phenoxyethyl)-1H-imidazol-5-yl)phenyl)ethanone (12d). Yellow viscous oil (0.233 g, 37%). 1H
NMR (300 MHz, CDCl3): δ = 2.11 (s, 3H, Me), 2.49 (s, 3H, Me), 2.70ꢀ2.76 (m, 2H, CH2), 3.69ꢀ3.79 (m, 1H, CH2), 3.94ꢀ
4.12 (m, 1H, CH2), 6.89ꢀ6.97 (m, 2H, CHAr), 7.04ꢀ7.07 (m, 1H, CHAr), 7.18ꢀ7.24 (m, 3H, CHAr), 7.51ꢀ7.62 (m, 2H, CHAr),
7.89ꢀ7.92 (m, 1H, CHAr).
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13C NMR (62.9 MHz, CDCl3): δ = 13.1, 27.8 (Me), 35.4, 46.7 (CH2), 127.0 (C), 128.5, 128.6, 128.7, 129.3 (CH), 129.3 (C),
130.1, 131.4, 131.8 (CH), 132.6, 136.8, 138.9, 143.9, 199.3 (C).
MS (GC, 70eV): m/z (%) = 365 (M+, 1), 319 (100).
HRMS (ESI): Calcd for C20H20N3O4 (M+H) 366.14483. Found 366.14499.
~
ꢀ1
ν
IR (ATR, cm ):
= 1699 (m), 1601 (w), 1531 (m), 1496 (s), 1442 (m), 1384 (m), 1319 (s), 1293 (s), 1275 (m), 1236 (s),
1205 (m), 1120 (w), 1092 (w), 1000 (w), 931 (w), 852 (s), 824 (m), 759 (m), 702 (s), 673 (m), 569 (m).
2-methyl-4-nitro-1-phenethyl-5-(4-(trifluoromethyl)phenyl)-1H-imidazole (12e). Green solid (0.326 g, 87%), mp 155ꢀ156
1
3
3
oC. H NMR (300 MHz, DMSO-d6): δ = 2.17 (s, 3H, Me), 3.10 (t, 2H, J = 7.1 Hz, CH2), 4.52 (t, 2H, J = 7.1 Hz, CH2),
7.08ꢀ7.11 (m, 2H, CHAr), 7.27ꢀ7.31 (m, 3H, CHAr), 7.69 (d, 2H, 3J = 8.0 Hz, CHAr), 7.87 (d, 2H, 3J = 8.0 Hz, CHAr).
19F NMR (235 MHz, DMSOꢀd6): δ = ꢀ62.8 (CF3).
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4
13C NMR (62.9 MHz, DMSOꢀd6): δ = 13.8 (Me), 36.5, 48.8 (CH2), 124.8 (q, J = 270.5 Hz, CF3), 125.0 (q, J = 3.7 Hz,
CHCCF3), 127.5, 128.8, 129.1, 130.0 (CH), 131.3 (q, 2J = 33.2 Hz, CCF3), 134.9, 136.5, 141.9, 148.7 (C).
MS (GC, 70eV): m/z (%) = 375 (M+, 10), 329 (100), 105 (58), 91 (49), 77 (26).
HRMS (EI): Calcd for C19H16N3O2F3 (M+) 375.11891. Found 375.11984.
~
ꢀ1
IR (ATR, cm ): ν
= 1714 (w), 1558 (w), 1506 (w), 1468 (m), 1359 (m), 1317 (s), 1186 (m), 1108 (s), 1067 (s), 1018 (m),
848 (s), 746 (s), 701 (s), 661 (w), 593 (m).
5-(4-tert-butylphenyl)-2-methyl-4-nitro-1-phenethyl-1H-imidazole (12f). Yellow viscous oil (0.258 g, 71%). 1H NMR (300
MHz, CDCl3): δ = 1.38 (s, 9H, tꢀBu), 2.55 (s, 3H, Me), 2.70 (t, 2H, 3J = 7.2 Hz, CH2), 3.97 (t, 2H, 3J = 7.2 Hz, CH2), 6.76ꢀ
6.80 (m, 2H, CHAr), 7.19ꢀ7.21 (m, 5H, CHAr), 7.50 (d, 2H, 3J = 8.5 Hz, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 13.3 (Me), 31.2 (tꢀBu), 34.9 (CtꢀBu), 36.2, 46.4 (CH2), 124.1 (C), 125.8, 127.3, 128.6,
129.0, 129.7 (CH), 132.5, 136.3, 143.7, 153.2 (C).
MS (GC, 70eV): m/z (%) = 363 (M+, 100), 348 (89), 244 (15), 115 (11), 105 (97), 91 (28), 77 (27).
HRMS (ESI): Calcd for C22H26N3O2 (M+H) 364.20195. Found 364.2019.
~
IR (ATR, cmꢀ1):
= 2960 (w), 1575 (w), 1544 (w), 1504 (s), 1452 (m), 1398 (m), 1383 (s), 1331 (s), 1294 (s), 1248 (s),
ν
1201 (w), 1100 (w), 1048 (w), 1029 (w), 1003 (m), 867 (s), 832 (m), 769 (m), 744 (s), 698 (s), 669 (m), 629 (w), 577 (m),
558 (m).
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