The Chan-Evans-Lam N-Arylation of 2-Imidazolines

Article abstract of DOI:10.1021/acs.joc.6b02404

N-Arylation of 2-imidazolines with arylboronic acids promoted by copper(II) acetate in DMSO provides an attractive alternative to the earlier reported transition metal-catalyzed approaches employing (hetero)aryl halides as it taps into the vast reagent sp

Full text of DOI:10.1021/acs.joc.6b02404

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The Chan-Evans-Lam N-Arylation of 2-Imidazolines
Dmitry Dar'in, and Mikhail Krasavin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02404 • Publication Date (Web): 21 Nov 2016
Downloaded from http://pubs.acs.org on November 22, 2016
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The Chan-Evans-Lam N-Arylation of 2-Imidazolines
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Dmitry Dar’in and Mikhail Krasavin*
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Institute of Chemistry, Saint Petersburg State University, 26 Universitetsky prospekt, Peterhof
198504, Russia
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ABSTRACT: NꢀArylation of 2ꢀimidazolines with arylboronic acids promoted by copper(II)
acetate in DMSO provides an attractive alternative to the earlier reported transition metalꢀ
catalyzed approaches employing (hetero)aryl halides as it taps into the vast reagent space of
commercially available boronic acids and proceeds at ambient temperature. Many of the
resulting compounds are distinctly leadlike, thus positioning the method developed well within
the toolbox of leadꢀoriented synthesis.
Although 2ꢀimidazolines are traditionally considered pharmacological tools for modulating
imidazoline receptors,1 they are, in fact, truly privileged motifs2 as the range of biological
activities displayed by these compounds extends far beyond modulating the class of targets
which was named after them.3 Selected illustrative examples include P2X7 ion channel blocker 1
for the treatment of inflammatory conditions,4 proteasome inhibitor 2 for multiple myeloma,5
estrogen receptor modulator 3 for oncology applications6 and Nutlinꢀ3 (4),7 which disrupts the
oncogenic p53ꢀmdm2 proteinꢀprotein interactions (Figure 1).
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Figure 1. Examples of biologically active imidazolines.
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Nꢀ(Hetero)arylꢀsubstituted 2ꢀimidazolines had been scarce in the medicinal chemistry literature
prior to the introduction of efficient metalꢀcatalyzed methods for 2ꢀimidazoline Nꢀarylation with
(hetero)aryl halides by us8 and the Bull group9 in 2012 and 2013, respectively. Subsequently, we
have validated Nꢀ(hetero)aryl 2ꢀimidazolines as a privileged motif on its own by discovering
selective cyclooxygenaseꢀ2 inhibitors,10 selective kinase inhibitors,11 antitubercular agents12 and
isoformꢀselective carbonic anhydrase inhibitors13 based on this scaffold (Figure 2). This is a
particularly encouraging development in light of a strong emphasis recently put on the nonꢀflat,14
more saturated (higherꢀFsp3)15 scaffolds in the development of smallꢀmolecule libraries for early
drug discovery. Moreover, the hydrophilicꢀcore Nꢀ(hetero)aryl imidazolines are distinctly leadꢀ
like,16 allowing ample room for medicinal chemistry optimization in terms of both lipophilicity
and molecular weight.8 The readily available (hetero)aryl halides correspond to a significant
chemistry space that can be accessed via the direct 2ꢀimidazoline Nꢀarylation methods
employing palladium8 and copper9 catalysts. However, the complimentary copperꢀcatalyzed
approach to Nꢀarylation using arylboronic acids (the ChanꢀEvansꢀLam coupling17) has not been
described in the literature for 2ꢀimidazolines.18 We thought it particularly worthwhile to test the
applicability of the ChanꢀEvansꢀLam (CEL) protocol to these heterocycles as substrates as it
would allow tapping into the boronic acid reagent space, which is particularly desired when the
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respective electronꢀneutral or electronꢀrich aryl halides are not available or fail to participate in
the metalꢀcatalyzed reaction. Moreover, the CEL coupling is generally known to proceed at
ambient temperature as opposed to 100–150 ºC range employed in the current procedures8ꢀ9 for
Nꢀarylation of 2ꢀimidazolines, therefore making CEL reaction the only practical option for the
thermally prone substrates. Herein, we disclose the CEL protocol for Nꢀarylation of 2ꢀ
imidazolines, which specifically caters to the above needs.
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Figure 2. Examples of biologically active Nꢀ(hetero)aryl 2ꢀimidazolines.
Aiming to identify the optimal protocol for the Nꢀarylation of 2ꢀimidazolines with boronic acids,
we chose not to alter the 1:2:1.5 molar ratio of the substrate, boronic acid and Cu(II) acetate
promoter originally reported by Chan17a and Lam17c and focus on finding the best practical
combination of the solvent and the base. Notably, using 1.0 and 1.5 equiv. of boronic acid
incomplete conversions, most likely due the competing boronic acid homocoupling and phenol
formation.19 The initial solvent optimization for the model reaction involving 2ꢀ(pꢀtolyl)ꢀ4,5ꢀ
dihydroꢀ1Hꢀimidazole (5a)20 and phenylboronic acid in the presence of pyridine (2 equiv.)
revealed that the best isolated yield was obtained in DMSO (Table 1).
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Table 1. Solvent optimization for the CEL Nꢀarylation of 5a.
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Isolated
yield (%)
34
Entry
Solventa
1
2
Dichloromethane
Toluene
23
3
MeOH
13
4
Acetonitrile
1,4ꢀdioxane
1,2ꢀdichloroethane
ethyl acetate
NMP
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13
39 (33b)
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trace
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DMF
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iꢀPrOH
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Pyridine
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57c
DMSO
EtOCH2CH2OH/H2O (1:1)
Trace
a 0.025M
b Air was bubbled through the reaction mixture.
c Using activated 4Ǻ molecular sieves17bꢀc did not alter the reaction yield.
However, we found it particularly cumbersome to purify polar 1ꢀphenylꢀ2ꢀ(pꢀtolyl)ꢀ4,5ꢀdihydroꢀ
1Hꢀimidazole (6a) from traces of pyridine. Therefore, it was decided to test the anhydrous
potassium carbonate (2.5 equiv.) as a base in this reaction, which simplified the isolation of the
product (6a) and led to a marked improvemet of the yield (83%) (Scheme 1) were adopted as a
general protocol and applied to an extended range of 2ꢀimidazoline CEL Nꢀarylation reactions
with results presented in Table 2.
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Scheme 1. The CEL Nꢀarylation of 2ꢀimidazolines developed in this work.
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Table 2. NꢀAryl 2ꢀimidazolines 6a-w accessed via the CEL protocol in this work.
Starting 2ꢀ
imidazoline
Isolated yield
Product
6a
R
Ar
(%)
83
5a
5b
5c
5d
5e
78
84
81
58
6b
6c
6d
6e
76
83
87
6f
6g
6h
5f
5g
5h
74
55
6i
6j
5i
5j
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6k
6l
5k
5l
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6m
5m
45a
79
6n
6o
6p
5n
5g
48b
5m
46a
24c
6q
6r
5i
5c
MeS
59
31
6s
6t
5o
5p
63
6u
5c
51a
69
6v
5a
5d
*
6w
N
a Conversion after 2 days was about 70%.
b Conversion after 3 days was about 60%.
c Conversion after 5 days was about 50%.
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From the data presented in Table 2, it is evident that the method is perfectly suitable for
introducing various aromatic groups at the nitrogen atom of the 2ꢀimidazoline nucleus.
Preliminarily, there appears to be a weak electronic influence from the substituents in position 2
as electronꢀneutral and electronꢀrich aromatic groups (e. g., in 5a, 5c or 5m) generally lead to
somewhat higher reaction yields compared to electronꢀpoor aromatics (as in 5n); however, 3ꢀ
pyridylꢀsubstituted imidazoline 5k acted as a perfectly competent substrate in this reaction. As
expected, steric encumbrance in the boronic acid exerts some influence on the product yield (6p
and 6r).
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The sensitivity of the reaction to the steric effects prompted us to compare the regioselectivity of
the CEL Nꢀarylation of unsymmetrical, 4ꢀmethylꢀsubstituted imidazoline 5q21aꢀb with that
reported for Pd(OAc)2ꢀcatalyzed (>9:1)10, 22 and CuIꢀcatalyzed procedure (6.4:1).9 The CEL
reaction wth 5q proved somewhat less regioselective delivering 3.6:1 ratio of regioisomers 6x
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and 6x' (according to H NMR analysis of the crude reaction mixture). The latter have been
isolated as individual compounds using column chromatography and their regiochemistry
unequivocally established from their NOESY spectra (Scheme 2).
Scheme 2. NꢀArylation regioselectivity for 4ꢀmethylꢀ4,5ꢀdihydroꢀ1Hꢀimidazole 5q (arrows
indicate the throughꢀspace interactions observable in the NOESY spectrum).
From their reactivity prospective, we consider 2ꢀimidazolines a standalone class of heterocycles
rather than a mere version of a cyclic amidine. Indeed, as we observed earlier, their ‘homologs’
1,4,5,6ꢀtetrahydropyrimidines are (somewhat surprisingly) much poorer substrates for Pdꢀ
catalyzed Nꢀarylation even with a highly reactive 2ꢀchloroꢀ3ꢀnitropyridine.23 In this work, too,
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1,4,5,6ꢀtetrahydropyrimidine 724 turned out to be completely inert under the CEL conditions
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(Scheme 3).
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Scheme 3. Attempted CEL Nꢀarylation of 1,4,5,6ꢀtetrahydropyrimidine 7.
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2ꢀMethythio and 2ꢀamino imidazolines 5o and 5p can also be arylated under the CEL conditions,
however, the yield of cyclic guanidine 6t was less satisfactory. 2ꢀMethylthio imidazoline 6q,
however, can be considered as a synthetic precursor that can be elaborated into a range of
diversely substituted guanidines 9a-c akin to 6t via a direct substitution of methyl mercaptane
with primary and secondary amines under conventional heating in 1,4ꢀdioxane (Scheme 4). In
conjunction with the CEL Nꢀarylation protocol reported herein, this approach provides a
streamlined entry into polysubstituted 2ꢀaminoimidazolines which are usually obtained by the
multiꢀstep synthesis.25
Scheme 4. Synthesis of 2ꢀalkylaminoꢀ1ꢀphenylꢀ4,5ꢀdihydroꢀ1Hꢀimidazoles 9a-c.
In summary, we have developed a convenient, amibientꢀtemperature procedure for Nꢀarylation of
2ꢀimidazolines. Considering the scope of the appendage variations around the 2ꢀimidazoline core
achievable with the aid of this protocol, the method clearly belongs to the toolbox of leadꢀ
oriented synthesis.16
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EXPERIMENTAL SECTION
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General. NMR spectroscopic data were recorded with a 400 spectrometer (400.13 MHz for H
and 100.61 MHz for 13C) in CDCl3 and were referenced to residual solvent proton signal (δH =
7.26 ppm) and solvent carbon signal (δC = 77.00 ppm). Mass spectra were recorded with a an
ESIꢀqTOF spectrometer (electrospray ionization mode). Column chromatography was performed
on 230–400 mesh silica gel.
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Imidazolines 5. Imidazolines 5a,20 5b-d,26 5e,27 5f,26 5g,21b 5h,28 5i,29 5j,21 5k-l,8 5m,21a 5n21b
and 5q21aꢀb are known compounds and were prepared from the respective aldehydes according to
the literature protocol26 employing NBS as an oxidant. Compounds 5o and 5p were acquired
from commercial sources.
General Experimental Procedure for the CEL N-Arylation of Imidazolines 5. A mixture of
imidazoline 5 (1.0 mmol), ArB(OH)2 (2.0 mmol), Cu(OAc)2 (1.5 mmol), K2CO3 (2.5 mmol) and
DMSO (3 mL) was stirred in an open flask at ambient temperature for 20–24 hours (reaction
progress was controlled by TLC). Reaction mixture was diluted with EtOAc (60 mL) containing
Et3N (2 mL), stirred for 10 min and filtered through a pad of celite. The filtrate was washed with
water (20 mL) and brine (15 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The
resulting crude material was subjected to column chromatography on silica gel to afford pure
compound 6. Eluent for compounds 6a-s: EtOAc/MeOH/Et3N system (from 100:0:0 to 94:5:1);
eluent for compound 6t: EtOAc/MeOH/Et3N system (from 50:40:10 to 45:45:10); eluent for
separation of isomers 6u and 6u': EtOAc/Et3N (from 99:1 to 98:2).
1-Phenyl-2-(p-tolyl)-4,5-dihydro-1H-imidazole (6a)9: Yield 197 mg (83%); pale beige solid,
1
mp 70–72 °C. H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.1 Hz, 2H), 7.18 (t, J = 7.9 Hz, 2H),
7.10 (d, J = 8.0 Hz, 2H), 7.00 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 7.6 Hz, 2H), 4.05 (s, 4H), 2.35 (s,
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3H). 13C NMR (100 MHz, CDCl3) δ 162.6, 143.4, 140.0, 128.8, 128.7, 128.6, 128.3, 123.2,
122.6, 54.1, 53.0, 21.4. HRMS m/z [M+H]+ calcd for C16H17N2 237.1386, found 237.1382.
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2-(4-Chlorophenyl)-1-(4-fluorophenyl)-4,5-dihydro-1H-imidazole (6b): Yield 214 mg (78%);
colorless solid, mp 83–84 °C. 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.5 Hz, 2H), 7.27 (d, J
= 8.5 Hz, 2H), 6.92 (t, J = 8.6 Hz, 2H), 6.87 – 6.79 (m, 2H), 4.13 – 3.94 (m, 4H). 13C NMR (100
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1
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MHz, CDCl3) δ 162.1, 159.5 (d, JCF = 244.7 Hz), 139.1 (d, JCF = 2.9 Hz), 136.3, 130.1, 128.8,
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128.5, 125.1 (d, JCF = 8.2 Hz), 115.8 (d, JCF = 22.6 Hz), 54.8, 52.8. HRMS m/z [M+H]+ calcd
for C15H13N2ClF 275.0746, found 275.0739.
1-(4-Chlorophenyl)-2-(4-methoxyphenyl)-4,5-dihydro-1H-imidazole (6c): Yield 242 mg
(84%); yellowish viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.8 Hz, 2H), 7.15 (d, J
= 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 4.10 – 3.97 (m, 4H), 3.81 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 162.0, 161.2, 141.8, 130.3, 128.8, 128.6, 123.8, 122.6,
113.7, 55.3, 54.0, 52.5. HRMS m/z [M+H]+ calcd for C16H16ClN2O 287.0946, found 287.0957.
Methyl 4-(1-phenyl-4,5-dihydro-1H-imidazol-2-yl)benzoate (6d)30: Yield 226 mg (81%);
reddish viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz,
2H), 7.19 (t, J = 7.9 Hz, 2H), 7.03 (t, J = 7.4 Hz, 1H), 6.80 (d, J = 7.7 Hz, 2H), 4.13 – 4.06 (m,
4H), 3.91 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 166.5, 162.1, 142.6, 135.2, 131.4, 129.4,
128.9, 128.7, 124.0, 122.9, 54.2, 52.9, 52.2. HRMS m/z [M+H]+ calcd for C17H17N2O2 281.1285,
found 281.1275.
1-(4-Methoxyphenyl)-2-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-imidazole (6e): Yield
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186 mg (58%); yellowish viscous oil. H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.3 Hz, 2H),
7.53 (d, J = 8.3 Hz, 2H), 6.86 – 6.80 (m, 2H), 6.79 – 6.73 (m, 2H), 4.14 – 4.05 (m, 2H), 4.02 –
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3.94 (m, 2H), 3.77 (s, 3H). C NMR (100 MHz, CDCl3) δ 162.5, 156.9, 136.1, 134.3, 131.6 (q,
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2JCF = 32.6 Hz), 129.1, 125.5, 125.0 (q, JCF = 3.8 Hz), 123.8 (d, JCF = 272.4 Hz), 114.4, 55.4,
55.3, 53.0. HRMS m/z [M+H]+ calcd for C17H16F3N2O 321.1209, found 321.1213.
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2-(2-Chlorophenyl)-1-(4-chlorophenyl)-4,5-dihydro-1H-imidazole (6f): Yield 221 mg (76%);
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colorless solid, mp 111–112 °C. H NMR (400 MHz, CDCl3) δ 7.53 – 7.48 (m, 1H), 7.40 – 7.29
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(m, 3H), 7.07 (d, J = 8.9 Hz, 2H), 6.61 (d, J = 8.9 Hz, 2H), 4.17 – 3.98 (m, 4H). C NMR (100
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MHz, CDCl3) δ 159.9, 139.4, 132.7, 131.1, 131.1, 130.8, 130.0, 128.8, 128.0, 127.1, 120.7, 52.9,
51.5. HRMS m/z [M+H]+ calcd for C15H13Cl2N2 291.0450, found 291.0458.
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2-(Naphthalen-1-yl)-1-phenyl-4,5-dihydro-1H-imidazole (6g)31: Yield 226 mg (83%); reddish
viscous oil. 1H NMR (400 MHz, CDCl3) δ 8.20 – 8.13 (m, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.87 –
7.83 (m, 1H), 7.53 (dd, J = 7.1, 1.3 Hz, 1H), 7.51 – 7.45 (m, 2H), 7.42 (dd, J = 8.2, 7.1 Hz, 1H),
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7.00 (t, J = 7.9 Hz, 2H), 6.84 (t, J = 7.4 Hz, 1H), 6.69 – 6.63 (m, 2H), 4.28 – 4.16 (m, 4H). C
NMR (100 MHz, CDCl3) δ 161.5, 141.5, 133.6, 131.0, 130.0, 129.2, 128.6, 128.2, 127.5, 126.8,
126.1, 125.5, 125.0, 122.7, 120.3, 53.1, 52.1. HRMS m/z [M+H]+ calcd for C19H17N2 273.1386,
found 273.1392.
1-(4-Fluorophenyl)-2-(3-methoxyphenyl)-4,5-dihydro-1H-imidazole (6h): Yield 236 mg
(87%); reddish viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.17 (t, J = 7.9 Hz, 1H), 7.08 (dd, J =
2.6, 1.6 Hz, 1H), 6.99 (dt, J = 7.6, 1.2 Hz, 1H), 6.94 – 6.86 (m, 3H), 6.85 – 6.80 (m, 2H), 4.20 –
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3.90 (m, 4H), 3.74 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 163.0, 159.3 (d, JCF = 244.0 Hz),
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159.3, 139.3 (d, JCF = 2.9 Hz), 131.7, 129.2, 124.9 (d, JCF = 8.2 Hz), 121.2, 116.7, 115.6 (d,
2JCF = 22.6 Hz), 113.5, 55.3, 54.6, 52.7. HRMS m/z [M+H]+ calcd for C16H16FN2O 271.1241,
found 271.1248.
1-Phenyl-2-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-imidazole (6i): Yield 230 mg (74%);
yellowish viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.22 (t, J = 7.8 Hz, 2H), 7.04 (t, J = 7.4 Hz,
1H), 6.88 (d, J = 7.8 Hz, 2H), 6.74 (s, 2H), 4.07 (s, 4H), 3.85 (s, 3H), 3.68 (s, 6H). 13C NMR
(100 MHz, CDCl3) δ 162.5, 152.7, 143.1, 139.6, 128.8, 125.6, 124.0, 123.2, 106.3, 60.9, 56.0,
54.2, 52.6. HRMS m/z [M+H]+ calcd for C18H21N2O3 313.1547, found 313.1552.
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2-Cyclohexyl-1-(4-fluorophenyl)-4,5-dihydro-1H-imidazole (6j): Yield 136 mg (55%);
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yellowish viscous oil. H NMR (400 MHz, CDCl3) δ 7.15 – 7.02 (m, 4H), 3.87 – 3.78 (m, 2H),
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3.76 – 3.67 (m, 2H), 2.22 – 2.13 (m, 1H), 1.80 – 1.67 (m, 4H), 1.66 – 1.57 (m, 1H), 1.56 – 1.42
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(m, 2H), 1.28 – 1.01 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 169.5, 160.4 (d, 1JCF = 245.5 Hz),
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138.3 (d, JCF = 2.9 Hz), 126.8 (d, JCF = 8.3 Hz), 116.2 (d, JCF = 22.5 Hz), 54.1, 52.0, 36.2,
30.9, 26.0, 25.8. HRMS m/z [M+H]+ calcd for C15H20FN2 247.1605, found 247.1616.
3-(1-(4-Methoxyphenyl)-4,5-dihydro-1H-imidazol-2-yl)pyridine (6k): Yield 209 mg (83%);
colorless solid, mp 73–74 °C. 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 2.0 Hz, 1H), 8.56 (dd, J
= 4.8, 1.7 Hz, 1H), 7.82 (dt, J = 7.9, 2.0 Hz, 1H), 7.21 (dd, J = 7.9, 4.8 Hz, 1H), 6.90 – 6.81 (m,
2H), 6.81 – 6.72 (m, 2H), 4.14 – 4.04 (m, 2H), 4.03 – 3.93 (m, 2H), 3.76 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 161.4, 157.1, 150.7, 149.7, 136.1, 135.7, 126.7, 125.8, 122.9, 114.5, 55.4, 55.2,
52.9. HRMS m/z [M+H]+ calcd for C15H16N3O 254.1288, found 254.1281.
2-(Furan-2-yl)-1-phenyl-4,5-dihydro-1H-imidazole (6l)31: Yield 183 mg (86%); pale beige
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solid, mp 75–76 °C. H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 2.0 Hz, 1H), 7.31 (t, J = 7.9 Hz,
2H), 7.17 (t, J = 7.4 Hz, 1H), 7.05 – 7.01 (m, 2H), 6.37 (d, J = 3.5 Hz, 1H), 6.34 (dd, J = 3.5, 2.0
Hz, 1H), 4.12 – 4.04 (m, 2H), 4.00 – 3.92 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 154.2, 144.6,
144.0, 142.9, 129.0, 125.1, 124.2, 113.8, 111.1, 54.7, 53.1. HRMS m/z [M+Na]+ calcd for
C13H12N2NaO 235.0842, found 235.0842.
1-(4-Methoxyphenyl)-2-(thiophen-2-yl)-4,5-dihydro-1H-imidazole (6m): Yield 221 mg
(85%); reddish viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.30 (dd, J = 3.9, 2.3 Hz, 1H), 7.11 –
7.06 (m, 2H), 6.89 – 6.84 (m, 4H), 4.07 – 4.00 (m, 2H), 3.93 – 3.86 (m, 2H), 3.82 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 158.4, 158.0, 136.1, 132.8, 129.8, 128.6, 127.6, 127.0, 114.5, 56.4,
55.4, 52.8. HRMS m/z [M+H]+ calcd for C14H15N2OS 259.0900, found 259.0888.
1-(3,4-Dimethoxyphenyl)-2-(3-nitrophenyl)-4,5-dihydro-1H-imidazole (6n): Yield 146 mg
(45%); reddish viscous oil. 1H NMR (400 MHz, CDCl3) δ 8.44 (t, J = 2.2 Hz, 1H), 8.20 (ddd, J =
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8.2, 2.2, 1.1 Hz, 1H), 7.83 (dt, J = 7.8, 1.1 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 6.71 (d, J = 8.6 Hz,
1H), 6.50 – 6.44 (m, 2H), 4.16 – 4.09 (m, 2H), 4.06 – 3.99 (m, 2H), 3.83 (s, 3H), 3.71 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 161.7, 149.3, 147.9, 146.9, 135.9, 134.5, 132.5, 129.2, 124.6,
123.8, 116.8, 111.4, 108.7, 56.0, 55.9, 55.5, 53.0. HRMS m/z [M+H]+ calcd for C17H18N3O4
328.1292, found 328.1281.
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1-(4-Fluorophenyl)-2-(naphthalen-1-yl)-4,5-dihydro-1H-imidazole (6o): Yield 146 mg
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(79%); reddish viscous oil. H NMR (400 MHz, CDCl3) δ 8.20 – 8.15 (m, 1H), 7.88 (d, J = 8.2
Hz, 1H), 7.87 – 7.82 (m, 1H), 7.51 (dd, J = 7.1, 1.3 Hz, 1H), 7.49 – 7.45 (m, 2H), 7.41 (dd, J =
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8.2, 7.1 Hz, 1H), 6.73 – 6.61 (m, 4H), 4.26 – 4.19 (m, 2H), 4.16 – 4.10 (m, 2H). C NMR (100
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MHz, CDCl3) δ 161.8, 158.7 (d, JCF = 243.0 Hz), 138.0 (d, JCF = 2.8 Hz), 133.6, 130.9, 130.1,
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128.8, 128.3, 127.6, 126.8, 126.2, 125.4, 124.9, 122.5 (d, JCF = 8.0 Hz), 115.4 (d, JCF = 22.6
Hz), 53.2, 52.7. HRMS m/z [M+H]+ calcd for C19H16FN2 291.1292, found 291.1282.
2-(Thiophen-2-yl)-1-(o-tolyl)-4,5-dihydro-1H-imidazole (6p): Yield 117 mg (48%); reddish
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viscous oil. H NMR (400 MHz, CDCl3) δ 7.30 – 7.26 (m, 2H), 7.24 (td, J = 7.3, 1.6 Hz, 1H),
7.18 (td, J = 7.5, 2.0 Hz, 1H), 7.10 (dd, J = 7.7, 1.6 Hz, 1H), 6.81 (dd, J = 5.1, 3.7 Hz, 1H), 6.72
(dd, J = 3.8, 1.1 Hz, 1H), 4.21 – 3.93 (m, 3H), 3.75 – 3.58 (m, 1H), 2.32 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 158.8, 141.8, 136.6, 133.1, 131.2, 129.2, 128.6, 128.1, 127.6, 127.2, 127.1, 54.9,
53.3, 17.8. HRMS m/z [M+H]+ calcd for C14H14N2S 243.0950, found 243.0945.
1-(3,4-Dimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-imidazole (6q): Yield
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171 mg (46%); dark red viscous oil. H NMR (400 MHz, CDCl3) δ 6.76 (br.s, 1H), 6.73 (d, J =
8.5 Hz, 2H), 6.50 (dd, J = 8.5, 2.4 Hz, 1H), 6.46 (d, J = 2.4 Hz, 1H), 4.12 – 3.94 (m, 4H), 3.83
(s, 3H), 3.82 (s, 3H), 3.69 (s, 6H), 3.68 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 163.2, 152.7,
149.0, 146.3, 139.5, 136.7, 125.5, 116.1, 111.3, 108.4, 106.2, 60.9, 56.1, 56.0, 55.8, 55.0, 52.3.
HRMS m/z [M+H]+ calcd for C20H25N2O5 373.1758, found 373.1756.
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2-(4-Methoxyphenyl)-1-(o-tolyl)-4,5-dihydro-1H-imidazole (6r): Yield 63 mg (24%);
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yellowish viscous oil. H NMR (400 MHz, CDCl3) δ 7.41 – 7.36 (m, 2H), 7.20 (dd, J = 7.4, 1.9
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Hz, 1H), 7.08 (td, J = 7.4, 1.5 Hz, 1H), 7.02 (td, J = 7.7, 1.9 Hz, 1H), 6.82 (dd, J = 7.7, 1.5 Hz,
1H), 6.74 – 6.67 (m, 2H), 4.23 – 3.92 (br.s, 3H), 3.74 (s, 3H), 3.68 – 3.42 (br.s, 1H), 2.34 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 164.6, 160.7, 143.3, 135.0, 131.1, 130.0, 127.3, 126.8,
126.3, 123.1, 113.3, 55.1, 54.4, 53.5, 18.1. HRMS m/z [M+H]+ calcd for C17H19N2O 267.1492,
found 267.1499.
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2-(Methylthio)-1-phenyl-4,5-dihydro-1H-imidazole (6s)32: Yield 114 mg (59%); colorless
viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.33 (m, 2H), 7.26 (d, J = 7.6 Hz, 2H), 7.16 (t,
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J = 7.3 Hz, 1H), 3.94 (s, 4H), 2.51 (s, 3H). C NMR (100 MHz, CDCl3) δ 163.3, 140.4, 129.1,
124.9, 122.7, 53.5, 52.9, 14.6. HRMS m/z [M+H]+ calcd for C10H13N2S 193.0794, found
193.0793.
1-(4-Chlorophenyl)-2-(pyrrolidin-1-yl)-4,5-dihydro-1H-imidazole (6t): Yield 78 mg (31%);
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colorless viscous oil. H NMR (400 MHz, CDCl3) δ 7.28 – 7.21 (m, 2H), 7.09 – 6.98 (m, 2H),
3.87 – 3.80 (m, 2H), 3.80 – 3.73 (m, 2H), 3.25 – 3.17 (m, 4H), 1.84 – 1.75 (m, 4H). 13C NMR
(100 MHz, CDCl3) δ 159.8, 143.5, 129.1, 128.6, 123.8, 55.7, 50.6, 48.9, 25.4. HRMS m/z
[M+H]+ calcd for C13H17ClN3 250.1106, found 250.1103.
5-(2-(4-Methoxyphenyl)-4,5-dihydro-1H-imidazol-1-yl)pyrimidine (6u): Yield 161 mg
(63%); colorless viscous oil. 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.18 (s, 2H), 6.41 (d, J
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= 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.20 – 3.98 (m, 4H), 3.82 (s, 3H). C NMR (100 MHz,
CDCl3) δ 161.5, 160.4, 152.2, 148.5, 138.1, 129.9, 122.0, 114.3, 55.3, 53.5, 52.4. HRMS m/z
[M+H]+ calcd for C14H15N4O 255.1240, found 255.1234.
1-(Thiophen-3-yl)-2-(p-tolyl)-4,5-dihydro-1H-imidazole (6v): Yield 124 mg (51%); yellowish
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viscous oil. H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H),
7.08 (dd, J = 5.2, 3.2 Hz, 1H), 6.51 (dd, J = 5.2, 1.5 Hz, 1H), 6.33 (dd, J = 3.2, 1.5 Hz, 1H), 4.10
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– 4.02 (m, 2H), 4.01 – 3.91 (m, 2H), 2.37 (s, 1H). C NMR (100 MHz, CDCl3) δ 162.6, 141.9,
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140.1, 128.9, 128.5, 128.3, 124.4, 123.0, 109.8, 53.6, 53.2, 21.4. HRMS m/z [M+H]+ calcd for
C14H15N2S 243.0950, found 243.0950.
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Methyl 4-(1-(pyridin-3-yl)-4,5-dihydro-1H-imidazol-2-yl)benzoate (6w): Yield 203 mg
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(69%); colorless solid, mp 89–90 °C. H NMR (400 MHz, CDCl3) δ 8.24 (dd, J = 4.7, 1.4 Hz,
1H), 8.18 (d, J = 2.7 Hz, 1H), 8.00 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.08 (dd, J =
8.3, 4.7 Hz, 1H), 6.99 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H), 4.20 – 4.03 (m, 4H), 3.91 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 166.3, 161.1, 144.5, 143.7, 139.3, 134.9, 131.7, 129.7, 128.8, 128.6,
123.2, 53.8, 53.5, 52.3. HRMS m/z [M+H]+ calcd for C16H16N3O2 282.1237, found 282.1228.
4-Methyl-1-phenyl-2-(p-tolyl)-4,5-dihydro-1H-imidazole (6x): Yield 161 mg (64%);
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yellowish viscous oil. H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.1 Hz, 2H), 7.23 – 7.15 (m,
2H), 7.10 (d, J = 8.1 Hz, 2H), 6.99 (t, J = 7.4 Hz, 1H), 6.80 (d, J = 7.6 Hz, 2H), 4.39 – 4.28 (m,
1H), 4.16 (dd, J = 9.9, 9.1 Hz, 1H), 3.64 (dd, J = 9.1, 8.0 Hz, 1H), 2.34 (s, 3H), 1.43 (d, J = 6.6
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Hz, 3H). C NMR (100 MHz, CDCl3) δ 161.2, 143.2, 140.2, 128.8, 128.8, 128.7, 128.0, 123.2,
122.4, 60.8, 59.3, 22.2, 21.4. HRMS m/z [M+H]+ calcd for C17H19N2 251.1543, found 251.1539.
5-Methyl-1-phenyl-2-(p-tolyl)-4,5-dihydro-1H-imidazole (6x'): Yield 43 mg (17%); yellowish
viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.2 Hz, 2H), 7.21 (t, J = 7.8 Hz, 2H), 7.11
– 7.02 (m, 3H), 6.94 – 6.87 (m, 2H), 4.28 – 4.10 (m, 2H), 3.64 (dd, J = 13.7, 6.7 Hz, 1H), 2.30
(s, 3H), 1.37 (d, J = 6.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 163.2, 142.9, 139.9, 128.9,
128.70, 128.69, 128.3, 125.1, 124.7, 61.6, 61.2, 21.4, 20.9. HRMS m/z [M+H]+ calcd for
C17H19N2 251.1543, found 251.1530.
2-(p-Tolyl)-1,4,5,6-tetrahydropyrimidine (7) is a known compound and was prepared as
reported in the literature.24
N-Isobutyl-1-phenyl-4,5-dihydro-1H-imidazol-2-amine (9a). In a screwꢀcapped tube a
solution of compound 6s (96 mg, 0.5 mmol) and isobutylamine (55 mg, 0.75 mmol) in dry nꢀ
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butanol (1 mL) was stirred at 110 °C for 24 hours. Volatiles were removed in vacuo and the
crude residue was subjected to column chromatography on silica gel (eluent MeOH to MeOHꢀ
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Et3N (5:1)) to afford pure titled compound. Yield 67 mg (62%), colorless viscous oil. H NMR
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(400 MHz, CDCl3) δ 7.35 (t, J = 7.6 Hz, 2H), 7.20 (d, J = 7.8 Hz, 2H), 7.10 (t, J = 7.4 Hz, 1H),
3.93 (br.s, 1H), 3.82 – 3.76 (m, 2H), 3.74 – 3.67 (m, 2H), 3.08 (d, J = 6.9 Hz, 2H), 1.90 – 1.74
(m, 1H), 0.91 (d, J = 6.7 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 157.3, 141.4, 129.6, 123.9,
121.7, 52.0, 51.0, 48.8, 28.4, 20.3. HRMS m/z [M+H]+ calcd for C13H20N3 218.1652, found
218.1655.
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General Experimental Procedure for the Preparation of 2-Alkylaminoimidazolines 9b,c. In
a screwꢀcapped tube a solution of compound 6s (96 mg, 0.5 mmol) and appropriate amine
(0.6 mmol) in dry 1,4ꢀdioxane (1 mL) was stirred at 110 °C during 7 days (for 9b) or 3 days (for
9c). Volatiles were removed in vacuo and the crude residue was subjected to column
chromatography on silica gel (eluent EtOAc/MeOH/Et3N from (94:5:1) to (88:10:2)) to afford
pure compounds 9b,c.
2-(1-Phenyl-4,5-dihydro-1H-imidazol-2-yl)-1,2,3,4-tetrahydroisoquinoline (9b): Yield 72 mg
(54%); colorless viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 7.6 Hz, 2H), 7.21 (d, J =
7.6 Hz, 2H), 7.19 – 7.14 (m, 2H), 7.13 – 7.03 (m, 3H), 4.46 (s, 2H), 4.00 – 3.91 (m, 2H), 3.85 –
3.76 (m, 2H), 3.37 (t, J = 5.9 Hz, 2H), 2.78 (t, J = 5.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ
161.1, 144.6, 134.2, 133.6, 129.1, 128.7, 126.5, 126.4, 126.0, 123.1, 121.3, 54.8, 50.0, 49.7,
45.6, 28.3. HRMS m/z [M+H]+ calcd for C18H20N3 278.1652, found 278.166.
N-(4-Methoxybenzyl)-1-phenyl-4,5-dihydro-1H-imidazol-2-amine (9c): Yield 103 mg (73%);
colorless solid, mp 73–75 °C. 1H NMR (400 MHz, CDCl3) δ 7.36 (t, J = 7.8 Hz, 2H), 7.30 – 7.23
(m, 4H), 7.11 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 4.43 (s, 2H), 3.90 – 3.85 (m, 2H),
3.83 (br.s, 1H), 3.80 (s, 3H), 3.78 – 3.74 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 158.9, 157.1,
140.8, 131.1, 129.6, 128.9, 124.2, 121.9, 114.0, 55.3, 51.9, 47.8, 47.4. HRMS m/z [M+H]+ calcd
for C17H20N3O 282.1601, found 282.1612.
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ASSOCIATED CONTENT
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Supporting Information
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Copies of 1H and 13C NMR (as well as NOESY) spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: m.krasavin@spbu.ru.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This research was supported by the Russian Scientific Fund (project grant 14ꢀ50ꢀ00069). NMR
and mass spectrometry studies were performed at the Research Centre for Magnetic Resonance,
the Centre for Chemical Analysis and Materials Research of Saint Petersburg State University
Research Park. The authors are grateful to Dr. Ivan Eliseev for preliminary adaptation of the
CEL protocol to 2ꢀimidazoline Nꢀarylation.
REFERENCES
1. Parini, A.; Moudanos, C. G.; Pizzinat, N.; Lanier, S. M. Trends Pharmacol. Sci. 1996, 17,
13.
2. Welsh, M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14, 347.
3. Krasavin, M. Eur. J. Med. Chem. 2015, 97, 525.
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