Synthesis and synthetic applications of 1-aryl-2-alkyl-4,5-dihydro-1 H-imidazoles

Article abstract of DOI:10.1080/00397911.2011.552155

An easy synthesis of 1-aryl-2-alkyl-4,5-dihydro-1H-imidazoles 1 by cyclo-condensation of N-acyl-N-arylethylenediamines 2 is described. Such precursors were synthesized by aminolysis of the corresponding N-(2-bromoethyl)amides 3. Cyclizations were performed using trimethylsilyl polyphosphate as a mild dehydrating agent, under microwave irradiation. Chemical properties of 1-aryl-2-alkyl-4,5-dihydro-1H-imidazoles, typical of the amidine system, were studied. Reduction of dihydroimidazoles with sodium cyanoborohydride leads regiospecifically to N-alkyl-N-arylethylenediamines 4, and nucleophilic attack to methyl iodide leads to the corresponding 1-aryl-2-alkyl-3-methyl-4,5-dihydro-1H-imidazolium salts 5.

Full text of DOI:10.1080/00397911.2011.552155

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Synthesis and Synthetic Applications of
1-Aryl-2-alkyl-4,5-dihydro-1H-imidazoles
Ana M. Reverdito a , Isabel A. Perillo a & Alejandra Salerno a
a Department of Organic Chemistry, Faculty of Pharmacy and
Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
Accepted author version posted online: 27 Oct 2011.Published
online: 26 Mar 2012.
To cite this article: Ana M. Reverdito , Isabel A. Perillo & Alejandra Salerno (2012) Synthesis and
Synthetic Applications of 1-Aryl-2-alkyl-4,5-dihydro-1H-imidazoles, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:14, 2083-2097,
DOI: 10.1080/00397911.2011.552155
To link to this article: http://dx.doi.org/10.1080/00397911.2011.552155
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Synthetic Communications1, 42: 2083–2097, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.552155
SYNTHESIS AND SYNTHETIC APPLICATIONS OF
1-ARYL-2-ALKYL-4,5-DIHYDRO-1H-IMIDAZOLES
Ana M. Reverdito, Isabel A. Perillo, and Alejandra Salerno
Department of Organic Chemistry, Faculty of Pharmacy and Biochemistry,
University of Buenos Aires, Buenos Aires, Argentina
GRAPHICAL ABSTRACT
Abstract An easy synthesis of 1-aryl-2-alkyl-4,5-dihydro-1H-imidazoles
1 by cyclo-
condensation of N-acyl-N0-arylethylenediamines 2 is described. Such precursors were synthe-
sized by aminolysis of the corresponding N-(2-bromoethyl)amides 3. Cyclizations were
performed using trimethylsilyl polyphosphate as a mild dehydrating agent, under microwave
irradiation. Chemical properties of 1-aryl-2-alkyl-4,5-dihydro-1H-imidazoles, typical of the
amidine system, were studied. Reduction of dihydroimidazoles with sodium cyanoborohydride
leads regiospecifically to N-alkyl-N0-arylethylenediamines 4, and nucleophilic attack to methyl
iodide leads to the corresponding 1-aryl-2-alkyl-3-methyl-4,5-dihydro-1H-imidazolium salts 5.
Keywords Alkylation; amidines; cyclization; 4,5-dihydro-1H-imidazoles; heterocycles;
reductions
INTRODUCTION
4,5-Dihydro-1H-imidazoles 1 (2-imidazolines) are compounds of interest
because of their interaction with specific imidazoline receptors, and this behavior
is reflected in a multiplicity of biological functions.[1] Thus, they have been studied
as antihypertensive,[2] hypoglycemic,[3] anti-inflammatory,[4] antidepressive,[5]
anticancer,[6] antimicrobial,[7] antihypercholesterolemic,[8] and anticoagulant[9]
agents. From a chemical point of view, the synthesis and study of such compounds
Received December 21, 2010.
Address correspondence to Alejandra Salerno, Department of Organic Chemistry, Faculty of
´
Pharmacy and Biochemistry, University of Buenos Aires, Junın 956 (1113), Buenos Aires, Argentina.
E-mail: asalerno@ffyb.uba.ar
2083

2084
A. M. REVERDITO, I. A. PERILLO, AND A. SALERNO
is of interest because the compounds are synthetic intermediates,[10] auxiliaries,[11]
and catalysts[12] for asymmetric synthesis. The imidazoline nucleus has also been
used as a source of carbon units in transfer reactions.[13]
The classical methods for the synthesis of the imidazoline nucleus involve
condensation of adequately substituted 1,2-diaminoethane with carboxylic acids[14]
or derivatives as esters,[15] orthoesters,[16] and nitriles[17] at high temperatures. Some
of these methods have been optimized by using alternative energy sources such as
ultrasonic irradiation[18] and microwave irradiation under green synthetic
conditions.[19] Besides, 2-imidazolines has been obtained via [3 þ 2]-cycloaddition
of aziridines with nitriles[20] as well as via multicomponent synthesis.[21] On the other
hand, synthesis of imidazolines through condensation of ethylenediamines with
aldehydes by means of a dehydrogenating reagent, which promotes oxidation of
the N1–C2 bond in the reaction medium, has also been reported.[22]
Compounds with H or alkyl groups in N1 have been extensively studied. Never-
theless, there are few reports on the synthesis of N-arylimidazolines. In previous work,
we developed a method for the synthesis of 1-aryl and 1,2-diarylimidazolines by ring
closure of the corresponding N-benzoyl(or formyl)-N0-arylethylenediamine.[23,24] In
this work, the synthesis of 1-aryl-2-alkyl-4,5-dihydro-1H-imidazoles 1, which involves
the ring closure of N-acyl-N0-arylethylenediamines (2) by trimethylsilyl polypho-
sphate (PPSE), employs microwave irradiation, a valuable technique that accelerates
chemical reactions and minimizes thermal decomposition of the products.[25]
Some chemical properties of compounds 1 typical of the amidine system, such
as reduction with a nucleophilic agent (sodium cyanoborohydride) and quaterniza-
tion with methyl iodide, were also studied.
RESULTS AND DISCUSSION
The synthetic route involves the preparation of the corresponding N-(2-bro-
moethyl)amide 3 from the 2-bromoethylamine hydrobromide by Schotten–Baumann
acylation with a suitable acylating agent. Reactions of compounds 3 with arylamines
lead to the expected N-acyl-N0-arylethylenediamines 2a–g (Fig. 1, Table 1) accompanied
by the N,N-bis-(2-amidoethyl)arylamine.
Figure 1. Synthesis of 1-aryl-2-alkyl-1H-4,5-dihydroimidazoles 1.

SYNTHESIS AND APPLICATIONS OF 1H-IMIDAZOLES
Table 1. 4,5-Dihydro-1H-imidazoles 1 and ethylenediamines 2
2085
Compounds 1 and 2
Ar
R
a
b
c
d
e
f
4-ClC6H4
CH3
C2H5
4-Cl C6H4
4-Cl C6H4
4-Cl C6H4
4-Cl C6H4
4-Cl C6H4
4-Cl C6H4
4-NO2C6H4
4-NO2C6H4
iso-C3H7
tert-C4H9
CH2-C6H5
CH2-(2-ClC6H4)
CH¼CHC6H5
iso-C3H7
g
h
i
tert-C4H9
To minimize bis derivative formation, the reaction was assayed under different
conditions (in toluene, without solvent, and at different temperatures), reaching the
best results when heating at 100 ꢀC in absence of solvent. This synthetic route was
not applicable to a 4-nitrophenyl derivatives because of the low nucleophilicity
of the corresponding arylamine. Thus, compounds 2h and i were synthesized by
acylation of N-(4-nitrophenyl)ethylenediamine, obtained through nucleophilic
displacement of 4-chloronitrobenzene (Fig. 1, Table 1).
Cyclization of compounds 2 was initially carried out with chloroform solution
of ethyl polyphosphate (PPE), which had been an appropriate agent to obtain 1,2-
diarylimidazolines.[23] However, under the same conditions, cyclization of compounds
2 is not fulfilled until 15 h of heating, and the corresponding imidazolines are obtained
with very poor yields in the presence of raw materials and by-products. Better results
have been achieved with methylene chloride solution of trimethylsilyl polyphosphate
(PPSE), an aprotic cyclizing agent.[26] The main limitation of this procedure is that
long reaction times are often required (10–12 h), resulting in poor yields of the pro-
ducts (35–50% yields). With the aims of enhancing the reaction yields and decreasing
the reaction times, the cyclization was optimized using microwave irradiation as the
energy source. The reactions were carried out in a Reactor Microwave Digestion
System WX-4000 at 80 ꢀC (300 W). Results are shown in Table 2. Under these con-
ditions, times decreased to 22–29 min with 78–98% yields. The method allowed the
Table 2. Conditions for conversion 2 ! 1
Conventional heating
Microwave irradiation (80 ꢀC, 300 W)
Product Reaction time (h) Yield (%)
Reaction time (min)
Yield (%)
1a
1b
1c
1d
1e
1f
10.5
11.5
11.0
12.0
11.5
10.0
10.5
11.5
10.5
42
45
31
39
47
49
38
33
49
25
23
28
22
25
29
28
24
26
83
78
89
90
89
92
98
95
94
1g
1h
1i

2086
A. M. REVERDITO, I. A. PERILLO, AND A. SALERNO
Figure 2. Chemical properties of 1-aryl-2-alkyl-4,5-dihydro-1H-imidazoles 1.
preparation of 1-arylimidazolines 2-substituted with primary (1a and b), secondary (1c
and h) and tertiary (1d and i) alkyl, benzyl (1e and f) and substituted vinyl groups (1-g).
To evaluate 4,5-dihydro-1H-imidazoles 1 as potential precursors of cyclic and
acyclic compounds carrying the ethylenediamine unit (>NCH2CH2N<), reactions
resulting from their C2 electrophilic character (reduction) and those to N3 nucleo-
philic properties (quaternization) were studied (Fig. 2).
Treatment of 1a–i with sodium cyanoborohydride in ethanol at room tempera-
ture led regiospecifically to N,N0-disubstituted ethylenediamines 4. We propose for this
reaction an initial hydride ion attack to the electrophilic C2, with formation of the cor-
responding 1-aryl-2-alkylimidazolidine in tautomeric equilibrium with the correspond-
ing aminoimine. It is well known that N1 and=or N3 unsubstituted imidazolidines
present ring (imidazolidine)-chain (aminoimine) tautomerism,[27] and usually both
species can be spectroscopically identified. Thus, the selective cleavage of the
C2-NAr bond may result from the direct reduction of the aminoimine or the reductive
cleavage of the imidazolidine.[23]
As expected because of its nature of cyclic amidines, compounds 1 have nucleo-
philic character because of the N3 lone pair. Alkylation reactions with alkyl iodides
led to 1,2,3-trisubstituted dihydroimidazolium ions 5, highly stabilized by resonance.
This behavior may explain the observed selectivity and the absence of N,N-dialky-
lated products.
Infrared (IR) spectra of compounds 5a–i confirmed their ionic structure, as can
be seen from the strong amidinium band at ca. 1600–1640 cmꢁ1. Mass spectrometry
(MS, IE) of compounds 5 showed thermal decomposition with loss of methyl iodide
before fragmentation.
Scheme 1.

SYNTHESIS AND APPLICATIONS OF 1H-IMIDAZOLES
2087
Based on structural and physical features, 4,5-dihydro-1H-imidazolium salts 5
belong to the family of ionic liquids. They also are a potential source of imidazoli-
dines and N,N,N0-trisubstituted ethylenediamines.[28]
In summary, an easy synthesis of 1-aryl-2-alkyl-4,5-dihydro-1H-imidazoles 1 by
cyclocondensation of N-acyl-N0-arylethylenediamines 2 is described. The method has
also been applied for the synthesis of 2-benzyl and 2-arylvinyl derivatives. We have also
shown that microwave irradiation is essential for rapid and high-yielding reactions: the
reaction times were dramatically reduced from 10–12 h (traditional heating) to
23–29 min using the microwave technique. Compounds 1 act as key intermediates for
the synthesis of cyclic and acyclic compounds with the ethylenediamine structural unit.
EXPERIMENTAL
Melting points were taken on a Buchi capillary apparatus and were uncorrected.
¨
1H NMR spectra were measured in CDCl3 or dimethylsulfoxide (DMSO-d6) solutions
on a Bruker MSL 300-MHz spectrometer at 25 ꢀC. Standard concentration of the
samples was 20 mg=mL. Chemical shifts are reported in parts per million (ppm, d)
relative to tetramethylsilane (TMS) as an internal standard. Coupling constant (J)
values are given in hertz (Hz). D2O was employed to confirm exchangeable protons.
Electron impact MS were recorded with a GC-MS Shimadzu QP-1000 spectrometer
operating at 70 eV. IR spectra were recorded on a Perkin-Elmer Spectrum One Four-
ier transform (FT)–IR spectrometer. The microwave-assisted reactions were carried
out in a Reactor Microwave Digestion System WX-4000 (EU Chemical Instruments).
Thin-layer chromatographic (TLC) analyses were carried out on silica-gel 60 F254
aluminum sheets. Column chromatography was performed on silica gel 60 (0.063–
0.200 mesh) with typically 30–50 g of stationary phase per gram of substance.
N-(2-Bromoethyl)amides 3 were prepared by reaction of 2-bromoethylamine
hydrobromide with a suitable acylating agent (acetic, propionic, or isobutyric
anhydride and pivaloyl chloride) under Schotten–Baumann conditions and were
used without previous purification.
N-Acyl-N’-(4-chlorophenyl)ethylenediamines 2a–g
General procedure. A mixture of the appropriate N-(2-bromoethyl)amide
3 (0.02 mol) and 4-chloroaniline (0.04 mol) was heated in a boiling water bath for
1 h. The crude product was treated with boiling water (3 ꢂ 20 mL) to eliminate
4-chloroaniline hydrobromide. The products were purified by column chromato-
graphy (ethyl acetate–chloroform, 8:2). Compounds 2b,c[29] were previously described.
N-Acetyl-N’-(4-chlorophenyl)ethylenediamine (2a). Yield: 62%. It was
1
obtained as an oil. H NMR (DMSO-d6) 1.90 (s, 3H CH3), 3.25 (t, J ¼ 5.7 Hz, 2H
CH2NHAr), 3.47 (q, J ¼ 5.7 Hz, 2H CH2NHCO), 3.54 (br s, 1H NHAr), 5.93 (bs,
1H NHCO), 6.54 (dd, J ¼ 6.9, 2.2 Hz, 2H aromatics), 7.12 (dd, J ¼ 6.9, 2.2 Hz, 2H
aromatics). IR (film) 3321, 2980, 1660, 1508, 1442, 1240, 1027, 816, 731 cmꢁ1. MS:
m=z 212, 214 (Mþ). Anal. calcd. for C10H13ClN2O: C, 54.47; H, 6.16; N, 13.17.
Found: C, 54.51; H, 6.12; N, 13.19.

2088
A. M. REVERDITO, I. A. PERILLO, AND A. SALERNO
N-(4-Chlorophenyl)-N’-(2,2-dimethylpropionyl)ethylenediamine (2d).
1
Yield: 74%. It was obtained as an oil. H NMR (DMSO-d6) 1.17 (s, 9H CH3),
3.23 (t, J ¼ 5.7 Hz, 2H CH2NHAr), 3.50 (q, J ¼ 5.7 Hz, 2H CH2NHCO), 3.55 (br
s, 1H NHAr), 5.96 (br s, 1H NHCO), 6.54 (dd, J ¼ 6.9, 2.2 Hz, 2H aromatics),
7.11 (dd, J ¼ 6.9, 2.2 Hz, 2H aromatics). IR (film) 3315, 2996, 2925 1659, 1520,
1520, 1452, 1380, 820, 740 cmꢁ1. MS: m=z 254, 256 (Mþ). Anal. calcd. for
C13H19ClN2O: C, 61.29; H, 7.52; N, 11.00. Found: C, 61.35; H, 7.47; N, 11.13.
N-(4-Chlorophenyl)-N’-phenylacetylethylenediamine (2e). Yield: 79%.
1
Mp: 119–121 ꢀC. H NMR (DMSO-d6) 3.05 (t, J ¼ 6.5 Hz, 2H CH2NHAr), 3.19
(q, J ¼ 6.5 Hz, 2H, CH2NHCO), 3.39 (s, 2H CH2CO), 5.84 (br s, 1H NHAr), 6.5
(dd, J ¼ 6.7, 2.0 Hz, 2H aromatics), 7.05 (dd, J ¼ 6.7, 2.0 Hz, 2H aromatics),
7.32–7.20 (m, 5H aromatics), 8.15 (br s, 1H HNCO). IR (film) 3341, 2975, 1649,
1434, 1252, 1137, 817, 736 cmꢁ1. MS: m=z 288, 290 (Mþ). Anal. calcd. for
C16H17ClN2O: C, 66.55; H, 5.93; N, 9.70. Found: C, 66.59; H, 6.11; N, 9.61.
N-(2-Chlorophenylacetyl)-N’-(4-chlorophenyl)ethylenediamine (2f).
1
Yield: 76%. It was obtained as an oil. H NMR (DMSO-d6) d: 3.05 (t, J ¼ 6.7 Hz,
2H CH2NHAr), 3.21 (q, J ¼ 6.7 Hz, 2H CH2NHCO), 3.57 (s, 2H CH2CO), 5.85
(br s, 1H HNAr), 6.5 (dd, J ¼ 6.7, 2.7 Hz, 2H aromatics), 7.08 (dd, J ¼ 6.7, 2.7 Hz,
2H aromatics), 7.41–7.20 (m, 4H aromatics), 8.15 (br s, 1H HNCO). IR (film)
3330, 2936, 2923, 1651, 1519, 1462, 1080, 827, 747 cmꢁ1. MS: m=z 322, 324, 326
(Mþ). Anal. calcd. for C16H16Cl2N2O: C, 59.46; H, 4.99; N, 8.67. Found: C,
59.55; H, 4.85; N, 8.71.
N-(4-Chlorophenyl)-N’-cinnamoylethylenediamine (2g). Yield: 82%. It
1
was obtained as an oil. H NMR (DMSO-d6) 3.25–3.01 (m, 4H CH2-CH2), 5.91
(br s, 1H NHAr), 6.50 (d, J ¼ 16.2 Hz, 1H HC ¼), 6.59 (dd, J ¼ 6.7, 2.0 Hz, 2H aro-
matics), 6.97 (d, J ¼ 16.2 Hz, 1H HC ¼), 7.08 (dd, aromatics, J ¼ 6.7, 2.0 Hz, 2H),
7.60–7.15 (m, 5H aromatics), 8.21 (br s, 1H NHCO). IR (film) 3325, 2945, 1633,
1517, 1430, 832, 740 cmꢁ1. MS: m=z 300, 302 (Mþ). Anal. calcd. for C17H17ClN2O:
C, 67.88; H, 5.70; N, 11.79. Found: C, 67.79; H; 5.78; N, 11.60.
N-Acyl-N’-(4-nitrophenyl)ethylenediamines 2h–i
General procedure. A mixture of N-(4-nitrophenyl)ethylenediamine
(0.01 mol) in chloroform (50 mL), the appropiate acylating agent (0.013 mol), and
triethylamine (0.016 mol) was refluxed for 1 h. After heating, the organic solution
was evaporated in vacuo. The resulting residue was triturated with an aqueous
solution of NaOH (5%), filtered, and washed with water, diluted HCl (5%), and
water once again. The pure products were isolated by column chromatography (ethyl
acetate–chloroform, 8:2) as yellow solids.
N-(4-Nitrophenyl)-N’-(2-methylpropionyl)ethylenediamine (2h). Yield:
1
80%. Mp: 105–107 ꢀC. H NMR (CDCl3) 1.15 (d, J ¼ 7.1 Hz, 6H CH3), 2.40 (m,
J ¼ 7.1 Hz, 1H CH), 3.34 (t, J ¼ 5.2 Hz, 2H CH2NHAr), 3.56 (q, J ¼ 5.2 Hz, 2H,
CH2NHCO), 5.55 (br s, 1H NH), 5.95 (br s, 1H NH), 6.50 (d, J ¼ 9.1 Hz, 2H aro-
matics), 8.04 (d, J ¼ 9.1 Hz, 2H aromatics). IR (film) 3412, 2931, 1635, 1540, 1324,

SYNTHESIS AND APPLICATIONS OF 1H-IMIDAZOLES
2089
831 cmꢁ1. MS: m=z 251 (Mþ). Anal. calcd. for C12H17N3O3: C, 57.36; H, 6.82; N,
16.72. Found: C, 57.45; H, 6.07; N, 16.65.
N-(4-Nitrophenyl)-N’-(2,2-dimethylpropionyl)ethylenediamine (2i).
Yield: 85%. Mp: 172–174 ꢀC. 1H NMR (CDCl3) 1.21 (s, 9H CH3), 3.34 (t, J ¼ 5.2 Hz,
Hz, 2H CH2NHAr), 3.58 (q, J ¼ 5.2 Hz, 2H CH2NHCO), 6.03 (br s, 1H NH), 5.56
(br s, 1H NH), 6.55 (d, J ¼ 9.1 Hz, 2H artomatics), 8.08 (d, J ¼ 9.1 Hz, 2H
aromatics). IR (film) 3392, 2930, 2871, 1620, 1324, 835 cmꢁ1. MS: m=z 265 (Mþ).
Anal. calcd. for C13H19N3O3: C, 58.85; H, 7.22; N, 15.84. Found: C, 58.76; H,
7.29; N, 15.95.
2-Alkyl-1-aryl-4,5-dihydro-1H-imidazoles 1a–i
General procedure for conventional heating. A mixture of N-acyl-N0-
arylethylenediamine (1 mmol) and a solution of PPSE[26] (2 mL) was refluxed and
monitored by TLC using chloroform–methanol 8:2 as elution solvent until disap-
pearance of starting diamine. The residue was cooled and extracted with water
(3 ꢂ 2 mL). The aqueous phases were pooled, neutralized with solid sodium carbon-
ate, and extracted with Cl2CH2 (3 ꢂ 2 mL). The organic phases were pooled and
washed with water. The organic solution was dried over anhydrous sodium sulfate
and evaporated in vacuo. The yellowish oily products were purified by column chro-
matography (chloroform-methanol, 8:2).
General procedure for microwave technique. N-acyl-N0-arylethylenedia-
mine (1 mmol) and a solution of PPSE (2 mL) were placed in a 10-mL glass tube.
The tube was closed with a septum and placed into the microwave cavity. The reac-
tion mixture was subjected to microwave irradiation at 300 W (80 ꢀC) for 20–29 min.
After allowing the mixture to cool to room temperature, the reaction vessel was
opened and the reaction product 1 was isolated, as indicated in the conventional
procedure.
1-(4-Chlorophenyl)-2-methyl-4,5-dihydro-1H-imidazole (1a). 1H NMR
(CDCl3) 2.05 (s, 3H CH3), 3.83 (s, 4H CH2-CH2), 7.03 (d, J ¼ 8.7 Hz, 2H aromatics),
7.30 (d, J ¼ 8.7 Hz, 2H aromatics). IR (film) 2959, 1615, 1491, 1083, 832, 712 cmꢁ1
.
MS: m=z 194, 196 (Mþ). Anal. calcd. for C10H11ClN2: C, 61.70; H, 5.70; N, 14.39.
Found: C, 61.58; H, 5.61; N, 14.46.
1-(4-Chlorophenyl)-2-ethyl-4,5-dihydro-1H-imidazol (1b). 1H NMR
(CDCl3) 1.12 (t, J ¼ 7.4 Hz, 3H CH3), 2.27 (q, J ¼ 7.4 Hz, 2H CH2), 3.78 (s, 4H
CH2-CH2), 7.01 (d, J ¼ 8.7 Hz, 2H aromatics), 7.29 (d, J ¼ 8.7, 2H aromatics). IR
(film) 2950, 1616, 1483, 1061, 829, 721 cmꢁ1. MS: m=z 208, 210 (Mþ). Anal. calcd.
for C11H13ClN2: C, 63.31; H, 6.28; N, 13.42. Found: C, 63.22; H, 6.39; N, 13.35.
1-(4-Chlorophenyl)-2-(1-methylethyl)-4,5-dihydro-1H-imidazole
(1c).
1H NMR (CDCl3) 1.13 (d, J ¼ 6.8 Hz, 6H CH3), 2.60 (m, J ¼ 6.8 Hz, 1H CH),
3.86–3.74 (m, 4H CH2-CH2), 7.05 (d, J ¼ 8.7 Hz, 2H aromatics), 7.33 (d, J ¼ 8.7 Hz,
Hz, 2H aromatics). IR (film) 2954, 1621, 1487, 1075, 840, 730 cmꢁ1. MS: m=z 222,
224 (Mþ). Anal. calcd. for C12H15ClN2: C, 64.72; H, 6.79; N, 12.58. Found: C,
64.65; H, 6.85; N, 12.66.

2090
A. M. REVERDITO, I. A. PERILLO, AND A. SALERNO
1-(4-Chlorophenyl)-2-(1,1-dimethylethyl)-4,5-dihydro-1H-imidazole (1d).
1H NMR (CDCl3) 1.30 (s, 9H CH3), 4.16 (s, 4H CH2-CH2), 7.28 (d, J ¼ 8.5 Hz, 2H
aromatics), 7.49 (d, J ¼ 8.5 Hz, 2H aromatics. IR (film) 2900, 1629, 1490, 1090, 811,
710 cmꢁ1. MS: m=z 236, 238 (Mþ). Anal. calcd. for C13H17ClN2: C, 65.95; H, 7.24;
N, 11.83. Found: C, 65.88; H, 7.33; N, 11.76.
2-Benzyl-1-(4-chlorophenyl)-4,5-dihydro-1H-imidazole (1e). 1H NMR
(CDCl3) 3.61 (s, 2H CH2), 3.87–3.78 (m, 4H CH2-CH2), 6.93 (d, J ¼ 8.8 Hz, 2H
aromatics), 7.12 (d, J ¼ 8.8 Hz, 2H aromatics), 7.23–7.20 (m, 5H aromatics). IR
(film) 2935, 1620, 1480, 1079, 823, 715 cmꢁ1. MS: m=z 270, 272 (Mþ). Anal. calcd.
for C16H15ClN2: C, 70.98; H, 5.58; N, 10.35. Found: C, 70.87; H, 5.66; N, 10.24.
2-(2-Chlorobenzyl)-1-(4-chlorophenyl)-4,5-dihydro-1H-imidazole
(1f).
1H NMR (CDCl3) 3.67 (s, 2H CH2), 3.89 (s, 4H CH2-CH2), 6.94 (d, J ¼ 8.8, 2 H
aromatics), 7.30–7.10 (m, 6H aromatics). IR (film) 2956, 1615, 1483, 1065, 833,
731 cmꢁ1. MS: m=z 304, 306, 308 (Mþ). Anal. calcd. for C16H14Cl2N2: C, 62.97;
H, 4.62; N, 9.18. Found: C, 62.79; H, 4.70; N, 9.26.
1-(4-Chlorophenyl)-2-(2-phenylvinyl)-4,5-dihydro-1H-imidazole (1g). 1H
NMR (CDCl3) 4.05–3.81 (m, 4H CH2-CH2), 6.52 (d, J ¼ 15.9, 1H CH ¼), 7.03 (d,
J ¼ 8.7, 2H aromatics), 7.50–7.15 (m, aromatics, 7H), 7.52 (d, J ¼ 15.9, 1H CH ¼).
IR (film) 2943, 1612, 1480, 1072, 836, 720 cmꢁ1. MS: m=z 282, 284 (Mþ). Anal. calcd.
for C17H15ClN2: C, 72.21; H, 5.35; N, 9.91. Found: C, 72.38; H, 5.39; N, 9.82.
2-(1-Methylethyl)-1-(4-nitrophenyl)-4,5-dihydro-1H-imidazole (1h). 1H
NMR (CDCl3) 1.29 (d, J ¼ 7.1, 6H CH3), 2.85 (m, CH, J ¼ 7.1, 1H), 3.95–3.80
(m, CH2-CH2, 4 H), 7.15 (d, aromatics, J ¼ 9.1, 2H), 8.20 (d, J ¼ 9.1, 2H aromatics).
IR (film) 2947, 1611, 1491, 1378, 1061, 835 cmꢁ1. MS: m=z 233 (Mþ). Anal. calcd. for
C12H15N3O2: C, 61.79; H, 6.48; N, 18.01. Found: C, 61.62; H, 6.55; N, 18.15.
2-(1,1-Dimethylethyl)-1-(4-nitrophenyl)-4,5-dihydro-1H-imidazole (1i).
1H NMR (CDCl3) 1.10 (s, 9H CH3), 3.90–3.70 (m, 4H CH2-CH2), 7.35 (d, J ¼ 9.1,
2H aromatics), 8.25 (d, J ¼ 9.1, 2H aromatics). IR (film) 2900, 1639, 1502, 1353,
111, 847 cmꢁ1. MS: m=z 247 (Mþ). Anal. calcd. for C13H17N3O2: C, 63.14; H,
6.93; N, 16.99. Found: C, 63.23; H, 6.05; N, 16.83.
N-Alkyl-N’-arylethylenediamines 4a–i
General procedure. Sodium cyanoborohydride (0.05 mol) was added for
5 min to a solution of the appropriate 1H-4,5-dihydroimidazole 1 (0.01 mol) in etha-
nol (20 mL) keeping the mixture at rt. When total transformation had occurred (ca.
30 min for compounds 4a–g and 50 min for compounds 4 h–i, the suspension was
extracted with chloroform (3 ꢂ 15 mL). The organic layers were pooled, washed with
water, dried over anhydrous sodium sulfate, and concentrated in vacuo affording
dark oily compounds 4a-i which were purified by column chromatography
(chloroform=methanol, 1:1).
1
N-(4-Chlorophenyl)-N’-ethylethylenediamine (4a). Yield: 67%. H NMR
(CDCl3) 1.10 (t, J ¼ 7.1 Hz, 3H CH3), 1.90 (br s, 1H NHR), 2.65 (q, J ¼ 7.1 Hz,
2H CH2-CH3), 2.85 (t, J ¼ 5.5 Hz, 2H CH2-NHR), 3.15 (t, J ¼ 5.5 Hz, 2H

SYNTHESIS AND APPLICATIONS OF 1H-IMIDAZOLES
2091
CH2-NHAr), 4.22 (br s, 1H NHAr), 6.55 (dd, J ¼ 6.7, 2.0 Hz, 2H aromatics), 7.10
(dd, J ¼ 6.7, 2.0 Hz, 2H aromatics). IR (film) 3378, 2930, 1601, 1502, 1457, 812,
756 cmꢁ1. MS: m=z: 198, 200 (Mþ). Anal. calcd. for C10H15ClN2: C, 60.45; H,
7.61; N, 14.10. Found: C, 60.41; H, 7.67; N, 14.06.
N-(4-Chlorophenyl)-N’-propylethylenediamine (4b). Yield: 72%. 1H
NMR (CDCl3) 0.90 (t, J ¼ 7.4 Hz, 3H CH3), 1.25 (br s, 1H NHR), 1.55 (m, 2H
CH2CH3), 2.60 (t, J ¼ 6.9 Hz, 2H CH2CH2CH3), 2.90 (t, J ¼ 5.4 Hz, 2H CH2NR),
3.25 (t, J ¼ 5.4 Hz, 2H CH2NAr), 4.75 (s, 1H NHAr), 6.55 (dd, J ¼ 6.7, 2.1 Hz, 2H
aromatics), 7.05 (dd, J ¼ 6.7, 2.1 Hz, 2H aromatics). IR (film) 3359, 2920, 1599,
1502, 1445, 816, 721 cmꢁ1. MS: m=z: 212, 214 (Mþ). Anal. calcd. for C11H17ClN2:
C, 62.11; H, 8.06; N, 13.17. Found: C, 62.20; H, 8.01; N, 13.20.
N-(4-Chlorophenyl)-N’-(2-methylpropyl)ethylenediamine
(4c). Yield:
1
69%. H NMR (CDCl3) 0.95 (d, J ¼ 6.6 Hz, 6H CH3), 1.55 (br s, 1H NHR), 1.70
(m, 1H, CH), 2.40 (d, J ¼ 6.6 Hz, 2H CH2-CH), 2.85 (t, J ¼ 5.4 Hz, 2H CH2NHR),
3.15 (t, J ¼ 5.48 Hz, 2H CH2NHAr), 4.22 (br s, 1H NHAr), 6.55 (dd, J ¼ 6.6, 2.1,
2H aromatics), 7.10 (dd, J ¼ 6.6, 2.1 Hz, 2H aromatics). IR (film) 3381, 2931,
1602, 1512, 1420, 811, 714 cmꢁ1. MS: m=z: 226, 228 (Mþ). Anal. calcd. for
C12H19ClN2: C, 63.56; H, 8.45; N, 12.35. Found: C, 63.50; H, 8.49; N, 12.31.
N-(4-Chlorophenyl)-N’-(2,2-dimethylpropyl)ethylenediamine
(4d).
1
Yield: 74%. H NMR (CDCl3) 0.98 (s, 9H, CH3), 1.65 (br s, 1H, NHR), 2.48 (s,
2H, CH2-C), 3.05 (t, J ¼ 5.5 Hz, 2H CH2NR), 3.30 (t, J ¼ 5.5 Hz, 2H CH2NAr),
4.35 (br s, 1H NHAr), 6.55 (dd, J ¼ 6.7, 2.0, Hz, 2H aromatics), 7.10 (dd, J ¼ 6.7,
2.0 Hz, 2H, aromatics). IR (film) 3380, 2926, 1601, 1504, 1410, 822, 799 cmꢁ1. MS:
m=z: 240, 242 (Mþ). Anal. calcd. for C13H21ClN2: C, 64.85; H, 8.79; N, 11.63.
Found: C, 64.89; H,8.72; N, 11.58.
N-(4-Chlorophenyl)-N’-(2-phenylethyl)ethylenediamine (4e). Yield: 70%.
1H NMR (CDCl3) 2.00 (br s, 1H NHR), 2.94–2.84 (m, 6H CH2NR and CH2-
CH2C6H5), 3.20 (t, J ¼ 5.6 Hz, 2H CH2NAr), 4.15 (br s, 1H NHAr), 6.55 (dd,
J ¼ 6.6, 2.0 Hz, 2H aromatics), 7.05 (dd, J ¼ 6.6, 2.0 Hz, 2H aromatics), 7.40–7.15
(m, 5H aromatics). IR (film) 3365, 2921, 1599, 1502, 1420, 821, 720 cmꢁ1. MS:
m=z: 274, 276 (Mþ). Anal. calcd. for C16H19ClN2: C, 69.93; H, 6.97; N, 10.19.
Found: C, 69.98; H, 7.05; N, 10.13.
N-(4-Chlorophenyl)-N’-[2(2-chlorophenyl)ethyl]ethylenediamine
(4f).
1
Yield: 73%. H NMR (CDCl3) 2.10 (br s, 1H NHR), 2.96-2.92 (m, 6H CH2NR
and CH2-CH2), 3.20 (t, J ¼ 5.4 Hz, 2H CH2NAr), 4.20 (br s, 1H NHAr), 6.53 (dd,
J ¼ 6.7, 2.0 Hz, 2H aromatics), 7.09 (dd, J ¼ 6.7, 2.0 Hz, 2H aromatics), 7.21–7.15
(m, 3H aromatics), 7.36–7.33 (m, 1H aromatic). IR (film) 3371, 2927, 1600, 1504,
1412, 816, 715 cmꢁ1. MS: m=z: 308, 310, 312 (Mþ). Anal. calcd. for C16H18Cl2N2:
C, 62.14; H, 5.87; N, 9.06. Found: C, 62.06; H, 5.95; N, 9.12.
N-(4-Chlorophenyl)-N’-(3-phenylallyl)ethylenediamine (4g). Yield:
1
67%. H NMR (CDCl3) 2.11 (br s, 1H NHR), 2.96–2.92 (m, 4H, CH2NR and
CH2-CH ¼), 3.20 (t, J ¼ 5.4 Hz, 2H CH2NAr), 4.25 (br s, 1H NHAr), 6.50 (d,
J ¼ 15.9, 1H CH ¼), 6.60 (dd, J ¼ 6.7, 2.0 Hz, 2H aromatics), 7.25 (d, J ¼ 15.9, 1H
CH ¼), 7.35–6.90 (m, 7H aromatics). IR (film) 3385, 2920, 1597, 1499, 1401, 811,

2092
A. M. REVERDITO, I. A. PERILLO, AND A. SALERNO
721 cmꢁ1. MS: m=z: 286, 288 (Mþ). Anal. calcd. for C17H19ClN2: C, 71.19; H, 6.68;
N, 9.77. Found: C, 71.25; H, 6.75; N, 9.70.
N-(2-Methylpropyl)-N’-(4-nitrophenyl)ethylenediamine
(4h). Yield:
1
75%. H NMR (CDCl3) 0.93 (d, J ¼ 6.7 Hz, 6H CH3), 1.81–1.75 (m, 2H NHR and
CH), 2.46 (d, J ¼ 6.7 Hz, 2H CH2CH), 2.94 (t, J ¼ 5.4 Hz, 2H CH2NHR), 3.27 (dt,
J ¼ 5.47, 4.9 Hz, 2H CH2NAr), 6.53 (d, J ¼ 9.1, Hz, 2H aromatics), 5.35 (br s,1H
NHAr), 8.08 (d, J ¼ 9.1 Hz, 2H aromatics). IR (film) 3410, 2921, 1602, 1505, 1406,
1324, 831 cmꢁ1. MS: m=z: 237 (Mþ). Anal. calcd. for C12H19N3O2: C, 60.74; H,
8.07; N, 17.71. Found: C, 60.79; H, 8.15; N, 17.65.
N-(2,2-dimethylpropyl)-N’-(4-nitrophenyl)ethylenediamine (4i). Yield:
74%. 1H NMR (CDCl3) 0.91 (s, 9H CH3), 1.35 (br s, 1H NHR), 2.35 (s, 2H
CH2C), 2.92 (t, J ¼ 5.6 Hz, 2H CH2NHR), 3.24 (dt, J ¼ 5.6, 4.8 Hz, 2H CH2NHAr),
5.37 (br s, 1H NHAr), 6.51 (d, J ¼ 9.2 Hz, 2H aromatics), 8.08 (d, J ¼ 9.2 Hz, 2H
aromatics). IR (film) 3415, 2920, 1601, 1510, 1412, 1320, 835 cmꢁ1. MS: m=z: 251
(Mþ). Anal. calcd. for C13H21N3O2: C, 62.13; H, 8.42; N, 16.72. Found: C, 62.05;
H, 8.48; N, 16.79.
2-Alkyl-1-aryl-3-methyl-4,5-dihydro-1H-imidazolium Iodides 5a–g
General procedure. A solution of the appropriate compound 1 (3 mmol) and
methyl iodide (4 mmol) in methylene chloride (20 mL) was refluxed, and the mixture
was monitored by TLC (benzene:methanol, 9:1) until disappearance of the starting
material. The solution was concentrated in vacuo affording a hygroscopic oil that
could not be crystallized. The products 5a–i were purified by column chromato-
graphy (chloroform=methanol, 1:1).
1-(4-Chlorophenyl)-2,3-dimethyl-4,5-dihydro-1H-imidazolium Iodide (5a).
1
Yield: 85%. H NMR (CDCl3) 2.70 (s, 3H C-CH3), 3.30 (s, 3H N-CH3), 4.37–4.16
(ms, 4H CH2-CH2), 7.40 (dd, J ¼ 6.7, 2.0, 2H aromatics), 7.62 (dd, J ¼ 6.7, 2.0,
2H aromatics). IR (film) 2901, 1635, 1497, 1250, 821, 691 cmꢁ1. MS: m=z: 194,
196 (M-ICH3)þ. Anal. calcd. for C11H14ClIN2: C, 39.25; H, 4.19; N, 8.32. Found:
C, 39.13; H, 4.28; N, 8.43.
1-(4-Chlorophenyl)-2-ethyl-3-methyl-4,5-dihydro-1H-imidazolium iodide
1
(5b). Yield: 88%. H NMR (CDCl3) 1.12 (t, J ¼ 7.8, 3H CH3), 2.50 (q, J ¼ 7.8, 2H
CH2), 3.26 (s, 3H NCH3), 4.33–4.16 (ms, 4H CH2-CH2), 7.40 (dd, J ¼ 6.7, 2.0, 2H
aromatics), 7.61 (dd, J ¼ 6.7, 2.0, 2 H aromatics). IR (film) 2917, 1615, 1500,
1249, 820, 699 cmꢁ1. MS: m=z: 208, 210 (M-ICH3)þ. Anal. calcd. for C12H16ClIN2:
C, 41.11; H, 4.60; N, 7.99. Found: C, 41.19; H, 4.54; N, 8.23.
1-(4-Chlorophenyl)-3-methyl-2-(1-methylethyl)-4,5-dihydro-1H-imida-
1
zolium iodide (5c). Yield: 85%. H NMR (CDCl3) 1.32 (d, J ¼ 7.2, 6H CH3),
2.93-2.75 (sept., J ¼ 7.2, 1H CH), 3.34 (s, 3H N-CH3), 4.40–4.20 (m, 4H CH2-
CH2), 7.40 (dd, J ¼ 6.7, 2.0, 2H aromatics.), 7.45 (dd, J ¼ 6.7, 2.0, 2H aromatics).
IR (film) 2930, 1630, 1505, 1249, 819, 702 cmꢁ1. MS: m=z: 222, 224 (M-ICH3)þ.
Anal. calcd. for C13H18ClIN2: C, 42.82; H, 4.98; N, 7.68. Found: C, 44.75; H,
4.82; N, 7.76.

SYNTHESIS AND APPLICATIONS OF 1H-IMIDAZOLES
2093
1-(4-Chlorophenyl)-3-methyl-2-(1,1-dimethylethyl)-4,5-dihydro-1H-imi-
dazolium iodide (5d). Yield: 88%. 1H NMR (CDCl3) 1.28 (s, 9H CH3), 3.40 (s, 3H
NCH3), 4.24 (s, 4H CH2-CH2), 7.37 (dd, J ¼ 6.7, 2.2, 2H aromatics), 7.67 (dd,
J ¼ 6.7, 2.2, 2H aromatics). IR (film) 2920, 1640, 1510, 1250, 812, 695 cmꢁ1. MS:
m=z: 236, 238 (M-ICH3)þ. Anal. Calcd for C14H20ClIN2: C, 44.40; H, 5.32; N,
7.40. Found: C, 44.32; H, 5.44; N, 7.31.
2-Benzyl-1-(4-chlorophenyl)-3-methyl-4,5-dihydro-1H-imidazolium iodide
1
(5e). Yield: 90%. H NMR (CDCl3) 3.20 (s, 3H NCH3), 4.00 (s, 2H CH2C6H5),
4.45–4.20 (m, 4H CH2-CH2), 7.05 (d, J ¼ 7.2, 2H aromatics), 7.31 (m, 3H aromatics),
7.38 (dd, J ¼ 6.7, 2.0, 2H aromatics), 7.60 (dd, J ¼ 6.7, 2.0, 2H aromatics). IR (film)
2955, 1621, 1515, 1247, 815, 721 cmꢁ1. MS: m=z: 270, 272 (M-ICH3) þ. Anal. calcd.
for C17H18ClIN2: C, 49.48; H, 4.40; N, 6.79. Found: C, 49.36; H, 4.47; N, 7.13.
2-(2-Chlorobenzyl)-1-(4-chlorophenyl)-3-methyl-4,5-dihydro-1H-imida-
zolium iodide (5f). Yield: 87%. 1H NMR (CDCl3) 3.21 (s, 3H NCH3), 4.15 (s, 2H
CH2C6H5), 4.40–4.25 (ms, 4H CH2-CH2), 7.24–7.02 (m, 2H aromatics), 7.26–7.25
(m, 2H aromatics), 7.32 (dd, J ¼ 7.6, 2.0, 2H aromatics), 7.56 (dd, J ¼ 7.6, 2.0, 2H
aromatics). IR (film) 2901, 1632, 1499, 1235, 823, 712 cmꢁ1. MS: m=z: 304, 306,
308 (M-ICH3)þ. Anal. calcd. for C17H17Cl2IN2: C, 45.66; H, 3.83; N, 6.26. Found:
C, 45.55; H, 3.87; N, 6.15.
1-(4-Chlorophenyl)-3-methyl-2-phenylvinyl-4,5-dihydro-1H-imidazo-
1
lium iodide (5g). Yield: 91%. H NMR (CDCl3) 3.43 (s, 3H NCH3), 4.45–4.30
(ms, 4H CH2-CH2), 6.37 (d, J ¼ 16.6, 1H CH ¼), 7.50–7.32 (m, 7H aromatics and
1H CH ¼), 7.55 (dd, J ¼ 6.8, 1.9, 2H aromatics). IR (film) 2933, 1643, 1505, 1493,
1260, 799, 693 cmꢁ1. Anal. calcd. for C18H18ClIN2: C, 50.90; H, 4.27; N, 6.60.
Found: C, 51.12; H, 4.36; N, 6.51. MS: m=z: 282, 284 (M-ICH3)þ.
3-Methyl-2-(1-methylethyl)-1-(4-nitrophenyl)-4,5-dihydro-1H-imidazo-
1
lium iodide (5h). Yield: 87%. H NMR (CDCl3) 1.38 (s, J ¼ 7.2, 6H (CH3)2CH),
2.92–2.83 [m, 1H CH(CH3)2], 3.38 (s, 3H NCH3), 4.50–4.28 (ms, 4H CH2-CH2),
7.98 (dd, J ¼ 8.9, 2.0, 2H aromatics), 8.34 (dd, J ¼ 8.9, 2.0, 2H aromatics). IR (film)
32967, 1637, 1496, 1324, 831 cmꢁ1. MS: m=z: 233 (M-ICH3)þ. Anal. calcd. for
C13H18IN3O2: C, 41.61; H, 4.84; N, 11.20. Found: C, 41.56; H, 4.92; N, 11.31.
3-Methyl-2-(1,1-dimethylethyl)-1-(4-nitrophenyl)-4,5-dihydro-1H-imida-
zolium iodide (5i). Yield: 88%. 1H NMR (CDCl3) 1.36 [s, 9H (CH3)3C], 3.50 (s, 3H
NCH3), 4.34 (s, 4H CH2-CH2), 8.09 (dd, J ¼ 8.9, 2.0, 2H aromatics), 8.33 (dd,
J ¼ 8.9, 2.0, 2H aromatics). IR (film) 2939, 1642, 1501, 1322, 833 cmꢁ1. MS: m=z:
247 (M-ICH3)þ. Anal. calcd for C14H20IN3O2: C, 43.20; H, 5.18; N, 10.80. Found:
C, 43.33; H, 5.11; N, 10.72.
ACKNOWLEDGMENTS
This work was financially supported by the Universidad de Buenos Aires and
´
Agencia Nacional de Promocion Cientıfica y Tecnologica. The collaboration of
Marıa de los Angeles Ramirez is also gratefully acknowledged.
´
´
´

2094
A. M. REVERDITO, I. A. PERILLO, AND A. SALERNO
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