Synthesis and evaluation of new difluoromethyl azoles as antileishmanial agents

Article abstract of DOI:10.1016/j.ejmech.2007.02.020

Several compounds of great pharmacological interest contain the triazole and imidazole rings. In order to find new drugs with antileishmanial activity we have synthesized and evaluated new imidazole and triazole compounds carrying either the carbaldehyde or the difluoromethylene functionalities against promastigote forms of Leishmania amazonensis. Among the compounds tested difluoromethylene azoles 4b and 8f have inhibited the parasite growth significantly. Our results show that the introduction of the difluoromethylene moieties has turned the inactive carbaldehydes into active antileishmanial compounds.

Full text of DOI:10.1016/j.ejmech.2007.02.020

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European Journal of Medicinal Chemistry 42 (2007) 1388e1395
http://www.elsevier.com/locate/ejmech
Short communication
Synthesis and evaluation of new difluoromethyl azoles
as antileishmanial agents
a
b
c
d
ˆ
´
Sabrina B. Ferreira , Marilia S. Costa , Nubia Boechat , Romulo J.S. Bezerra ,
Marcelo S. Genestra d, Marilene M. Canto-Cavalheiro d, Warner B. Kover a,
Vitor F. Ferreira b,
*
a Universidade Federal do Rio de Janeiro Departamento de Qu´ımica Orgaˆnica, Instituto de Qu´ımica,
Cidade Universita´ria, 21949-900 Rio de Janeiro, RJ, Brazil
b Universidade Federal Fluminense, Departamento de Qu´ımica Orgaˆnica, Instituto de Qu´ımica,
Outeiro de S~ao Jo~ao Baptista, CEP 24020-150 Nitero´i, RJ, Brazil
c Fundac¸~ao Oswaldo Cruz, Instituto de Tecnologia em Fa´rmacos, Departamento de S´ıntese Orgaˆnica, Manguinhos,
CEP 21041250 Rio de Janeiro, RJ, Brazil
d Fundac¸~ao Oswaldo Cruz, Instituto Oswaldo Cruz, Departamento de Imunologia, Fiocruz, 21041-250 Rio de Janeiro, RJ, Brazil
Received 2 October 2006; received in revised form 30 January 2007; accepted 26 February 2007
Available online 12 March 2007
Abstract
Several compounds of great pharmacological interest contain the triazole and imidazole rings. In order to find new drugs with antileishmanial
activity we have synthesized and evaluated new imidazole and triazole compounds carrying either the carbaldehyde or the difluoromethylene
functionalities against promastigote forms of Leishmania amazonensis. Among the compounds tested difluoromethylene azoles 4b and 8f
have inhibited the parasite growth significantly. Our results show that the introduction of the difluoromethylene moieties has turned the inactive
carbaldehydes into active antileishmanial compounds.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Antileishmanial activity; Difluoromethylation; Imidazole; 1,2,3-Triazole
1. Introduction
resistance and the increase of co-infections leishmaniasise
AIDS, in some countries, have worried the authorities. Thus,
the development of new, efficient, and safe drugs for the treat-
ment of this disease is imperative [3,4].
Leishmaniasis is caused by several species of protozoan
parasites transmitted by the bite of the female phlebotomine
sand fly [1]. This disease is currently prevalent in four conti-
nents, being endemic in 88 countries, 72 of which are develop-
ing countries, threatening 350 millions worldwide [1].
Classified as an extremely neglected disease eleishmaniasis
is still present as an additional difficulty in the long and inef-
ficient treatment that is dependent on old and highly toxic
drugs [2]. In addition, the development of the clinical
Azole antifungal drugs have been used as antileishmanial
agents since the 1980s [5]. Imidazole and triazole antifungals
inhibit the growth of Leishmania amastigotes in culture sys-
tems by inhibiting the cytochrome P-450-mediated 14a-deme-
thylation of lanosterol, blocking ergosterol synthesis, and
causing accumulation of 14a-methyl sterols [6]. The pharma-
cological interest of the triazole [7] and imidazole [8] rings has
been established and in order to find new drugs with antileish-
manial activity we have synthesized and evaluated new imid-
azole and triazole compounds against promastigote forms of
Leishmania amazonensis.
* Corresponding author. Tel.: þ55 21 26292345; fax: þ55 21 26292362.
E-mail address: cegvito@vm.uff.br (V.F. Ferreira).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.02.020

S.B. Ferreira et al. / European Journal of Medicinal Chemistry 42 (2007) 1388e1395
1389
2. Chemistry
3. Activity assay against L. amazonensis
Different methods for synthesizing imidazole and 1,2,3-
triazole are described in the literature [9,10]. The N-aryl-ami-
dines (1ae1l) and 2-bromomalonaldehyde (2) were prepared
and utilized as the starting materials for the synthesis of N-
substitued-phenyl-imidazole-5-carbaldehyde (3ae3l) (Scheme
1). The synthesis of N-aryl-amidines [11] (1ae1l) was accom-
plished, in good yields, by condensation of commercial aro-
matic amines with acetonitrile in the presence of hydrogen
chloride. The reaction time was dependent on substituent R1
in aromatic ring (Table 1).
The in vitro efficacies of the synthesized compounds were
performed on promastigotes of L. amazonensis (MHOM/BR/
77/LTB0016). Parasites were maintained by animal passage
and cryopreserved in liquid nitrogen. Promastigotes were cul-
tured at 25 ꢀC in Schneider’s Insect Medium of pH 7.2 contain-
ing 10% (v/v) of heat-inactivated fetal bovine serum [18]. For
the activity assay, the parasite culture was diluted with the fresh
medium to a final concentration of 5 ꢁ 106 parasites/mL. The
drugs were dissolved in dimethylsulfoxide (DMSO) and tested
within a concentration range of 0.16e320 mg mLꢂ1 (0.74e
1493.33 mM). Drugs were added to a 96-well microtitre plate
(up to 1.6% final DMSO concentration) and incubated at
26 ꢀC for 24 h with the parasites in their metacyclic phase
[19]. All the tests were carried out in triplicate and pentamidine
was used as the reference drug. Results represent the mean
values of three experiments and were expressed as IC50, i.e.,
the concentration of a compound that caused a 50% reduction
in survival/viability in comparison to identical cultures without
the compounds. The procedure used to observe the drugs effects
was the MTT reduction, using 3-[4,5-dimethylthiazol-2-yl]-
2,5-diphenyl-tetrazolium bromide (MTT, Sigma, MO, USA)
and the result could be read on an ELISA reader at 490 nm
[20]. The percentage of inhibition was estimated and compared
with the control. Antileishmanial activity was calculated as
shown in Table 2. To ensure that the solvent had no effect on
parasite growth a control test was performed with test medium
and DMSO at the same dilution as used in the experiment.
The 2-bromomalonaldehyde (2) was prepared, 90% yield,
by the procedure described by Trofimenko [12]. The conden-
sation reaction between 1ae1l and 2 in isopropanol, using
acetic acid and triethylamine as catalysts, leads exclusively
to the formation of 5-carbaldehyde imidazole, which had it’s
1
structure confirmed by H and 13C NMR spectra. The target
compounds 3ae3l were obtained in 85e96% yield and fully
characterized by 1H NMR, 13C NMR, IR and EI-MS
spectroscopies.
The carbaldehyde moieties in 3ae3l were readily converted
into difluoromethyl groups for generating 4ae4l (Scheme 1),
by using N,N-diethylaminosulfur trifluoride (DAST) [13],
with excellent yield (89e97%). The 1H NMR spectra of
4ae4l showed difluoromethylene (CHF2) proton as a triplet
at d 6.42e6.51 ppm (JHF ¼ 56.0 Hz).
The 1,2,3-triazolic compounds 7ae7l were prepared from
diazomalonaldehyde (5) and aromatic amine hydrochlorides
(6ae6l) (Scheme 2). Diazomalonaldehyde (5) was prepared
by the procedure described by Arnold and co-workers [14].
The reaction of 5 with the appropriate aniline hydrochlorides
(6ae6l), in aqueous solution, yielded N-substitued-phenyl-
1,2,3-triazole-4-carbaldehyde (7ae7l) in good yields. The
4-difluoromethyl-1,2,3-triazoles (8ae8l) were obtained in
90e98% yields on reaction of 6ae6l with DAST (Scheme 2).
The structures of compounds 7ae7l and 8ae8l were con-
firmed by Microanalysis, EI-MS, IR, 1H NMR, 13C NMR
spectroscopy, X-ray diffraction [15,16] and for 8ae8l, also
4. Results and discussion
All the compounds were tested against the parasite; how-
ever, only the significant antileishmanial activities are reported
in Table 2. Among them, the carbaldehyde 7f and the difluor-
methylated azoles 4b and 8f showed IC50 below 3.0 mM (2.8,
1.7, and 2.6 mM, respectively). From these data, it is possible
to argue if the introduction of the difluoromethyl (CHF2)
group in the azole rings may lead to compounds with any sig-
nificant antileishmanial activity. In particular, the difluoro-
methyl imidazole 4b (1.7 mM) is the only active imidazole
compound in the series.
1
by 19F NMR spectroscopy. The H NMR spectra of 7ae7l
showed carbaldehyde (CHO) proton as singlet at d 10.21e
10.24 ppm. Furthermore, the absence of this singlet and the
presence of a triplet at d 6.95e6.97 ppm (JHF ¼ 55.5 Hz) in
It is important to note that in vitro antituberculosis
screening of 7ae7l and 8ae8l revealed an opposite trend
between carbaldehyde and difluoromethyl groups. For the
1
the H NMR spectra of 8ae8l indicated the conversion of
the carbaldehyde into the difluoromethyl (CHF2) [17].
N
N
NH2
CHO
H3C
H3C
CHF2
NH2
N
N
Br
N
CH3
HO
O
AcOH,Et3N
i-PrOH
HCl(g)
CH3CN
reflux
DAST
CH2Cl2
r.t -24h
+
H
H
R
R
R
R
1a-1l
4a-4l
2
3a-3l
R =a) H; b) 4-Cl; c) 4-Br; d) 4-F; e) 4-NO2; f) 4-CF3;g) 4-CN;
h) 4-CH3; i) 4-OCH3; j) 2,6-F; k) 2-CH3; l) 3-OCF3
Scheme 1. Synthetic methods for the preparation of imidazole derivatives 3ae3l and 4ae4l.

1390
S.B. Ferreira et al. / European Journal of Medicinal Chemistry 42 (2007) 1388e1395
Table 1
Reaction times and yields obtained in the preparation of N-aryl-amidines
6. Experimental protocols
Amidine
R1
Time (h)
Yield (%)
Melting points were determined with a Buchi Model B-545
instrument and are uncorrected. Infrared (IR) spectra were re-
corded on a Perkin-Elmer model 1420 FT-IR Spectrophotom-
eter in KBr pellets. 1H and 13C NMR spectra were recorded on
Bruker Advance 500 plus 400.00 and 500.00 MHz, employing
tetramethylsilane as the internal reference at room tempera-
ture. 19F NMR spectra were recorded on Bruker UltraShield
plus 376.0 MHz, employing CFCl3 as internal reference at
room temperature. The chemical shifts (d) are reported in
ppm and the coupling constant (J ) in Hz. Mass spectra were
recorded on GCeMS (Hewlett Packard Model AT-6890N)
auto sampler/direct injection (EI/CI). Reactions were routinely
monitored by thin layer chromatography (TLC) on silica gel
precoated F254 Merck plates. Microanalyses were performed
on Perkin-Elmer Model 2400 instrument and all values were
within ꢃ0.4% of the calculated compositions. Compounds
7ae7l and 8ae8l were previously prepared by Ferreira and
co-workers [17].
1a
1b
1c
1d
1e
1f
H
4-Cl
5.0
6.5
95
96
95
88
85
84
90
91
90
83
87
88
4-Br
4-F
6.5
8.0
4-NO2
4-CF3
4-CN
4-CH3
4-OCH3
2,6-diF
2-CH3
3-CF3
10.0
10.0
4.5
1g
1h
1i
4.0
4.0
1j
20.0
4.5
1k
1l
6.0
mycobacterium the triazole-4-carbaldehylde derivatives were
more effective than the 4-difluoromethyl derivatives (8ae8l)
[17]. These results indicated that the positive effect of intro-
ducing fluorine atoms in these compounds is specific to their
antileishmanial activity. The introduction of fluorine atom(s)
may strongly modify the physical and chemical properties of
a molecule and thus alter its biological activity [21]. Usually,
incorporation of a fluorine atom increases lipophilicity thereby
enhancing absorption of the biological membranes as well as
favoring the docking with drug receptor(s).
Chemicals obtained from commercial supplies were used
without purification, unless otherwise stated.
6.1. Chemistry
Alvarez’s group [22] verified that a possible mechanism of
action of imidazolidinone compounds is related to inhibition
of protein kinase C (PKC) family isoenzymes, which mediate
a wide range of signal transduction pathways in many different
cells lines, including leishmania [23]. Previous studies from
our group verified the calcium independent-PKC activity in
L. amazonensis promastigotes and some works describe that
PKC plays a critical role in the invasion process [24]. Thus
leishmaniaePKC activity could be a relevant therapeutic tar-
get of these novel imidazole antileishmanial candidates.
6.1.1. General procedure for the preparation of
N-aryl-amidines (1ae1l)
To a stirred solution of amine (10.75 mmol) in acetonitrile
42.91 mL (822.70 mmol) was bubbled hydrogen chloride. A
precipitate was formed immediately. The resulting suspension
was stirred at reflux and eventually becomes homogeneous.
Thin layer chromatography was used to monitor the progress
of the reaction. Upon complete reaction, the mixture was con-
centrated at reduced pressure and the residue partitioned be-
tween CH2Cl2 and saturated aqueous NaHCO3. The aqueous
layer was washed (3ꢁ) with CH2Cl2, and the combined or-
ganic layers were dried over sodium sulfate, filtered, and the
filtrate concentrated under reduced pressure. The following
compounds were prepared according this general procedure.
5. Conclusion
In conclusion, the high in vitro leishmanicidal activity of 4b
and 8f makes these compounds promising hits for the develop-
ment of an effective therapeutic agent. However, additional
tests with amastigote/macrophage in vitro models and in
vivo (mouse) toxicity/mouse models need to be carried out
in order prove the usefulness of this class of compounds.
6.1.1.1. (1E/Z )-N-Phenylacetamidine (1a). Obtained in 95%
yield as white solid; mp 62e64 ꢀC; IR (KBr) nmax (cmꢂ1
)
3441; 3310; 3197; 1643; 1445; H NMR (500 MHz; CDCl3/
Me4Si): d 2.02 (s, 3H, CH3); 4.26 (bs, 2H, NH2); 6.86 (dd,
1
CHO
CHF2
N
N
NH2
NH3Cl
R1
N
N2
N
HCl(g)
N
DAST
CH2Cl2
r.t - 24h
N
H
H
+
C3H6O
r.t -1h
H2O
r.t - 24h
O
O
R1
R1
7a-7l
R1
8a-8l
6a-6l
5
R1 = a) 4-Cl; b) 4-Br; c) 4-CH3; d) 4-OCH3; e) 2,5-OCH3; f) 3-Cl; g) 3,5-Cl;
h) 3-CN; i) 4-CN; j) 4-NO2; k) 2-OCH3; l) 3,4-OCH3
Scheme 2. Reaction conditions for the synthesis of 1,2,3-triazoles 7ae7l and 8ae8l.

S.B. Ferreira et al. / European Journal of Medicinal Chemistry 42 (2007) 1388e1395
1391
Table 2
In vitro potency of azole compounds active over L. amazonensis promastigote
forms
(CAreNO2); 126.0; 155.6; 150.2 (H2NeC]N); EI-MS (m/z):
179 (Mþ, 51%); 164 (Mþ ꢂ 15, 12.5%); 149 (Mþ ꢂ 30,
11.3%); 138 (Mþ ꢂ 41, 11.8%); 118 (Mþ ꢂ 61, 31%); 108
(Mþ ꢂ 71, 100%).
Azole compounds
IC50 ꢃ S.D. (mM)a
4b
7f
1.7 ꢃ 0.4
2.8 ꢃ 0.0
6.1.1.6. (1E/Z )-N-( p-Trifluoromethylphenyl)acetamidine (1f).
Obtained in 84% yield as yellow solid; mp 115e117 ꢀC;
IR (KBr) nmax (cmꢂ1) 3460; 3312; 3096; 1648; 1602;
1402; 1H NMR (500 MHz; CDCl3/Me4Si): d 2.03 (s, 3H,
CH3); 4.54 (bs, 2H, NH2); 6.94 (d, 2H, J ¼ 8.0 Hz); 7.53
(d, 2H, J ¼ 8.0 Hz); 13C NMR (125 MHz; CDCl3/Me4Si):
d 22.8 (CH3); 122.0; 125.0 (CAreCF3); 125.9; 155.5; e
155.0 (H2NeC]N); 121.5e125.1 (d, CF3, J ¼ 170.0 Hz);
EI-MS (m/z): 202 (Mþ, 84.5%); 187 (Mþ ꢂ 15, 62%); 161
(Mþ ꢂ 41, 64%); 145 (Mþ ꢂ 57, 100%); 125 (Mþ ꢂ 77,
19%).
8f
2.6 ꢃ 0.43
0.46 ꢃ 0.07
Pentamidineb
a
Concentrations required to reduce the number of viable L. amazonensis
promastigote forms by 50% as observed by the MTT reduction method [20];
S.D. ¼ standard deviations (n ¼ 3).
b
Reference drug.
2H, J ¼ 4.0 Hz); 7.29 (t, 2H, J ¼ 8.0 Hz); 7.02 (ddd, 1H,
J ¼ 8.0 Hz); 13C NMR (125 MHz; CDCl3/Me4Si): d 20.2
(CH3); 121.8; 122.6; 129.1; 149.2; 156.0 (H2NeC]N); EI-
MS (m/z): 134 (Mþ, 79%); 119 (Mþ ꢂ 15, 42%); 93
(Mþ ꢂ 41, 84%); 77 (Mþ ꢂ 57, 100%); 65 (Mþ ꢂ 69, 21%).
6.1.1.7. (1E/Z )-N-( p-Cyanophenyl)acetamidine (1g). Obtained
in 90% yield as yellow solid; mp 97e98 ꢀC; IR (KBr) nmax
(cmꢂ1) 3591; 3397; 3223; 1662; 1619; 1494; 1H NMR
(500 MHz; CDCl3/Me4Si): d 2.20 (s, 3H, CH3); 4.63 (bs, 2H,
NH2); 6.95 (d, 2H, J ¼ 8.0 Hz); 7.67 (d, 2H, J ¼ 8.0 Hz); 13C
NMR (125 MHz; CDCl3/Me4Si): d 22.8 (CH3); 119.5 (CAre
CN); 122.7; 133.2 (CN); 133.7; 155.0; 160.1 (H2NeC]N);
EI-MS (m/z): 159 (Mþ, 99%); 144 (Mþ ꢂ 15, 70%); 118
(Mþ ꢂ 41, 100%); 102 (Mþ ꢂ 57, 86%); 90 (Mþ ꢂ 69, 12%).
6.1.1.2. (1E/Z )-N-( p-Chlorophenyl)acetamidine (1b). Obtained
in 96% yield as white solid; mp 116e117 ꢀC; IR (KBr) nmax
(cmꢂ1) 3451; 3295; 3079; 1640; 1586; 1482; 1H NMR
(500 MHz; CDCl3/Me4Si): d 1.99 (s, 3H, CH3); 4.53 (bs, 2H,
NH2); 6.77 (d, 2H, J ¼ 8.0 Hz); 7.24 (d, 2H, J ¼ 8.0 Hz); 13C
NMR (125 MHz; CDCl3/Me4Si): d 21.59 (CH3); 122.5;
121.1; 128.6; 144.6; 155.3 (H2NeC]N); EI-MS (m/z): 168
(Mþ, 68%); 153 (Mþ ꢂ 15, 38%); 127 (Mþ ꢂ 41, 100%); 111
(Mþ ꢂ 57, 54%); 75 (Mþ ꢂ 93, 42%).
6.1.1.8. (1E/Z)-N-( p-Methylphenyl)acetamidine (1h). Obtained
in 91% yield as yellow solid; mp 199e203 ꢀC; IR (KBr) nmax
(cmꢂ1) 3460; 3299; 3019; 1650; 1604; 1454; 1H NMR
(500 MHz; CDCl3/Me4Si): d 2.00 (s, 3H, CH3); 2.30 (s, 3H,
CH3); 4.54 (bs, 2H, NH2); 6.65 (d, 2H, J ¼ 8.0 Hz); 7.07 (d,
2H, J ¼ 8.0 Hz); 13C NMR (125 MHz; CDCl3/Me4Si): d 20.7
(CH3); 22.4 (CH3); 121.8; 129.7; 132.1; 146.4; 168.9 (H2Ne
C]N); EI-MS (m/z): 148 (Mþ, 80%); 133 (Mþ ꢂ 15, 38%);
106 (Mþ ꢂ 42, 100%);91 (Mþ ꢂ 57, 68%); 77 (Mþ ꢂ 71, 29%).
6.1.1.3. (1E/Z )-N-( p-Bromophenyl)acetamidine (1c). Obtained
in 95% yield as white solid; mp 207e208 ꢀC; IR (KBr) nmax
(cmꢂ1) 3448; 3301; 3118; 1636; 1579; 1478; 1H NMR
(500 MHz; CDCl3/Me4Si): d 1.97 (s, 3H, CH3); 4.57 (bs, 2H,
NH2); 6.69 (d, 2H, J ¼ 8.0 Hz); 7.35 (d, 2H, J ¼ 8.0 Hz); 13C
NMR (125 MHz; CDCl3/Me4Si): d 21.7 (CH3); 123.0; 114.7;
131.5; 148.1; 154.5 (H2NeC]N); EI-MS (m/z): 212 (Mþ,
74%); 197 (Mþ ꢂ 15, 32%); 171 (Mþ ꢂ 41, 100%); 155
(Mþ ꢂ 57, 42%); 92 (Mþ ꢂ 120, 30%).
6.1.1.9. (1E/Z )-N-( p-Methoxyphenyl)acetamidine (1i). Obtained
in 90% yield as yellow solid; mp 107e109 ꢀC; IR (KBr) nmax
(cmꢂ1) 3458; 3323; 3182; 1644; 1465; 1441; 1H NMR
(500 MHz; CDCl3/Me4Si): d 2.01 (s, 3H, CH3); 3.77 (s, 3H,
CH3eO); 4.40 (bs, 2H, NH2); 6.79 (d, 2H, J ¼ 8.0 Hz); 6.85
(d, 2H, J ¼ 8.0 Hz); 13C NMR (125 MHz; CDCl3/Me4Si):
d 21.0 (CH3); 55.4 (CH3eO); 114.6; 122.7; 142.6; 155.4;
163.5 (H2NeC]N); EI-MS (m/z): 164 (Mþ, 44%); 149
(Mþ ꢂ 15, 21%); 123 (Mþ ꢂ 41, 22%); 108 (Mþ ꢂ 56,
100%); 80 (Mþ ꢂ 84, 42%); 63 (Mþ ꢂ 101, 20%); 52
(Mþ ꢂ 112, 22%).
6.1.1.4. (1E/Z )-N-( p-Fluorophenyl)acetamidine (1d). Obtained
in 88% yield as white solid; mp 174e176 ꢀC; IR (KBr) nmax
(cmꢂ1) 3452; 3316; 3065; 1658; 1615; 1498; 1H NMR
(500 MHz; CDCl3/Me4Si): d 1.99 (s, 3H, CH3); 4.53 (bs, 2H,
NH2); 6.77 (d, 2H, J ¼ 8.0 Hz); 7.24 (d, 2H, J ¼ 8.0 Hz); 13C
NMR (125 MHz; CDCl3/Me4Si): d 21.0 (CH3); 128.6 (t,
J ¼ 165.0 Hz); 155.3 (CAreF); 122.5 (t, J ¼ 156.0 Hz); 147.5;
156.2 (H2NeC]N); EI-MS (m/z): 152 (Mþ, 70%); 137
(Mþ ꢂ 15, 40%); 111 (Mþ ꢂ 41, 100%); 95 (Mþ ꢂ 57, 84%);
83 (Mþ ꢂ 69, 18%).
6.1.1.10. (1E/Z )-N-(2,6-Difluorophenyl)acetamidine (1j).
Obtained in 83% yield as yellow solid; mp 179e182 ꢀC; IR
1
6.1.1.5. (1E/Z )-N-( p-Nitrophenyl)acetamidine (1e). Obtained
in 85% yield as yellow solid; mp 227e229 ꢀC; IR (KBr) nmax
(KBr) nmax (cmꢂ1) 3444; 3290; 3088; 1650; 1606; 1467; H
NMR (500 MHz; CDCl3/Me4Si): d 1.98 (s, 6H, 2CH3); 5.35
(bs, 4H, 2NH2); 6.87e6.93 (m, 3H); 13C NMR (125 MHz;
CDCl3/Me4Si): d 17.3 (CH3); 111.5 (dd, CAreF, J ¼ 25.0 Hz);
122.1 (t, J ¼ 2.1 Hz); 122.9 (t, J ¼ 8.4 Hz); 155.5 (ddd,
J ¼ 210.2 Hz); 161.1 (H2NeC]N); EI-MS (m/z): 170 (Mþ,
1
(cmꢂ1) 3411; 3330; 3146; 1661; 1578; 1484; 1402; H NMR
(500 MHz; CDCl3/Me4Si): d 2.51 (s, 3H, CH3); 4.80 (bs, 2H,
NH2); 7.62 (d, 2H, J ¼ 8.0 Hz); 8.40 (d, 2H, J ¼ 8.0 Hz); 13C
NMR (125 MHz; CDCl3/Me4Si): d 23.0 (CH3); 122.9; 143.7

1392
S.B. Ferreira et al. / European Journal of Medicinal Chemistry 42 (2007) 1388e1395
100%); 155 (Mþ ꢂ 15, 71%); 129 (Mþ ꢂ 41, 83%); 113
(Mþ ꢂ 57, 14.3%); 108 (Mþ ꢂ 62, 15%).
d 2.29 (s, 3H,); 7.19 (d, 2H, J ¼ 8.0 Hz); 7.49 (d, 2H,
J ¼ 8.0 Hz); 7.80 (s, 1H) and 9.59 (s, 1H, HC]O); 13C
NMR (100 MHz; CDCl3/Me4Si): d 13.6; 128.2; 129.7;
132.9; 134.4; 135.5; 141.9; 152.5; 177.5 (HC]O); EI-MS
(m/z): 220 (Mþ, 64%); 191 (Mþ ꢂ 29, 10%); 185 (Mþ ꢂ 35,
15%); 150 (Mþ ꢂ 70, 100%); 123 (Mþ ꢂ 97, 22%).
6.1.1.11. (1E/Z )-N-(o-Methylphenyl)acetamidine (1k). Obtained
in 87% yield as colorless oil; IR (KBr) nmax (cmꢂ1) 3456; 3328;
1
3103; 1647; 1482; 1439; H NMR (500 MHz; CDCl3/Me4Si):
d 2.01 (CH3); 2.12 (s, 3H, CH3); 3.59 (bs, 2H, NH2); 6.75 (d,
1H, J ¼ 8.0 Hz); 6.93 (d, 1H, J ¼ 8.0 Hz); 7.10 (d, 1H,
J ¼ 8.0 Hz); 7.14 (t, 1H, J ¼ 8.0 Hz); 13C NMR (125 MHz;
CDCl3/Me4Si): d 17.5 (CH3); 21.4 (CH3); 121.5; 122.9 (CAre
OCH3); 126.9; 129.7; 130.6; 147.8; 161.0 (H2NeC]N); EI-
MS (m/z): 148 (Mþ, 64%); 133 (Mþ ꢂ 15, 65%); 106
(Mþ ꢂ 42, 100%); 91 (Mþ ꢂ 57, 50%); 77 (Mþ ꢂ 71, 40%);
65 (Mþ ꢂ 83, 48%).
6.1.2.3. 1-(4-Bromophenyl)-2-methyl-1H-imidazole-5-carbal-
dehyde (3c). Obtained in 91% yield as orange oil (Rf ¼ 0.6;
9:1 CHCl3/MeOH); IR (KBr) nmax (cmꢂ1) 3087; 3030;
2812; 2742; 1667 (n C]O); 1H NMR (400 MHz; CDCl3/
Me4Si): d 2.33 (s, 3H); 7.13 (d, 2H, J ¼ 10.0 Hz); 7.67 (d,
2H, J ¼ 10.0 Hz); 7.84 (s, 1H) and 9.60 (s, 1H, HC]O);
13C NMR (100 MHz; CDCl3/Me4Si): d 13.8 (CH3); 123.3;
123.5; 128.4; 132.7; 134.7; 141.5; 151.2; 177.4 (HC]O);
EI-MS (m/z): 264 (Mþ, 59%); 196 (Mþ ꢂ 68, 78%); 185
(Mþ ꢂ 79, 22%); 156 (Mþ ꢂ 108, 100%); 115 (Mþ ꢂ 149,
76%).
6.1.1.12. (1E/Z )-N-(m-Trifluoromethylphenyl)acetamidine (1l).
Obtained in 88% yield as white solid; mp IR (KBr) nmax
(cmꢂ1) 3468; 3320; 3178; 1650; 1604; 1485; 1H NMR
(500 MHz; CDCl3/Me4Si): d 2.00 (s, 3H, CH3); 4.51 (bs,
2H, NH2); 7.02 (d, 1H, J ¼ 32.0 Hz); 7.26 (d, 1H,
J ¼ 4.0 Hz); 7.39 (t, 1H, J ¼ 8.0 Hz); 13C NMR (125 MHz;
CDCl3/Me4Si): d 22.8 (CH3); 119.4; 118.7; 125.5 (CF3, q,
J ¼ 270.0 Hz); 125.3; 129.8; 131.0 (m, CAreCF3); 150.1;
155.4 (H2NeC]N); EI-MS (m/z): 202 (Mþ, 70%); 187
(Mþ ꢂ 15, 50%); 161 (Mþ ꢂ 41, 72%); 145 (Mþ ꢂ 57,
100%); 125 (Mþ ꢂ 77, 15.5%); 95 (Mþ ꢂ 107, 22.5%).
6.1.2.4. 1-(4-Fluorophenyl)-2-methyl-1H-imidazole-5-carbal-
dehyde (3d). Obtained in 90% yield as orange oil (Rf ¼ 0.6;
9:1 CHCl3/MeOH); IR (KBr) nmax (cmꢂ1) 3330; 3070; 2926;
1
2853; 1674 (n C]O); H NMR (400 MHz; CDCl3/Me4Si):
d 2.32 (s, 3H); 7.40 (d, 2H, J ¼ 8.0 Hz); 7.80 (d, 2H,
J ¼ 8.0 Hz); 7.84 (s, 1H) and 9.62 (s, 1H, HC]O); 13C
NMR (100 MHz; CDCl3/Me4Si): d 32.9 (CH3); 96.4; 147.6;
149.1; 152.0; 153.7; 154.8; 161.2; 175.5 (CAreF) and 196.9
(HC]O); EI-MS (m/z): 204 (Mþ, 77%); 175 (Mþ ꢂ 29,
13%); 134 (Mþ ꢂ 70, 100%); 108 (Mþ ꢂ 96, 39%); 95
(Mþ ꢂ 109, 31%).
6.1.2. General procedure for the preparation of N-
substitued-phenyl-imidazole-5-carbaldehydes (3ae3l)
A mixture of isopropanol (102.07 mmol), corresponding
amidine (1ae1l, 3.73 mmol), triethylamine (3.44 mmol) and
acetic acid (3.92 mmol) was stirred for 5 min at room temper-
ature. 2-Bromomalonaldehyde (2, 3.48 mmol) in isopropanol
(14 mL) was added dropwise and the reaction mixture was
heated for 1 h. The reaction mixture was stirred for 17 h at
room temperature. The solvent was evaporated, water was
added and mixture was washed with ether (3 ꢁ 10 mL). The
washed organic layers were dried over sodium sulfate, filtered
and the filtrate concentrated under reduced pressure. The fol-
lowing compounds were prepared according this general
procedure.
6.1.2.5. 2-Methyl-1-(4-nitrophenyl)-1H-imidazole-5-carbalde-
hyde (3e). Obtained in 86% yield as orange oil (Rf ¼ 0.6;
9:1 CHCl3/MeOH); IR (KBr) nmax (cmꢂ1) 3338; 3116; 2927;
1
2830; 1674 (n C]O); H NMR (400 MHz; CDCl3/Me4Si):
d 2.31 (s, 3H); 7.43 (d, 2H, J ¼ 8.0 Hz); 8.38 (d, 2H,
J ¼ 8.0 Hz); 7.83 (s, 1H) and 9.63 (s, 1H, HC]O); 13C
NMR (100 MHz; CDCl3/Me4Si): d 12.9 (CH3); 112.5; 124.1;
127.4; 132.1; 142.0; 147.3; 151.6; 176.7 (HC]O); EI-MS
(m/z): 231 (Mþ, 100%); 202 (Mþ ꢂ 29, 36.7%); 161
(Mþ ꢂ 70, 32.3%); 131 (Mþ ꢂ 100, 30.9%); 114 (Mþ ꢂ 117,
23.5%).
6.1.2.1. 2-Methyl-1-phenyl-1H-imidazole-5-carbaldehyde (3a).
Obtained in 90% yield as orange oil (Rf ¼ 0.6; 9:1 CHCl3/
MeOH); IR (KBr) nmax (cmꢂ1) 3131; 2853; 1674 (n C]O);
1H NMR (400 MHz; CDCl3/Me4Si): d 2.29 (s, 3H); 7.52 (t,
1H, J ¼ 3.6 Hz); 7.26 (dd, 4H, J ¼ 5.2 Hz and 3.6 Hz); 7.82
(s, 1H) and 9.56 (s, 1H; HC¼O); 13C NMR (100 MHz;
CDCl3/Me4Si): d 13.6; 120.7; 126.9; 129.4; 133.1; 135.7;
141.0; 152.4; 177.8 (HC¼O); EI-MS (m/z): 186 (Mþ,
100%); 157 (Mþ ꢂ 29, 17%); 116 (Mþ ꢂ 70, 98%); 108
(Mþ ꢂ 78, 40%); 89 (Mþ ꢂ 97, 46%); 77 (Mþ ꢂ 109, 57%).
6.1.2.6. 2-Methyl-1-(4-(trifluoromethyl)phenyl)-1H-imidazole-
5-carbaldehyde (3f). Obtained in 87% yield as orange oil
(Rf ¼ 0.5; 9:1 CHCl3/MeOH); IR (KBr) nmax (cmꢂ1) 3113;
3056; 2929; 2829; 1675 (n C]O); 1H NMR (400 MHz;
CDCl3/Me4Si): d 2.32 (s, 3H); 7.40 (d, 2H, J ¼ 8.0 Hz); 7.80
(d, 2H, J ¼ 8.0 Hz); 7.84 (s, 1H) and 9.63 (s, 1H, HC]O);
13C NMR (100 MHz; CDCl3/Me4Si): d 14.2 (CH3); 121.3;
127.2; 128.1; 132.1 (t, CF3, J ¼ 49.0 Hz); 133.4; 139.6;
142.7; 153.6; 178.0 (HC]O); EI-MS (m/z): 254 (Mþ,
100%); 225 (Mþ ꢂ 29, 34%); 184 (Mþ ꢂ 70, 93%); 145
(Mþ ꢂ 109, 42%); 134 (Mþ ꢂ 120, 34%).
6.1.2.2. 1-(4-Chlorophenyl)-2-methyl-1H-imidazole-5-carbal-
dehyde (3b). Obtained in 93% yield as orange oil (Rf ¼ 0.6;
9:1 CHCl3/MeOH); IR (KBr) nmax (cmꢂ1) 3091; 3031; 2799;
6.1.2.7. 2-Methyl-1-(4-cyanophenyl)-1H-imidazole-5-carbalde-
hyde (3g). Obtained in 90% yield as orange oil (Rf ¼ 0.6; 9:1
1
2744; 1667 (n C]O); H NMR (400 MHz; CDCl3/Me4Si):

S.B. Ferreira et al. / European Journal of Medicinal Chemistry 42 (2007) 1388e1395
1393
CHCl3/MeOH); IR (KBr) nmax (cmꢂ1) 3366; 3217; 2924;
1
2850; 1675 (n C]O); H NMR (400 MHz; CDCl3/Me4Si):
(Mþ ꢂ 43, 9%); 142 (Mþ ꢂ 58, 37.5%); 130 (Mþ ꢂ 70,
72.4%).
d 2.31 (s, 3H); 7.39 (d, 2H, J ¼ 8.0 Hz); 7.83 (d, 2H,
J ¼ 8.0 Hz); 7.43 (s, 1H) and 9.63 (s, 1H, HC]O); 13C
NMR (100 MHz; CDCl3/Me4Si): d 13.7 (CH3); 100.3; 114.4;
117.6 (CN); 128.0; 133.2; 133.8; 142.6; 152.3; 177.4
(HC]O); EI-MS (m/z): 211 (Mþ, 100%); 182 (Mþ ꢂ 29,
44%); 141 (Mþ ꢂ 70, 96%); 114 (Mþ ꢂ 97, 60%); 108
(Mþ ꢂ 103, 72%).
6.1.2.12. 2-Methyl-1-(3-(trifluoromethyl)phenyl)-1H-imidaz-
ole-5-carbaldehyde (3l). Obtained in 89% yield as orange
oil (Rf ¼ 0.4; 9:1 CHCl3/MeOH); IR (KBr) nmax (cmꢂ1
)
3068; 2930; 2824; 1674 (n C]O); 1H NMR (400 MHz;
CDCl3/Me4Si): d 2.31 (s, 3H); 7.47 (d, 1H, J ¼ 8.0 Hz); 7.53
(s, 1H); 7.66 (t, 1H, J ¼ 8.0 Hz); 7.79 (d, 1H, J ¼ 8.0 Hz);
7.82 (s, 1H) and 9.61 (s, 1H, HC]O); 13C NMR (100 MHz;
CDCl3/Me4Si): d 13.6 (CH3); 117.4; 126.3; 129.8 (d, CF3,
J ¼ 41.8 Hz); 130.5; 130.9; 131.7 (d, JCF ¼ 32.8 Hz); 136.4
(d, JCF ¼ 23.3 Hz); 134.3 (q, CF3, J ¼ 197.8 Hz); 142.1;
152.5; 177.5; EI-MS (m/z): 254 (Mþ, 42%); 225 (Mþ ꢂ 29,
16%); 184 (Mþ ꢂ 70, 76%); 145 (Mþ ꢂ 109, 38%); 134
(Mþ ꢂ 120, 40%); 108 (Mþ ꢂ 146, 100%).
6.1.2.8. 2-Methyl-1-p-tolyl-1H-imidazole-5-carbaldehyde (3h).
Obtained in 96% yield as orange oil (Rf ¼ 0.5; 9:1 CHCl3/
MeOH); IR (KBr) nmax (cmꢂ1) 3344; 3038; 2924; 2857;
1
1676 (n C]O); H NMR (400 MHz; CDCl3/Me4Si): d 2.26
(s, 3H); 2.30 (s, 3H, CH3); 7.40 (d, 2H, J ¼ 8.0 Hz); 7.79 (d,
2H, J ¼ 8.0 Hz); 7.83 (s, 1H) and 9.65 (s, 1H, HC]O); 13C
NMR (100 MHz; CDCl3/Me4Si): d 13.9 (CH3); 29.7 (CH3);
120.7; 126.7; 127.6; 132.8; 139.0; 142.3; 152.5; 177.5
(HC]O); EI-MS (m/z): 200 (Mþ, 83%); 130 (Mþ ꢂ 70,
100%); 109 (Mþ ꢂ 91, 30%); 103 (Mþ ꢂ 97, 22%); 92
(Mþ ꢂ 108, 76%).
6.1.3. General procedure for the preparation of N-
substitued-phenyl-imidazole-5-difluoromethyl (4ae4l)
A solution of a carbaldehyde derivative (7.5 mmol) in di-
chloromethane (15 mL) was added dropwise to DAST
(2 equiv) at room temperature. The reaction mixture was
stirred for 24 h at room temperature, poured onto a saturated
sodium bicarbonate solution at 0 ꢀC and extracted with di-
chloromethane. The combined organic layers were washed
with brine, dried over sodium sulfate, filtered, and the filtrate
concentrated under reduced pressure. The solid residue was
purified by column chromatography using chloroform as elu-
ent. The following compounds were prepared according this
general procedure.
6.1.2.9. 1-(4-Methoxyphenyl)-2-methyl-1H-imidazole-5-carbal-
dehyde (3i). Obtained in 94% yield as orange oil (Rf ¼ 0.4;
9:1 CHCl3/MeOH); IR (KBr) nmax (cmꢂ1) 3111; 3056; 3005;
2935; 2838; 1675 (n C]O); 1H NMR (400 MHz; CDCl3/
Me4Si): d 2.28 (s, 3H); 3.87 (s, 3H, OCH3); 7.01 (d, 2H,
J ¼ 8.0 Hz); 7.16 (d, 2H, J ¼ 8.0 Hz); 7.80 (s, 1H) and 9.55
(s, 1H, HC]O); 13C NMR (100 MHz; CDCl3/Me4Si):
d 13.5 (CH3); 55.5 (OCH3); 114.7; 121.9; 128.2; 133.2;
140.9; 152.7; 160.1; 177.9 (HC¼O); EI-MS (m/z): 216 (Mþ,
68.3%); 146 (Mþ ꢂ 70, 54.8%); 131 (Mþ ꢂ 85, 10.5%); 108
(Mþ ꢂ 108, 100%); 77 (Mþ ꢂ 139, 9.9%).
6.1.3.1. 5-(Difluoromethyl)-2-methyl-1-phenyl-1H-imidazole
(4a). Obtained in 92% yield as oil (Rf ¼ 0.5; 7:3 ethyl ace-
tate/hexane); IR (KBr) nmax (cmꢂ1) 2926; 2851; 1422; 1265
(n CeF); 1382 (ds CH3); 1H NMR (400 MHz; CDCl3/
6.1.2.10. 1-(2,6-Difluorophenyl)-2-methyl-1H-imidazole-5-car-
baldehyde (3j). Obtained in 85% yield as orange oil
(Rf ¼ 0.4; 9:1 CHCl3/MeOH); IR (KBr) nmax (cmꢂ1) 3066;
2933; 2834; 1674 (n C]O); 1H NMR (400 MHz; CDCl3/
Me4Si): d 2.31 (s, 3H, CH3); 7.10 (t, 1H); 7.45e7.52 (m,
2H); 7.84 (s, 1H) and 9.65 (s, 1H, HC]O); 13C NMR
Me4Si):
d 2.23 (s, 3H, CH3); 6.42 (t, 1H, CHF2,
JHF ¼ 56.0 Hz); 7.28e7.30 (m, 5H); 7.51 (t, 1H, J ¼ 8.0 Hz);
13C NMR (125 MHz; CDCl3/Me4Si): d 13.4 (CH3); 104.5 (t,
CHF2, JCF ¼ 200.0 Hz); 119.9; 127.5; 129.0; 129.5; 129.6;
141.0; 144.0; 19F NMR (376.0 MHz, CDCl3/CFCl3): d e
109.6 (2F, CHF2); EI-MS (m/z): 208 (Mþ, 100%); 189
(Mþ ꢂ 19, 6%); 166 (Mþ ꢂ 42, 15%); 148 (Mþ ꢂ 60,
17.5%); 147 (Mþ ꢂ 61, 57%).
(100 MHz; CDCl3/Me4Si):
d
12.9 (CH3); 112.2 (d,
J ¼ 21.9 Hz); 113.7 (t, CeF; J ¼ 13.5 Hz); 131.1 (t, CeF,
J ¼ 9.8 Hz); 132.6; 142.4; 153.1; 157.9 (d, J ¼ 249.5 Hz);
177.5 (HC]O); EI-MS (m/z): 222 (Mþ, 66.5%); 193
(Mþ ꢂ 29, 18%); 152 (Mþ ꢂ 70, 100%); 125 (Mþ ꢂ 97,
16%); 108 (Mþ ꢂ 114, 40%).
6.1.3.2. 1-(4-Chlorophenyl)-5-(difluoromethyl)-2-methyl-1H-
imidazole (4b). Obtained in 95% yield as oil (Rf ¼ 0.5; 7:3
ethyl acetate/hexane); IR (KBr) nmax (cmꢂ1) 3095; 2984;
2929; 1425; 1497 (n CeF); 1H NMR (400 MHz; CDCl3/
Me4Si): d 2.23 (s, 3H, CH3); 6.46 (t, 1H, CHF2, JHF ¼ 52.0 Hz);
7.50 (d, 2H, J ¼ 8.0 Hz); 7.29 (t, 1H, J ¼ 4.0 Hz); 7.25 (d, 2H,
J ¼ 8.0 Hz); 13C NMR (125 MHz; CDCl3/Me4Si): d 13.6
(CH3); 109.0 (t, CHF2, JCF ¼ 232.3 Hz); 126.5 (t,
JCF ¼ 26.6 Hz); 128.8; 129.4 (t, JCF ¼ 5.7 Hz); 129.9; 134.0;
135.8; 148.7; 19F NMR (376.0 MHz, CDCl3/CFCl3):
d ꢂ109.2 (2F, CHF2); EI-MS (m/z): 242 (Mþ, 100%); 223
6.1.2.11. 1-(2-Methoxyphenyl)-2-methyl-1H-imidazole-5-car-
baldehyde (3k). Obtained in 94% yield as orange oil
(Rf ¼ 0.4; 9:1 CHCl3/MeOH); IR (KBr) nmax (cmꢂ1) 3053;
2930; 2854; 1677 (n C]O); 1H NMR (400 MHz; CDCl3/
Me4Si): d 1.98 (s, 3H, CH3); 2.20 (s, 3H, CH3); 7.14 (d,
1H, J ¼ 8.0 Hz); 7.31e7.44 (m, 3H); 7.84 (s, 1H) and
9.54 (s, 1H, HC]O); 13C NMR (100 MHz; CDCl3/
Me4Si): d 13.3 (CH3); 17.4 (CH3); 116.6; 127.6; 129.8;
131.0; 132.8; 135.2; 141.0; 152.1; 177.7 (HC]O); EI-MS
(m/z): 200 (Mþ, 100%); 183 (Mþ ꢂ 17, 40%); 157

1394
S.B. Ferreira et al. / European Journal of Medicinal Chemistry 42 (2007) 1388e1395
(Mþ ꢂ 19, 12%); 215 (Mþ ꢂ 27, 14%); 200 (Mþ ꢂ 42, 13%);
181 (Mþ ꢂ 61, 42%).
CHF2); EI-MS (m/z): 276 (Mþ, 100%); 257 (Mþ ꢂ 19,
30%); 235 (Mþ ꢂ 41, 25%); 215 (Mþ ꢂ 61, 48%); 184
(Mþ ꢂ 92, 58%).
6.1.3.3. 1-(4-Bromophenyl)-5-(difluoromethyl)-2-methyl-1H-
imidazole (4c). Obtained in 94% yield as oil (Rf ¼ 0.5; 7:3
ethyl acetate/hexane); IR (KBr) nmax (cmꢂ1) 3035; 1422;
6.1.3.7. 4-(5-(Difluoromethyl)-2-methyl-1H-imidazol-1-yl)ben-
zonitrile (4g). Obtained in 95% yield as oil (Rf ¼ 0.5; 7:3 ethyl
acetate/hexane); IR (KBr) nmax (cmꢂ1) 3368; 2924 (n CeHAr);
1
1495 (n CeF); H NMR (400 MHz; CDCl3/Me4Si): d 2.29
1
(s, 3H, CH3); 6.45 (t, 1H, CHF2, J ¼ 56.0 Hz); 7.66 (d, 2H,
J ¼ 12.0 Hz); 7.29 (t, 1H, J ¼ 4.0 Hz); 7.18 (d, 2H,
J ¼ 8.0 Hz); 13C NMR (125 MHz; CDCl3/Me4Si): d 13.4
(CH3); 109.0 (t, CHF2, JCF ¼ 232.2 Hz); 123.8; 126.5 (t,
JCF ¼ 35.0 Hz); 129.1; 129.7 (t, JCF ¼ 10.0 Hz); 132.9;
134.6; 148.6; 19F NMR (376.0 MHz, CDCl3/CFCl3):
d ꢂ109.0 (2F, CHF2); EI-MS (m/z): 286 (Mþ, 100%); 225
(Mþ ꢂ 61, 22%); 194 (Mþ ꢂ 92, 44%); 180 (Mþ ꢂ 106, 69%).
1423 (da CH3); 1508 (n CeF); H NMR (400 MHz; CDCl3/
Me4Si): d 2.25 (s, 3H, CH3); 6.51 (t, 1H, CHF2, J ¼ 56.0 Hz);
7.31 (t, 1H, J ¼ 4.0 Hz); 7.46 (d, 2H, J ¼ 8.0 Hz); 7.84 (d,
2H, J ¼ 8.0 Hz); 13C NMR (125 MHz; CDCl3/Me4Si): d 13.5
(CH3); 108.9 (t, CHF2, JCF ¼ 232.4 Hz); 114.4; 117.5 (CN);
126.4 (t, JCF ¼ 25.0 Hz); 128.6; 130.5 (t, JCF ¼ 6.5 Hz);
133.5; 139.6; 148.5; 19F NMR (376.0 MHz, CDCl3/CFCl3):
d ꢂ108.2 (2F, CHF2); EI-MS (m/z): 233 (Mþ, 100%); 214
(Mþ ꢂ 19, 7%); 192 (Mþ ꢂ 41, 22.2%); 182 (Mþ ꢂ 51, 7%);
172 (Mþ ꢂ 61, 23%).
6.1.3.4. 5-(Difluoromethyl)-1-(4-fluorophenyl)-2-methyl-1H-
imidazole (4d). Obtained in 95% yield as oil (Rf ¼ 0.6; 7:3
ethyl acetate/hexane); IR (KBr) nmax (cmꢂ1) 3078; 3390;
2927; 1430; 1513 (n CeF); 1H NMR (400 MHz; CDCl3/
6.1.3.8. 5-(Difluoromethyl)-2-methyl-1-p-tolyl-1H-imidazole
(4h). Obtained in 96% yield as oil (Rf ¼ 0.4; 7:3 ethyl ace-
tate/hexane); IR (KBr) nmax (cmꢂ1) 3052; 1423; 1265 (n Ce
Me4Si):
d 2.25 (s, 3H, CH3); 6.46 (t, 1H, CHF2,
1
J ¼ 56.0 Hz); 7.22 (t, 2H, J ¼ 8.0 Hz); 7.30 (d, 3H,
J ¼ 8.0 Hz); 7.31 (d, J ¼ 4.0 Hz); 13C NMR (125 MHz;
CDCl3/Me4Si): d 13.1 (CH3); 99.0 (t, CHF2, JCF ¼ 250.0 Hz);
108.0; 113.0; 116.8 (d, JCF ¼ 23.0 Hz); 129.4 (d,
JCF ¼ 8.7 Hz); 140.0; 150.0; 164.5 (d, JCF ¼ 69.6 Hz); 19F
NMR (376.0 MHz, CDCl3/CFCl3): d ꢂ109.7 (2F, CHF2);
ꢂ110.2 (1F); EI-MS (m/z): 226 (Mþ, 100%); 207 (Mþ ꢂ 19,
15%); 184 (Mþ ꢂ 42, 18%); 165 (Mþ ꢂ 61, 57%); 134
(Mþ ꢂ 92, 74%).
F); H NMR (400 MHz; CDCl3/Me4Si): d 2.26 (s, 3H, CH3);
2.44 (s, 3H, CH3); 6.43 (t, 1H, CHF2, J ¼ 52.0 Hz); 7.18 (d,
2H, J ¼ 8.0 Hz); 7.31 (d, 2H, J ¼ 8.0 Hz); 7.35 (sl, 1H); 13C
NMR (125 MHz; CDCl3/Me4Si): d 13.1 (CH3); 21.2 (CH3);
109.1 (t, CHF2, J ¼ 250.0 Hz); 126.7 (t, JCF ¼ 20.0 Hz);
127.1; 128.0; 130.3; 132.4; 140.0; 148.5; 19F NMR
(376.0 MHz, CDCl3/CFCl3): d ꢂ110.1 (2F, CHF2); EI-MS
(m/z): 222 (Mþ, 100%); 195 (Mþ ꢂ 27, 17%); 194
(Mþ ꢂ 28, 11%); 180 (Mþ ꢂ 42, 22%); 161 (Mþ ꢂ 61, 8%).
6.1.3.5. 5-(Difluoromethyl)-2-methyl-1-(4-nitrophenyl)-1H-im-
idazole (4e). Obtained in 90% yield as oil (Rf ¼ 0.5; 7:3 ethyl
acetate/hexane); IR (KBr) nmax (cmꢂ1) 3116; 2920; 2850;
1422; 1500 (n CeF); 1H NMR (400 MHz; CDCl3/Me4Si):
d 2.24 (s, 3H, CH3); 6.51 (t, 1H, CHF2, J ¼ 52.0 Hz); 7.29
(t, 1H, J ¼ 4.0 Hz); 7.52(d, 2H, J ¼ 8.0 Hz); 8.37 (d, 2H,
J ¼ 8.0 Hz); 13C NMR (125 MHz; CDCl3/Me4Si): d 14.0
(CH3); 109.5 (t, CHF2, JCF ¼ 232.5 Hz); 125.5; 126.9 (t,
JCF ¼ 25.5 Hz); 129.3; 131.1 (t, JCF ¼ 6.0 Hz); 141.7; 148.7;
149.1; 19F NMR (376.0 MHz, CDCl3/CFCl3): d ꢂ108.5 (2F,
CHF2); EI-MS (m/z): 253 (Mþ, 100%); 234 (Mþ ꢂ 19, 8%);
182 (Mþ ꢂ 71, 12%); 166 (Mþ ꢂ 87, 36%); 131 (Mþ ꢂ 122,
12%).
6.1.3.9. 5-(Difluoromethyl)-1-(4-methoxyphenyl)-2-methyl-1H-
imidazole (4i). Obtained in 97% yield as oil (Rf ¼ 0.5; 7:3
ethyl acetate/hexane); IR (KBr) nmax (cmꢂ1) 3412; 2982 (n
1
CeHar); 1458 (da CH3); 1114 (n CeF); H NMR (400 MHz;
CDCl3/Me4Si): d 2.35 (s, 3H, CH3); 3.86 (s, 3H, OCH3);
6.50 (t, 1H, CHF2, J ¼ 52.0 Hz); 7.03 (d, 2H, J ¼ 8.0 Hz);
7.28 (d, 2H, J ¼ 8.0 Hz); 7.53 (sl, 1H); 13C NMR (125 MHz;
CDCl3/Me4Si): d 12.4 (CH3); 55.6 (OCH3); 108.4 (t, CHF2,
J ¼ 233.2 Hz); 115.0; 125.1; 126.3; 127.3 (t, JCF ¼ 27.7 Hz);
128.5; 148.6; 160.8; 19F NMR (376.0 MHz, CDCl3/CFCl3):
d ꢂ111.7 (2F, CHF2); EI-MS (m/z): 238 (Mþ, 100%); 211
(Mþ ꢂ 27, 21%); 196 (Mþ ꢂ 42, 15.5%); 187 (Mþ ꢂ 51,
18%); 170 (Mþ ꢂ 68, 43%).
6.1.3.6.
5-(Difluoromethyl)-2-methyl-1-(4-(trifluoromethyl)-
6.1.3.10. 5-(Difluoromethyl)-1-(2,6-difluorophenyl)-2-methyl-
1H-imidazole (4j). Obtained in 89% yield as oil (Rf ¼ 0.4;
7:3 ethyl acetate/hexane); IR (KBr) nmax (cmꢂ1) 3391; 2925;
1417 (da CH3); 1514 (n CeF); H NMR (400 MHz; CDCl3/
Me4Si): d 2.24 (s, 3H, CH3); 6.54 (t, 1H, CHF2,
phenyl)-1H-imidazole (4f). Obtained in 93% yield as oil
(Rf ¼ 0.5; 7:3 ethyl acetate/hexane); IR (KBr) nmax (cmꢂ1
)
2930; 1425; 1324 (n CeF); 1H NMR (400 MHz; CDCl3/
1
Me4Si):
d
2.25 (s, 3H, CH3); 6.49 (t, 1H, CHF2,
J ¼ 52.0 Hz); 7.33 (t, 1H, J ¼ 4.0 Hz); 7.81 (d, 2H,
JHF ¼ 52.0 Hz); 7.12 (dd, 1H, JHF ¼ 8.0 Hz); 7.36 (t, 1H,
J ¼ 4.0 Hz); 7.48e7.54 (m, 2H); 13C NMR (125 MHz;
CDCl3/Me4Si): d 12.6 (CH3); 108.7 (t, CHF2, JCF ¼ 233.0 Hz);
112.3 (dd, JCF ¼ 23.0 Hz); 112.9 (t, JCF ¼ 17.9 Hz); 126.4 (t,
JCF ¼ 22.7 Hz); 129.9 (t, JCF ¼ 6.3 Hz); 131.8 (t, J ¼ 9.3 Hz);
149.5; 158.4 (d, JCF ¼ 254.6 Hz); 19F NMR (376.0 MHz,
CDCl3/CFCl3): d ꢂ112.4 (2F, CHF2); ꢂ117.5 (2F); EI-MS
J ¼ 8.0 Hz); 7.47 (d, 2H, J ¼ 8.0 Hz); 13C NMR (125 MHz;
CDCl3/Me4Si):
d
13.4 (CH3); 108.9 (t, CHF2,
JCF ¼ 232.5 Hz); 124.3 (q, CF3, JCF ¼ 270.7 Hz); 126.8;
127.6 (q, JCF ¼ 10.0 Hz); 128.2; 129.8 (t, JCF ¼ 5.9 Hz);
131.9 (t, JCF ¼ 32.8 Hz); 138.6; 148.6; 19F NMR
(376.0 MHz, CDCl3/CFCl3): d ꢂ62.7 (3F, CF3); ꢂ108.9 (2F,

S.B. Ferreira et al. / European Journal of Medicinal Chemistry 42 (2007) 1388e1395
1395
(m/z): 244 (Mþ, 100%); 225 (Mþ ꢂ 19, 17%); 217 (Mþ ꢂ 27,
References
8.5%); 193 (Mþ ꢂ 51, 22%); 183 (Mþ ꢂ 61, 8%).
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tate/hexane); IR (KBr) nmax (cmꢂ1) 3400; 2925; 2852; 1420
(da CH3); 1159 (n CeF); 1H NMR (400 MHz; CDCl3/
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CHF2, JHF ¼ 56.0 Hz); 7.23 (d, 1H, J ¼ 4.0 Hz); 7.32e7.44
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¼ 26.9 Hz); 127.2; 128.0; 129.8; 130.3; 131.3; 133.9;
CF
6.1.3.12. 5-(Difluoromethyl)-2-methyl-1-(3-(trifluoromethyl)-
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3400; 2985; 1458 (da CH3); 1130 (n CeF); 1H NMR
(400 MHz; CDCl3/Me4Si): d 2.25 (s, 3H, CH3); 6.49 (t, 1H,
CHF2 JHF ¼ 52.0 Hz); 7.32 (t, 1H, J ¼ 4.0 Hz); 7.53 (d, 1H,
J ¼ 8.0 Hz); 7.60 (s, 1H, CH3); 7.68 (t, 1H, J ¼ 8.0 Hz);
7.81 (t, 1H, J ¼ 8.0 and 4.0 Hz); 13C NMR (125 MHz;
CDCl3/Me4Si): 13.4 (CH3); 108.9 (t, CHF2, JCF ¼ 232.5 Hz);
124.6 (d, J ¼ 5.8 Hz); 123.5 (q, CF3, J ¼ 270.2 Hz); 126.3 (t,
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(m/z): 276 (Mþ, 100%); 257 (Mþ ꢂ 19, 22.5%); 235
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Acknowledgments
Fellowships granted by CAPES and CNPq (Brazil) are
gratefully acknowledged. This work was partially supported
by CNPq, FAPERJ, IOC/FIOCRUZ, UFRJ and UFF.
~
ˆ
~
´
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