Structural study of diarylazoles related to Rimonabant

Article abstract of DOI:10.1016/j.molstruc.2008.10.020

The structures of three diarylazoles (two pyrazoles and one 1,2,4-triazole) related to Rimonabant have been determined by X-ray crystallography. The conformation of both aryl groups in the new structures is discussed with regard to other related compounds

Full text of DOI:10.1016/j.molstruc.2008.10.020

Journal of Molecular Structure 920 (2009) 82–89
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Structural study of diarylazoles related to Rimonabant
b,
a
Ibon Alkorta a, Mario Alvarado a, José Elguero a, , Santiago García-Granda , Pilar Goya ,
*
*
Laura Torre-Fernández b, Laura Menéndez-Taboada b
a Instituto de Química Médica, CSIC, Juan de la Cierva, 3, E-28006 Madrid, Spain
b Departamento de Química Física y Analítica, Facultad de Química, Universidad de Oviedo, E-33006 Oviedo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The structures of three diarylazoles (two pyrazoles and one 1,2,4-triazole) related to Rimonabant have
been determined by X-ray crystallography. The conformation of both aryl groups in the new structures
is discussed with regard to other related compounds reported in the Cambridge Structural Database.
The secondary structure of the three compounds is very different. Compound 2 forms a helix, compound
3 forms a structure with the hydrocarbon layers parallel and compound 4 crystallizes forming a double
chain. In the solid state, the conformation of both aryl groups, the N-aryl and the C-aryl, was compared
with similar compounds reported in the literature. GIAO calculations afford absolute shieldings that were
compared with experimental chemical shifts.
Received 19 September 2008
Received in revised form 17 October 2008
Accepted 17 October 2008
Available online 1 November 2008
Keywords:
Rimonabant
Crystallography
GIAO
Ó 2008 Elsevier B.V. All rights reserved.
Pyrazoles
Triazoles
1. Introduction
angles of both phenyl rings retrieved from the CSD [12]. The data
of Rimonabant 1 [13] are also included.
Rimonabant (1) is the first selective CB1 receptor blocker used in
many countries for patients with metabolic syndrome and related
illnesses, like diabetes and dyslipidaemia [1–3]. Our group has
been active in this field preparing and evaluating a large series of
compounds related to 1 [4–11]. During these studies we have
determined the X-ray molecular structure of intermediates 2, 3
and 4 (Scheme 1).
A search in the CSD [12] on 1,5-diarylpyrazoles and 1,5-diaryl-
1,2,4-triazoles was carried out to explore their conformation and to
confirm that the structure of Rimonabant 1 was not known, reason
why we have determined it [13]. It is worth mentioning that there
is a great interest on the polymorphism of 1 and related com-
pounds [14–18].
2.2. Crystallographic results concerning compounds 2–4
We have represented the three studied molecules in Figs. 1 and
2 (two independent molecules in the unit cell) and 3 (two indepen-
dent molecules in the unit cell).
The single crystal X-ray structures of compounds 2–4 are listed
in Table 1 and the hydrogen-bonding geometries in Tables 2–4
(compound 2), 3 (compound 3) and 4 (compound 4), respectively.
The molecular structure of compound 2 is shown in Fig. 1.
The crystal packing for compound 2 shows a helix type propaga-
tion along the c axis shown in Fig. 4a. The helical structure is
supported by a weak H-bond involving nitrogen (N2) and carbon
(C10–H10).
The molecular structure of compound 3 is shown in Fig. 2. The
molecular packing of compound 3 is made up of a network of
hydrogen bonding interactions stabilizing hydrocarbon layers par-
allel to the bc plane. Every layer contains two molecules connected
to another molecule of the neighbor layer. Within the layers the
aromatic rings are stacked. This molecular packing is shown in
Fig. 4b.
2. Results and discussion
2.1. Crystallography: literature results
We have collected in a Table (see Supplementary data) the per-
tinent information on 1,5-diarylpyrazoles and 1,5-diaryl-1,2,4-tria-
zoles including the nature of the substituents and the torsion
The molecular structure of compound 4 is shown in Fig. 3. Com-
pound 4 contains two forms of hydrogen bonds: the Oꢀ ꢀ ꢀH bonds
along the chain (O03–H14A) and the Oꢀ ꢀ ꢀH bonds between chains
(O01ꢀ ꢀ ꢀH11A) packing like a double chain (Figs. 5 and 6). The dou-
ble chain is packed by Van der Waals interactions (Fig. 7). Chains
* Corresponding authors. Tel.: +34 1 914110874; fax: +34 1 5644853 (J. Elguero),
tel.: +34 1 985103477; fax: +34 1 985103125 (S. García-Granda).
E-mail addresses: iqmbe17@iqm.csic.es (J. Elguero), sgg@uniovi.es (S. García-
Granda).
0022-2860/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2008.10.020

I. Alkorta et al. / Journal of Molecular Structure 920 (2009) 82–89
83
O
N
O
N
O
N
O
N
C16H33
N
OC2H5
Cl
N
OCH3
H3C
N
N
H
H
N
N
N
N
Cl
Cl
Cl
Cl
Cl
Cl
Cl
1
3
4
2
Scheme 1. Rimonabant and related compounds.
Table 1
Crystal data and structure refinement for compounds 2, 3 and 4.
Compound 2
Compound 3
Compound 4
CCDC [12]
Empirical formula
Formula weigh
Crystal system
Space group
a (Å)
664037
C18H15ClN2O2
326.77
Monoclinic
P21/c (14)
10.6740(7)
8.3670(5)
19.7420(15)
90.0
111.669(2)
90.0
1638.55(19)
4
664038
C32H43Cl2N3O
556.59
Triclinic
P-1(2)
9.7627(3)
10.0704(4)
33.6580(10)
97.110(2)
93.353(2)
104.335(2)
3167.68(18)
4
700182
C16H11N3O2Cl2
348.188
Triclinic
P-1(2)
9.4194(2)
10.9035(3)
16.1944(5)
105.339(2)
95.656(2)
93.277(2)
1590.16(8)
4
b (Å)
c (Å)
a
(°)
b (°)
c
(°)
Fig. 1. X-ray molecular structure of compound 2.
V (Å3)
Z
l
(mmꢁ1
)
2.154
2.047
3.786
F (000)
680
1192
712
Temperature (K)
Wavelength (Å)
Reflections collected
Unique reflections
Rint
293(2)
1.54184
3006
3006
0.019
293(2)
1.54184
9431
9431
0.098
293(2)
1.54184
50751
5727
0.0416
R1[I > 2
r(I)]
0.053
0.053
0.0443
wR2 (all data)
0.152
0.150
0.1448
Table 2
Hydrogen-bonding geometry (Å, °) for 2.
D–Hꢀ ꢀ ꢀA
D–H (Å)
Hꢀ ꢀ ꢀA (Å)
Dꢀ ꢀ ꢀA (Å)
D–Hꢀ ꢀ ꢀA (°)
Symmetrya
C17–H172ꢀ ꢀ ꢀO2
C10–H10ꢀ ꢀ ꢀN2
C6–H6ꢀ ꢀ ꢀO2
0.97
0.93(3)
0.93(3)
2.25
2.50(3)
2.52(3)
2.687(5)
3.318(3)
3.412(3)
106.5
147(2)
161(2)
1
2
3
a
Symmetry codes: (1) x, y, z; (2) ꢁx, y ꢁ 1/2, ꢁz + 1/2; (3) ꢁx, ꢁy + 1, ꢁz + 1.
sented in Scheme 2. They correspond to compounds with both an-
gles being large, which is understandable for the congested
GEWQUU but not for CILLOY and FETRIG. Note that Rimonabant
1 is also close to these compounds.
The complementarity of the /1 and /5 angles means that in the
interval 0° (/1 = /5 = 0°) to 180° (/1 = /5 = 90°) the most common
situation is /1 + /5 = 90°. Deviations are much more frequent to-
wards situations with both phenyl rings almost perpendicular
(see Fig. 9).
Fig. 2. X-ray molecular structure of compound 3.
are growing in the direction of c axis. The hydrogen-bonding geom-
etries, which give the molecular packing, are shown in Table 4.
When a phenyl ring adjacent to a pyridine-like N atom bears an
o-hydroxy group (no example in the pyrazole series) then an intra-
molecular O–Hꢀ ꢀ ꢀN hydrogen bond is formed and the correspond-
ing torsion angle is small. This happens in the 1,2,4-triazole series
for the 5-aryl group (/5, Scheme 3) with the notable exception of
SAJFIT, where the OH of the 5-aryl group is involved in intermolec-
ular HBs.
It was expected that the dihedral angle /2 would depend on the
substituent at position 4: in the absence of substituent (1,2,4-tria-
zoles) or when this substituent is an H atom (several pyrazoles),
the angle should be lower than for 4-substituted pyrazoles. Fig. 8b
2.3. Discussion of the dihedral angles /1 and /5
We have always considered the dihedral angles to be 690°, both
being positive because the rings adopt a parallel disposition in all
cases save when the angles are 0° or 90° (GEMNIW). The 0°/90° sit-
uation evokes the T-shaped structure of benzene dimer while all
others are similar to the parallel-displaced structure. A plot of /1
vs. /5 is shown in Fig. 8a.
The three compounds that deviate from the general trend in
Fig. 9 (when /1 increase /2 decrease and reciprocally) are repre-

84
I. Alkorta et al. / Journal of Molecular Structure 920 (2009) 82–89
considers triazole 4 where the calculated angles are 49.4° and
33.6°, respectively, in the crystal there are two independent mole-
cules, one close (molecule 1°, 53.3° and 29.5°) but other far away
(molecule 2°, 74.7° and 9.8°). Thus, the two angles are related
and their sum tends to be 90° but there is a large freedom to move
away from the 50°/35° average (see Fig. 10).
Using the GIAO approximation, we have calculated the absolute
shieldings (r
, ppm) and compared them to the 1H and 13C experi-
mental chemical shifts (d, ppm, see experimental part) that were
assigned through routine 2D experiments [19] and by analogy to
similar compounds [20–23]. Carbons bearing halogen substituents
deviate [24–26] and to fit them a dummy variable must be added.
The three following equations were obtained:
Without CACl : d13C ¼ ð175:5 ꢂ 0:4Þ ꢁ ð0:964 ꢂ 0:006Þ
¼ 46; R2 ¼ 0:998
r
13C;n
Fig. 3. X-ray molecular structure of compound 4.
With CACl : d13C ¼ ð175:1 ꢂ 0:5Þ ꢁ ð0:960 ꢂ 0:008Þ
r
13C
ꢁ ð8:2 ꢂ 0:9ÞC ꢁ Cl;n ¼ 51; R2 ¼ 0:996
Table 3
Hydrogen-bonding geometry (Å, °) for 3.
d1H ¼ ð30:5 ꢂ 0:3Þ ꢁ ð0:95 ꢂ 0:01Þd1H;n ¼ 16; R2 ¼ 0:998
D–Hꢀ ꢀ ꢀA
D–H (Å)
Hꢀ ꢀ ꢀA (Å)
Dꢀ ꢀ ꢀA (Å)
D–Hꢀ ꢀ ꢀA (°)
Symmetrya
These equations are similar to those we reported previously for
other compounds [23]. For carbon atoms bearing chlorine substitu-
ents a correction of ꢁ8.2 ppm should be applied (the correction is
ꢁ17.6 ppm for bromine substituted carbons [26]). For the last equa-
tion we used only the values assigned in the experimental part.
N11–H11ꢀ ꢀ ꢀN12
N21–H21ꢀ ꢀ ꢀN22
N21–H21ꢀ ꢀ ꢀO1
C215–H215ꢀ ꢀ ꢀO2
0.86
0.86
0.86
0.93
2.38
2.34
2.06
2.43
2.745(4)
2.725(4)
2.832(4)
3.360(5)
105.7
107.5
148.1
174.3
1
1
2
3
a
Symmetry codes: (1) x, y, z; (2) ꢁx + 1, ꢁy + 2, ꢁz + 1; (3) x + 1, y, z.
3. Conclusions
Table 4
Hydrogen-bonding geometry (Å, °) for 4.
φ5
φ1
N
D–Hꢀ ꢀ ꢀA
D–H (Å) Hꢀ ꢀ ꢀA (Å) Dꢀ ꢀ ꢀA (Å) D–Hꢀ ꢀ ꢀA (°) Symmetrya
C14A–H14Aꢀ ꢀ ꢀO03 0.93
2.56
2.36
3.406(3)
3.275(3)
151.7
168.9
1
2
C11A–H11Aꢀ ꢀ ꢀO01 0.93
a
Symmetry codes: (1) ꢁx + 1, ꢁy + 1, ꢁz + 2; (2) ꢁx + 1, ꢁy + 1, ꢁz + 1.
The structure of the three compounds we have determined in this
work affords new values for the torsion angles /1 and /5. Together
with those reported in the literature (see Table in the Supplemen-
tary data), a relationship between both angles has been found, the
two extreme situations for the adjacent phenyl rings being T-
shaped and parallel. The secondary structure of the three com-
pounds is very different, forming helices (compound 2), parallel ex-
tended saturated chains (compound 3) and double chains
(compound 4).
shows that this is in general the case, although GEWQUU and SAJFIT
clearly deviate. For GEWQUU the explanation is ortho-steric effects.
2.4. Computational study
We have calculated compounds 1, 2, 30 (with n-propyl instead of
hexadecyl as the substituent of the amide) and 4. First, the geom-
etries were optimized at the B3YP/6-311++G(d,p) level and then,
we used these geometries to calculate the absolute shieldings
(GIAO).
4. Experimental
In what concerns the /1 + /5 sum the values are comprised be-
tween 81.4 (X-ray 2) and 90.0 (calculations of 3, see Table 1) show-
ing that the tendency of Fig. 9 is followed. However, if one
All reagents and solvents were used as commercially received
with exception of CH2Cl2 which was distilled from P2O5 prior to
Fig. 4. (a) Helical structure of compound 2 and (b) supramolecular structure of compound 3.

I. Alkorta et al. / Journal of Molecular Structure 920 (2009) 82–89
85
Fig. 5. Hydrogen bonded chain of compound 4 view along c axis.
Fig. 6. Hydrogen bonded chain of compound 4, down ab plane.
Fig. 7. Van der Waals interactions in compound 4.
use. TLC: precoated silica-gel 60 F254 plates (Merck), detection by
UV light (254 nm). Flash-column Chromatography (FC): Kieselgel
60 (230–400 mesh; Merck). Melting points (mp) were determined
in open capillaries with a Gallenkamp capillary melting-points
apparatus and are uncorrected.
none and diethyl oxalate in basic medium [27], was added an
amount equimolar of the arylhydrazine. The reaction mixture
was refluxed and later poured into water. The yellowish oil was
separated by extraction with ether (3 ꢃ 50 mL) and the organic ex-
tract was washed with NaHCO3 solution (10%) (3 ꢃ 15 mL) and
water (3 ꢃ 15 mL). The extract was dried (Na2SO4) and the solvent
was removed under reduced pressure to give predominantly the
1H-pyrazole-3-carboxylate isomer [28–30] as a viscous yellow
oil. The residue was purified by flash chromatography (FC) and
crystallization.
1H and 13C NMR spectra were recorded on Bruker Advance 300
spectrometer operating at 300.13 and 75.47 MHz, respectively, in
CDCl3 as solvent and Me4Si as the internal standard. Chemical
shifts are reported in ppm on the d scale. The mass spectra (EI-
MS; 70 eV) were determined on a MSD 5973 Hewlett Packard
instrument. Elemental analyses were performed on a Heraeus
CHN–O Rapid Analysis at the Centro de Química Orgánica ‘‘Manuel
Lora Tamayo” (CSIC).
4.2. Ethyl 5-(4-chlorophenyl)-1-phenylpyrazole-3-carboxylate (2)
4.1. General procedure for the preparation of ethyl 1,5-diarylpyrazole-
3-carboxylates (2 and 8) (Scheme 4)
The title compound was prepared according to the previously
described general procedure by refluxing 4-(4-chlorophenyl)-2,4-
To a solution of ethyl 4-(4-chlorophenyl)-2,4-dioxobutanoate 7
dioxobutanoate
7
(3.0 g, 11.8 mmol) and phenylhydrazine
in glacial acetic acid, obtained through condensation of acetophe-
(1.27 g, 11.8 mmol) in glacial acetic acid (10 mL) during 24 h. The

86
I. Alkorta et al. / Journal of Molecular Structure 920 (2009) 82–89
100
100
90
80
70
60
50
40
30
20
10
a
b
GEMNIW
90
80
70
60
50
40
30
20
10
0
GEWQUU
SAJFIT
CILLOY
GEWKUU
FETRIG
4
IIZAZEO
IZAYUD
1
4
3
3
2
φ 5 (pyrazoles)
φ 5 (triazoles)
HAHRIS
GEMNIW
SAJFIT
-10
-20
0
20
40
60
80
100
-.2
0
.2
.4
.6
.8
1
1.2
φ
2
H4/R4
Fig. 8. (a) The straight line (excluding CILLOY, FETRIG and GEWQUU) corresponds to /1 = (81 4) ꢁ (0.77 0.09) /2, n = 55, R2 = 0.58. (b) H4 or N in position 4 (triazoles) = 0;
R4 in position 4 = 1.
12
11
10
9
8
7
6
5
4
3
2
1
0
GEWQUU
CILLOY
HAHRIS
Rimonabant
130
60
70
80
90
100
110
120
140
150
160
170
φ
φ
1+ 5
Fig. 9. Histogram of the /1 + /5 sum.
product was purified by FC (SiO2; EtOAc/n-hexane 1:9) and crystal-
lization (79% yield). Yellowish solid, mp: 94–5 °C (EtOH); MS/EI: m/
z (%) = 328 [M+1]+ (34), 326(91), 254(100); 1H NMR (300 MHz,
CDCl3): d = 7.29–7.18 (m, 7H), 7.07 (d, J = 8.5 Hz, 2H, ortho 5-p-
ClPh), 6.95 (s, 1H, pyrazole H4), 4.38 (q, J = 7.0 Hz, 2H, CH2), 1.34
(t, J = 7.0 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): d = 162.2 (CO),
144.3 (C, pyrazole C3), 143.3 (C, pyrazole C5), 139.2 (C, ipso 1-
Ph), 134.8 (C, para 5-p-ClPh), 129.8 (CH, ortho 5-p-ClPh), 129.0
(CH, meta 1-Ph), 128.8 (CH, meta 5-p-ClPh), 128.7 (C, ipso 5-p-
ClPh), 127.9 (C, para 1-Ph), 125.6 (CH, ortho 1-Ph), 109.9 (CH, pyr-
azole C4), 61.1 (CH2), 14.3 (CH3); elemental analysis calcd (%) for
C18H15ClN2O2 (326.08): C 66.16, H 4.63, N 8.57, found: C: 66.23;
H: 4.55; N: 8.52.
4.3. Ethyl 1,5-bis(4-chlorophenyl)pyrazole-3-carboxylate (8)
The title compound was prepared by refluxing 4-(4-chloro-
phenyl)-2,4-dioxobutanoate 7 (3.0 g, 11.8 mmol) and 4-chloro-
phenyl-hydrazine chlorhydrate (2.1 g, 11.8 mmol) in glacial acetic
acid (10 mL) during 48 h. The product was purified by FC (SiO2;
EtOAc/n-hexane 1:9) and crystallization (60% yield). Yellowish so-
lid, mp: 120–1 °C (EtOH); MS/EI: m/z (%) = 362 [M+1]+ (59),
360(94), 288(100); 1H NMR (300 MHz, CDCl3): d = 7.29–7.23 (m,
4H), 7.20 (d, J = 8.5 Hz, 2H, ortho 1-p-ClPh), 7.08 (d, J = 8.3 Hz, 2H,
ortho 5-p-ClPh), 6.95 (s, 1H, pyrazole H4), 4.39 (q, J = 7.1 Hz, 2H,
CH2), 1.35 (t, J = 7.1 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3):
d = 162.0 (CO), 144.7 (C, pyrazole C3), 143.4 (C, pyrazole C5),

I. Alkorta et al. / Journal of Molecular Structure 920 (2009) 82–89
87
CONHR
PhHNOCOC
CO2Me
PhOC
CO2H
OMe
N
N
N
N
N
N
EtO
iPr
MeO
GEWQUU
CILLOY
FETRIG
CONHRR'
Me
φ
=72.5, 2= 89.9
φ
φ1
1=89.5,φ2= 68.2
φ1=68.8,φ2= 70.8
Scheme 2. Compounds with both aryl groups almost perpendicular.
R3
H
H
O
O
N
N
N
O
O
H
O
N
N
N
H
H
N
N
N
SAJFIT
Scheme 3. The /5 dihedral angle in 1,5-diaryl-1,2,4-triazoles.
GEMNIV, GEMNOC, GEMNUI. QOPFAC
QOPFAC
CO2H
137.7 (C, ipso 1-p-ClPh), 135.1 (C, para 5-p-ClPh), 134.3 (C, para 1-
p-ClPh), 129.9 (CH, ortho 5-p-ClPh), 129.3 (CH, metha 5-p-ClPh),
129.0 (CH, metha 1-p-ClPh), 127.6 (C, ipso 5-p-ClPh), 126.7 (CH,
ortho 1-p-ClPh), 110.2 (CH, pyrazole C4), 61.2 (CH2), 14.3 (CH3);
elemental analysis calcd (%) for C18H14Cl2N2O2 (360.04): C 59.85,
H 3.91, N 7.76, found: C: 60.02; H: 3.87; N: 7.74.
(0.25 g, 0.7 mmol) dissolved in dry CH2Cl2 (100 mL) was added
and the mixture was heated at reflux during 20 h. The reaction
was quenched by slow and careful addition of a solution 2N HCl
(50 mL). The organic layer was then separated and washed with
a solution 2N HCl (3 ꢃ 15 mL), dried (Na2SO4) and evaporated to
dryness. The product was purified by FC (SiO2; EtOAc/n-hexane
1:4) and crystallization (90% yield). White solid, mp: 78–9 °C (n-
hexane); MS/EI: m/z (%) = 557 [M+1]+ (10), 555(15), 315(100); 1H
NMR (300 MHz, CDCl3): d = 7.30–7.19 (m, 4H), 7.17 (d, J = 8.7 Hz,
2H, ortho 1-p-ClPh), 7.07 (d, J = 7.0 Hz, 2H, ortho 5-p-ClPh), 6.96
(s, 1H, pyrazole H4), 3.38 (q, J = 7.0 Hz, 2H), 1.58–1.49 (m, 2H),
1.29–1.17 (m, 26H), 0.82 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d = 161.3 (CO), 147.7 (C, pyrazole C3), 143.7 (C, pyrazole
C5), 137.8 (C, ipso 1-p-ClPh), 135.0 (C, para 5-p-ClPh), 134.2 (C, para
1-p-ClPh), 129.9 (CH, ortho 5-p-ClPh), 129.3 (CH, meta 5-p-ClPh),
129.0 (CH, meta 1-p-ClPh), 128.3 (C, ipso 5-p-ClPh), 126.9 (CH, ortho
1-p-ClPh), 108.9 (CH, pyrazole C4), 39.6 (CH2), 32.3 (CH2), 30.1–
29.7 (CH2), 27.3 (CH2), 23.0 (CH2), 14.5 (CH3); elemental analysis
calcd (%) for C32H43Cl2N3O (555.28): C 69.05, H 7.79, N 7.55, found:
C: 68.89; H: 7.51; N: 7.73.
4.4. Preparation of N-(1-hexadecyl)-1,5-bis(4-chlorophenyl)-1H-
pyrazole-3-carboxamide (3)
To the N-hexadecylamine (0.83 g, 3.5 mmol) dissolved in dry
CH2Cl2 was added dropwise during 5 min a commercial solution
2 M Al(CH3)3 in heptane (1.73 mL, 3.5 mmol). [31,32]. The reaction
mixture was stirred during 1 h at room temperature. Then, a solu-
tion of ethyl 1,5-bis(4-chlorophenyl)pyrazole-3-carboxylate
8
80
75
Xray 4 mol 2
70
65
60
4.5. Preparation of methyl 1,5-bis(4-chlorophenyl)-1H-1,2,4-triazole-
3-carboxylate (4) (Scheme 5)
The title compound was obtained [33] by reaction of aroyl chlo-
ride 9 with 2-aminodimethylmalonate hydrochloride to give 10 in
74% yield. Diazotation of the 4-chloroaniline followed by reaction
with10affordedtheazointermediate11inhighyield, whichreacted
with sodium methanolate to produce the triazole methyl ester 4.
Product 4 was purified by FC (SiO2; EtOAc/n-hexane 1:3) and crystal-
lization(85%yield). Lightpink solid, mp:144–5 °C (2-Propanol);MS/
EI: m/z (%) = 349 [M+1]+ (47), 347(66), 210(62), 125(100). 1H NMR
(300 MHz, CDCl3): d = 7.45–7.42 (m, 4H), 7.36–7.31 (m, 4H), 4.04
(s, 3H, Me); 13C NMR (75 MHz, CDCl3): d = 160.0 (CO), 154.7 (C, tria-
zoleC3), 154.5(C, triazoleC5), 137.2 (C, para5-p-ClPh), 135.9 (C, para
1-p-ClPh), 135.7 (C, ipso 1-p-ClPh), 130.3 (CH, ortho 5-p-ClPh), 129.9
(CH, meta 1-p-ClPh), 129.1 (CH, meta 5-p-ClPh), 126.7 (CH, ortho 1-p-
ClPh), 124.8 (C, ipso 5-p-ClPh), 53.0 (CH3); elemental analysis calcd
(%) for C16H11Cl2N3O2 (347.02): C 55.19, H 3.18, N 12.07, found: C:
55.21; H: 3.46; N: 12.20.
55
Xray 4 mol 1
50
45
40
35
30
X-ray 3 mol 1
Calc 4
X-ray 3 mol 2
Calc 3
Calc 2
X-ray 2
0
10
20
30
40
50
60
Fig. 10. Calculated and experimental dihedral angles for molecules 2–4. The line
corresponds to /1 = (81 4) ꢁ (0.87 0.11) /5, n = 8, R2 = 0.92.

88
I. Alkorta et al. / Journal of Molecular Structure 920 (2009) 82–89
O
O
OH
O
EtONa
EtOH
OEt
OEt
+
EtO
O
O
Cl
Cl
7
R1
NHNH2
AcOH
O
O
CH3(CH2)15NH2
EtO
N
H
N
N
N
Al(CH3)3 / CH2Cl2
N
Cl
Cl
R1
Cl
2 R1 = H, 8 R1 = Cl
3
Scheme 4. Synthesis of pyrazoles 2 and 3 (from 8).
CO2Me
Cl
H3N
CO2Me
CO2Me
Cl
CONH
CONH
Cl
COCl
O
CO2Me
10 74%
9
, NaNO2
NH2
1) Cl
2)
NaOAc
N
OMe
N
CO2Me
N
Cl
N=N
Cl
Cl
NaOMe, MeOH
CO2Me
Cl
4
98%
11
84%
Scheme 5. Synthesis of triazole 4.
5. Crystallography
6. Computational methods
Data collection was performed on a Nonius Kappa CCD single
crystal diffractometer for compounds 2 and 3 and on a Xcalibur
The optimization of the geometries of the structures were first
*
carried out at the B3LYP/6-31G and then reoptimized at the
**
Nova single crystal diffractometer for compound 4, using Cu K
(k = 1.54180 Å) in all cases. The intensities of the three compounds
were measured using the CCD rotation images, and u scans. An
a
B3LYP/6-311++G computational level [45–50] within the Gauss-
ian-03 package [51] Frequency calculations at both levels were car-
ried out to confirm that the obtained structures correspond to
energy minima. GIAO absolute shieldings [52,53] were calculated
x
empirical method was used for the absorption correction in all
compounds. The crystal structures were solved by direct methods.
The refinements were performed using full-matrix least squares on
F2. All non-H atoms were anisotropically refined. All H atoms were
geometrically placed for the three compounds. For compound 2, H-
atoms parameters were mixed refined, that is, some parameters
were constrained refined while others parameters were indepen-
dent refined. For compounds 3 and 4, H-atoms parameters were re-
fined with constrained geometries.
Crystallographic calculations were made at the University of
Oviedo, on the X-ray group computers, using the following pro-
grams: Collect [34] for 2 and 3 data collection; CrysAlis CCD [35]
for 4 data collection; HKL Denzo and Scalepack [36] for 2 and 3 cell
refinement and data reduction; CrysAlis RED [35] for 4 cell refine-
ment and data reduction; SIR92 [37] for structure solutions; SHEL-
XL-97 [38] for structure refinements; XABS2 [39] for absorption
corrections; PARST97 [40] and PLATON [41] for the geometrical
calculations; ORTEP-3 for windows for molecular graphics [42]
and Wingx [43] publication routines to prepare material for publi-
cation [44].
**
on the B3LYP/6-311++G optimized geometries at the same com-
putational level.
Acknowledgements
This work was carried out with financial support from the Min-
isterio de Educación y Ciencia (Project No. CTQ2007-61901/BQU)
and Comunidad Autónoma de Madrid (Project MADRISOLAR, ref.
S-0505/PPQ/0225). Mario Alvarado acknowledges a grant from
RETICS RD06/001/0014 (Instituto de Salud Carlos III). SG-G grate-
fully acknowledges the financial support from MEC, projects
MAT2006-01997 and Consolider Ingenio-2010, ‘Factoría Española
de Cristalización’.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.molstruc.2008.10.020.

I. Alkorta et al. / Journal of Molecular Structure 920 (2009) 82–89
[27] T.S. Gardner, E. Wenis, J. Lee, J. Org. Chem. 26 (1961) 1514.
89
References
[28] I.L. Finar, R.J. Hurlock, J. Chem. Soc. (1958) 3259.
[29] W.T. Ashton, G.A. Doss, J. Heterocycl. Chem. 30 (1993) 307.
[30] W.V. Murray, M.P. Wachter, J. Heterocycl. Chem. 26 (1989) 1389.
[31] S.M. Weinreb, M. Lipton, A. Basha, Tetrahedron Lett. 48 (1977) 4171.
[32] P.H. Seeberger, T. Gustafsson, F. Pontén, Chem. Commun. (2008) 1100.
[33] J.H.M. Lange, H.H. van Stuivenberg, H.K.A.C. Coolen, T.J.P. Adolfs, A.C. McCreary,
H.G. Keizer, H.C. Wals, W. Veerman, A.J.M. Borst, W. de Looff, P.C. Verveer, C.G.
Kruse, J. Med. Chem. 48 (2005) 1823.
[1] S.M. Wright, C. Dikkers, J.J. Aronne, Curr. Atheroscler. Rep. 10 (2008) 71.
[2] J. Elguero, P. Goya, N. Jagerovic, A.M.S. Silva, Targets Heterocycl. Syst. 6 (2002) 52.
[3] N. Jagerovic, C. Fernández-Fernández, P. Goya, Curr. Topics Med. Chem. 8
(2008) 205.
[4] P. Goya, N. Jagerovic, Exp. Op. Ther. Pat. 10 (2000) 1529.
[5] P. Goya, N. Jagerovic, L. Hernández-Folgado, M.I. Martín, Mini Rev. Med. Chem.
3 (2003) 765.
[6] N. Jagerovic, L. Hernández-Folgado, I. Alkorta, P. Goya, M. Navarro, A. Serrano,
F. Rodríguez de Fonseca, M.T. Dannert, A. Alsasua, M. Suardíaz, D. Pascual, M.I.
Martín, J. Med. Chem. 47 (2004) 2939.
[7] N.E. Campillo, C. Montero, P. Goya, J.A. Paéz, Eur. J. Med. Chem. 40 (2005) 75.
[8] N. Jagerovic, L. Hernández-Folgado, I. Alkorta, P. Goya, M.I. Martín, M.T.
Dannert, A. Alsasua, J. Frigola, M.R. Cuberes, A. Dordal, J. Holenz, Eur. J. Med.
Chem. 41 (2006) 114.
[9] F.J. Pavón, A. Bilbao, L. Hernández-Folgado, A. Cipitelli, N. Jagerovic, G. Abellán,
M.I. Rodríguez-Franco, A. Serrano, M. Macias, R. Gómez, M. Navarro, P. Goya, F.
Rodríguez de Fonseca, Neuropharmacology 51 (2006) 358.
[10] V.M.L. Silva, A.M.S. Silva, D.C.G.A. Pinto, N. Jagerovic, L.F. Callado, J.A.S.
Cavaleiro, J. Elguero. Monatsch. Chem. 138 (2007) 797.
[11] F.J. Pavón, A. Serrano, V. Pérez-Valero, N. Jagerovic, L. Hernández-Folgado, F.J.
Bermúdez-Silva, M. Macías, P. Goya, F.R. de Fonseca, J. Neuroendocrin. 20
(2008) 116.
[12] CSD database version 5.28 (November 2006). Jan-07 and May-07 updates. F.H.
Allen, Acta Crystallogr. Sect. B 58 (2002) 380. F.H. Allen, W.D.S. Motherwell,
Acta Crystallogr. Sect. B 58 (2002) 407.
[13] I. Alkorta, M. Alvarado, J. Elguero, S. García-Granda, P. Goya, M.L. Jimeno, L.
Menéndez-Taboada, Eur. J. Med. Chem., in press.
[14] A. Alcade, G. Anne-Archard, C. Gavory. O. Monnier, United States Patent
20050043356, Publication Date: 02/24/2005.
[15] J.S. Babu, G.J. Chavan, C.H. Khanduri, Eur. Pat. Appl. EP 1816125 A1 8 Aug 2007.
Chem. Abstr. 147 (2007) 243166.
[16] V. Bolugoddu, V. Kotagiri, S. Kumar, S. Suthrapu, P. Kolkonda, R. Akula, A.
Bhimireddy, PCT Int. Appl. WO 2007103711 A2 13 Sep 2007. Chem. Abstr. 147
(2007) 350666.
[17] H.M.H. Huang, C.G. Huang, US Pat. Appl. Publ. US 2008004313 A1 3 Jan 2008.
Chem. Abstr. 148 (2008) 106211.
[18] P. Reddy, R. Reddy, R. Reddy, M. Reddy, S. Chander Reddy, WO/2008/026219.
[19] S. Berger, S. Braun, 200 and More NMR Experiments: A Practical Course, Wiley-
VCH, Weinheim, 2004.
[20] M. Begtrup, J. Elguero, R. Faure, P. Camps, C. Estopa, D. Ilavsky, A. Fruchier, C.
Marzin, J. de Mendoza, Magn. Reson. Chem. 26 (1988) 134.
[21] M. Begtrup, G. Boyer, P. Cabildo, C. Cativiela, R.M. Claramunt, J. Elguero, J.I.
Garcia, C. Toiron, P. Vedsø, Magn. Reson. Chem. 31 (1993) 107.
[22] I. Alkorta, J. Elguero, Struct. Chem. 14 (2003) 377.
[23] F. Blanco, I. Alkorta, J. Elguero, Magn. Reson. Chem. 45 (2007) 797.
[24] R.M. Claramunt, C. López, M.A. García, M.D. Otero, M.R. Torres, E. Pinilla, S.H.
Alarcón, I. Alkorta, J. Elguero, N. J. Chem. 25 (2001) 1061.
[25] A. Frideling, R. Faure, J.-P. Galy, A. Kenz, I. Alkorta, J. Elguero, Eur. J. Med. Chem.
39 (2004) 37.
[34] Collect, Bruker AXS BV, 1997–2004.
[35] Oxford Diffraction (2006). CrysAlis CCD and CrysAlis RED. Version 1.171.31.5
(release 28-08-2006 CrysAlis171.NET) (compiled Aug 28, 2006, 13:05:05).
Oxford Diffraction Ltd., Abingdon, Oxfordshire, England.
[36] Z. Otwinowski, W. Minor, Methods Enzymol. 276 (1997) 307–326.
[37] A. Altamore, G. Cascarano, C. Giacovazzo, A. Guagliardi, M.C. Burla, G. Polidori,
M. Camalli, J. Appl. Cryst. 27 (1994) 435.
[38] G.M. Sheldrick. SHELXL-97. Univ. of Gottingen.
refinement of crystal structures, 1997.
A computer program for
[39] S. Parkin, B. Moezzi, H. Hope, J. Appl. Crystallogr. 28 (1995) 53.
[40] M. Nardelli, Comput. Chem. 7 (1983) 95–98.
[41] A.L. Spek, PLATON. A Multipurpose Crystallographic Tool, Utrecht University,
Utrecht, The Netherlands, 2001.
[42] L.J. Farrugia, J. Appl. Cryst 30 (1997) 565.
[43] L.J. Farrugia, J. Appl. Cryst. 32 (1999) 837–838.
[44] The crystallographic data (excluding structure factors) for the structures of
compounds 2, 3 and 4 has been deposited at the Cambridge Crystallographic
Data Centre as supplementary publications numbers CCDC 664037, 664038 &
700182. Copies for the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: C44 1223 336033 or e-
mail: deposit@ccdc.cam.ac.uk].
[45] A.D. Becke, Phys. Rev. A 38 (1988) 3098.
[46] A.D. Becke, J. Chem. Phys. 98 (1993) 5648.
[47] C. Lee, W. Yang, R.G. Parr, Phys. Rev. B 37 (1988) 785.
[48] P.A. Hariharan, J.A. Pople, Theor. Chim. Acta 28 (1973) 213.
[49] R. Ditchfield, W.J. Hehre, J.A. Pople, J. Chem. Phys. 54 (1971) 724.
[50] M.J. Frisch, J.A. Pople, R. Krishnam, J.S. Binkley, J. Chem. Phys. 80 (1984)
3265.
[51] Gaussian 03, M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R.
Cheeseman, J.A. Montgomery Jr., T. Vreven, K.N. Kudin, J.C. Burant, J.M. Millam,
S.S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega,
G.A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J.
Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li,
J.E. Knox, H.P. Hratchian, J.B. Cross, C. Adamo, J. Jaramillo, R. Gomperts, R.E.
Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, P.Y.
Ayala, K. Morokuma, G.A. Voth, P. Salvador, J.J. Dannenberg, V.G. Zakrzewski, S.
Dapprich, A.D. Daniels, M.C. Strain, O. Farkas, D.K. Malick, A.D. Rabuck, K.
Raghavachari, J.B. Foresman, J.V. Ortiz, Q. Cui, A.G. Baboul, S. Clifford, J.
Cioslowski, B.B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R.L.
Martin, D.J. Fox, T. Keith, M.A. Al-Laham, C.Y. Peng, A. Nanayakkara, M.
Challacombe, P.M.W. Gill, B. Johnson, W. Chen, M.W. Wong, C. Gonzalez, J.A.
Pople, Gaussian Inc., Pittsburgh, PA, 2003.
R. Ditchfield, Mol. Phys. 27 (1974) 789.
[52]
[53] F. London, J. Phys. Radium 8 (1937) 397.
[26] S. Trofimenko, G.P.A. Yap, F.A. Jove, R.M. Claramunt, M.A. García, M.D. Santa
María, I. Alkorta, J. Elguero, Tetrahedron 63 (2007) 8104.