Preparation and crystal structure determination of adducts of copper(II) chloride with 3-aryl-1-(imino-pyridin-2-yl-methyl)-5-hydroxy-5-trifluoromethyl-4,5-dihydro -1H-pyrazoles

Article abstract of DOI:10.1016/S1387-7003(03)00073-X

1,1,1-Trifluoro-4-methoxy-4-aryl-but-3-en-2-ones react with 2-pyridylcarboxamidrazone to produce the corresponding 1,1,1- trifluoro-4-aryl-4-(N¹-pyridine-2-carboxamidrazone)-3-buten-2- ones. The butenones react with copper(II) chloride to give

Full text of DOI:10.1016/S1387-7003(03)00073-X

Inorganic Chemistry Communications 6 (2003) 646–649
www.elsevier.com/locate/inoche
Preparation and crystal structure determination of adducts
of copper(II) chloride with 3-aryl-1-(imino-pyridin-2-yl-methyl)-
5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-pyrazoles
ꢀ
Helio G. Bonacorso, Ernesto S. Lang, Hilario Lewandowski, Marcos A.P. Martins,
*
Clovis Peppe , Nilo Zanatta
´
Lab de Materials Inorganicos, Departamento de Quımica, Universidade Federal de Santa Maria, Campus UFSM, Santa Maria-RS 97105-900, Brazil
Received 20 January 2003; accepted 11 February 2003
Abstract
1,1,1-Trifluoro-4-methoxy-4-aryl-but-3-en-2-ones react with 2-pyridylcarboxamidrazone to produce the corresponding 1,1,1-
trifluoro-4-aryl-4-(N1-pyridine-2-carboxamidrazone)-3-buten-2-ones. The butenones react with copper(II) chloride to give 1:1
adducts, in which the donor molecules were shown to isomerize to their cyclic pyrazolic forms. The crystal structure of the 4-fluoro-
phenyl derivative, dichloro-[3-(4-fluorophenyl)-1-(imino-pyridin-2-yl-methyl)-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-pyraz-
ole]-copper(II), was solved by X-ray crystallography. The structural results are compared with those of other copper(II) chloride
adducts of similar ligands containing the amidrazone pharmacophore, which have been tested as anticancer drugs.
Ó 2003 Elsevier Science B.V. All rights reserved.
Keywords: Amidrazone pharmacophore; Dihydropyrazoles; Copper complex; Crystal structure determination
Recent studies have demonstrated the anticancer ac-
tivity of some compounds containing the amidrazone
pharmacophore, such as thiosemicarbazones [1] and 2-
pyridylcarboxamidrazones [2,3]. A significant enhance-
ment on the biological activity of these compounds is
achieved [1–3] upon complexation with a suitable metal
ion, particularly copper(II). Therefore, research on the
preparation of other structurally related compounds and
their copper complexes is of great relevance. With this in
mind, we have set up to study the reaction between 2-
pyridylcarboxamidrazone, 1 with b-methoxyvinyl tri-
fluoromethyl ketones, 2. The coordination chemistry of
the products derived from this reaction, 3 with cop-
per(II) chloride was also investigated (Scheme 1).
products were obtained [4]. We have determined now
that 2 react with 1 in dichloromethane leading to the
corresponding substitution products, 3 (Table 1).
Molecular formulae for 3 were derived from micro-
analysis (C, H, N) and confirmed by mass spectrometry.
It is difficult to assign the NMR spectra of compounds 3
due to the following facts: b-aminovinyltrifluoromethyl
ketones show, in solution, a dynamic equilibrium be-
tween their E and Z isomers [4]; for both isomers it is
possible to detect, in the NMR time scale, different ro-
tamers resulting from rotation around the vinylic car-
bon–N bond [5]; and finally compounds 3 are known to
undergo isomerization to 5-hydroxy-5-trifluoromethyl-
4,5-dihydropyrazoles [6] (Scheme 2). Accordingly, we
1
b-Alkoxyvinyl trifluoromethyl ketones, 2 react with
ammonia, primary amines and anilines to produce the
corresponding b-aminovinyltrifluoromethyl ketones in
good yields [4,5]; with diamines, the N; N-diamino
noted very complex patterns in the Hand 13C NMR
spectra of compounds 3a–e; especially the 13C NMR
spectra that contain a number of carbon resonances far
superior than the number predicted by the correspond-
ing b-amidrazonetrifluoromethyl ketone structure. For
some compounds there are two quartets at ca. 172 and 94
ppm (J ¼ 30–35 Hz), which have been assigned, respec-
tively, to the carbonyl CðOÞCF3 and to the carbinolic
* Corresponding author. Tel.: +55-55-220-8868; fax: +55-55-220-
8031.
E-mail address: peppe@quimica.ufsm.br (C. Peppe).
1387-7003/03/$ - see front matter Ó 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S1387-7003(03)00073-X

H.G. Bonacorso et al. / Inorganic Chemistry Communications 6 (2003) 646–649
647
Scheme 1.
Table 1
Preparative,a physical and analytical data for 3a–e
Product
Yieldb (%)
Melting point (°C)c
% Found (calcd)
C
MþÅ (g molÀ1
)
H
N
3a C16H13F3N4O
3b C17H15F3N4O
3c C17H15F3N4O2
3d C16H12F4N4O
3e C16H12ClF3N4O
80
87
83
84
82
118–120
148–150
139–141
105–107
146–149
57.58 (57.48)
58.58 (58.62)
3.97 (3.89)
4.52 (4.34)
16.96 (16.76)
15.96 (16.08)
334
348
364
352
368d
–
–
–
–
52.13 (52.12)
–
3.66 (3.28)
–
15.51 (15.19)
a Representative example for 3a: equimolar amounts of 2-pyridylcarboxamidrazone and 1,1,1-trifluoro-4-methoxy-4-phenyl-3-butene-2-one (2
mmol) were dissolved in 10 ml of CH2Cl2, and the solution was kept under reflux for 3 h (TLC), after which all the solvent was removed under
reduced pressure and the residue was recrystallized from cyclohexane; 3a was isolated in 80% of yield.
b Isolated yield.
c Uncorrected.
d For 35Cl.
carbon CðOHÞCF3 substituents in related vinyl trifluo-
romethyl ketones [6] and 5-hydroxy-5-trifluoromethyl-
4,5-dihydropyrazoles [7] derivatives. This suggests the
cyclization to some extent of compounds 3, in DMSO-
d6 solution, to their corresponding cyclic pyrazole de-
rivatives, 30 (Scheme 2).
The infrared spectra of 3a–e, in KBr pellets, show a
set of 3 (or 4) absorption bands from 3338 to 3676
cmÀ1, which can be attributed to N–Hstretching
modes and a strong absorption in the range 1625–1660
cmÀ1 arising from a conjugated carbonyl stretching
mode.
Scheme 2.

648
H.G. Bonacorso et al. / Inorganic Chemistry Communications 6 (2003) 646–649
The reaction between (E)-1,1,1-trifluoro-4-ethoxy-3-
buten-2-one with 1 Eq. (1) produced the related
(Z)-1,1,1-trifluoro-4-(N1-pyridine-2-carboxamidrazone)-
3-buten-2-one, 3f, which was fully characterized by an-
alytical [yellow solid (mp 168–170 °C); calculated % for
C10H9F3N4O: C, 46.52; H, 3.51; N, 21.70; found: C,
46.81; H, 3.66; N, 21.62] and spectroscopic means [MþÅ
(70 eV) ¼ 258 g molÀ1; 1HNMR (CDCl ; d): 5.68 (1H,
3
d, 8Hz), 6.13 (2H, s, br), 7.49 (1H, m), 7.89 (2H, m), 8.27
(1H, d, 8 Hz), 8.69 (1H, d, 4.2 Hz), 13.19 (1 H, s, br);
and 13C NMR (DMSO-d6, d): 86.71, 117.97 (q, 290 Hz),
121.05, 125.35, 137.22, 147.63, 148.33, 149.16, 149.40,
174.82 (q, 30.9 Hz)]. Contrasting to 3a–e
ꢁ
Fig. 1. ORTEP representation of 4d. Bond distances (A): Cu–Cl(1)
2.259(1); Cu–Cl(2) 2.309(1); Cu–Cl(2#) 2.644(1); Cu–N(1) 1.946(4);
Cu–N(12) 2.033(3); N(1)–C(1) 1.268(5); N(2)–C(1) 1.374(5); C(1)–
C(11) 1.503(5). Bond angles (°): Cl(1)–Cu–Cl(2) 93.04(5); Cl(1)–Cu–
Cl(2#) 100.05(5); Cl(1)–Cu–N(1) 163.3(1); Cl(1)–Cu–N(12) 94.9(1);
Cl(2)–Cu–Cl(2#) 95.84(4); Cl(2)–Cu–N(1) 90.5(1); Cl(2)–Cu–N(12)
166.0(1); Cl(2#)–Cu–N(1) 95.8(1); Cl(2#)–Cu–N(12) 94.0(1); N(1)–
Cu–N(12) 78.6(2); Cu–N(12)–C(11) 115.3(3); N(12)–C(11)–C(1)
110.6(4); N(1)–C(1)–C(11) 114.2 (4); Cu–N(1)–C(1) 119.2(3).
ð1Þ
NMR spectroscopy established, for 3f, a rigid struc-
ture in solution. Its infrared spectrum contains the same
general features observed for 3a–e, including the set of
three N–Hstretching absorptions and the carbonyl
stretching at 1665 cmÀ1, suggesting for 3a–e the b-
amidrazonetrifluoromethyl ketone structure, in the solid
state.
Equimolar amounts of compounds 3 and copper(II)
chloride react, in refluxing ethanol, to give the
corresponding [3-aryl-1-(imino-pyridin-2-yl-methyl)-5-
hydroxy-5-trifluoromethyl-4,5-dihydro-1H-pyrazole]-di-
chloro-copper(II) adduct, 4 (Table 2). The products
spontaneously precipitate on cooling the solution and
suitable crystals for X-ray analysis were grown follow-
ing this procedure.
The molecular formulae for the copper complexes
4a–e were derived from microanalysis. The infrared
spectra of 4a–e show the same general features (a single
sharp absorption in the range 3363–3413 cmÀ1; and two
strong absorptions at ca. 1610 and 1570 cmÀ1), sug-
gesting the same general structure for 4a–e. The structure
was confirmed by resolution of the crystal structure of
the p-fluoro-phenyl derivative, 4d by X-ray methods [8].
Fig. 1 shows an ellipsoid representation of the com-
plex, in which ligand 3d is coordinated to the metal
center using its cyclic form 3d0. The ligand acts as a
bidentate donor using the pyridine and the imine ni-
trogen atoms. The geometrical arrangement around the
copper ion is a distorted square planar pyramid. The
square basis is made of the copper central atom, two
chlorines and the two coordinating nitrogens of the li-
gand. The sum of the angles around the central ion is
357.1° at the basis. The largest deviation from the least
ꢁ
squares mean plane of 0.194 A was observed for Cu. An
intermolecular interaction between the copper atom and
a chloride ligand of a second molecule that constitutes
ꢁ
the unit cell [Cu–Cl(2#) ¼ 2.644 A] completes the
penta-coordinated arrangement around the copper
atom. The two Cu–Cl bond distances of 2.259(1) and
ꢁ
2.309(1) A at the square basis are within the range of
ꢁ
2.23–2.32 A observed for other tetra-coordinated square
planar and penta-coordinated square planar pyramidal
copper complexes of ligands containing the pyridine-2-
Table 2
Preparative,a physical and analytical data for 4a–e
Product
Yieldb (%)
Melting point (°C)c
Found (calcd)
C
H
N
4a C16H13Cl2CuF3N4O
4b C17H15Cl2CuF3N4O
4c C17H15Cl2CuF3N4O2
4d C16H12Cl2CuF4N4O
4e C16H12Cl3CuF3N4O
47
44
63
54
81
207–210
211–214
212–215
206–209
213–216
40.98 (41.00)
42.56 (42.29)
41.03 (40.94)
37.87 (39.48)
38.32 (38.19)
2.77 (2.80)
3.40 (3.13)
3.26 (3.03)
3.79 (2.48)
2.18 (2.40)
11.95 (11.95)
11.37 (11.61)
11.22 (11.23)
11.25 (11.51)
11.15 (11.13)
a Representative example for 4a: equimolar amounts of 3a and CuCl2 ꢀ 2H2O (2 mmol) were refluxed in 10 ml of anhydrous ethanol for 2 h;
product 4a spontaneously crystallizes from the solution upon cooling, it was filtered, washed with CH2Cl2 and dried under vacuo.
b Isolated yield.
c Uncorrected.

H.G. Bonacorso et al. / Inorganic Chemistry Communications 6 (2003) 646–649
649
[2] N. Gokhale, S. Padhye, D. Rathbone, D. Billington, P. Lowe,
C. Schwalbe, C. Newton, Inorg. Chem. Commun. 4 (2001)
26–29.
carboxamidrazone moiety [2,3]. Similar Cu–N bond
ꢁ
distances between 4d (1.946 and 2.033 A) and these
ꢁ
complexes (from 1.992 to 2.038 A) were also observed.
[3] N.H. Gokhale, S.S. Padhye, S.B. Padhye, C.E. Anson, A.K.
Powell, Inorg. Chim. Acta 319 (2001) 90–94.
There seems to be no doubt that copper complexes of
amidrazone ligands improve the intracellular transpor-
tation of the active drug against certain melanoma cells
[10], and we hope that the new ligands and their copper
(II) complexes described here contribute for a combi-
natorial library of amidrazone complexes of copper
aiming to determine the most potent drug and its action
pathway as an anticancer agent.
[4] I.I. Gerus, M.G. Gorbunova, S.I. Vdovenko, Y. Yl, V.P. Kukhar,
Zhur. Org. Khim. 26 (1990) 1877–1883.
[5] N. Zanatta, A.M.C. Squizani, L. Fantinel, F.M. Nachtigall,
H.G. Bonacorso, M.A.P. Martins, Synthesis (2002) 2409–
2415.
[6] H.G. Bonacorso, A.P. Wentz, S.R.T. Bittencourt, L.M.L. Mar-
ques, N. Zanatta, M.A.P. Martins, Synth. Commun. 32 (2002)
335–341.
[7] H.G. Bonacorso, A.D. Wastowski, M.N. Muniz, N. Zanatta,
M.A.P. Martins, Synthesis (2002) 1079–1083.
ꢂ
[8] Crystal data for C6H12Cl2CuF4N4O, 4d: triclinic P1, a ¼ 7:295ð1Þ,
Acknowledgements
b ¼ 9:739ð2Þ, c ¼ 13:734ð3Þ, a ¼ 88:388ð4Þ, b ¼ 87:646ð4Þ, c ¼
ꢁ3
78:913ð4Þ, V ¼ 956:6ð3ÞA , Z ¼ 2. Bruker SMART CCD, Mo-Ka
ꢁ
radiation (k ¼ 0:71073 A), T ¼ 293ð2Þ K, 5532 reflections mea-
The authors gratefully acknowledge FAPERGS-RS
(Brazil) for financial support.
sured, 3854 independent, 301 parameters. Structure solution and
refinement: Shelxs97, Shelx197 [9], R1 ¼ 0:1231, wR2 ¼ 0:0824.
Further details have been deposited with the Cambridge Crystal-
lographic Data Centre under the deposition number CCDC
197185.
References
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Refinement of Crystal Structures, University of Gottingen,
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