Naphthoquinoidal [1,2,3]-triazole, a new structural moiety active against Trypanosoma cruzi

Article abstract of DOI:10.1016/j.ejmech.2007.10.015

[1,2,3]-Triazole derivatives of nor-β-lapachone were synthesized and assayed against the infective bloodstream trypomastigote form of Trypanosoma cruzi, the etiological agent of Chagas disease. All the derivatives were more active than the original quinones, with IC₅₀/1 day values in the range of 17 to 359 μM, the apolar phenyl substituted triazole 6 being the most active compound. These triazole derivatives of nor-β-lapachone emerge as interesting new lead compounds in drug development for Chagas disease.

Full text of DOI:10.1016/j.ejmech.2007.10.015

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 1774e1780
http://www.elsevier.com/locate/ejmech
Short communication
Naphthoquinoidal [1,2,3]-triazole, a new structural
moiety active against Trypanosoma cruzi
a
b
c
Eufr aˆ nio N. da Silva Jr. , Rubem F.S. Menna-Barreto , Maria do Carmo F.R. Pinto ,
c
c
a
Raphael S.F. Silva , Daniel V. Teixeira , Maria Cec ´ı lia B.V. de Souza ,
d
b,
a
c
Carlos Alberto De Simone , Solange L. De Castro *, Vitor F. Ferreira , Ant oˆ nio V. Pinto
a
Departamento de Qu ´ı mica Org aˆ nica, Instituto de Qu ´ı mica, UFF, Campus do Valouguinho, 24020-150, Niter o´ i, RJ, Brazil
b
Laborat o´ rio de Biologia Celular, Instituto Oswaldo Cruz, FIOCRUZ, Av. Brasil 4365, Manguinhos, 21045-900, Rio de Janeiro, RJ, Brazil
c
N u´ cleo de Pesquisas em Produtos Naturais, UFRJ, 21944-971, Rio de Janeiro, RJ, Brazil
d
Instituto de Qu ´ı mica e Biotecnologia, UFAl, Tabuleiro do Martins, 57072-970 Macei o´ , Alagoas, Brazil
Received 25 June 2007; received in revised form 1 October 2007; accepted 11 October 2007
Available online 22 October 2007
Abstract
1,2,3]-Triazole derivatives of nor-b-lapachone were synthesized and assayed against the infective bloodstream trypomastigote form of
[
Trypanosoma cruzi, the etiological agent of Chagas disease. All the derivatives were more active than the original quinones, with IC50/1 day
values in the range of 17 to 359 mM, the apolar phenyl substituted triazole 6 being the most active compound. These triazole derivatives of
nor-b-lapachone emerge as interesting new lead compounds in drug development for Chagas disease.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Chagas disease; Trypanosoma cruzi; Chemotherapy; [1,2,3]-Triazoles; Naphthoquinones
1
. Introduction
two drugs nitroheterocycles, benznidazole and nifurtimox.
Their use to treat the acute phase of the disease is widely ac-
cepted, while the treatment of the chronic phase is controver-
sial [3]. The undesirable side effects of both drugs have
a major drawback in their uses, frequently forcing the aban-
donment of the treatment [4].
In this context, an intensive research program has been fo-
cused upon the search for alternative natural, semi-synthetic
and synthetic drugs. Among several naturally occurring qui-
nones, emerge the naphthoquinones with a broad distribution
in the plant kingdom and involved in oxidative processes
such as photosynthesis and electron transfer reactions [5]. In
folk medicine, plants containing naphthoquinones have been
employed for the treatment of many diseases, especially
among Indian populations [6]. The involvement of quinones
in numerous biochemical processes has led to the study of
a wide variety of their synthetic derivatives. The facile reduc-
tioneoxidation of the quinone moiety appears to be the basis
for the participation of a number of different quinones in elec-
tron transport and oxidative-phosphorylation processes.
Chagas’ disease, caused by the parasite Trypanosoma cruzi,
is endemic in Latin America [1]. The infection is transmitted
by triatomine insects while blood feeding on a human host.
The trypomastigote form ingested by the vector via the blood
of an infected individual differentiates into epimastigote form,
which, after proliferation, reaches the posterior intestine and
differentiates into metacyclic trypomastigote. This latter infec-
tive form, following invasion of vertebrate cells, undergoes
differentiation into amastigote, which, after several reproduc-
tive cycles, transforms into trypomastigote, responsible for
the dissemination of the infection. Acute infections are usually
asymptomatic, but the ensuing chronic T. cruzi infections have
been associated with high ratios of morbidity and mortality
[
2]. Currently, treatment is unsatisfactory, being limited to
*
Corresponding author. Tel.: þ55 21 2598 4330; fax: þ55 21 2598 4577.
E-mail address: solange@ioc.fiocruz.br (S.L. De Castro).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.10.015

E.N. da Silva Jr. et al. / European Journal of Medicinal Chemistry 43 (2008) 1774e1780
1775
The biological activities of the naphthoquinone lapachol
extracted from the heartwood of trees of the genus Tabebuia
cycloaddition reaction [23] between substituted acetylenes
and an alkyl azide derivative. This reaction originates two re-
gioisomers, 1,4- and 1,5-triazoles. However, recently it was
demonstrated that copper(I) salt’s regioselectivity promotes
formation of the 1,4-triazole adduct. The improvement for
this reaction was reported independently by the groups of
Sharpless and Meldal [24] demonstrating that it can be car-
ried out at room temperature in aqueous media under cop-
per(I) catalysis.
[1,2,3]-Triazoles are an important class of heterocyclic
compounds due to their wide range of activities such as anti-
platelet agents [25], dopamine D2 receptor ligands related to
schizophrenia [26], anticonvulsants [27], anti-inflammatory,
anti-allergic [28], antiviral [29] and antimicrobial agents [30].
Structure of 4 was confirmed by X-ray diffraction (Fig. 1).
All the interatomic distances and angles are within the ex-
pected values for similar chemical bondings [31].
(
Bigoniaceae) and its cyclization product, b-lapachone, have
been intensively studied [7]. Previous work of our group
showed the activity of new heterocyclic naphthoimidazole de-
rivatives obtained from the reaction of naphthoquinones with
amino-compounds [7e13]. Recently, our group also reported
the synthesis and trypanocidal activity of new naphthofuran-
quinones [14] and of heterocyclic oxyranes [15,16]. Continu-
ing our studies on the chemical reactivity of quinones from
the Brazilian flora, we now focus on the search of compounds
with naphthofuranquinoidal endowed linked to a triazolic
moiety. We synthesized and characterized five derivatives of
nor-lapachol (1), and assayed their activity against infective
bloodstream forms of T. cruzi.
The triazolic nucleus and the naphthoquinone ring are moi-
eties with independent biological activities [5,17e19] and in
this context the Huisgen cyclization under copper catalysis
was employed in the present work for the obtention of naph-
thoquinones coupled to 1,4-triazolic nuclei and analysis and
their potential trypanocidal activity was evaluated.
The naphthoquinonic ring is planar with maximum devia-
˚
tion for C6 [0.022(2) A]. The distances of atoms O1 and
C12 of furan ring to the average reference plane are
˚
0.012(3) A and 0.006(2) A, respectively. Atoms O2 and O3
˚
˚
are practically inside this plane with distances of 0.002(4) A
˚
and 0.012(2) A, respectively. The furan ring adopts a pure
2
. Chemistry
envelope conformation with Puckering parameters [q ¼
2
˚
ꢀ
Lapachol was extracted in large scale from the heartwood
of Tabebuia sp. and purified by a series of recrystalizations, as
previously described [20]. Nor-lapachol (1, 2-hydroxy-3-(2 -
methyl-1-propenyl)-1,4-naphthoquinone) was obtained from
0.006(1) A and 4 ¼ 292(1) ]. Atoms C12, C15, O4 and atoms
of the triazole ring are all inside of the same plane of least
˚
squares with maximum distances for O4 [0.1215(4) A]. The
0
dihedral angle between this least squares plane and that of
ꢀ
lapachol by Hooker oxidation, and bromo-b-nor-lapachone
2, 3-bromo-2,2-dimethyl-2,3-dihydro-naphtho[1,2-b]furan-4,
-dione) was prepared through cyclization of 1 with bromine
the naphthoquinonic ring is 89.47 . In the crystal structure
packing molecules interact through strong intermolecular
(
5
O4eH11/N2 hydrogen bond [symmetry code: (x ꢁ 1,y,z)
˚
in chloroform. From 2, through nucleophilic substitution with
sodium azide in dichloromethane was obtained the azide (3, 3-
azido-2,2-dimethyl-2,3-dihydro-naphtho[1,2-b]furan-4,5-dione),
the key intermediate for the synthesis of quinones coupled to
the triazolic nucleus, employing 1,3-dipolar reaction between
the azidoquinone and an alkyne, catalyzed by Cu(I), known as
with O4/N2 ¼ 2.890(4), H11/N2 ¼ 1.899(3) A and O4e
ꢀ
H11/N2 ¼ 156(2) , forming a network (Fig. 2).
In order to analyze the role of the triazole substitution pat-
tern on the furan ring moiety of 3, it was planned to prepare
compounds 4e8, whose structures are dependent on the avail-
able alkynes: (a) triazoles containing polar groups (4, 5 and 7);
(b) a derivative containing an aromatic apolar group, such as
(6) and (c) a triazole possessing a polar group (8).
‘‘click chemistry’’. Through this type of reaction, the naphtho-
quinoidal triazoles 4e8 were obtained and their physical and
spectroscopic data are in agreement with the structures de-
picted in Scheme 1. The atoms of carbons present in mole-
cules 3 and 4e8 were differentiated using the spectra of
The triazolic quinones 4, 5 and 7 present a hydroxyl group
(leaving group), susceptible to elimination as exemplified in
the Scheme 2, by elements of the biological milieu, including
blood components, leading to the formation of an ammonium
salt, suggesting a detoxification mechanism reducing the con-
centration (bioavailability) of the original compound and con-
sequently leading to lower trypanocidal activity. Compound 8
being a hemiacetal could be hydrolyzed in aqueous medium
leading to the generation of an intermediate with chemical
characteristics similar to 4, 5 and 7. On the other hand, the
most active compound, 6, does not present such a leaving
group, not suffering similar detoxification reaction and, due
to its higher lipophylic character when compared with the
other triazoles, could display a better penetration through the
parasite’s plasma membrane.
1
3
C-APT (attached proton test), where the carbons CH and
CH are positive phases and C (quaternary) and CH are neg-
ative phases. The regioselectivity of the reactions was fully as-
3
2
certained through X-ray crystallography study of derivative 4.
3
. Results and discussion
1,2,3]-Triazoles have gained increasing attention in drug
[
discovery since the introduction of the concept of ‘‘click’’
chemistry by Sharpless [21,22]. This kind of substances can
actively participate in hydrogen bonding and dipoleedipole
interactions due to their strong dipole moments, being ex-
tremely stable to hydrolysis and oxidative/reductive condi-
tions. Several different procedures have been described for
their synthesis, but the most suitable method is the 1,3-dipolar
The activity of these triazoles against trypomastigote forms
of T. cruzi is shown in Table 1. All the derivatives were more
active than the original quinone, nor-lapachol, being the IC /1
5
0

1776
E.N. da Silva Jr. et al. / European Journal of Medicinal Chemistry 43 (2008) 1774e1780
O
O
O
OH
O
Br2
CHCl3
Br
O
2
1
NaN3
CH Cl2
2
O
O
O
OH
O
O
O
O
O
O
O
OH
CuSO .5H O
CuSO4.5H2O
Na-ascorbate
N
4
2
N
N3
N
Na-ascorbate
CH2Cl2/H2O
N
N
N
CH Cl /H O
O
O
2
2
2
8
4
3
O
HO
OH
CuSO .5H O
4
2
CuSO .5H O
4
2
CuSO .5H O
4 2
Na-ascorbate
CH Cl /H O
Na-ascorbate
Na-ascorbate
CH Cl /H O
2
2
2
CH Cl /H O
2
2
2
2
2
2
O
O
O
O
OH
O
O
HO
N
N
N
N
N
N
N
N
N
7
5
6
O
O
O
5
´
4´
2´
O
6´
4
3´
6
5
a
O
5
7
8
5
4
1´
3a
9
a
N
N
9b
3
9
1
3
N
2
2
O
1
11
10
Scheme 1. Synthesis of the naphthoquinoidal triazoles obtained through 1,3-dipolar reaction with the azide intermediate 3.
day values in the range of 17e359 mM. Among them, the
triazole 6 is the most active one. Statistical analysis showed
the following order of decreasing activity ( p < 0.05): 6 > 3 ¼
7
> 4 > 8 > 5. In the same experimental condition, the IC /1
50
day value for crystal violet, the standard drug, is 536.0 ꢂ
3
.0 mM [8] and for benznidazole 103.6 ꢂ 0.6.
Compounds 3 and 4e8 were synthesized and assayed
against the infective bloodstream trypomastigote form of
T. cruzi. All the derivatives were more active than the original
quinone, with IC /1 day values in the range of 17e359 mM,
5
0
showing that the triazolic nucleus acted in the increase of
the biological activity, the apolar substituted triazole 6 being
the most active. These triazole derivatives of nor-b-lapachone
emerge as interesting new lead compounds in drug develop-
ment for the treatment of Chagas disease.
Fig. 1. Projection ORTEP-3 of triazole 4.

E.N. da Silva Jr. et al. / European Journal of Medicinal Chemistry 43 (2008) 1774e1780
1777
Fig. 2. Packing diagram showing the H-bonding.
4
. Experimental protocols
(130 mg, 2 mmol) was added as a solid and stirred overnight.
The azide-quinone was removed by filtration and dried at
room temperature to produce 3 (269 mg, 1 mmol, 100% yield)
Melting points were determined on a Reichert micro hot
ꢀ
1
stage and are uncorrected. Analytical grade solvents were
used. The solvents were previously purified as described in
the literature [32]. Column chromatography was performed
on silica gel (Acros Organics 0.035e0.070 mm, pore diameter
ca 6 nm). Infrared spectra were recorded on a PerkineElmer
FT-IR Spectrometer. H NMR and C NMR spectra were
recorded at room temperature using a Varian Unity Plus 300
instrument, in the solvents indicated, with TMS as internal
standard. Chemical shifts (d) are given in ppm and coupling
constants (J ) in Hertz. High-resolution electron-impact mass
spectra (70 eV) were obtained using a MAT8500 instrument.
The main fragments were described as a relation between
atomic mass units and the charge (m/z) and the relative abun-
dance in percentage of the base peak intensity.
as an orange solid (mp 200e202 C). H NMR (300 MHz,
CDCl ) d: 8.14 (1H, ddd, J ¼ 6.9, 2.1, 0.9), 7.72e7.65 (3H,
3
1
m), 4.77 (1H, s), 1.67 (3H, s), 1.55 (3H, s). C NMR
3
(75 MHz, CDCl ) d: 180.3 (CaO), 175.2 (CaO), 170.2 (C ),
3
0
134.5 (CH), 132.7 (CH), 131.1 (C ), 113.5 (C ), 129.5 (CH),
0
0
1
13
125.1 (CH), 126.7 (C ), 95.5 (C ), 67.3 (CH), 27.1 (CH ),
0
0
3
21.9 (CH ). IR (film) n
3
1655 (CaO), 1644 (CaO), 2109
max
ꢁ
1
(N ) cm . EI-HRMS (70 eV, m/z) 269.08000. Calcd for
3
C H O N : 269.08004; (%) 227 (100), 199 (18), 104 (14),
1
4 11 3 3
173 (8), 76 (10), 42 (6), 50 (4), 269 (2), 181 (3), 157 (5),
128 (6).
4.2. General procedure for the synthesis of 4 to 8
Compound 3 (223.4 mg, 0.83 mmol) in 12 mL CH Cl /
2
2
4
.1. Synthesis of 3-azido-2,2-dimethyl-2,3-dihydro-
H O 1:1 is reacted with CuSO $5H O (9.3 mg, 0.04 mmol)
2 4 2
naphtho[1,2-b]furan-4,5-dione (3)
and sodium ascorbate (22 mg, 0.11 mmol) and the desired
substituted alkyne (see below). The mixture was maintained
under agitation at room temperature till the total formation
of the product, monitored by thin layer chromatography. The
organic phase was extracted with dichloromethane, dried
A solution of 1 (228 mg, 1 mmol) in 25 ml of dichlorome-
thane and 2 ml bromine (26 mg, 38 mmol) was stirred until an
orange precipitate was formed. To this mixture, sodium azide
+
O
O
OH
O
O
N
N
N
N
N
N
O
O
Scheme 2. Mechanism of formation of cationic species in compound 4.

1778
E.N. da Silva Jr. et al. / European Journal of Medicinal Chemistry 43 (2008) 1774e1780
Table 1
Activity of compounds 3e8 against trypomastigote forms of T. cruzi
NMR (300 MHz, CDCl ) d: 6.02 (1H, s), 8.21 (1H, dd,
3
J ¼ 6.8, 2.4), 7.84e7.71 (3H, m), 1.25 (3H, s), 1.79 (3H, s),
1
3
Compound
IC50/1 day (mM)
7.30 (1H, s), 7.84e7.33 (5H, m). C NMR (75 MHz,
DMSO-d ) d: 95.3 (C ), 66.3 (C ), 111.1 (C ), 174.7
a
Nor-lapachol
3
1281.0 ꢂ 167.0
50.2 ꢂ 3.8
6
2
3
3a
(CaO), 179.8 (CaO), 132.0 (C ), 130.6 (C ), 134.8 (CH),
5a 1’
4
151.9 ꢂ 8.0
348.1 ꢂ 44.2
17.3 ꢂ 2.0
133.2 (CH), 129.1 (CH), 125.2 (CH), 126.7 (C ), 170.0
9a
5
(
(
C ), 21.0 (C or C ), 27.2 (C or C ), 131.7 (C ), 146.4
9b 10 11 10 11 5
C ), 129.0 (CH), 128.8 (CH), 128.7 (CH), 128.1 (CH),
4
6
7
57.8 ꢂ 5.6
8
256.7 ꢂ 38.7
125.3 (CH).
a
Crystal violet
Benznidazole
536.0 ꢂ 3.0
103.6 ꢂ 0.6
4.2.4. Synthesis of 3-[4-(1-hydroxy-cyclohexyl)-
a
Ref. [8].
[
[
1,2,3]triazol-1-yl]-2,2-dimethyl-2,3-dihydro-naphtho-
1,2-b]furan-4,5-dione (7)
Yield: 90%; yellow solid; mp 186e188 C. IR (KBr) n
ꢀ
max
with NaSO and concentrated under reduced pressure. The
4
2
(
854e2981 (CH , CH ), 1662 (CaO), 1623 (CaO), 3372
2 3
residue obtained was purified by column chromatography on
silica gel using as eluent a gradient mixture of hexane/ethyl
acetate with increasing polarity up to 100% ethyl acetate.
The alkynes employed were the following: for 4, 2-methyl-
but-3-yn-2-ol; for 5, prop-2-yn-1-ol; for 6, ethynyl-benzene;
for 7, 1-ethynyl-cyclohexanol and for 8, 2-prop-2-ynyloxy-
tetrahydro-pyran.
ꢁ1
OH) cm . H NMR (300 MHz, CDCl ) d: 5.95 (1H, s),
3
1
8
1
.17 (1H, dd. J ¼ 6.6, 2.2), 7.82e7.69 (3H, m), 1.17 (3H, s),
13
.75 (3H, s), 7.40 (1H, s), 1.96e1.52 (10H, m). C NMR
(75 MHz, DMSO-d ) d: 95.5 (C ), 66.0 (CH), 111.3 (C ),
6 0 0
174.7 (CaO), 179.9 (CaO), 132.0 (C ), 134.7 (CH), 133.1
0
(
(
(
CH), 128.8 (CH), 125.1 (CH), 127.0 (C ), 169.8 (C ), 20.7
0 0
CH ), 27.1 (CH ), 121.5 (CH), 155.5 (C ), 68.0 (C ), 37.9
0
3
3
0
CH ), 25.3 (CH ), 21.9 (CH ).
2
2
2
4
.2.1. Synthesis of 3-[4-(1-hydroxy-1-methyl-ethyl)-
[
[
1,2,3]triazol-1-yl]-2,2-dimethyl-2,3-dihydro-naphtho-
1,2-b]furan-4,5-dione (4)
4
.2.5. Synthesis of 2,2-dimethyl-3-[4-(tetrahydro-pyran-
ꢀ
2-yloxymethyl)-[1,2,3]triazol-1-yl]-2,3-dihydro-naphtho-
Yield: 90%; orange solid; mp 220e222 C. IR (KBr) n
926e2981 (CH , CH ), 1656 (CaO), 1615 (CaO), 3423
2 3
max
[
1,2-b]furan-4,5-dione (8)
Yield: 90%; orange solid; mp 190e192 C. IR (film) n
937e2985 (CH , CH ), 1655 (CaO), 1698 (CaO) cm
2
(
ꢀ
ꢁ1
1
OH) cm . H NMR (300 MHz, CDCl ) d: 5.95 (1H, s),
max
1
3
ꢁ
2 .
H NMR (300 MHz, CDCl ) d: 5.97 (1H, s), 8.19 (1H, dd,
8
.17 (1H, dd, J ¼ 6.6, 2.1), 7.82e7.64 (3H, m), 1.75 (3H, s),
2
3
1
1
.18 (3H, s), 7.4 (1H, s), 1.59 (6H, s). C NMR (75 MHz,
3
1
DMSO-d ) d: 95.5 (C ), 66.1 (CH), 111.3 (C ), 174.2
3
J ¼ 6.1, 1.9), 7.83e7.73 (3H, m), 1.20 (3H, s), 1.76 (3H, s),
6
0
0
7
.48 (1H, s), 4.84 (1H, dd, J ¼ 12.7, 5.4), 4.63 (1H, dd,
(
CaO), 180.0 (CaO), 132.1 (C ), 134.7 (CH), 133.1 (CH),
0
1
3
J ¼ 12.7, 3.6), 4.68 (1H, t, J ¼ 3.9), 1.95e1.46 (8H, m). C
NMR (75 MHz, DMSO-d ) d: 95.1 (C ), 66.1 (CH), 111.3
1
2
3
28.8 (CH), 125.1 (CH), 126.8 (C ), 170.0 (C ), 27.1 (CH ),
0 0 3
0.8 (CH ), 121.0 (CH), 155.9 (C ), 67.2 (C ), 30.8 (CH ),
3
6
0
0
0
3
(C ), 174.7 (CaO), 179.8 (CaO), 132.0 (C ), 134.7 (CH),
0 0
0.7 (CH ). EI-HRMS (70 eV, m/z) 353.13750. Calcd for
3
1
2
3
33.0 (CH), 128.7 (CH), 125.0 (CH), 126.7 (C ), 169.9 (C ),
0 0
C H O N : 353.13756; (%) 227 (100), 353 (12), 213 (6),
9 19 4 3
1
0.7 (CH ), 27.0 (CH ), 124.1 (CH), 97.2 (CH) 143.7 (C ),
3
1
(
99 (18), 183 (2), 171 (7), 157 (5), 128 (7), 115 (4), 105
3), 43 (5).
3
0
0.0 (CH ), 24.9 (CH ), 61.4 (CH ), 61.3 (CH ), 19.0 (CH ).
2
2
2
2
2
4
1
4
.2.2. Synthesis of 3-(4-hydroxymethyl-[1,2,3]triazol-
-yl)-2,2-dimethyl-2,3-dihydro-naphtho[1,2-b]furan-
,5-dione (5)
4.3. X-Ray analysis
Crystallographic data for compound 4: C H N O ;
1
9 18 3 4
ꢀ
˚
Yield: 92%; yellow solid; mp 212e214 C. IR (KBr) n
937e2987 (CH , CH ), 1655 (CaO), 1614 (CaO), 3342
M ¼ 704.74; triclinic, space group P-1; a ¼ 7.1998(3) A,
max
˚ ˚
ꢀ
2
(
b ¼ 9.5301(7) A, c ¼ 13.5644(12) A; a ¼ 89.742(3) , b ¼
˚
c
2
3
ꢁ1
1
OH) cm . H NMR (300 MHz, CDCl ) d: 5.97 (1H, s),
ꢀ
ꢀ
3
3
89.350(5) , g ¼ 71.586(4) ; V ¼ 883.01(11) A ; Z ¼ 2; D ¼
ꢁ
1
˚
8
.19 (1H, ddd, J ¼ 6.4, 2.4, 0.5), 7.81e7.73 (3H, m), 1.21
1.325 g cm
;
l
(Mo K ) ¼ 0.71013 A; F(000) ¼ 370;
a
1
3H, s), 1.76 (3H, s), 7.5 (1H, s), 4.77 (2H, s). C NMR
3
(
(
(
T ¼ 293 K; colorless sheet, size 0.15 ꢃ 0.11 ꢃ 0.09 mm;
2
5185 measured reflections, refinement based on F to give
75 MHz, CDCl ) d: 95.3 (C ), 66.1 (CH), 111.4 (C ), 174.7
0
CaO), 179.9 (CaO), 132.0 (C ), 134.7 (CH), 133.1 (CH),
0
3
0
2
2
R [F > 2s(F )] ¼ 0.070 and w ¼ 0.215 for 3730 observed
1
2
1
2
28.8 (CH), 125.1 (CH), 126.7 (C ), 169.8 (C ), 20.8 (CH ),
0
reflections, and 240 parameters. The Flack absolute structure
parameter was determined to be 0.8(5) and the refinement of
the opposite enantiomer resulted in a value of 1.32(2). Unfor-
tunately, the weak distinguishing value of the Flack parameter
(which should be 0.0 for the correct enantiomer) cannot be
used to definitively assign the absolute stereochemistry. The
positions of H atoms bonded to C were determined based on
0
3
7.1 (CH ), 123.1 (CH), 148.1 (C ), 55.2 (CH ).
3
0
2
4
.2.3. Synthesis of 2,2-dimethyl-3-(4-phenyl-[1,2,3]
triazol-1-yl)-2,3-dihydro-naphtho[1,2-b]furan-4,5-dione (6)
ꢀ
Yield: 100%; yellow solid; mp 177e179 C. IR (KBr) n
ꢁ1 1
max
2
926e2980 (CH , CH ), 1612 (CaO), 1650 (CaO) cm . H
2
3

E.N. da Silva Jr. et al. / European Journal of Medicinal Chemistry 43 (2008) 1774e1780
1779
stereochemical parameters and their displacement parameters
calculated as 1.5Ueq (C-methyl) or 1.2Ueq (other).
References
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0
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